Pharmaceutical Calculations Module

Tutorial 1: Units and Conversions

About This Tutorial

This tutorial was developed by the Victorian College of Pharmacy, Monash University in
conjunction with the Australian Pharmacy Examining Council Incorporated (APEC Inc)
(now known as the Faculty of Pharmacy and Pharmaceutical Sciences, Monash University
and the Australian Pharmacy Examining Committee respectively).It remains the property of
Monash University. The tutorial cannot be used or copied without prior authorisation.

This tutorial is intended as an aid for students enrolled in Monash University’s Bachelor of
Pharmacy & Pharmacy Internship programs.

• Original tutorial prepared by in1996:

Arthur Pappas Lecturer in Pharmacy Practice
Dr Louis Roller Head, Department of Pharmacy Practice

with the assistance of :

May Admans Senior Assistant-Lecturer in Pharmaceutics

Dr Denis Morgan Reader in Pharmaceutics
Dr Kay Stewart Lecturer in Pharmacy Practice
Prof Peter Stewart Professor of Pharmaceutics

• Original Tutorial Manual produced by Arthur Pappas - December 1996

• Adaptation & updating of the material for online delivery to students of Monash
University was undertaken by Phil Bergen, Assistant Lecturer in Pharmacy Practice -
February 2005

© Copyright 2005
This publication is copyright. Apart from any fair dealing for the purpose of private study, research, criticism or
review as permitted under the Copyright Act, no part may be reproduced by any process or placed in computer
memory without written permission. Any assembled extracts each attract individual copyright and enquiries
about reproduction of this material should be addressed to the appropriate publishers. Enquiries about all other
material should be made to the Faculty named above.
Last amended by EM- November 2008

ii
Pharmaceutical Calculations 1. Units and Conversions

1. Units and Conversions

Topic Index
Page
1.1 Introduction 2
1.2 Objectives 2
1.3 Metric System 2
1.3.1 Unit of mass (weight) 3
1.3.2 Units of volume (capacity) 3
1.3.3 Units of length 4
1.3.4 Units of amount of substance 5
1.4 Apothecary System 5
1.4.1 Units of weight 6
1.4.2 Units of volume 6
1.5 Avoirdupois System 6
1.6 Temperature Units 6
1.7 Concentration Units 7
1.8 General Conversion Tables 7

1
 Pharmaceutical Calculations 1. Units and Conversions

1.1 Introduction

All units of pharmaceutical measurement are defined in terms of metric standards in Australia. Two other
systems, which are not currently used in Australia are the apothecary system and the avoirdupois
(household) system. However, you should still be aware of these because of historical interest and the present
use in other countries.

It is important when solving calculations that the appropriate units are used in formulae. Mistakes are usually
made because the units used throughout the calculation have not been consistent.

Care needs to be taken in converting from one unit to another and from one system to another.

1.2 Objectives

The aim of this tutorial is to briefly discuss each system and then you will be provided the opportunity to convert
from one set of units to another and from one system to another.

At the end of this tutorial you should be able to:

a) Indicate the metric units for weight, volume and length

b) Indicate the relationship within each type of unit
c) Be aware of apothecary and avoirdupois units
d) Be capable of converting metric to apothecary and avoirdupois units (and vice versa)

1.3 Metric System

1.3.1 Unit of mass (weight)

The basic unit of mass in the metric system is the gram (g). The gram (g) is 1/1000 of a kilogram (kg).

-3
1 g = 0.001 kg = 1x10 kg

Worked Example 1.1

a) Express 0.430 kg of paracetamol in gram units

Working: 1 kg = 1000g Therefore: 0.430kg = 430g

b) Express 12.5 g of aspirin in kilogram units

-3
Working: 1g = 1x10 kg Therefore: 12.5g = 0.0125 kg

Table 1.1 Relationship between metric units of mass

Name Abbreviation Equivalent

3
1 kilogram kg 1000g = 10 g
3
1 gram g 1000mg = 10 mg
3
1 milligram mg 1000 ug (meg) = 10 mcg
3
1 microgram ug (meg) 1000 ng= 10 ng
3
1 nanogram ng 1000pg = 10 pg
1 picogram pg 1/1000 ng

2
 Pharmaceutical Calculations 1. Units and Conversions

Quiz Question 1.1

a) Express 2 mg in terms of gram units

Answer: 1mg = 1 x 10-3g Therefore: 2mg = 0.002 g

b) Express 2.5 kg in terms of milligram units

Answer: 1kg = 1 x 106 mg Therefore: 2.5kg = 2.5 x 106mg

c) Express 1.5 g in terms of microgram units

6 6
Answer: 1g = 1 x 10 mcg Therefore: 1.5g = 1.5 x 10 mcg

d) Express 70 ng in term of milligram units

-6 -5
Answer: 1ng = 1 x 10 mg Therefore: 70ng = 7 x 10 mg

e) Express 0.050 mg in terms of gram units

-3 -5
Answer: 1 mg = 1 x 10 g Therefore: 0.050mg = 5 x 10 g

f) Express 145 mg in terms of microgram units

3 5
Answer: 1mg = 1 x 10 mcg Therefore: 145mg = 1.45 x 10 mcg

1.3.2 Units of volume (capacity)

Although the litre [symbol l in the British Pharmacopoiea (BP) and symbol L in the United States
Pharmacopoeia (USP)] is not part of the International System of Units (SI), its use as the unit of volume is
likely to continue. The use of litre and millilitre is virtually universal in pharmaceutical practice.

Table 1.2 Relationship between metric units of volume

Name Abbreviation Equivalent

1 litre 3
L (dm ) 1000mL = 103mL
1 millilitre 3
mL (cm ) 1000 L=103 L
1 microlitre 1/1000 mL
L

3 3
1 L = 1000 mL (1000 cm or 1 dm )

(Note: 10 cm = 1 dm Therefore: 1 dm3 = 10 cm x 10 cm x 10 cm = 1000 cm3)

Worked Example 1.2

a) Express 1.5 mL in terms of microlitre units

Working: 1 mL = 1 x 103 L Therefore: 1.5mL = 1.5 x 103 L

b) Express 10 mL in terms of litre units

Working: 1mL = 1 x 10-3 L Therefore: 10mL = 1 x 10-2 L

c) Express 3.2 L in terms of millilitre units

Working: 1L = 1 x 103 mL Therefore: 3.2L = 3.2 x 103 mL

3
 Pharmaceutical Calculations 1. Units and Conversions

Quiz Question 1.2

a) Express 5.5 mL in terms of cm3

Answer: 1 mL = 1 cm3 Therefore: 5.5mL = 5.5cm3

b) Express 0.5 mL in terms of microlitre units

Working: 1mL= 1 x 103 L Therefore: 0.5mL = 500 L

1.3.3 Units of length

Even when dispensing prescriptions a knowledge of units of length is important (eg: wound dressing sizes,
transdermal patches). It is also vital to know and understand the metric system in order to perform a variety of
scientific calculations.

Table 1.3 Relationship between metric units of length

Name Abbreviation Equivalent

2
1 metre m 100 cm = 10 cm
3
1 metre m 1000 mm = 10 mm
3
1 millimetre mm 1000 pm = 10 um
3
1 micrometre m 1000nm = 10 nm

1m = 102cm = 103 mm = 106 m = 109 nm

Worked Example 1.3

a) Express 200 cm in terms of mm units

Working: 1 cm = 10mm Therefore: 200 cm = 2 x 103 mm

b) Express 0.02m in terms of centimetre units

Working: 1m = 100 cm Therefore: 0.02m = 2.0 cm

c) Express 8mm in terms of nanometre units

Working: 1mm = 106nm Therefore: 8mm = 8 x 106nm

Quiz Question 1.3

a) Express 0.5m in terms of millimetre units

Answer: 1m = 10 mm Therefore: 0.5m = 500 mm

b) Express 0.05 m in terms of centimetre units

Answer: 1m = 100 cm Therefore: 0.05 m = 5.0 cm

4
 Pharmaceutical Calculations 1. Units and Conversions

1.3.4 Units of amount of substance

The base unit of amount of substance is the mole (mol).

One mole is the amount of substance of a system containing as many formula units (atoms, molecules,
ions, electrons, quanta or other entities as there are in 12 g of the pure nuclide carbon12

The various terms for amount of substance used in pharmacy are as follows:

Table 1.4 Relationship between units of amount of substance

Name Abbreviation Equivalent

1 mole mol 1000 mmol

1 millimole mmol 1000 mol
1 micromole mol (mcmol) 1/1000 mmol

The following equations are important to remember when determining amount of substance:

n = number of moles
m = mass (g)
M = Molecular Weight (MW)

C = concentration (g per L or g per dm3)

n - number of mole
3
V = volume (L or dm )

m = mass (g)
C = concentration (mol per L or mol per dm3)
V = volume (L or dm3)

Worked Example 1.4

a) How many mole of Aspirin (MW = 180.2) is in a 300 mg tablet of Aspirin ?

Working:

1.4 Apothecary System

This system is included here as a reference and for interest only. It is unlikely that any questions will be
asked in an APEC exam involving the conversion of these units to metric units.
Pharmaceutical Calculations 1. Units and Conversions

1.4.1 Units of weight

The basic unit of the apothecary system is the grain (gr)

The gram (g) is equivalent to 15.432 grains (gr)
Be careful in using or interpreting these two symbols !

Table 1.5 Apothecary weight units

20 gr =1 scruple
60 gr = 1 dram
480 gr = 8 drams = 1 apothecary ounce

1.4.2 Units of volume

This system is important in some countries (eg: United States of America) since a lot of packaging is
stated in these units.

Table 1.6 Apothecary volume units

60 minims = 1 fluidram
8 fluidram = 1 fluidounce
16 fluid ounce = 1 pint
2 pints = 1 quart
4 quarts = 1 gallon

1.5 Avoirdupois System

This system is also included here as a reference and for interest only. It is unlikely that any questions will
be asked in an APEC exam involving the conversion of these units to metric units.

437.5 grains (gr) = 1 ounce (1 oz)

16 oz = 1 pound (Ib)

Note: The apothecary grain and the avoirdupois grain are the same.
However, the "oz" and the apothecary ounce are different. See Table 1.8

1.6 Temperature Units

Always make sure that the units of temperature are appropriate for the formula you are using.

a) Fahrenheit (°F) converted to Centigrade (°C) scale:

( °F - 3 2 ) x 5 / 9 = °C

b) Centigrade (°C) converted to Fahrenheit (°F) scale:

(°C x 9/5) + 32 = °F

c) Fahrenheit (°F) converted to Kelvin (°K) scale:

1 degree Fahrenheit (°F) = 5/9 degree Kelvin (°K)

d) Centigrade (°C) converted to Kelvin (°K) scale:

1 degree Kelvin (°K) = 1 degree Centigrade (°C) + 273

Pharmaceutical Calculations }, Units and Conversions

Worked Example 1.5

Convert 38 degrees Centigrade to degrees Fahrenheit.

Working:
Using the formula: (°C x 9/5) + 32 = °F
(38 x 9/5) + 32 = °F
68.4 + 32 =°F
100.4 = °F
Quiz Question 1.4

Convert 120 degrees Fahrenheit to degrees Centigrade.

Answer:
Using the formula: (°F-32) x 5/9 = °C
(120 - 32) x 5/9 = °C
88 x 5/9 = °C
48.9 = °C

1.7 Concentration Units

3
In SI units, concentration may be expressed either as mass concentration (e.g. g per dm , conventionally
’
expressed as g per litre) or as 'amount of substance concentration (e.g. mol per litre). Always make sure
that the units of concentration are appropriate for the formula you are using.

1.8 General Conversion Tables

These are included here for general reference only. All calculations in the APEC exam will involve metric
units. If a conversion is required, the conversion formula will be stated in the question.

Table 1 .7 Imperial equivalents of metric units

Metric Imperial

1 gram (g) 15.432 grains (gr.)

1 kilogram (kg) 2.2046 pounds (Ib.)
1 millilitre (mL) or cm3 16.894 minims (m.)
3
1 litre (L) or dm 35.196 fluidounces (fl.oz.)
2.54 centimetres (cm) 1 inch (in)
30.48 centimetres (cm) 1 foot (ft)
91.44 centimetres (cm) 1 yard (yd)
3
1.6093 x10 metres (m) 1 mile

Table 1.8 Metric Equivalents of Imperial Units

Imperial Metric

1 grain (gr.) 0.0648 gram (g)

1 ounce Avoirdupois (oz) 28.3495 gram (g)
[equivalent to 437.5 gr.]
1 ounce Apothecary 31.104 grams (g)
[equivalent to 480 gr.]
1 pound Avoirdupois (Ib.) 453.59 grams (g)
3
1 ton 1.0161 x10 kilograms (kg)
3
1 minim (m.) 0.0592 millilitres (mL) or cm
1 fluidounce (fl.oz.) 28.412 millilitres (mL) or cm3
1 pint (pt.) 568.261 millilitres (mL) or cm3
1 gallon (gal.) 4.546 litres (L) or dm3
 Pharmaceutical Calculations Module
Tutorial 2: Percentages and Conversions

About This Tutorial

This tutorial was developed by the Victorian College of Pharmacy, Monash University in
conjunction with the Australian Pharmacy Examining Council Incorporated (APEC Inc)
(now known as the Faculty of Pharmacy and Pharmaceutical Sciences, Monash University
and the Australian Pharmacy Examining Committee respectively).It remains the property of
Monash University. The tutorial cannot be used or copied without prior authorisation.

This tutorial is intended as an aid for students enrolled in Monash University’s Bachelor of
Pharmacy & Pharmacy Internship programs.

• Original tutorial prepared by in1996:

Arthur Pappas Lecturer in Pharmacy Practice
Dr Louis Roller Head, Department of Pharmacy Practice

with the assistance of :

May Admans Senior Assistant-Lecturer in Pharmaceutics

Dr Denis Morgan Reader in Pharmaceutics
Dr Kay Stewart Lecturer in Pharmacy Practice
Prof Peter Stewart Professor of Pharmaceutics

• Original Tutorial Manual produced by Arthur Pappas - December 1996

• Adaptation & updating of the material for online delivery to students of Monash
University was undertaken by Phil Bergen, Assistant Lecturer in Pharmacy Practice -
February 2005

© Copyright 2005
This publication is copyright. Apart from any fair dealing for the purpose of private study, research, criticism or
review as permitted under the Copyright Act, no part may be reproduced by any process or placed in computer
memory without written permission. Any assembled extracts each attract individual copyright and enquiries
about reproduction of this material should be addressed to the appropriate publishers. Enquiries about all other
material should be made to the Faculty named above.
Last amended by EM- November 2008

ii
Pharmaceutical Calculations 2, Percentages and Conversions

2. Percentages
and Conversions
Topic Index

Page
2.1 Introduction 9
2.2 Objectives 9
2.3 Definitions 9
2.4 Expression of percentage in formulations 9
2.5 Conversion of percentage 10
2.5.1 Percentage to decimal 10
2.5.2 Calculating the value of a percent
of a quantity 10
2.5.3 Calculating the percent represented
by some component 10
2.5.4 Percentage to parts per million 11
2.5.5 Parts to percentage 11
Pharmaceutical Calculations 2. Percentages and Conversions

2.1 Introduction

The strength of many formulations is often expressed as a percentage. This is a universally

accepted expression and also fairly well understood by the general public.

As a pharmacist you must be aware of the TYPE of percentage calculation intended for an
ingredient of a particular formulation. In other words, you must be clear if the percentage is in
terms of weight or volume. Generally speaking, the use of percentages is an integral part to
solving a range of pharmaceutical calculations.

2.2 Objectives

The aim of this tutorial is to discuss the concept of '

percentage'and how to convert various
proportions into a percentage number.

At the end of this tutorial you should be able to:

a) understand different expressions of percentage in pharmaceutical formulations

b) calculate the value of a percent of a quantity
c) calculate the percent represented by some quantity
d) convert percent to parts per million (and vice versa)
e) convert parts to percent (and vice versa)

2.3 Definitions

The word ' percentage'is simply a term to express the number of units of something relative to
100 units.

Worked Example 2.1

Express 70 mL of pure alcohol dispersed with water to a total volume of 120 mL as a

percentage:
Working:
70 mL
--------- x 100 = 58.33%
120 mL

2.4 Expression of percentage in formulations

When a pharmaceutical formula is expressed as a percentage without specifying the units of

weight or measure, liquids (irrespective of density) are measured by volume, and solids by
weight. (Ref APF 15)

Table 2.1
Expressions of percentage in pharmaceutical preparations
Expression Meaning
1%w/w 1 g of a solid in 100 g of product
1%w/v 1 g of a solid in 100 mL of product
1% v/v 1 mL of a liquid in 100 mL of product
1%v/w 1 mL of a liquid in 100 g of product

w/w = weight in weight

w/v = weight in volume
v/v = volume in volume
v/w = volume in weight
 Pharmaceutical Calculations 2. Percentages and Conversions

Quiz Question 2.1

How much Aspirin is in 10 mL of a 100 mL mixture of Aspirin of strength 10% w/v?

Answer:
10% w/v = 10g in 100 mL
xg : 10 mL
Therefore x = 1 g Aspirin.

2.5 Conversion of percentage

2.5.1 Percentage to decimal

When using percentage values in formulas or calculations, it is vital to convert these values to
decimal numbers first. You do this by moving the decimal point two places to the left.

Worked Example 2.2

a) Express 45.6% as a decimal

Working: 1% = 0.01 Therefore 45.6% = 0.456

b) Express 67.89 % as a decimal

Working: 1 % =0.01 Therefore 67.89% = 0.6789

2.5.2 Calculating the value of a percent of a quantity

Firstly, change the percent to a decimal by moving the decimal point two places to the left and
then multiply by the quantity.

Worked Example 2.3

What is 50% of 150 mL?

Working:
50% = 0.50
Therefore: 0.50 x 150 mL = 75 mL

2.5.3 Calculating the percent represented by some component

Firstly, divide that component value by the total quantity and multiply by 100

Worked Example 2.4

What percentage value is 23 mL out of a total of 125 mL ?

Working:

23 mL
------- x 100 =18.4%
125 mL

Quiz Question 2.2

What percentage of 150 mg is a 10 mg quantity ?

Answer:

10 mg
--------- x 100 = 6.67%
150 mg

10
Pharmaceutical Calculations 2. Percentages and
Conversions

Please Note: The units on the numerator and denominator must be the same in order for
them to cancel.

2.4.4 Percentage to parts per million

1 part per million is equivalent to: 1 g in 1,000,000 ml

or 1mg in 1,000mL (1 litre)

Worked Example 2.5

You are asked to convert the Fluoride concentration in a community'
s drinking water from 0.8
parts per million to a percentage value.
Working:
We have 0.8 ppm

This means: 0.8 mg in 1000 mL

i.e. 0.08 mg in 100 mL

To convert to % w/v, the weight must be in grams.

0.08x10 -3 g
----------------- x 100 = 0.00008 % w/v = 8 x 10-5 % w/v
100 mL

2.4.5 Parts to percentage

Parts are often used to denote concentration. To convert parts to percentage a simple cross
multiplication is required:

Worked Example 2.6

Express "1 in 500" phenol in water as a percentage.

Working:
1 in 500 means 1 g in 500 mL
To express something as a percentage, it involves expression per 100 mL

Therefore: 1 g : 500 mL
xg : 100 mL x = 0.2 g

ie: 0.2g per 100 mL or 0.2 % w/v

Quiz Question 2.3

What is the concentration of Sulphur in the following formulation expressed in terms of

parts? Formulation: 20% w/w Sulphur in 100g Sorbolene Cream.

Answer:
20% w/w is equivalent to: 20g Sulphur in 100g formulation
Simplified (divide by 20g): 1 in 5

'
1'refers to the component of Sulphur

'
5'refers to the whole formulation
 Pharmaceutical Calculations Module:
Tutorial 3: Density and Specific Gravity

About This Tutorial

This tutorial was developed by the Victorian College of Pharmacy, Monash University in
conjunction with the Australian Pharmacy Examining Council Incorporated (APEC Inc)
(now known as the Faculty of Pharmacy and Pharmaceutical Sciences, Monash University
and the Australian Pharmacy Examining Committee respectively).It remains the property of
Monash University. The tutorial cannot be used or copied without prior authorisation.

This tutorial is intended as an aid for students enrolled in Monash University’s Bachelor of
Pharmacy & Pharmacy Internship programs.

• Original tutorial prepared by in1996:

Arthur Pappas Lecturer in Pharmacy Practice
Dr Louis Roller Head, Department of Pharmacy Practice

with the assistance of :

May Admans Senior Assistant-Lecturer in Pharmaceutics

Dr Denis Morgan Reader in Pharmaceutics
Dr Kay Stewart Lecturer in Pharmacy Practice
Prof Peter Stewart Professor of Pharmaceutics

• Original Tutorial Manual produced by Arthur Pappas - December 1996

• Adaptation & updating of the material for online delivery to students of Monash
University was undertaken by Phil Bergen, Assistant Lecturer in Pharmacy Practice -
February 2005

© Copyright 2005
This publication is copyright. Apart from any fair dealing for the purpose of private study, research, criticism or
review as permitted under the Copyright Act, no part may be reproduced by any process or placed in computer
memory without written permission. Any assembled extracts each attract individual copyright and enquiries
about reproduction of this material should be addressed to the appropriate publishers. Enquiries about all other
material should be made to the Faculty named above.
Last amended by EM- November 2008

ii
Pharmaceutical Calculations 3. Density and Specific Gravity

3. Density and Specific

Gravity

Index

Page
3.1 Introduction 13
3.2 Objectives 13
3.3 Definitions 13
3.3.1 Density 13
3.3.2 Specific Gravity 15
Pharmaceutical Calculations 3. Density and Specific Gravity

3.1 Introduction

It is important in pharmacy to understand the meaning of "density" (mass per unit volume of
a substance) as it is crucial to the correct manufacture of formulations. Specific gravity is
another term used which may be defined as the ratio of the density of a substance to the
density of water. Understanding the definitions of each term will help you convert weight to
volume or volume to weight in a formulation.

Please Note:
1. Density and specific gravity are determined in air and at a specified temperature, this
usually being room temperature.

2. The official compendia such as the British Pharmacopoeia, the United State
Pharmacopoeia and the Australian Pharmaceutical Formulary all stipulate that unless
otherwise indicated all solids are taken by weight and all liquids are taken by volume.

3.2 Objectives

The aim of this tutorial is to discuss the concept of '

density'and '
specific gravity'and how to
use this information to determine other information about a substance.

At the end of this tutorial you should be able to:

a) understand the concept of density and specific gravity

b) know the formula for determining density
c) be able to determine the volume occupied by a substance, given density and mass
d) be able to determine the mass of a substance, knowing its density and volume
e) be able to determine the density of a substance, knowing its mass and volume
f) understand the relationship between density and specific gravity

3.3 Definitions

3.3.1 Density

Density is defined as the mass per unit volume of a particular substance.

It is defined bv the formula:

In the metric system, density is expressed in g/mL

Note: Temperature does have an effect on volume. However, for room temperature
fluctuations, the error introduced is small for the purpose of pharmaceutical formula
manufacture.

Worked Example 3.1

An ointment formulation to treat sprains includes 6g of Methyl Salicylate per 100 g of

ointment. What volume of Methyl Salicylate do you need to measure?
(Data: density of Methyl Salicylate is 1.18 g/mL)

Working:
Using the formula:

13
 Pharmaceutical Calculations 3. Density and Specific Gravity

Quiz Question 3.1

An ointment formulation requires 3% w/w Salicylic Acid and 5% w/w Liquid Paraffin to be
incorporated into a White Soft Paraffin base. What volume of Liquid Paraffin is required to
make 100g of product?
(Data: density of Liquid Paraffin = 0.83 - 0.89 g/mL)

Answer:
Take the density as being a midpoint of that range, ie: 0.86 g/mL

d = m/v
Therefore: 0.86 g/mL = 5 g/V
Therefore: V = 5.8 mL

Quiz Question 3.2

A topical formulation contains 15 % w/w Sesame Oil in aqueous cream. What volume of oil
is required for 50 g of cream ?
(Date: density of Sesame Oil = 0.915 - 0.923 g/mL)

Answer:
Take the density as being the midpoint of that range, ie: 0.919 g/mL

In 100 g of product there is 15 g of Sesame Oil.

Therefore in 50 g of product there is 7.5 g of Sesame Oil.

Using the formula: d = m/v 0.919 g/mL = 7.5 g/ V

Therefore V = 8.16 mL

Quiz Question 3.3

What would be the weight (in grams) of 25 mL of Arachis Oil (Peanut Oil) ?
(Data: density of Arachis Oil = 0.909 - 0.916 g/mL)

Answer:
Take the density as being the midpoint of that range, ie: 0.912 g/mL

Using the formula: d = m/v 0.912 g/mL = m/25 mL

Therefore m = 22.8 g

Quiz Question 3.4

What is the volume of 100 g of Liquid Paraffin?

(Data: density of Liquid Paraffin = 0.83 - 0.89 g/mL)

Answer:
Take the density as being a midpoint of that range, ie: 0.86 g/mL

Using the formula: d = m/V 0.86 g/mL = 100 g/V

Therefore V = 116.3 mL

Quiz Question 3.5

How much does 100 mL of Glycerol weigh?

(Data: density of Glycerol = 1.258 -1.263 g/mL)

Answer:
Take the density as being the midpoint of that range, ie: 1.260 g/mL

Using the formula: d = m/V 1.260 g/mL = m/100mL

Therefore m = 126 g

14
 Pharmaceutical Calculations 3. Density and Specific
Gravity

3.3.2 Specific Gravity

Many references do not list density but specific gravity (sp g). Specific gravity may be
defined as the ratio of the density of a substance to that of some reference. Water is used
as the reference for solids and liquids.

density of substance
sp g = ---------------------------
density of water

Because it is a ratio, specific gravity is a dimensionless quantity. Therefore both the

numerator and denominator must be expressed in the same units.

Note:
(i) Specific gravity can be used to convert between weight and volume (see (ii))
(ii) You can use the definition of specific gravity to find the density of a substance.
Since the density of water is 1.00 g/mL, therefore the density of a substance,
in g/mL, is numerically equivalent to its specific gravity,
(iii) Only when density is expressed in units of g/mL are density and specific gravity
numerically equal.

Worked Example 3.2

The specific gravity of Peppermint Oil is 0.91
What is the density of this oil?
Working:
Using the formula:
density of substance density of substance
sp g = --------------------------- = 0.91 = -----------------------------

density of water 1.00 g/mL

Therefore the density of the oil is: 0.91 g/mL

Quiz Question 3.6

The specific gravity of Dimethicone (an ingredient used in barrier creams) is 0.97
What weight of this substance is required to fill a 200 mL bottle ?

Answer:
With a specific gravity of 0.97 the density is 0.97 g/mL

Using the formula: d = m/v

0.97 g/mL = m/200mL
Therefore: m = 0.97 g/mL x 200mL = 194 g

Quiz Question 3.7

The specific gravity of Yellow Beeswax is 0.96 (It is used as an ingredient of ointments and
enables water to be incorporated to produce water-in-oil emulsions)

What volume (in mL) does 5 kg occupy ?

Answer:
With a specific gravity of 0.96, the density is 0.96 g/mL

Using the formula: d = m/V

0.96 g/mL = 5000g/V

Therefore V = 5,208.3 mL 15
 Pharmaceutical Calculations Module
Tutorial 4:
Manipulating Pharmaceutical Formulations
About This Tutorial

This tutorial was developed by the Victorian College of Pharmacy, Monash University in
conjunction with the Australian Pharmacy Examining Council Incorporated (APEC Inc)
(now known as the Faculty of Pharmacy and Pharmaceutical Sciences, Monash University
and the Australian Pharmacy Examining Committee respectively).It remains the property of
Monash University. The tutorial cannot be used or copied without prior authorisation.

This tutorial is intended as an aid for students enrolled in Monash University’s Bachelor of
Pharmacy & Pharmacy Internship programs.

• Original tutorial prepared by in1996:

Arthur Pappas Lecturer in Pharmacy Practice
Dr Louis Roller Head, Department of Pharmacy Practice

with the assistance of :

May Admans Senior Assistant-Lecturer in Pharmaceutics

Dr Denis Morgan Reader in Pharmaceutics
Dr Kay Stewart Lecturer in Pharmacy Practice
Prof Peter Stewart Professor of Pharmaceutics

• Original Tutorial Manual produced by Arthur Pappas - December 1996

• Adaptation & updating of the material for online delivery to students of Monash
University was undertaken by Phil Bergen, Assistant Lecturer in Pharmacy Practice -
February 2005

© Copyright 2005
This publication is copyright. Apart from any fair dealing for the purpose of private study, research, criticism or
review as permitted under the Copyright Act, no part may be reproduced by any process or placed in computer
memory without written permission. Any assembled extracts each attract individual copyright and enquiries
about reproduction of this material should be addressed to the appropriate publishers. Enquiries about all other
material should be made to the Faculty named above.
Last amended by EM- November 2008

ii
Pharmaceutical Calculations 4, Manipulating Pharmaceutical Formulations

4. Manipulating Pharmaceutical
Formulations

Topic Index

Page
4.1 Introduction 17
4.2 Objectives 17
4.3 Types of formula manipulations 17
4.3.1 Expansions 17
4.3.2 Contractions 18
4.3.3 Combinations 19
4.3.4 Additions 21
4.3.5 Converting parts to quantities 22
 Pharmaceutical Calculations 4. Manipulating Pharmaceutical Formulations

4.1 Introduction
It is important for a pharmacist to be confident in manipulating (or altering) a formula to suit
the purpose desired eg: an expansion of a formula written in a dose unit format to a format
describing the quantities of the final product. Scaling of a formula accordingly would involve
simple multiplication (for expansion) or division (for contraction) of the amount of each
ingredient by a suitable factor.

4.2 Objectives
The aim of this tutorial is to gain confidence in handling pharmaceutical formulations to suit
the required purpose.

At the end of this tutorial you will be able to:

a) expand and contract formulae

b) express parts as quantities
c) combine formulae
d) add components to a formula

4.3 Types of formula manipulations

4.3.1 Expansions
This describes calculating the quantities for a final product, given the original formula written
in terms of a single dosage unit.

Worked Example 4.1

Prepare 200 mL of Pseudoephedrine and Codeine Mixture APF

Working:
The formula is available from the Australian Pharmaceutical Formulary 15 (APF 15) page
420, and states quantities required per 10 mL dose.

Pseudoephedrine HCI 30 mg
Codeine Phosphate 10 mg
Tolu Syrup 1 mL
Concentrated Anise Water 0.25 mL
Compound Hydroxybenzoate Solution 0.1 mL
Purified Water to 10 mL

We are asked to supply 200 mL

Final volume 200
Factor to multiply = ---------------- = ------- = 20
Unit volume 10

We therefore need to multiply the quantity of each of the ingredients in our 10 mL doses by
20 to obtain the quantities required to prepare 200 mL.
The easiest way to do this and avoid errors is to set up a quantities dispensed column (QD
column) as follows:
QD (x 20)
Pseudoephedrine HCI 30 mg 600 mg
Codeine Phosphate 10 mg 200 mg
Tolu Syrup 1 mL 20 mL
Concentrated Anise Water 0.25 mL 5 mL
Compound Hydroxybenzoate Solution 0.1 mL 2 mL
Purified Water to 10 mL to 200 mL

17
 Pharmaceutical Calculations 4. Manipulating Pharmaceutical Formulations

Quiz Question 4.1

Write the full formula for 100 mL Aspirin Mixture APF 13. The
formulation for a 10 mL dose is as follows:

Aspirin 500 mg
Compound Tragacanth Powder 250 mg
Orange Syrup 1 mL
Concentrated Chloroform water 0.25 mL
Purified Water to 10 mL
Answer:
Multiply the unit dose formula by a factor 100/10=10.
of QD(x 10)
Aspirin 500 mg 5g
Compound Tragacanth Powder 250 mg 2.5 g
Orange Syrup 1 mL 10 mL
Concentrated Chloroform Water 0.25 mL 2.5 mL
Purified Water to 10 mL to 100 mL

Quiz Question 4.2

A hospital pharmacy department uses the following formulation for manufacturing

prednisolone capsules:
Prednisolone 5.0 mg
Lactose 195 mg
(per capsule)
Please calculate the formula for 200 capsules.

Answer:
Multiply each of the above quantities by a factor of 200.

eg: Prednisolone 5.0mg x 200 = 1000 mg = 1g

Lactose 195mg x 200 = 39,000 mg = 39g

4.3.2 Contractions

This describes calculating the quantities of a final product that is proportionately smaller than
the quantity quoted in the original formula.

Some formularies have their formulations written in volumes of 1000mL or weights of 1000g.
To produce the usual quantity of 100g or 100mL, there needs to be a proportional contraction
of the formula.

Worked Example 4.2

Write the formula for preparing 100 g of the following topical formulation:
Simple Eye Ointment BP 1993

Wool Fat 100g

Yellow Soft Paraffin 800g
Liquid Paraffin to 1000g

Working:
Multiply all quantities by a factor of 100/1000 = 0.10 to give:
QD(multiply by 0.10)
Wool Fat 100g 10g
Yellow Soft Paraffin 800g 80g
Liquid Paraffin to 1000g 100g

18
 Pharmaceutical Calculations 4. Manipulating Pharmaceutical Formulations

Quiz Question 4.3

Write the formula for preparing 15 mL of the following ear drop formulation:

Sodium Bicarbonate Ear Drops BP 1993

Sodium Bicarbonate 5g
Glycerol 30mL
Purified Water to 100mL

Answer:
Multiply all quantities by a factor of 15/100 = 0,15
QD(multip!yby0.15)
Sodium Bicarbonate 5g 0.75g
Glycerol 30mL 4.5mL
Purified Water to 100mL 15mL

Quiz Question 4.4

Write the formula for preparing 90mL of the following topical solution:
Strong Coal Tar Solution BP 1993
Coal Tar 400g
Polysorbate 80 50g
Ethanol (96%) to 1000mL

Answer:
Multiply all quantities by a factor of 90/1000 = 0.09
QD(multiply by 0.09)
Coal Tar 400g 36g
Polysorbate 80 50g 4.5g
Ethanol (96%) to 1000mL to 90mL

4.3.3 Combinations
Pharmacists may be required to prepare a formulation which involves the combination of other
basic formulations.

Worked Example 4.3

Prepare 100 g of Resorcinol and Sulphur Paste B.P. 1980

Working:
Step 1: Write the formula and calculate for 100g
This involves multiplying the BP formulation by a factor of 100/1000 = 0.10
Resorcinol and Sulphur Paste B.P.
QD (multiply by 0.10)
Resorcinol, finely sifted 50g 5g
Precipitated Sulphur 50g 5g
Zinc Oxide, finely sifted 400g 40g
Emulsifying Ointment BP 500g 50g
1000g 100g

Step 2: Assuming it is not ready prepared, we will also need to prepare Emulsifying Ointment
BP. We will need 50g of this. Emulsifying Ointment B.P.
QD (multiply by 0.05)
Emulsifying Wax 300g 15g
White Soft Paraffin 500g 25g
Liquid Paraffin 200g 10g
1000g 50g

19
 Pharmaceutical Calculations 4. Manipulating Pharmaceutical Formulations

Step 3: Final Formulation

The final formula for 100 g of Resorcinol & Sulphur Paste is derived by combining the above
two formulae

Resorcinol 5g
Precipitated Sulphur 5g
Zinc Oxide 40 g
Emulsifying Wax 15 g
White Soft Paraffin 25 g
Liquid Paraffin 10g
100 g

Quiz Question 4.5

Write the formula for preparing 200mL of Ferrous Sulphate Mixture APF15
You are provided with the following formulae:

1. Ferrous Sulphate Mixture APF15

Ferrous Sulphate 300mg
Ascorbic Acid 10mg
Orange Syrup 0.5mL
Benzoic Acid Solution 0.2mL
Purified Water to 10mL

2. Benzoic Acid Solution APF15

Benzoic Acid 5g
Propylene Glycol 75mL
Purified Water to 100mL

Answer:
Step 1.
Write the formulation for 200mL of Ferrous Sulphate Mixture
This involves multiplying the APF formulation by a factor of 200/10 = 20
QD(x20)
Ferrous Sulphate 300mg 6g
Ascorbic Acid l0mg 200mg
Orange Syrup 0.5mL 10mL
Benzoic Acid Solution 0.2mL 4mL
Purified Water to 10mL 200mL
From this formula, you can see that we need 4mL of Benzoic Acid Solution

Step 2.
Write the formulation for 4mL of Benzoic Acid Solution
This involves multiplying the APF formulation by a factor of 4/100 = 0.04
QD(x0.04)
Benzoic Acid 5g 200mg
Propylene Glycol 75mL 3mL
Purified Water to 100mL 4mL

Step 3
The final formulation then becomes:
Ferrous Sulphate 6g
Ascorbic Acid 200mg
Orange Syrup 10mL
Benzoic Acid 200mg
Propylene Glycol 3mL
Purified Water to 200mL

20
 Pharmaceutical Calculations 4. Manipulating Pharmaceutical Formulations

4.3.4 Additions

Pharmacists may also be required to incorporate an additional component to a proprietary

product. This may be a single ingredient or a separate formulation.

Worked Example 4.4

A physician prescribes the following:

Mr A Jones
22 Bond St
Carlton

Phenobarbitone 30 mg
Benadryl® Elixir to 5 mL

Supply 100 mL
K Smith MBBS
Working:
Firstly, determine the factor for multiplication of the above formula.
This is 100/5 = 20

QD (x 20)
Phenobarbitone 30 mg 600 mg
Benadryl® Elixir to 5 mLto 100 mL

Secondly, you must consider the following issues:

i) the Phenobarbitone is a compound with poor solubility and must therefore be

suspended
ii) the Benadryl® is required at a dose of 5 mL, i.e. 12.5 mg of Diphenhydramine
Hydrochloride.

One way of suspending the phenobarbitone is using Mucilage of Tragacanth (usually 15%
v/v). However, we cannot displace 15% of the Benadryl® Elixir as this is part of the required
dose. So, we must INCREASE the dose volume to take into account the volume of
mucilage. Lets arbitrarily choose an appropriate volume of 120 mL for the final product.

The formulation then becomes:

Phenobarbitone 600 mg
Benadryl® Elixir 100 mL
Mucilage of Tragacanth 18 mL*
Purified Water to 120 mL

* Note: 18 mL of Mucilage of Tragacanth is calculated from 15% v/v of 120 mL

The dose volume must now be adjusted such that the patient receives 20 doses each dose
containing 30 mg of Phenobarbitone and 12.5 mg of Diphenhydramine Hydrochloride.
Therefore dose of mixture to be given = 120 mL/20 = 6mL

21
Pharmaceutical Calculations 4. Manipulating Pharmaceutical Formulations

Quiz Question 4.6

A prescription calls for 1% w/v of Phenol in 100mL Calamine Lotion APF 15

The formula of Calamine Lotion APF 15 is:
Calamine 5g
Zinc Oxide 5g
Bentonite, sterilised 3g
Sodium Citrate 0.5g
Liquefied Phenol 0.5mL
Glycerol 5mL
Purified Water to 100mL

How much liquefied phenol needs to be added to the above formulation?

[Data: Liquefied Phenol BP 1988 = 80% w/w Phenol; density 1.06 g/mL]

Answer:

Firstly, work out the weight of liquefied phenol in the Calamine Lotion

d = m/V m = d x V = 1.06 g/mL x 0.5mL = 0.53g of Liquefied Phenol

Amount of phenol present = 80/100 x 0.53g = 0.424g

We therefore need to add the following amount of Phenol to the Calamine Lotion:
1.0g - 0.424g = 0,576g phenol

Now convert this amount to an equivalent weight of Liquefied Phenol. 80

g :100g

0.576g : yg
y = 0.72 g Liquefied Phenol
Finally, convert this weight to a volume of Liquefied Phenol
d = m/v v= m/d = 0.72g
-------- = 0.68 mL
1.06g/mL

4.3.5 Converting parts to quantities

Some formulations have ingredients expressed in term of PARTS rather than specific units
of mass or volume. Such an expression indicate the ratio of quantities to each other. It is
important to remember that for a particular formula, any unit of mass or volume can be used
as long as it is applied to ALL the components of the formulation.

Worked Example 4.5

Express the following formulation in units of grams and kilograms:

Zinc Oxide 2 parts
Salicylic Acid 1 part
Yellow Soft Paraffin 4 parts

Working:
Expressed in units of grams:
Zinc Oxide 2g
Salicylic Acid 1g
Yellow Soft Paraffin 4g

Expressed in units of kilograms:

Zinc Oxide 2kg
Salicylic Acid 1 kg
Yellow Soft Paraffin 4kg
22
Pharmaceutical Calculations 4. Manipulating Pharmaceutical
Formulations

Quiz Question 4.7

How much of each ingredient is required to make 100g of the following formulation ?

Sulphur 1.5 parts

Salicylic Acid 1.5 parts
Aqueous Cream 97 parts

Answer:
Formula adds up to 100 parts. We want 100g of formula. Therefore 1 part = 1 gram
Formula becomes:

Sulphur 1.5g
Salicylic Acid 1.5g
Aqueous Cream 97g

Quiz Question 4.8

A formula for an headache powder contains:

Aspirin 5 parts
Caffeine 1 part
Lactose 4 parts

How many grams of Aspirin are required to make 1kg of powder mix ?

Answer:
Total number of parts = 10 parts or 10 g (these are the units we will use)
To determine factor of multiplication: 1000g/10g = 100
Therefore:

Aspirin 500g
Caffeine 100g
Lactose 400g

1000g

23
 Pharmaceutical Calculations Module
Tutorial 5: Weighing and Measuring

About This Tutorial

This tutorial was developed by the Victorian College of Pharmacy, Monash University in
conjunction with the Australian Pharmacy Examining Council Incorporated (APEC Inc)
(now known as the Faculty of Pharmacy and Pharmaceutical Sciences, Monash University
and the Australian Pharmacy Examining Committee respectively).It remains the property of
Monash University. The tutorial cannot be used or copied without prior authorisation.

This tutorial is intended as an aid for students enrolled in Monash University’s Bachelor of
Pharmacy & Pharmacy Internship programs.

• Original tutorial prepared by in1996:

Arthur Pappas Lecturer in Pharmacy Practice
Dr Louis Roller Head, Department of Pharmacy Practice

with the assistance of :

May Admans Senior Assistant-Lecturer in Pharmaceutics

Dr Denis Morgan Reader in Pharmaceutics
Dr Kay Stewart Lecturer in Pharmacy Practice
Prof Peter Stewart Professor of Pharmaceutics

• Original Tutorial Manual produced by Arthur Pappas - December 1996

• Adaptation & updating of the material for online delivery to students of Monash
University was undertaken by Phil Bergen, Assistant Lecturer in Pharmacy Practice -
February 2005

© Copyright 2005
This publication is copyright. Apart from any fair dealing for the purpose of private study, research, criticism or
review as permitted under the Copyright Act, no part may be reproduced by any process or placed in computer
memory without written permission. Any assembled extracts each attract individual copyright and enquiries
about reproduction of this material should be addressed to the appropriate publishers. Enquiries about all other
material should be made to the Faculty named above.
Last amended by EM- November 2008

ii
Pharmaceutical Calculations 5. Weighing and Measuring

5. Weighing and
Measuring

Topic Index

Page
5.1 Introduction 25
5.2 Objectives 25
5.3 Weighing 25
5.3.1 Types of balances 25
5.3.2 Sensitivity of balance 26
5.3.3 Percent (inherent) error in weighing 26
5.3.4 Minimum weighable mass 27
5.4 Measuring 28
5.4.1 Dispensing measures 28
5.4.2 Dispensing pipettes 29
5.4.3 Percent (inherent) error in measuring 29
5.4.4 Minimum measurable volume 30
Pharmaceutical Calculations 5. Weighing and Measuring

5.1 Introduction
Even though the frequency of dispensing extemporaneous prescriptions is significantly less
today than 10 years ago, it is vitally important to have an understanding of the capability of
equipment used in measuring and weighing of ingredients. All instruments have limitations.
This understanding will enable you to prepare products that are accurate to within defined
limits.

Despite the best precautions, errors in measurement will happen. Small random deviations
may be due to such factors as temperature changes, accidental vibrations, wind breeze and
limitations in vision. Systematic errors result from equipment faults and incorrect operator
technique.

Some degree of error is inevitable during weighing, measuring and compounding. In order to
standardise the quality of products, we must decide what tolerance is allowable. In
dispensing, the overall tolerance which is permitted is 10 per cent. This figure takes into
account errors from all sources, but since we cannot possibly calculate all contributing errors
we must keep the total error that we can determine below 5 per cent.

5.2 Objectives
The aim of this tutorial is for you to gain an appreciation of the capability and limitations of
weighing and measuring equipment and an awareness of the importance of selecting the
right apparatus for a particular purpose.

At the end of this tutorial you will be able to:

a) understand what is meant by the ' sensitivity'of a balance
b) be able to determine the inherent error of a weighing or measurement
c) be able to determine the minimum weighable mass for a particular balance
d) be able to select an appropriate measure for a specific volume

5.3 Weighing

5.3.1 Types of balances

The balances used in pharmacy are of three types: the Dispensing Balance (a scale B beam
balance or Two-Pan Balance), the Top-Pan Balance (or top loading balance) and the
Electronic Balance. The sensitivity of a balance determines the minimum quantity that can
be weighed in order to keep the error in weighing to below a certain level. Certain balances
are designed to be more accurate than others. The balance you choose will depend on your
purpose.

a)The Dispensing (Two-Pan) Balance

With the Two-Pan Balance, the substance being weighed is the variable and is placed on the
right hand pan. However if the balance is used to determine the mass of an unknown, the
weights become the variable and are therefore placed on the right hand pan. Of course the
reverse situation applies if a person is left handed.

Two-Pan Balances are allowed a maximum sensitivity of 32.5mg (The Weights and
Measures Regulations 1968 (Victoria)). Accordingly the minimum weighable mass on such a
balance is 20 x 32.5mg = 650mg in order to prevent weighing errors greater than 5%
occurring (discussed later). This balance has the capacity to weigh quantities of up to about
100-150g (depending on the density of the material)

b) Top-Pan Balance and Electronic Balance

They are a single pan balances comprising a series of counterweights within the balance or
electronics. These balances are available with sensitivities of 1mg (capacities 160g and
320g) and 10mg (capacity of 1200g)

25
Pharmaceutical Calculations 5. Weighing and Measuring

5.3.2 Sensitivity of balance

There are several sources of error involved in weighing including the operator, balance,
weights, transfer losses and temperature fluctuations.
An estimate of the error contribution made by the balance can be made using the '
sensitivity'
.

The 'sensitivity' of a dispensing balance is defined as the mass, usually expressed in

milligrams, required to produce a pointer deflection of one scale division.

Worked Example 5.1

A two-pan balance pointer rests at zero mark with no mass and at 2 divisions with a 20 mg
weight on the right scale pan. What is the sensitivity of this balance ?
Working:
The 20mg weight has caused 2 scale divisions deflection.
In other words, 10mg has caused 1 scale division deflection
The sensitivity of the balance is therefore 10mg.

Note: In making this statement, it is assumed that an operator can estimate the pointer
reading at least to within 1 scale division. This estimation to within 1 scale division is taken
to be the maximum error inherent in each weighing.

Worked Example 5.2

For a balance of 10mg sensitivity what is the possible range of a mass weighed at "200 mg"?
Working:
The ' weight'is therefore: 200mg +/- 10mg
In other words it could be anywhere between: 190mg and 210mg

Quiz Question 5.1

What is the sensitivity of a dispensing balance if a 100 mg weight causes a 5-scale division
deflection?
Answer:
Sensitivity = the weight causing one scale division deflection (definition)
10Omg : 5 scale deflections
x mg : 1 scale deflection
Therefore x = sensitivity = 20mg

5.3.3 Percent (inherent) error in weighing:

sensitivity (units of weight)

% error in weighing = ----------------------------------------- x 100
amount weighed (units of weight)

In dispensing practice, the inherent error in a weighing must be less than ± 5% of the amount
weighed.
Table 5.1
Effect of amount weighed on percent error
(Assuming the sensitivity of the balance is 10mg)
Amount Weighed Percent Error (+/-)
10mg 100%
20mg 50%
50mg 20%
100mg 10%
200mg 5% ***
300mg 3.33%
400mg 2.5%

26
Pharmaceutical Calculations 5. Weighing and Measuring

The larger the weight, the lower the percent error. The above table indicates that if a quantity
of 200mg or more is weighed, the error will be 5% or less.

Worked Example 5.3

What is the percentage error in weighing 450mg of Aspirin on a dispensing balance with a
sensitivity of 12.5 mg?
Working:
sensitivity of balance
% error = ------------------------------ x100
amount weighed

= 12.5 mg
--------- x 100 = 2.78%
450mg

Quiz Question 5.2

What is the percentage error in weighing 30mg of Prednisolone on a dispensing balance with
a sensitivity of 10mg?

Answer:
sensitivity of balance
% error = ----------------------------- x100
amount weighed

= 10 mg
---------- x 100 = 33.33% (Of course, this is unacceptably high)
30 mg

5.3.4 Minimum Weighable Mass

It is important to know what is the minimum mass that can be weighed in order not to exceed
an error of 5%.
In other words:

sensitivity (mg) 5%
amount weighed (mg)

amount weighed (mg) 100 x sensitivity (mg)

5

amount weighed (mg) 20 x sensitivity (mg)

The Minimum Weighable Mass (MWM), on a particular balance, is equivalent to 20

times its sensitivity.

Worked Example 5.4

If a dispensing balance has a sensitivity of 15mg, what is the minimum weight which will
incur a 5% error ?
Working:
MWM = 20 x sensitivity of balance
= 20x 15mg
= 300mg

Quiz Question 5.3

If a top-loading balance has a sensitivity of 1 mg what mass could be weighed in order to
have an error of 2%

27
 Pharmaceutical Calculations 5. Weighing and Measuring

Answer:
sensitivity of balance
% error = ------------------------------ x100
amount weighed

2% = 1 mg
--------- x 100
xmg
(Divide both sides by 100)
1 mg
0.02 = -------
xmg

Therefore x = 50mg

5.4 Measuring
Dispensing measures or pipettes are used in pharmacy for measuring volume. Different sizes
will not achieve the same level of accuracy (see 'Hints for Using Dispensing Measures'
below). Which dispensing measure you choose will depend on the volume to be measured
and the degree of accuracy required.

5.4.1 Dispensing Measures

Dispensing measures come in two types: conical or cylindrical.
Conical measures are easier to clean, but because the meniscus is relatively wide, they are
less accurate than the cylindrical type. In a typical pharmacy there is required by law to be an
assortment of measures: eg: 200mL, 100mL, 50mL, and 10mL which have been approved
for dispensing. Such measures are calibrated at 20 degrees Centigrade to a certain level of
error eg: +/- 1mL for a 50mL measure at 20 degrees Centigrade. This information is usually
stamped on the top of a measure. It is therefore important that measures should not be
washed in very hot water or used for measurement of very hot liquids.

Here is a brief description of dispensing measures:

(Please Note: other sizes may also be available)

10mL Measure
Has graduations of 1mL (starting at 1mL)
So you should only measure 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10 mL volumes

50mL Measure
Has graduations of 5mL (starting at 5mL)
So you should only measure 5, 10, 15, 20, 25, 30, 35, 40, 45 and 50 mL volumes

100mL Measure
Has graduations of 5mL (starting at 10mL)
So you should only measure 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80,
85, 90, 95 and 100 mL volumes

200mL measure
Has graduations of 10mL (starting at 10mL)
So you should only measure 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130,
140, 150, 160, 170, 180, 190 and 200 mL volumes

Hints for Using Dispensing Measures

1. Choose a measure appropriate to the volume of liquid requiring measurement

ie: use the smallest measure for the volume required
2. Hold the measure at eye level, with front and rear graduations in alignment

28
 Pharmaceutical Calculations J. Weighing and Measuring

3. The bottom of the liquid meniscus must be on the graduation mark

4. There may be difficulty in reading the bottom of the meniscus of coloured or dark
liquids. In these situations read the top of the meniscus.
5. When measuring viscous liquids, the liquid should be allowed to drain or where
possible, it should be washed out of the measure. Another method is to measure the
volume delivered by difference (eg: 30mL mark to 10mL mark = 20mL delivered)

5.4.2 Dispensing Pipettes

The accurate measurement of mobile liquids in volumes less than 5mL requires the use of a
pipette. Only pipettes approved for dispensing should be used. In a pharmacy there should
be several size pipettes to measure a range of volumes eg: 2mL, 10mL and 25mL Such
pipettes are calibrated at 20 degrees Centigrade to a certain level of error eg: +/- 0.02mL for
a 2mL pipette at 20 degrees Centigrade. It is therefore important that pipettes should not be
washed in hot water or used for measurement of hot liquids.

Here is a brief description of dispensing pipettes:

(Please Note: other sizes may also be available)

2mL pipette
Has graduations of 0.02mL
From 0 to 2mL

10m L pipette
Has graduations of 0.1 mL
From 0 to 10mL

25mL pipette
Has graduations of 0.1 mL
From 0 to 25mL

Hints for using Dispensing Pipettes

1. Select an appropriately graduated pipette whose capacity is appropriate to the

volume of liquid requiring measurement
2. Use the appropriate method of emptying the pipette
If the pipette is not stamped "blow out" then you can assume it is a normal
"drainage" pipette and the appropriate method should be used to empty it
3. For corrosive or toxic liquids do not use the mouth for suction. Attach a rubber bulb
to the stem of the pipette

Special problems in measuring certain liquids

1. Viscous liquids should not be measured by pipette.

2. There may be difficulty in reading the bottom of the meniscus of coloured or dark
liquids. In these situations read the top of the meniscus.

5.4.3 Percent (inherent) errors in measuring

Which of the above measuring instruments do you select ? As a general rule, to measure a
given volume select a measure that will be filled as close as possible to its capacity. This will
minimise the percent error. The graduation markings on a dispensing measure will indicate to
you the size of the volumes you can quantitate. These markings are calibrated at 20 degrees
Centigrade (usually to an error of between 1 to 2%).

Another factor that is important to consider is the potency of the ingredient to be measured. If
it is a small volume of a potent drug (eg: methadone) then the measurement accuracy is
more important than, for example, measuring a flavouring or sweetening agent like Red
Syrup.

29
Pharmaceutical Calculations S. Weighing and
Measuring

If a 10mL measure only has markings every 1mL, ideally you should only measure whole
value quantities even though the closest value you could discriminate is maybe half way
between these points (ie: every 0.5mL). If you wished to measure 8.5mL accurately, it would
be best to use a 10mL pipette.

The minimum percent error in measuring a volume, using markings on the measure, is
the calibration error at that temperature. Obviously vision problems in reading the
measure and whether you have it at eye level and are reading the bottom of the
meniscus can also increase the size of the error.

Worked Example 5.5

If you were to measure 75mL, which measure(s) would you select ?

Working:
Best to select the 10OmL measure with a graduation marking at 75mL
Assuming correct technique, this produces a certain systematic error.
However, selecting a 50mL measure twice (once to measure 50mL and once to measure
25mL) increases the total error, because two separate readings are made.

Quiz Question 5.4

If you needed to measure 2mL of a preservative solution which of the following instruments
would be more accurate ?
a) a 2mL pipette
b) a 25mL pipette
b) a 10mL dispensing measure

Answer:
All of the instruments above are capable of measuring 2mL volume, but to a different
accuracy. Given the principle of selecting the smallest apparatus to do the job, it is therefore
appropriate to use the 2mL pipette. Assuming it is read properly, there is less error in
measuring that quantity than the other two instruments.

5.4.4 Minimum measurable volume

A pharmacist should use the smallest dispensing measure or pipette to measure the volume
required. As a general rule, an instrument should not be used to measure a volume that is
less than 20 percent of its capacity.

Quiz Question 5.5

If you wanted to measure 15 mL of Ferrous Sulphate Mixture APF 15 how acceptable is it to
use a 100mL dispensing measure ?

Answer:
Ideally not. This is applying the principle of not measuring volumes less than 20 percent of
the maximum volume of a measuring instrument (in the case of a 100mL measure this is
20mL). For a 15mL volume it is best to use the 50mL measure or even a 25mL pipette.

30
 Pharmaceutical Calculations Module
Tutorial 6: Dilution of Liquid Formulations

About This Tutorial

This tutorial was developed by the Victorian College of Pharmacy, Monash University in
conjunction with the Australian Pharmacy Examining Council Incorporated (APEC Inc)
(now known as the Faculty of Pharmacy and Pharmaceutical Sciences, Monash University
and the Australian Pharmacy Examining Committee respectively).It remains the property of
Monash University. The tutorial cannot be used or copied without prior authorisation.

This tutorial is intended as an aid for students enrolled in Monash University’s Bachelor of
Pharmacy & Pharmacy Internship programs.

• Original tutorial prepared by in1996:

Arthur Pappas Lecturer in Pharmacy Practice
Dr Louis Roller Head, Department of Pharmacy Practice

with the assistance of :

May Admans Senior Assistant-Lecturer in Pharmaceutics

Dr Denis Morgan Reader in Pharmaceutics
Dr Kay Stewart Lecturer in Pharmacy Practice
Prof Peter Stewart Professor of Pharmaceutics

• Original Tutorial Manual produced by Arthur Pappas - December 1996

• Adaptation & updating of the material for online delivery to students of Monash
University was undertaken by Phil Bergen, Assistant Lecturer in Pharmacy Practice -
February 2005

© Copyright 2005
This publication is copyright. Apart from any fair dealing for the purpose of private study, research, criticism or
review as permitted under the Copyright Act, no part may be reproduced by any process or placed in computer
memory without written permission. Any assembled extracts each attract individual copyright and enquiries
about reproduction of this material should be addressed to the appropriate publishers. Enquiries about all other
material should be made to the Faculty named above.
Last amended by EM- November 2008

ii
Pharmaceutical Calculations 6. Dilution of Liquid Formulations

6. Dilution of Liquid
Formulations

Topic Index

Page
6.1 Introduction 32
6.2 Objectives 32
6.3 Dilution of Liquid Formulations 32
6.3.1 Decision to make a dilution 32
6.3.2 Ratio Strength 33
6.3.3 Ratio Dilution or Dilution Factor 33
6.3.4 Amount of drug in a stock solution 34
6.3.5 Diluting a stock solution 35
6.3.6 Amount of drug to prepare a stock solution 36
6.4 Alligation Technique 38
6.4.1 Formula 38
6.4.2 Examples using Ethanol 39
6.4.3 Miscellaneous Examples 43
Pharmaceutical Calculations 6. Dilution of Liquid Formulations

6.1 Introduction
Pharmacists are often asked to prepare a range of pharmaceutical formulations that contain
low concentrations of potent ingredients. Care needs to be taken when incorporating small
quantities of drug into a formulation to make sure that the amount transferred is within the
error range allowed. In other words consideration should be given to the sensitivity of the
balance and therefore its Minimum Weighable Mass (MWM) when weighing an ingredient.
Similarly the capability of dispensing measures needs to be taken into account when trying to
measure small volumes. (Refer Tutorial 5: Weighing and Measuring)

We may need to make a dilution (in the case of a mixture) or an attenuation or trituration (in
the case of a powder or semi-solid formulation) to enable us to obtain a small quantity
without exceeding our error limit.

Making a dilution, in the case of a mixture, firstly involves the preparation of a concentrated
solution of the active ingredient. From this concentrate, a specific volume is taken which will
contain the amount of active ingredient required.

The solution containing the higher concentration of active ingredient is referred to as the
'
stock'solution.

6.2 Objectives

The aim of this tutorial is to give you an appreciation of the concept of dilution of liquids and
how this is related to creating an accurate formulation given the constraints of available
equipment.

At the end of this tutorial you will be able to:

a) understand when you need to make a dilution

b) understand the concept of ratio strength
c) understand the concept of dilution factor
d) determine the amount of a stock solution of a given strength that will contain a
desired amount of active ingredient
e) understand how to make a dilution of a stock solution to a desired strength
f) determine the amount of active ingredient in a given volume of a diluted solution
g) understand how to use the alligation formula for dilution

6.3 Dilution of Liquid Formulations

6.3.1 Decision to make a dilution

A decision to make a dilution is related to the sensitivity of the weighing and measuring
instruments you have available and the quantity that has to be weighed or measured. All
active ingredients should be measured or weighed with the highest accuracy. This is
especially important if the drug has a narrow therapeutic index (ie: it is ineffective below a
certain blood level and toxic above another which is not markedly higher). The aim is to
measure all quantities with the lowest possible error.

Worked Example 6.1

Consider this formulation for nasal drops:
Phenylephrine HCI 0.15%
Propylene Glycol 5%
Purified Water to 100%
Make 15mL

How much Phenylephrine would you weigh and what method would you use ?
(Assume a balance sensitivity of 12.5mg)

32
 Pharmaceutical Calculations 6. Dilution of Liquid Formulations

Working:
Firstly, determine the Minimum Weighable Mass of the balance (for a 5% error)
This is 20 times the sensitivity = 20 x 12.5 mg = 250mg
(Refer Tutorial 5: Weighing and Measuring)

Secondly, determine how much Phenylephrine is contained in 15mL of the formulation.

0.15% w/v = 0.15g per 100mL or 150mg per 100mL
Therefore for 15mL xmg per 15mL
Therefore x = 22.5mg Phenylephrine HCI

Next weigh 250mg Phenylephrine HCI and dilute this to say 100mL with purified water.
The resulting concentration will be 25mg per 10mL Finally, to work out the volume
containing 22.5mg of drug:
25mg per 10mL
22.5mg per ymL

Therefore: y= 9mL required.

Final Formula:
Phenylephrine HCI solution (25mg/10mL) 9mL
Propylene Glycol 0.75mL
Purified Water to 15mL

6.3.2 Ratio Strength

This term describes the concentration of an active ingredient in terms of a ratio.

Worked Example 6.2

Express a 1:50 solution of Calcium Hydroxide in terms of: mg per mL and % w/v
Working: a)
1:50 means 1g in 50mL
(divide by 50) 0.02g = 20mg in 1 mL b)
% w/v is in units of grams per 100mL
Therefore:
We have: 1g in 50mL
or 2gin100mL
ie: 2 % w/v

Quiz Question 6.1

Express a 1:1000 solution of Atropine Sulphate in terms of mg per mL.

Answer:
1 :1000 means 1 g in 1000mL
We want: xg in 1mL
Therefore x = 0.001g ie: 0.001g per mL or 1mg per mL

6.3.3 Ratio Dilution or Dilution Factor

This term describes the factor by which a solution (or any formulation) is diluted. Eg: If a
solution is diluted 1 in 10, then 1 mL of this solution is taken and made up to 10mL with a
diluent liquid (eg: water or some other vehicle). This could also be expressed as the solution
being diluted by a factor of 10.

Worked Example 6.3

Ferrous Sulphate Mixture APF 15 contains 300mg Ferrous Sulphate per 10mL. What is the
dilution factor needed to make 100mL of a mixture containing 6mg/mL Ferrous Sulphate?

33
 Pharmaceutical Calculations 6. Dilution of Liquid Formulations

Working:
Firstly, determine how much Ferrous Sulphate is in 100ml_ of 6mg/mL; this is 600mg.
Secondly, determine the volume of Ferrous Sulphate Mixture containing 600mg drug.

300mg : 10mL mixture

600mg : x mL Therefore x = 20mL

This 20mL of mixture will need to be diluted to 100mL

Simplified: 20 in 100 is the same as 1 in 5 dilution (dilution factor)
(Note: the 80mL of vehicle to dilute the mixture, could incorporate not only water, but
additional flavouring, preserving and anti-oxidant ingredients)

Quiz Question 6.2

By what factor must a 1 mL ampoule of nebuliser solution of Salbutamol Sulphate (5mg/mL)
be diluted to produce a concentration of 2mg/mL

Answer:
Factor is: 2mg/mL
--------- = 0.4
5mg/mL

This is equivalent to: 4 : 1 0

or 1 :2.5

Check this:
If we take 1mL of (5mg/mL) solution this will contain 5mg drug. If this is diluted to 2.5mL, it
will contain 5mg/2.5mL or 2mg/mL

Worked Example 6.4

Methyl Hydroxybenzoate (MHB) Solution APF 15 contains:
MHB 5
Propylene Glycol to 100
It should be diluted 1 in 100 for preserving mixtures.

How much MHB would be present in 250mL of Potassium Citrate Mixture APF 15?

Working:
Firstly, determine the amount of MHB Solution APF 15 in 250ml_ of Potassium Citrate
Mixture APF15
MHB Solution APF15 should be present in the Pot.Citrate Mixture in the concentration of
1 in 100. ie: 1mL in 100mL mixture. Since we have 250mL mixture we will need 2.5mL
MHB Solution.

Since there is: 5g of MHB per 100mL of MHB Solution

Therefore: xg per 2.5mL of MHB Solution

So x=0.125g = 125mgMHB

6.3.4 Amount of drug in a stock solution

You often need to know the amount of active ingredient in a certain volume of stock solution
in order to make subsequent calculations.

Worked Example 6.5

You have a 100mL mixture of Morphine HCI of concentration 1 in 200. You are required to
make 200mL of a mixture containing Morphine HCI of concentration 100mg per 10mL.
Assuming you use the entire contents of the 100mL mixture, how much additional Morphine
HCI must be added?

34
Pharmaceutical Calculations 6. Dilution of Liquid Formulations

Working:
Firstly, determine how much Morphine HCI is in the 1 in 200 mixture (100mL).
1 in 200 means 1 g in 200 mL
We have 100mL, therefore the amount of Morphine HCI is 0.5g or 500mg.

Secondly, determine how much Morphine HCI is needed in the 100mg/10mL mixture(200mL)
100mg Morphine HCI : 10mL mixture

x mg Morphine HCI : 200mL mixture

Therefore x= 2000mg drug

Finally, the amount of morphine HCI to be added to the first mixture (and diluted to 200mL)
is:
2000mg - 500mg = 1500 mg

Quiz Question 6.3

You have a stock solution of 50 mL of Aminacrine HCI of concentration 1 in 250. Please
prepare 200mL of a solution containing Aminacrine HCI of concentration 10mg per 10mL
Assuming you use the entire contents of the 50mL bottle, how much additional Aminacrine
HCI must be added ?

Answer:
Firstly, determine how much Aminacrine HCI is in the 1 in 250 solution (50mL).
1 in 250 means 1 g in 250 mL
We have 50mL.
Therefore the amount of Aminacrine HCI is: (1g / 250mL)x 50mL = 0.2g = 200mg

Secondly, determine how much Aminacrine HCI is needed in the 10mg/10mL solution
(200mL)
10mg Aminacrine HCI : 10mL mixture
x mg Aminacrine HCI : 200mL mixture
Therefore x = 200mg drug

Finally, the amount of Aminacrine HCI to be added to the first mixture (and diluted to
200mL) is:
200mg - 200mg = 0 mg

ie: Dilute the 50mL of the stock solution to 200mL with distilled water to produce a final
concentration of 10mg/10mL

6.3.5 Diluting a stock solution

Often a portion of a stock solution needs to be used to produce a certain volume of a desired
concentration.

Worked Example 6.6

A topical formulation calls for 10% w/v Prepared Coal Tar. How much topical formulation can
be made from a volume of 25mL Strong Coal Tar Solution APF 15 ?
(Strong Coal Tar Solution APF 15 contains 40% w/v Prepared Coal Tar)

Working:
Firstly, determine how much Prepared Coal Tar is in 25mL of Strong Coal Tar Solution APF
15.
40% w/v = 40 g per 100 mL solution
We have x g per 25 mL solution
Therefore x = 10g Prepared Coal Tar
35
 Pharmaceutical Calculations 6. Dilution of Liquid Formulations

Secondly, determine how much topical formulation (10%w/v) can be made from 10g
Prepared Coal Tar.
10g per 100 mL topical formulation
We have 10g per y mL
Therefore y = 100mL

ie: 25mL of Strong Coal Tar Solution APF 15 is diluted 1 in 4 to produce 100mL of a topical
formulation of 10% w/v Prepared Coal Tar

Quiz Question 6.4

A prescription calls for 2% w/w Sulphur in Aqueous Cream. How much cream can be made
from a jar containing 21 g of 20% w/w Sulphur in Aqueous Cream?

Answer:
Firstly, determine how much Sulphur is in 21 g of 20%w/w Sulphur in Aqueous Cream.
20% w/v = 20 g per 100g cream
We have xg per 21 g cream
Therefore x = 4.2g Sulphur

Secondly, determine how much cream (2%w/w) can be made from 4.2g Sulphur.
2g per 100g cream
We have: 4.2g per yg cream
Therefore y = 210g

ie: 210g of 2% w/w Sulphur in Aqueous Cream can be made from 21 g of 20%w/w Sulphur in
Aqueous Cream.
Quick Check: 20% to 2% is a 1 :10 dilution. Therefore 21 g diluted 1:10 gives 210g.

6.3.6 Amount of drug to prepare a stock solution

You sometimes need to work out the amount of active ingredient for a small volume of stock
solution which when diluted produces the required concentration.

Worked Example 6.7

How many milligrams of salbutamol sulphate would be required to prepare 10 mL of a

solution such that when it is diluted to a final volume of 50 litres, a final concentration of 0.2
mcg/mL of salbutamol sulphate would be produced?

Working:
Method 1:
Using logic:
Firstly work out the amount of salbutamol sulphate in 50,000mL of solution
(0.2mcg/mL)
ie: 50,000 mL x 0.2mcg/mL = 10,000mcg = 10mg

This 10mg is the amount that is required to be present in the 10mL of the concentrate.

Method 2:
Using a formula:

amount of drug (mg) amount (mg)

-------------------------- x dilution factor =----------------------
quantity required (mL) unit dose (mL)

36
 Pharmaceutical Calculations 6. Dilution of Liquid Formulations
xmg 10 mL 0.2mg
------- x --------- = -----------
10mL 50,000mL 1000mL
Therefore:x= 10mg

Note: Utilising this method is a good shortcut designed to reduce decimal point mistakes, but
CARE must be taken to ensure that solids are all in the same unit (i.e. mcg, mg or g) and all
volumes are in the same unit (i.e. mL or L).

Therefore, in the above example, it is important to ensure that the 0.2 mcg/mL is expressed
as mg/1000mL.

Quiz Question 6.5

How many milligrams of Terbutaline Sulphate would be required to prepare 100 mL of a
solution such that when 1mL is diluted to 5mL, a final concentration of 500 mcg/mL of
Terbutaline Sulphate would be produced ?

Answer:

Using a formula:

amount of drug (mg) amount (mg)

-------------------------- x dilution factor =--------------------
quantity required (mL) unit dose (mL)

xmg 1mL 0.5mg

------- x ------- = ---------
100mL 5mL 1mL

Therefore x = 250 mg Terbutaline Sulphate

Worked Example 6.8

How much Atropine Sulphate is required to prepare 100 mL of a concentrated solution such
that when diluted 1 in 10, the resulting solution has a concentration of 1.0 mg/10 mL ?

Method 1: Working
Firstly work out the amount of Atropine Sulphate in 100mL of final solution
(1 mg/10mL) ie: 100mL x 1 mg/10mL = 10mg
This is the amount required in the 10 mL concentrate, (ie: 1 in 10 or 10 in 100 dilution)
Therefore in a 100mL concentrate there would be 10mg/10mL x 100mL = 100mg

Method 2: Working
Using a formula:

amount of drug (mg) amount (mg)

-------------------------- x dilution factor = -------------------

quantity required (mL) unit dose (mL)

xmg 1 1 mg
---------- x -------- = ------------
100mL 10 10mL
Therefore x = 100mg Atropine Sulphate

Note: Always check the solubility of a drug before considering making a stock solution.

37
Pharmaceutical Calculations 6. Dilution of Liquid Formulations

Quiz Question 6.6

How much Betamethasone Sodium Phosphate is required to prepare 15 mL of a

concentrated solution such that when diluted 1 in 8, the resulting solution has a concentration
of 4mg/1 mL ?

Answer:

amount of drug (mg) amount (mg)

-------------------------- x dilution factor = -------------------

quantity required (mL) unit dose (mL)

xmg 1 4mg
------ x ------- = --------
15mL 8 1mL

Therefore: x = 480mg Betamethasone Sodium Phosphate

6.4 Alligation Technique

This is a dilution method for determining the proportion of two products of different strengths
required to be combined to produce the desired strength in a final product. This technique
can be used for dilution of liquid or semi-solid formulations.

6.4.1 Formula

Where a = % Product A

b = % Product B

c = % Product C

x = Parts of Product A

y = Parts of Product B

Using algebra:
ax + by = c (x+y)
ax + by = cx + cy
ax - cx = cy - by

x (a-c) = y (c-b)
ie: x (c-b)
---- = --------
y (a-c)
In other words:
The parts required of Product A = x = (% Product C - % Product B) The parts
required of Product B = y = (% Product A - % Product C)
Total parts = x + y
38
 Pharmaceutical Calculations 6. Dilution of Liquid Formulations

6.4.2 Examples using Ethanol

Dilute Ethanol of various strengths may be prepared by diluting 95% Ethanol with distilled
water. See Table 6.1 for the proportions of Ethanol required.

It is important to know that before a mixture of Ethanol and water is finally adjusted to
volume it should be cooled to the same temperature (about 20°C), as that at which the
Ethanol was measured.

Table 6.1
Preparing Dilutions of Ethanol
Strength of Ethanol Volume Final volume
Required (v/v) 95% Ethanol of mixture
20% 210mL 1000mL
25% 263mL 1000ml.
45% 474mL 1000mL
50% 526mL 1000mL
60% 632mL 1000mL
70% 737mL 1000mL
80% 842mL 1000mL
90% 947mL 1000mL

(Ref: Pharmaceutical Handbook 19th Edition)

If the strength of the Ethanol available is not known, it may be determined from the specific
gravity. This is determined at 20°C by means of a hydrometer and the corresponding
percentage ethanol is read off a reference table (eg; Pharmaceutical Handbook 19th Edition
pages 228-230)

In order to test the alligation formula with the values presented in Table 6.1, let'
s use the
following example.

Worked Example 6.9

What volumes of Ethanol 95% and distilled water should be mixed to produce 1000mL of
Ethanol 70% ?

Working:

Using the formula:

% Parts Required
% Given Desired

% Given %Desired Parts Required '

70

95% 70% 70 (ie: 70 - 0)

0% 25 (ie: 95 – 70)

95

In other words 25 parts of distilled water and 70 parts of Ethanol 95% will result in a mixture
containing Ethanol 70%. The next step is to use these proportions or parts to determine the
volumes of Ethanol 95% and distilled water.
 Pharmaceutical Calculations 6. Dilution of Liquid Formulations

Volume of Ethanol 95% required:

70
— x 1000 = 736.8mL Ethanol 95% (Refer Table 6.1)
95

Volume of distilled water required:

25
— x 1000 = 263.2mL of distilled water (theoretical value)
95

Note: For liquids like Ethanol (and Sulphuric Acid), make the final adjustment after the
mixture has cooled to the same temperature as that at which the Ethanol was measured.

Looking at this previous worked example, a simple rule could be used when diluting Ethanol
with distilled water:

To prepare X% Ethanol, take X parts of Ethanol (Y%) and dilute to Y parts using distilled
water.

Test this: To prepare 70% Ethanol, take 70 parts of Ethanol 95% and dilute to 95 parts using
distilled water. (This is what was actually found in the previous example)

This rule applies to any liquid diluted with distilled water.

Quiz Question 6.7

Prepare 1000mL of Ethanol 20% using Ethanol 95% and distilled water.
What volume of Ethanol 95% is needed ?

Answer:
Take 20 parts of Ethanol (95%) and dilute to 95 parts with distilled water,
ie: 20mL (95%) : 95mL total volume
xmL (95%) : 1000mL total volume

Therefore x = 210.5mL Ethanol 95% (Refer Table 6.1)

Worked Example 6.10

Prepare 1000mL of Ethanol 80% using Ethanol 95%.

What volume of Ethanol 95% is needed ?

Working:
Take 80 parts of Ethanol (95%) and dilute to 95 parts with distilled water,
ie: 80mL(95%) : 95mL total volume
xmL (95%) : 1000mL total volume

Therefore x = 842.1 mL Ethanol 95% (See Table 6.1)

Quiz Question 6.8

What proportions of distilled water and 95% Ethanol are required to prepare 65% v/v
Ethanol?

Answer:
Take 65 parts of Ethanol (95%) and dilute to 95 parts with distilled water.40
 Pharmaceutical Calculations 6, Dilution of Liquid Formulations

Quiz Question 6.9

Prepare 100mLof Ethanol 10% using Ethanol 95%.

What volume of Ethanol 95% is needed ?

Answer:
Take 10 parts of Ethanol (95%) and dilute to 95 parts with distilled water.
ie 10mL(95%) : 95mL total volume
xmL (95%) : 100mLtotal volume
Therefore x = 10.5mL Ethanol 95%

Quiz Question 6.10

Prepare 1000mL of Ethanol 50% using Ethanol 95%.

What volume of Ethanol 95% is needed ?

Answer:
Take 50 parts of Ethanol (95%) and dilute to 95 parts with distilled water.
ie 50mL(95%) : 95mL total volume
xmL (95%) : 1000mL total volume
Therefore x = 526.3mLEthanol 95% (Refer Table 6.1)

Quiz Question 6.11

In what proportions should Ethanol 95% v/v and Ethanol 50% v/v be mixed to make Ethanol
70% v/v ?

Answer:

In other words:
20 parts of Ethanol 95% is required
25 parts of Ethanol 50% is required ie: 4 : 5

Worked Example 6.11

What volumes of Ethanol 10% v/v and Ethanol 78% v/v need to be combined to produce
480mL of Ethanol 30% v/v?

Working Using the formula:

To determine volume of Ethanol 10%:

48
----- x 480mL = 338.8 mL
68

41
Pharmaceutical Calculations 6. Dilution of Liquid Formulations

To determine volume of Ethanol 78%

20
----- x480mL= 141.2 mL

68

Quiz Question 6.12

How much Ethanol 90% v/v is required to prepare 1000 mL of Ethanol 45% v/v?

Answer:
Take 45 parts of Ethanol (90%) and dilute to 90 parts with distilled water.
ie 45mL (90%) : 90mL total volume
xmL (90%) : 1000mL total volume
Therefore: x = 500mL Ethanol 90%

Check: 500mL Ethanol 90% diluted to 1000mL is a 1:2 dilution. The

resulting concentration should be 45% v/v.

Worked Example 6.12

What volume of distilled water must be added to 500 mL of Ethanol 70% v/v to
reduce the concentration to 45% v/v

Working out:

Take 45 parts of Ethanol (70%) and dilute to 70 parts with distilled water

ie 45mL (70%) : 70mL total volume

500mL(70%) : y mL total volume

Therefore: x = 777.8mL total volume

Therefore volume of water to be added = total volume - volume of Ethanol 70%

= 777.8mL - 500mL
= 277.8mL

Note: Make the final adjustment with distilled water after the mixture has cooled to the same
temperature as that at which the Ethanol 45% was measured.

Volumes of water and ethanol are not simply additive, in other words a volume contraction
will occur. To reduce error, volume adjustment should be made at the same temperature at
which the alcohol was measured.

Consider the above example again, but this time using weights in our calculations.

Remember, weight is constant, even though volume may not be. (density
of Ethanol 70% v/v = 0.890g/mL; Ethanol 45% v/v = 0.943g/mL)

Using the formula: m= d x V

Weight of water added = Weight of Ethanol 45% - Weight of Ethanol 70%

= (777.8mLx 0.943g/mL) - (500mL x 0.890g/mL) =
733.47g - 445g
= 288.47g

Since density of water is 1.00g/mL then 288.47mL water should be added.

42
Pharmaceutical Calculations 6. Dilution of Liquid
Formulations

The contraction volume is based on the following principle:

Contraction Volume = (Volume of Strong Ethanol + Volume of Water) - Final Volume

= 500 mL + 288.47 mL - 777.8 mL
= 10.67 mL
= 10.7 mL
Note: even though there is a contraction in volume the %v/v is correct using the
above calculation.

6.4.3 Miscellaneous Examples

Worked Example 6.13

Prepare 100mL of Benzoic Acid 5%w/v using Benzoic Acid 8%w/v (in Propylene Glycol)
and
Propyiene Glycol.
What volume of Benzoic Acid 8%w/v is needed ?

Answer:
Take 5 parts of Benzoic Acid (8%) and dilute to 8 parts with Propylene
Glycol.
ie: 5mL (8%w/v) : 8mL total volume
xmL (8%w/v) : 100mL total volume

Therefore x = 62.5mL Benzoic Acid 8% w/v

Check:
62.5mL x 8g/100mL = 5g. This 5g is diluted to 100mL giving 5%w/v

Quiz Question 6.13

You are required to make 100mL of Lemon Spirit APF15 (10% v/v Lemon Oil in
Ethanol
(96%).
What volumes of 5% v/v Lemon Oil in Ethanol (96%) and 15% v/v Lemon Oil in
Ethanol
(96%) are needed ?

Answer
:
Workin
g:

Using the formula:

To determine volume of 15% v/v Lemon Oil:

5
----- x 100mL = 50 mL
10
To determine volume of 5% v/v Lemon
Oil: 5
----- x 100mL= 50 mL
10
Check: 50mL of 15%v/v contains 7.5mL Lemon Oil. 50mL of 5% v/v contains 2.5mL
Lemon Oil. Therefore 7.5mL + 2.5mL = 10mL (10mL Lemon Oil in 100mL volume =
10%v/v) 43
 Pharmaceutical Calculations Module:
Tutorial 7: Dilution of Solid/Semi-Solid
Formulations

About This Tutorial

This tutorial was developed by the Victorian College of Pharmacy, Monash University in
conjunction with the Australian Pharmacy Examining Council Incorporated (APEC Inc)
(now known as the Faculty of Pharmacy and Pharmaceutical Sciences, Monash University
and the Australian Pharmacy Examining Committee respectively).It remains the property of
Monash University. The tutorial cannot be used or copied without prior authorisation.

This tutorial is intended as an aid for students enrolled in Monash University’s Bachelor of
Pharmacy & Pharmacy Internship programs.

• Original tutorial prepared by in1996:

Arthur Pappas Lecturer in Pharmacy Practice
Dr Louis Roller Head, Department of Pharmacy Practice

with the assistance of :

May Admans Senior Assistant-Lecturer in Pharmaceutics

Dr Denis Morgan Reader in Pharmaceutics
Dr Kay Stewart Lecturer in Pharmacy Practice
Prof Peter Stewart Professor of Pharmaceutics

• Original Tutorial Manual produced by Arthur Pappas - December 1996

• Adaptation & updating of the material for online delivery to students of Monash
University was undertaken by Phil Bergen, Assistant Lecturer in Pharmacy Practice -
February 2005

© Copyright 2005
This publication is copyright. Apart from any fair dealing for the purpose of private study, research, criticism or
review as permitted under the Copyright Act, no part may be reproduced by any process or placed in computer
memory without written permission. Any assembled extracts each attract individual copyright and enquiries
about reproduction of this material should be addressed to the appropriate publishers. Enquiries about all other
material should be made to the Faculty named above.
Last amended by EM- November 2008

ii
Pharmaceutical Calculations 7, Dilution of Solid/Semi Solid Formulations

7. Dilution of Solid/Semi-
Solid Formulations

Topic Index

Page
7.1 Introduction 45
7.2 Objectives 45
7.3 Dilution of Solid/Semi Solid Formulations 45
7.3.1 Decision to make a dilution 45
7.3.2 Ratio Strength 49
7.3.3 Ratio Dilution or Dilution Factor 50
7.3.4 Amount of drug in a stock formulation 51
7.3.5 Diluting a stock formulation 51
7.3.6 Amount of drug to prepare a stock
formulation 52
7.4 Alligation Technique 54
7.4.1 Formula 54
7.4.2 Examples using Salicylic Acid 55
7.4.3 Miscellaneous Examples 58
 Pharmaceutical Calculations 7, Dilution of Solid/Semi Solid Formulations

7.1 Introduction

The principles outlined in Tutorial 6: Dilution of Liquid Formulations also apply here. Most of
the examples in this tutorial involve solid or semi-solid formulations. However, there may be
some examples involving liquids.

When a pharmacist needs to prepare a solid (powder) or semi-solid (cream, ointment, gel)
formulation containing low concentrations of active ingredient, care is needed to make sure
that the amount transferred is within the error range allowed. In other words consideration
should be given to the sensitivity of the balance and therefore its Minimum Weighable Mass
(MWM) when weighing an ingredient. (Refer Tutorial 5: Weighing and Measuring)

We may need to make an attenuation (in the case of a powder) or trituration (in the case of a
semi-solid formulation) to enable us to obtain a small quantity of drug without exceeding our
error limit. The use of the term ' attenuation'implies a dilution. This may be achieved
physically by mixing in a mortar or by trituration on an ointment slab.

Making an attenuation, in the case of a powder, firstly involves the preparation of a

concentrated powder mix of the active ingredient. From this concentrate, a specific weight is
taken which will contain the amount of active ingredient required.

Making a trituration, in the case of a semi-solid formulation, can either involve the
preparation of:
a) a concentrated powder mix of the active ingredient, from which a specific weight is taken
containing the amount of drug required. This is then mixed into the remaining formulation.
OR
b) a concentrated mix of the active ingredient in a semi-solid base, from which a specific
weight is taken containing the amount of drug required. This is then mixed into the remaining
formulation.

The powder or semi-solid containing the higher concentration of active ingredient is referred
1
to as the '
stock powder or '
stock'ointment or cream or just generally 'stock'formulation

7.2 Objectives

The aim of this tutorial is to give you an appreciation of the concept of dilution of powder and
semi-solid formulations and how this is related to creating an accurate formulation given the
constraints of available equipment.

At the end of this tutorial you will be able to:

a) understand when you need to make a dilution

b) understand the concept of ratio strength
c) understand the concept of dilution factor
d) determine the amount of a stock formulation of a given strength that will contain a
desired amount of active ingredient
e) understand how to make a dilution of a stock formulation to a desired strength
f) determine the amount of active ingredient in a given mass of a diluted formulation
g) understand how to use the alligation formula for dilution

7.3 Dilution of Solid/Semi-Solid Formulations

7.3.1 Decision to make a dilution.

A decision to make a dilution is related to the sensitivity of the balance you have available
and the quantity that has to be weighed. All active ingredients should be measured or
weighed with the highest accuracy. This is especially important if the drug has a narrow
therapeutic index (ie: it is ineffective below a certain blood level and toxic above another
which is not much higher). The aim is to measure all quantities with the lowest possible error.

45
 Pharmaceutical Calculations 7. Dilution of Solid/Semi Solid Formulations

Worked Example 7.1

Consider the following powder formulation:
Atropine Sulphate 0.5 mg
Lactose q.s.
Ft Capsules m.9
Sig 1 b.i.d.

How much Atropine Sulphate would you weigh and what method would you use?
(Assume a balance sensitivity of 10mg)

Working:
Note: Generally, Lactose is used in powder formulation. The usual weight of a capsule/
powder (drug and Lactose) is 100 to 300mg.
Let us make 10 x 200mg capsules which each consist of 0.5mg Atropine Sulphate and
199.5mg Lactose. We make one or two extra capsules to allow for loss of material during
transfer.

Firstly, determine the Minimum Weighable Mass (MWM) of the balance (for a 5% error)
This is 20 times the sensitivity = 20 x 10mg = 200mg

(Refer Tutorial 5: Weighing and Measuring)

Method 1: Using logic

Formula is: Atropine Sulphate 0.5mg
Lactose 199.5mg

200.0mg

1. Amount of Atropine Sulphate needed: 0.5mg/capsule x 10 capsules = 5mg

2. Amount of Lactose needed = 199.5mg x 10 = 1995mg

3. First Dilution.
Weigh the MWM (200mg) of Atropine Sulphate and dilute to say, 10g with Lactose.
This will contain 200mg drug : 10,000mg powder mix
We want: 5mg drug : xmg powder mix

Therefore x = 250mg (5mg of which is Atropine sulphate)

Note that this amount is greater than the MWM.

4. Amount of additional lactose to be added is: 1995mg - 245mg = 1750mg Lactose.

5. Second Dilution.
Take the 250mg powder mix and triturate with the 1750mg Lactose.

6. Weigh 200mg quantities of powder (containing 0.5mg of drug) and place into gelatin
capsules

Method 2: Using a formula

amount of drug (mg) amount (mg)

--------------------------- x dilution factor = -------------------
quantity required (mg) unit dose (mg)

46
 Pharmaceutical Calculations 7, Dilution of Solid/Semi Solid Formulations

200mg 0.5mg
------------ x dilution factor =----------
10,000mg 200mg

Therefore the dilution factor = 0.125 or 1 in 8

What the above formula means:

1. 200 mg of Atropine Sulphate is weighed
2. This is attenuated to a total weight 10 g (using 9.8 g Lactose).
3.1 g of this mix is weighed out and attenuated to 8 g with Lactose (ie: using 7g of Lactose).
4. 200 mg of that second mix is weighed out (which should contain 0.5 mg of Atropine
Sulphate).

Check:
200mg 1000mg 0.5mg
---------- x ------------- = ---------

10,000mg 8000mg 200mg

0.0025 = 0.0025 (Left Hand Side = Right Hand Side)

Worked Example 7.2

What are the errors incurred in these weighings?

We add up the error for each weighing in order to get the total error in the final concentration.
Note: that is the maximum error that could occur. In reality, some errors may possibly cancel.

a) 200mg Atropine Sulphate

10mg
------- x100 = 5%
200mg

b) 9.8g lactose

10mg
------ x 100 = 0.102%

9800mg

c) 1000mg of powder mix 1

10mg
------- x100 = 1.0%

1000mg

d) 7g of Lactose

10mg
------- x 100 = 0.143%

7000mg

e) 200mg of powder mix 2

10mg
-------x 100 = 5%
200mg

Adding all the individual errors produces: 11.245% 47

Pharmaceutical Calculations 7, Dilution of Solid/Semi Solid Formulations

Note: This exceeds our final allowable error of 10% for a formulation. It is therefore advisable
that the 200mg lots of powder be weighed on a top-loading balance with a sensitivity of 1mg.
This will bring the total error to less than 10%.

Quiz Question 7.1

Outline the method required to make 3 paediatric powders with the following formulation:
(Assume the balance sensitivity is 5mg)
Propranolol Hydrochloride 10mg
Lactose 110mg

Answer:
Prepare for one extra powder to allow for manipulation losses.
The formula then becomes: (QD x4)
Propranolol 10mg 40mg
Lactose 110mg 440mg

The Minimum Weighable Mass for a 5% error = 20 x sensitivity = 20 x 5mg = 100mg

Weigh 100mg of Propranolol and dilute to say, 500mg with Lactose. Determine what
quantity of this powder mix we need to contain 40mg drug:
100mg drug : 500 mg powder mix
40mg drug : x mg powder mix
Therefore x = 200mg
(This consists of 40mg drug and 160mg Lactose)
Therefore the amount of additional Lactose required is: 440mg-160mg = 280mg
Summary:
Weigh 100mg Propranolol, dilute to 500mg with Lactose. Take 200mg of this mix and dilute
further with 280mg Lactose. Weigh 120mg powders (containing 10mg drug).

Quiz Question 7.2

In making up capsules of a very potent drug the following procedure was followed:

a) 400 mg of the drug was weighed out and diluted to 10 g with Lactose;
b) 1g of this powder mix was further diluted to 10 g with Lactose
c) 1g of this second mix was again diluted to 10 g with Lactose
d) 1g of this third mix was diluted to 10 g with Lactose
e) 1g of this fourth mix was diluted to 12g with Lactose
f) 400 mg of the final mix was filled into No.1 empty gelatin capsules.

What is the amount of drug in each capsule?

Answer:
Using the formula below:

amount of drug (mg) amount (mg)

-------------------------- x dilution factor = -------------------

quantity required (mg) unit dose (mg)

Note: The dilution factor in this case consists of a series of dilutions.

400mg 1,000mg 1,000mg 1,000mg 1,000mg xmg

--------- x --------------- x ----------- x ------------ x ------------ = ----------

10,000mg 10,000mg 10,000mg 10,000mg 12,000mg 400mg
-3
x = 1.33 x 10 mg drug (per capsule)

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 Pharmaceutical Calculations 7. Dilution of Solid/Semi Solid Formulations

Quiz Question 7.3

If you have a dispensing balance with a sensitivity of 10 mg to dispense the capsules

outlined in the above question, what would be the approximate percentage error in their
manufacture ?

Answer:
If we add up all the errors for each weighing:

a) weight of drug
10mg
-------- x 100 = 2.5%
400mg

b) weight of Lactose
10mg
--------- x 100 = 0.104%
9,600mg

d) weight of powder mix 1

10mg
----------- x100= 1.0%
1,000mg

c2) weight of lactose for powder mix 1

10mg
-------- x 100 = 0.11%
9,000mg

This process is repeated for powder mix 2 and 3, therefore:

(c1 + c2) x 3 = error for powder mix 1,2,3 = (1.0 + 0.11) x 3 = 3.33%

d) weight of powder mix 3

10mg
---------- x 100 = 1.0%
1000 mg

e) weight of lactose to make powder mix 4

10mg
---------- x 100 = 0.091
11 .000 mg

f) weight of 400mg final mix

10mg
--------- x 100 = 2.5%
400mg

Total error = 9.53%

7.3.2 Ratio Strength

This term describes the concentration of an active ingredient in terms of a ratio.

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 Pharmaceutical Calculations 7. Dilution of Solid/Semi Solid Formulations

Worked Example 7.2

Express a 1:500 powder mixture of Saccharin Sodium in Lactose as % w/w

Working:
1:500 means 1g in 500g

% w/w is in units of grams per 100q

Therefore:
We have: 1g in 500g
or xg in 10Og
ie: x = 0.2 % w/w

Quiz Question 7.4

Express a 1:1000 powder mixture of Vanillin in terms of mg per g.

Answer:
1 : 1000 means 1 g in 1000g
We want: xg in 1g
Therefore x = 0.001g ie: 0.001g Vanillin per gram powder mix or1mg/g

7.3.3 Ratio Dilution or Dilution Factor

This term describes the factor by which a powder or semi-solid is diluted.
Eg: If a cream is diluted 1 in 10, then 1g of this cream is taken and made up to 10g
with a diluent base (usually the same base). This could also be expressed as the cream
being diluted by a factor of 10.

Worked Example 7.3

An ointment jar contains 50g of Dithranol 2% in White Soft Paraffin.
a) What is the dilution factor needed to produce 200 g of Dithranol Paste APF 15 ?
b) What quantity of Dithranol 2% is required ?

(Dithranol Paste APF 15 contains 0.1% w/w Dithranol in Zinc and Salicylic Acid Paste APF 15)

Working:
a) Dilution factor:
Note: The dilution factor is constant regardless of the quantities involved,
ie: 0.1%
------- = 0.05 or 1 in 20
2%

You can double check this later, after you have determined the quantities involved.

b) Quantity of Dithranol 2% required:

Firstly, determine how much Dithranol is in 200g of 0.1% Dithranol Paste:

This is 0.1g/100g or 0.2g/200g

Secondly, determine the mass of 2% Dithranol in WSP that contains 0.2 g Dithranol.
2g : 100g
0.2g : xg Therefore x = 10g

This 10g of 2% ointment will need to be diluted to 200g with Zinc and Salicylic Acid Paste
Simplified: 10 in 200 is the same as: 1 in 20 dilution (dilution factor)

50
Pharmaceutical Calculations 7. Dilution of Solid/Semi Solid Formulations

Quiz Question 7.5

By what factor must a 10mL aliquot of Salicylic Acid Paint APF15 (10% w/v Salicylic Acid in
Flexible Collodion) be diluted to produce a final concentration of 4% w/v Salicylic Acid ? How
much Flexible Collodion needs to be added ?

Answer:
a) Factor is: 4%w/v
______ = 0.4
10%w/v

This is equivalent to: 4 : 1 0 or

1 :2.5
b) 10mL of the paint needs to be diluted to 25mL with Flexible Collodion,
ie: 15mL of Flexible Collodion is needed.

Check this:
If we take 10mL of (10g/100mL) solution this will contain 1g drug. If this is diluted to 25mL, it
will contain 1g/25mL or4g/100mL (4%w/v).

7.3.4 Amount of drug in a stock formulation

We may need to know the amount of active ingredient in a certain weight of powder or semi-
solid formulation in order to make subsequent calculations.

Worked Example 7.4

You have 100g of Cocaine and Adrenaline Paste APF15 (containing 1 in 10 cocaine HCI).
You are required to make 200g of paste containing 1 in 4 cocaine HCI.
Assuming you use the contents of the 100g paste, how much additional cocaine HCI must be
added?

Working:
Firstly, determine how much Cocaine HCI is in the 1 in 10 paste (100g).
1 in 10 means 1g cocaine in 10g paste
We have 100g paste, therefore the amount of Cocaine HCI is 10g

Secondly, determine how much cocaine HCI is needed in the 1 in 4 paste (200g)
1 in 4 means: 1g Cocaine HCI in 4g paste.
We want: x g Cocaine HCI in 200g paste
x= 50g Cocaine HCI

Finally, the amount of Cocaine HCI to be added to the first paste (and diluted to 200g) is:
50g -10g = 40g

7.3.5 Diluting a stock formulation

Often a portion of a stock powder or semi-solid formulation needs to be used to produce a
certain volume of a desired concentration.

Worked Example 7.5

A shampoo for seborrhoea is requested containing 15% Cetrimide. How much shampoo can
be made from 30mL Cetrimide Shampoo APF 15 ? (Cetrimide Shampoo APF 15 contains
40% w/v Cetrimide)

51
 Pharmaceutical Calculations 7. Dilution of Solid/Semi Solid Formulations

Working:
Firstly, determine how much Cetrimide is in 30mL of Cetrimide Shampoo APF 15.
40% w/v = 40 g per 100 mL solution
We have x g per 30 mL solution
Therefore x = 12g Cetrimide

Secondly, determine how much topical formulation (15%w/v) can be made from 12g
Cetrimide.
15g per 100 mL topical formulation
We have: 12g per y mL
Therefore y = 80 mL

ie: 30mL of Cetrimide Shampoo APF 15 is diluted with 50mL (of a equivolume mixture of
ethanol and water- ie: same vehicle as in the APF formulation) to produce 80mL of 15% w/v
Cetrimide.

Quiz Question 7.6

An aqueous cream for eczema is requested containing 5% w/w Calamine. How much cream
can be made from 40g of 15% w/w Calamine in Aqueous Cream ?

Answer:
Firstly, determine how much Calamine is in 40g of 15% w/w Calamine in Aqueous Cream ?
15% w/w = 15 g per 100g cream
We have x g per 40g cream
Therefore x = 6g Calamine

Secondly, determine how much cream (5%w/w) can be made from 6g Calamine.
5g per 100g cream
We have 6g per y g cream
Therefore y = 120g
Check: 5%
— = 0.333 ie: 1 in 3 Therefore 40g should be diluted to (3 x 40g) 120g
15%

7.3.6 Amount of drug to prepare a stock formulation

You sometimes need to work out the amount of active ingredient for a small quantity of stock
formulation which when diluted produces the required concentration.

Worked Example 7.6

How many milligrams of Digoxin would be required to prepare 10 g of a powder such that
when it is diluted to 50 g with Lactose, a final concentration of 20 mcg/100mg of Digoxin
would be produced?

Working:
Method 1:
Using logic:
Firstly work out the amount of digoxin in 50 g of final powder mix (20mcg/100mg)
ie: 50g x20mcg/0.1g = 10,000mcg = 10mg Digoxin
This 10mg is the amount that is required to be present in the 10g of the concentrate.

Method 2: Using a formula:

amount of drug (mg) amount (mg)
--------------------------- x dilution factor = -------------------
quantity required (mg) unit dose (mg)

52
 Pharmaceutical Calculations 7. Dilution of Solid/Semi Solid Formulations
-3
xmg 10,000mg 20x10 mg
---------- x ------------- = --------------
10,000 mg 50,000mg 100mg

Therefore x = 10mg Digoxin

Note: Utilising this method is a good shortcut designed to reduce decimal point mistakes, but
CARE must be taken to ensure that solids are all in the same unit (i.e. mcg, mg or g).
Therefore, in the above example, it is important to ensure that the 20mcg is converted to
20x10 - 3 mg

Quiz Question 7.7

How many milligrams of Phenobarbitone would be required to prepare 50g of a powder such
that when 1g is diluted to 5g with Lactose, a final concentration of 10mg/100mg of
Phenobarbitone would be produced?

Answer:

Using a formula:

amount of drug (mg) amount (mg)

-------------------------- x dilution factor = ------------------

quantity required (mg) unit dose (mg)

xmg 1,000 mg 10mg

--------- x ------------------ = ------------
50,000 mg 5,000mg 100mg

Therefore x = 25,000mg = 25g Phenobarbitone

Worked Example 7.7

How much Dipyridamole (coronary vasodilator) is required to prepare 5g of a powder such

that when diluted 1 in 10, the resulting powder mix has a concentration of 1.0 mg/100mg ?

Working:

Method 1
Firstly work out the amount of Dipyridamole in 10,000mg of diluted powder mix (1mg/100mg)
ie: 10,000mg x 1mg/100mg = 100mg
This is also the amount required in the 1000mg of concentrate. (1 in 10 dilution)
Therefore in a 5g or 5,000mg of concentrated powder there would be:

100mgdrug
-------------------------- x 5,000mg concentrate = 500mg Dipyridamole
1,000mg concentrate

Method 2
Using a formula:

amount of drug (mg) amount (mg)

--------------------------- x dilution factor = --------------------
quantity required (mg) unit dose (mg)

53
 Pharmaceutical Calculations 7. Dilution of Solid/Semi Solid Formulations
x mg 1 1 mg
-------- x ---------- = --------
5,000mg 10 100mg

Therefore: x = 500mg Dipyridamole

Quiz Question 7.8

How much Potassium Iodide is required to prepare 10g of a powder such that when 500mg is
diluted to 5g, the resulting powder mix contains 300 micrograms per 200mg capsule ?

Using a formula:

amount of drug (mg) amount (mg)

--------------------------- x dilution factor ---------------------
quantity required (mg) unit dose (mg)

x mg 500mg 0.3mg
------------- x ----------- = --------------
10,000mg 5,000mg 200mg
Therefore: x = 150mg Potassium Iodide

7.4 Alligation Technique

This is a dilution method for determining the proportion of two products of different strengths
required to be combined to produce the desired strength in a final product. This technique
can be used for dilution of liquid (See Tutorial 6) or semi-solid formulations.

7.4.1 Formula

Where a = % Product A
b = % Product B
c = % Product C
x = Parts of Product A
y = Parts of Product B

Using algebra:
ax + by = c (x+y)
ax + by = cx + cy
ax - cx = cy - by
x (a-c) = y (c-b)
ie: x (c-b)
---- = -----
y (a-c)

54
Pharmaceutical Calculations 7. Dilution of Solid/Semi Solid Formulations

In other words:
The parts required of Product A = x = (% Product C - % Product B)
The parts required of Product B = y = (% Product A - % Product C)
Total parts = x + y

7.4.2 Examples using Salicylic Acid Formulations

Worked Example 7.8

What parts of 20% Salicylic Acid in WSP and WSP should be combined to produce 100g of
5% Salicylic Acid ?

20

In other words 15 parts of WSP and 5 parts of 20% Salicylic Acid in WSP will result in an
ointment containing 5% salicylic acid. The next step is to use these proportions or parts to
determine the weights of WSP and 20% Salicylic Acid in WSP.

Weight of 20% Salicylic Acid in WSP required:

5
— x 100g = 25g
20

Weight of WSP required:

15
— x 100g = 75g
20

Looking at this previous worked example, a simple rule could be used when diluting a semi-
solid formulation containing an active ingredient with a base.

To prepare X% of drug in a suitable base, take X parts of a suitable base containing Y%

of drug and dilute to Y parts using a suitable base.

Quiz Question 7.9

Prepare 1000g of 2.5% Salicylic Acid in aqueous cream using 20% Salicylic Acid (in
aqueous cream) and Aqueous Cream APF.
What weight of Salicylic Acid cream (20%) is needed ?

Answer:
Take 2.5 parts of Salicylic Acid cream (20%) and dilute to 20 parts with Aqueous Cream
APF.
ie: 2.5g(20%) : 20g total weight
xg (20%) : 1000g total volume
Therefore x = 125g of 20% Salicylic Acid in aqueous cream.

55
Pharmaceutical Calculations 7. Dilution of Solid/Semi Solid Formulations

Worked Example 7.9

Prepare 50g of 7.5% Salicylic Acid in YSP using 15% and 5% Salicylic Acid in YSP.
What weight of each ointment is required ?

Working:

Weight of 15% Salicylic Acid in YSP required:

2.5
— x50g = 12.5g
10

Weight of 5% Salicylic Acid in YSP required:

7.5
— x 50g = 37.5g
10

Quiz Question 7.10

What proportions of Wool Alcohols Ointment and Salicylic Acid Ointment APF are required
to make 0.5% Salicylic Acid Ointment ?
(Salicylic Acid Ointment APF contains 2% Salicylic Acid in Wool Alcohols Ointment)

Answer:
Take 0.5 parts of Salicylic Acid Ointment APF and dilute to 2 parts with Wool Alcohols
Ointment.
ie: in whole numbers:
1 part and dilute to 4 parts.
Check: 1g of Salicylic Acid Ointment APF contains 0.02g. If we dilute this to 4g, then the
strength of Salicylic Acid is 0.02g/4g x 100 = 0.5%w/w

Quiz Question 6.9

Prepare 150g of 10% Salicylic Acid in YSP using 25% Salicylic Acid in YSP.
What weight of 25% ointment is required.

Answer:
Take 10 parts of 25% Salicylic Acid in YSP and dilute to 25 parts with YSP.
ie: 10g(25%) : 25g total weight
xg (25%) : 150g total weight

Therefore x = 60g of 25% ointment required.

Quiz Question 7.11

Prepare 250g of 5% Salicylic Acid in Sorbolene Cream using 7.5% Salicylic Acid in
Sorbolene Cream.
What weight of Sorbolene Cream is needed ?

Answer:

Take 5 parts of 7.5% Salicylic Acid in Sorbolene Cream and dilute to 7.5 parts with
Sorbolene Cream.

56
 Pharmaceutical Calculations 7. Dilution of Solid/Semi Solid Formulations
ie 5g(7.5%) : 7.5g total weight
xg (7.5%) : 250g total weight
Therefore x = 166.67g of 7.5% Salicylic Acid in Sorbolene Cream
Therefore weight of Sorbolene Cream required is: 250g -166.67g = 83.33g

Quiz Question 7.12

In what proportions should 5% Salicylic Acid in Zinc Paste and 8% salicylic acid in Zinc Paste be
mixed to make a paste containing 6.5% Salicylic Acid ?

Answer:

In other words:
1.5 parts of 5% Salicylic Acid paste is required
1.5 parts of 8% Salicylic Acid paste is required
ie: equal proportions.
This makes sense since 6.5% is mid way between 5 and 8%.

Worked Example 7.10

How much Salicylic Acid is required to be added to a 64g batch of a 4% ointment in order to
make it 10% strength?

Working:
Using the formula:

a) Firstly determine the total weight of ointment:

90
— x total weight = 64g Therefore total weight of ointment = 68.27g
96

b) Secondly determine the amount of Salicylic Acid required:

6
--- x 68.27g = 4.27g 96

Check:
Total amount of Salicylic Acid 2.56g + 4.27g
--------------------------------------- x 100 = ---------------------- x 100 = 10.0%
Total weight of ointment 68.27g

57
Pharmaceutical Calculations 7. Dilution of Solid/Semi Solid Formulations

7.4.3 Miscellaneous Examples

Worked Example 7.11

Prepare 150g of BenzoicAcid 5%w/w using BenzoicAcid 10%w/w (in Propylene Glycol) and
Propylene Glycol.
What weight of Benzoic Acid 10%w/w is needed ?

Working:

Take 5 parts of Benzoic Acid (10%w/w) and dilute to 10 parts with Propylene Glycol.
ie: 5g(10%w/w) : 10g total weight
xg (10%w/w) : 150g total weight

Therefore x = 75g Benzoic Acid 10% w/w

Check:
75g x 10g/100g = 7.5g. This 7.5g Benzoic Acid is diluted to 150g giving 5%w/w

Quiz Question 7.13

In what proportions should 15% w/w Boric Acid ointment be mixed with WSP to produce 2%
w/w Boric Acid ointment?

Answer:
Using the formula:

ie:
2 parts of 15% w/w Boric Acid ointment should be mixed with 13 parts of WSP.

Quiz Question 7.14

How much Ichthammol would be required to be added to 5% w/w Ichthammol in WSP in
order to prepare 200g of a 30% w/w Ichthammol in WSP ointment ?
Answer:
Using the formula:

Amount of ichthammol required to be added is:

25
— x 200g = 52.63g
95

Check: Amount Ichthammol in 70 parts of 5% ointment is: 5/100 x 70/95 x 200g = 7.37g Now:

7.37g + 52.63g = 60g Ichthammol (total) 60g/200g x 100 = 30% w/w

58
 Pharmaceutical Calculations Module
Tutorial 8: Body Cavity Delivery Systems

About This Tutorial

This tutorial was developed by the Victorian College of Pharmacy, Monash University in
conjunction with the Australian Pharmacy Examining Council Incorporated (APEC Inc)
(now known as the Faculty of Pharmacy and Pharmaceutical Sciences, Monash University
and the Australian Pharmacy Examining Committee respectively).It remains the property of
Monash University. The tutorial cannot be used or copied without prior authorisation.

This tutorial is intended as an aid for students enrolled in Monash University’s Bachelor of
Pharmacy & Pharmacy Internship programs.

• Original tutorial prepared by in1996:

Arthur Pappas Lecturer in Pharmacy Practice
Dr Louis Roller Head, Department of Pharmacy Practice

with the assistance of :

May Admans Senior Assistant-Lecturer in Pharmaceutics

Dr Denis Morgan Reader in Pharmaceutics
Dr Kay Stewart Lecturer in Pharmacy Practice
Prof Peter Stewart Professor of Pharmaceutics

• Original Tutorial Manual produced by Arthur Pappas - December 1996

• Adaptation & updating of the material for online delivery to students of Monash
University was undertaken by Phil Bergen, Assistant Lecturer in Pharmacy Practice -
February 2005

© Copyright 2005
This publication is copyright. Apart from any fair dealing for the purpose of private study, research, criticism or
review as permitted under the Copyright Act, no part may be reproduced by any process or placed in computer
memory without written permission. Any assembled extracts each attract individual copyright and enquiries
about reproduction of this material should be addressed to the appropriate publishers. Enquiries about all other
material should be made to the Faculty named above.
Last amended by EM- November 2008

ii
Pharmaceutical Calculations 8. Body Cavity Delivery Systems

8. Body Cavity Delivery Systems

Topic Index

Page
8.1 Introduction 60
8.2 Objectives 60
8.3 Definitions 60
8.4 Rationale for use of suppositories 61
8.5 Rectal absorption 61
8.6 Extemporaneous Manufacture 61
8.6.1 Types of Suppository Bases 61
8.6.2 Method of preparing suppositories/pessaries 63
8.6.3 Formula specifying the drug by percentage 63
8.6.4 Formula specifying the drug as a unit dose 63
8.6.5 Combined unit dose and percentage strength 69

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 Pharmaceutical Calculations 8. Body Cavity Delivery Systems

8.1 Introduction
Rectal and vaginal administration of drugs usually involves a semi-solid (cream or ointment)
or solid (suppository, pessary, tablet, capsule) delivery system. Although not commonly
made in community pharmacy practice, suppositories and pessaries are regularly made in
hospitals to treat a variety of conditions. Most prescriptions in community practice are for
commercially available products.

8.2 Objectives

The aim of this tutorial is to briefly explain the role of body cavity delivery systems and
provide you with the opportunity to correctly handle their extemporaneous manufacture.

At the end of this tutorial you should be able to:

a) understand the definition of various body cavity delivery systems

b) understand the rationale of using suppositories and pessaries
c) recognise the types of suppository bases available
d) write a formula for a suppository where the drug is specified by percentage
e) write a formula for a suppository where the drug is specified by dose
f) understand the concept of displacement value for a drug

8.3 Definitions

a) Suppositories
These are solid bodies suitably shaped for rectal administration. They usually contain
medicaments which are intended for local or for systemic action. They may either melt at
body temperature or dissolve or disperse in the mucous secretions of the cavity. When
ordered without further specification, 1.0 g suppositories are used. Suppositories are normally
made by pouring the melted mass into suitable moulds.

b) Pessaries
Pessaries are solid medicated preparations designed for insertion into the vagina where they
melt or dissolve. The medicaments may then exert a local action or in some cases may be
absorbed from the vaginal mucosa. There are three types. Moulded pessaries are cone
shaped and prepared in a similar way to moulded suppositories. Compressed pessaries, or
vaginal tablets, are made in a variety of shapes and are prepared by compression in a similar
manner to oral tablets. Vaginal capsules are similar to soft gelatin capsules differing only in
size and shape and usually contain an active ingredient dispersed in a cream or lotion base.

c) Bougies
These are suppositories which weigh between 0.5 and 1 g but are longer and narrower than
rectal suppositories, therefore being suitable for insertion into the urethra, the nasal passages
or the ear.

d) Enemas
These are aqueous or oily solutions or suspensions for rectal administration. An enema is
placed in the rectum or colon to cause evacuation or to bring about a local or systemic
therapeutic action. The volume used is 100 - 200 mL and ideally they should be warmed
before administration. Over the last few years considerable use has been made of
microenemas which are solutions of drugs for either evacuation or systemic use. The volume
of this type of delivery system is only 1-2 mL and hence is more readily administered than
the traditional large volume enemas.

60
 Pharmaceutical Calculations 8. Body Cavity Delivery Systems

8.4 Rationale for use of suppositories

a) To exert a direct action on the rectum (localised effect)

(eg: for pain and irritation of haemorrhoids)
Can contain: local anaesthetics eg: benzocaine, lignocaine
astringents eg: bismuth subgallate
anti-inflammatory agents eg: hydrocortisone

b) To provide a systemic effect

(eg: for the treatment of pain, nausea and vomiting)
Examples: Ergotamine (migraine)
Indomethacin, Aspirin, Naproxen, Ketoprofen (arthritic problems)
Paracetamol (temperature and pain)
Prochlorperazine (nausea/vomiting)
Note: A rectal route may be selected to provide a systemic effect for the following
reasons:
- patient may be vomiting and unable to keep oral medication down
- drug may irritate the g.i.t.
- presence of gastric ulcers
- patient may be unconscious
- to avoid first pass effect and increase bioavailability
- to avoid drug incompatibilities
- absorption from the gut may be limited due to disease or surgery
- drug unstable in gastric acid
- patient has difficulty in swallowing
- patient is mentally disturbed
- children may refuse or are unable to swallow

c) To promote evacuation of the bowel

Examples: glycerol (lubricates the rectum and has osmotic effect)
bisacodyl (stimulates intestinal soft muscle to effect evacuation)

8.5 Rectal Absorption

When a drug is released from the dose form, it diffuses to the mucosa where absorption
takes place. The drug passes into inferior, middle or superior haemorrhoidal veins depending
on how high the suppository has been positioned in the rectum. Inferior veins are part of the
circulation to the vena cava and bypass the liver. Superior veins are part of the circulation to
the liver.

There are several factors that can affect absorption of the drug from the rectum:
- partition coefficient lipid/water solubility
- variable volume of contents in the rectum
- pH of rectal secretions which can affect the ionisation state of the drug
- vehicle in which drug is formulated.
eg: fatty base more suitable for drugs required to act locally

8.6 Extemporaneous Manufacture

Please note that the principles for manufacture apply to suppositories, pessaries and
bougies. Most of the examples within this tutorial use suppositories.

8.6.1 Types of Suppository Bases

Ideally the base should melt or otherwise deform or dissolve to release the drug at 37°C. The
base should be non-irritating, non-toxic and non-sensitising; it should be readily moulded into
a stable, rigid shape which will maintain uniform drug-release characteristics upon storage.

Suppository bases can be divided into fatty or water-soluble bases. The first two bases below
are fatty bases, the other two are "water-soluble".

61
 Pharmaceutical Calculations 8. Body Cavity Delivery Systems

a) Theobroma Oil B.P. (Cocoa butter)

This is a bland, non-irritating fat, pressed from ground cocoa beans, and possessing the
quality of maintaining its firmness to within a few degrees of body temperature, 37°C, when it
readily melts to a liquid, without passing through an appreciable softening stage. The melting
point is 30°-35°C. Theobroma Oil suffers from the disadvantage of a small amount of
shrinkage upon solidification which gives poor moulding properties. It also is subject to
rancidity.

Theobroma Oil, like many triglycerides, exhibits polymorphism, that is to say, it can exist in
several crystalline forms, each with a different melting point. Polymorphism is much more
pronounced in a relatively simple and chemically homogenous triglyceride, like Theobroma
Oil, than in more complex mixtures, e.g. Massuppol®, Novata B®, Witepsol®.

This polymorphic character of Theobroma Oil can cause difficulty in making suppositories by
the fusion method, and consequently is now not used in pharmaceutical practice to any
considerable extent.

The non-homogenous Hard Fat alternatives may replace Theobroma Oil even if called for in
an official compendium.

b) Hard-fat alternatives to Theobroma Oil

These are esterified, hydrogenated or fractionated vegetable oils together with synthetic
triglyceride mixtures. They do not exhibit significant polymorphism due to the heterogenicity
of structure. They have little risk of rancidity and possess good moulding properties.

Commercial products such as Massuppol® or Witepsol® or Novata B® are much easier to

handle and work with than is Theobroma Oil. It is suggested that these alternatives are
always used as the fatty base of choice.

c) Glyco-Gelatin Bases (Glycerinated gelatins)

These are all translucent, resilient, gelatinous solids that tend to dissolve or disperse slowly
in the mucous secretions of the rectum. (Refer A.P.F.and B.P.)

i Glyco-gelatin Base A.P.F., is the basic preparation in which water soluble

ingredients may be added.

ii. Not to be confused with Glycerol Suppositories B.P. and Glycerol

Suppositories A.P.F. (both contain 70% w/w glycerol) which are intended as
actual dose-forms of glycerol.

iii When glycerol suppositories are ordered without further qualification,

Glycerol Suppositories B.P. should be dispensed, (same formula as APF 15)

Glyco-gelatin Base A.P.F. has been formulated with an increased firmness by increasing the
percentage of Gelatin and decreasing the Glycerol as a more suitable basis for suppositories
in general. Suppositories made with Glycerol and Gelatin must be stored in a well closed
container in a cool place. When a base containing Gelatin is used as a pessary base, it
should be maintained at 100°C for one hour before incorporation of the other medicaments,
replacing any water lost by evaporation.

d) Macrogols (PEG'S)

Polyethylene Glycols (P.E.G.) "Carbowaxes". These have the general formula HOCH2
(CH20CH2)nCH20H and are available with molecular weights ranging from 300 to 6,000; the

62
 Pharmaceutical Calculations 8. Body Cavity Delivery Systems

numerical designation referring, in general, to the average molecular weights of the

polymers, e.g. Polyethylene Glycol 1000 has a mean molecular weight between 950 and
1050. The solid polymers despite their appearance resembling paraffin, are water soluble.
The miscibility of macrogol suppositories with aqueous fluids permits the formulation of
suppositories that slowly disperse in mucous secretions.

N.B. When a PEG base is used, the label on the container of the suppositories must
contain words to the effect.... "Moisten with warm water before use".

Thus, it is possible to formulate suppositories with melting points higher than body
temperature. As these suppositories dissolve slowly, there is a near absence of leakage from
body orifices.

Two common formulae are: Macrogol 400 1 (by weight)

Macrogol 4000 4
and
Macrogol 300 1 (by weight)
Macrogol 4000 4

Many other combinations are also used.

8.6.2 Method of preparing suppositories/pessaries

Table 8.1 Method for incorporating a drug into a suppository/pessary formulation

1. Clean moulds and lubricate

- If the base is Theobroma Oil or Hard Fat use Soap Liniment BP.
- If the base is Glyco-gelatin, PEG or Polysorbate base use Almond Oil.

2. Melt base by gentle heating in an evaporating dish over a hot water bath.

3. If the drug is soluble in the base, it is stirred until dissolved.

4. If the drug is insoluble in the base, it should be finely powdered and triturated
on a warmed ointment slab with a portion of the melted base. This is then
transferred to the evaporating dish and stirred with the rest of the base.

5. When there is an even dispersion of the drug within the base, take the evaporating
dish off the water bath and pour into the suppository mould. Fill each cavity to
overflowing as contraction of the base will occur on cooling.

6. When the suppositories have set, trim and remove from the moulds.
Wipe any remaining traces of lubricant.

7. Suppositories are individually wrapped in aluminium foil.

Q
8. Label appropriately, including "For Rectal Use Only" and "Store below 25 C"

Note: You always need to calculate for one or two more suppositories to allow for losses. The
examples shown in this tutorial do not reflect this.

8.6.3 Formula specifying the drug by percentage

In this situation no allowance is made for the volume occupied by the drug in each
suppository.

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Pharmaceutical Calculations 8. Body Cavity Delivery Systems

Worked Example 8.1

Prepare 10 suppositories containing 5% Benzocaine in a Fatty Base (eg: Massuppol ®)

Working out:
Firstly, determine amount of Benzocaine required for 10 x 1 g suppositories each containing
5% Benzocaine.

5
-----x10g = 0.5g

100

Secondly, amount of fatty base required is:

= 10g-0.5g = 9.5g

Therefore, the formula for 10 suppositories is:

Benzocaine 0.5 g
Massuppol ® 9.5 g
10.0 q

Quiz Question 8.1

Prepare 15 suppositories containing 4% Lignocaine HCI in a PEG base (Macrogol 400 (1part)
and Macrogol 4000 (4 parts))

Answer:

Firstly, determine amount of Lignocaine HCl required for 15 x 1 g suppositories each

containing 4% Lignocaine HCI.

4
----- x 15g = 0.6g
100

Secondly, amount of fatty base required is:

= 15g-0.6g = 14.4g
Therefore, the formula for 15 suppositories is:

Benzocaine 0.6 g
Macrogol 400 1/5 x 14.4g 2.88 g
Macrogol 4000 4/5 x 14.4g 11.52 g

15.0 g

8.6.4 Formula specifying the drug as a unit dose

In this situation an appropriate allowance for the drug volume has to be made, since the
density of the drug usually differs from that of the base. The formula used to make this
allowance includes a "Displacement Value" (DV) of the drug.

THE DISPLACEMENT VALUE OF A DRUG IS THE WEIGHT OF DRUG THAT OCCUPIES

THE SAME VOLUME AS 1.0 g OF EITHER TYPE OF FATTY BASE OR 1.2 g of EITHER
TYPE OF WATER-SOLUBLE BASE.

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Pharmaceutical Calculations 8. Body Cavity Delivery Systems

The lists of displacement values to be found in the A.P.F., the Pharmaceutical Codex, or the
Pharmaceutical Handbook, are lists of densities relative to that for fatty bases taken as 1.0
g/mL
Table 8.2 Displacement Values of Drugs

Drug Displacement Value

Alum 2.0
Aminophylline 1.4
Aspirin 1.3
Bismuth Subgallate 3.0
Bismuth Subnitrate 5.0
Boric Acid 1.5
Castor Oil 1.0
Chloral Hydrate 1.5
Cinchocaine HCI 1.3
Cocaine HCI 1.5
Hamamelis dry extract 1.6
Hydrocortisone 1.6
Hydrocortisone Acetate 1.6
Ichthammol 1.0
lodoform 4.0
Lead Acetate 3.0
Lead Iodide 5.0
Mercury Ointment 1.5
Metronidazole 1.7
Morphine HCI 1.5
Morphine Sulphate 1.5
Opium Powder 1.0
Paracetamol 1.5
Peru Balsum 1.0
Phenobarbitone 1.2
Procaine HCI 1.3
Phenol 1.0
Quinine HCI 1.0
Resorcinol 1.5
Silver Proteinate 1.5
Tannic Acid 1.0
Zinc Oxide 5.0
Zinc Sulphate 2.0
Aqueous Solutions 1.0

Calibration of a suppository mould

Before making the suppositories, the moulds have to be calibrated. This is because not all
moulds are of the same size. This is usually done with Hard Fat. Commonly used suppository
moulds hold 1g of base. Pessary moulds hold up to 4g of base. The weight of base which a
mould will contain naturally varies with the nature of the base. To ensure accuracy of dosage
it is necessary to calibrate the mould.

The method used is to melt an excess of Hard Fat and pour into the mould to be used and
allow to set. The top is trimmed of excess fat, the suppositories are removed from the mould
and the average weight is determined. This average weight is the calibration weight for that
mould using that particular base.

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Pharmaceutical Calculations 8. Body Cavity Delivery Systems

Formula for unit dose suppository.

Drug dose (g)
Weight of base = (Mould calibration - ---------------------) x Base Density x Y
for Y suppositories DVof drug

Y = number of suppositories

DV = Displacement Value of drug

Worked Example 8.2

Write the formula for preparing 10 suppositories of Hydrocortisone 25 mg in P.E.G. base

Data: Calibration of mould = 0.9 g Hard Fat DV

Hydrocortisone = 1.6 (A.P.F. p 435)

Density of P.E.G. base = 1.2 g/mL

Working out:

Using the formula:

Drug dose (g)
Weight of base = (Mould calibration - -------------------- ) x Base Density x Y
for Y suppositories DVof drug

0.025g
Weight of base = (0.9 g - .......................) x 1.2g/mL x 10
for 10 suppositories 1.6g/mL

= 10.61g

Therefore, the formula for 10 suppositories would be:

Hydrocortisone 250 mg

Macrogol Base 10.61 g

Quiz Question 8.2

Write the formula for preparing 10 suppositories of Hydrocortisone 25 mg in Hard Fat base

Data: Calibration of mould - 0.9 g Hard Fat

DV Hydrocortisone = 1.6 (A.P.F. p 435)

Density of hard fat base = 1.0 g/mL

Answer:
Using the formula:
Drug dose (g)
Weight of base = (Mould calibration - .......................... ) x Base Density x Y
for Y suppositories DV of drug

0.025g
Weight of base = (0.9 g - ...................... ) x 1.0g/mL x 10
for 10 suppositories 1.6g/mL
= 8.84g
Therefore, the formula for 10 suppositories would be:
Hydrocortisone 250 mg
Hard Fat 8.84g
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Pharmaceutical Calculations 8. Body Cavity Delivery Systems

Quiz Question 8.3

Write the formula for preparing 15 pessaries of Metronidazole 400mg in PEG Base
consisting of PEG 300 (1 part by weight) and PEG 4000 (4 parts by weight).

Data: Calibration of mould = 4.0g hard fat

DV Metronidazole = 1.7 (A.P.F. p 435)
Density of PEG base = 1.2 g/mL

Answer:
Using the formula:
Drug dose (g)
Weight of base = (Mould calibration - ........ --------------- ) x Base Density x Y
for Y pessaries DVof drug

0.400g
Weight of base = (4.0 g - ..............……) x 1.2g/mL x 15
for 15 pessaries 1.7g/mL
= 67.76g

Therefore, the formula for 15 pessaries would be:

Metronidazole 6.00g
PEG 300 (67.76x1/5) 13.55g
PEG 4000 (67.76x4/5) 54.21g

73.76g

Worked Example 8.3

How much Hard Fat would be required to prepare 25 x 1 g suppositories each containing 300
mg Theophylline?

Data: Calibration of mould = 0.94 g hard fat

DV Theophylline = 1.75

Density of Hard Fat base = 1.0 g/mL

Working:

Using the formula:

Drug dose (g)
Weight of base = (Mould calibration - ---------------------) x Base Density x Y
for Y suppositories DVof drug

0.300g
Weight of base = (0.94 g -................. ) x 1.0g/mL x 25
for 25 suppositories 1.75g/mL
= 19.21g

The formula would then become (for 25 suppositories);

Theophylline 7.5 g
Hard Fat 19.21g

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Pharmaceutical Calculations 8. Body Cavity Delivery Systems

Quiz Question 8.4

You are now required to prepare 25 x 1 g suppositories each containing 300 mg Theophylline
utilising PEG Base consisting of PEG 300 (1 part by weight) and PEG 4000 (4 parts by
weight). What would be the formula of the base required ?

Data: Calibration of mould = 0.94 g Hard Fat

DV Theophylline = 1.75

Density of PEG base = 1.2 g/mL

Answer:

Using the formula:

Drug dose (g)
Weight of base = (Mould calibration - --------- ---------- ) x Base Density x Y
for Y suppositories DV of drug

0.300g
Weight of base = (0.94 g - ................) x 1.2g/mL x 25
for 25 suppositories 1.75g/mL
= 23.05 g

Therefore, the formula for 25 suppositories would be:

Theophylline 7.5 g
PEG 300 23.05 x 1/5 = 4.61 g
PEG 4000 23.05x4/5 = 18.44g

Worked Example 8.4

What would be the percentage error involved if a displacement value was used to calculate
for 20 x 1 g suppositories (in Massuppol ®) containing 10% w/w Bismuth Subnitrate ? (DV =
5). Assume the calibration of the mould is with Massuppol ® is 1.00g.

a) Correct Method
Firstly, determine the amount of drug required for 20 x 1 g suppositories each containing
10% Bismuth Subnitrate.

10
-----x 20g = 2g
100

Secondly, determine the amount of fatty base required.

Total weight - weight of drug = weight of base

20g-2g =18g

b) Using displacement values

0.100g
Weight of base = (1.00 g .................. ) x 1.0g/mL x 20
for 20 suppositories 5g/mL
= 19.6g

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 Pharmaceutical Calculations 8. Body Cavity Delivery Systems

c) Calculating the percent error

19.6g-18g
% error = --------------- x 100 = 8.9%

18g

Note: Quite large errors can occur if displacement values are used when not appropriate.

Worked Example 8.5

You are required to prepare 10 x 1 g suppositories each containing 250 mg Paracetamol

utilising PEG Base consisting of PEG 300 (1 part by weight) and PEG 4000 (4 parts by
weight). What would be the formula of the base required ?

Data: Calibration of mould = 0.94g

DV Paracetamol = 1.5

Density of PEG base = 1.2 g/mL

Working:

Using the formula:

Drug dose (g)
Weight of base = (Mould calibration - ----------------) x Base Density x Y
for Y suppositories DV of drug

0.250g
Weight of base = (0.94 g - ..............) x 1.2g/mL x 10
for 10 suppositories 1.5g/mL
= 9.28 g

Therefore, the formula for 10 suppositories would be:

Paracetamol 2.5 g
PEG 300 9.28 x 1/5 = 1.86 g

PEG 4000 9.28x4/5 = 7.42 g

11.78g

8.6.5 Combined unit dose and percentage strength

These calculations need to be dealt with carefully and sequentially.

Worked Example 8.6

Write the formula for 10 suppositories containing 30mg Hydrocortisone and 6% Benzocaine
in Massuppol ®
Data: DV Hydrocortisone is 1.6
Calibration of mould using Massuppol ® = 1.0g

Working:
Step 1: Do the dose part of the calculation first.

0.030g
Weight of base = (1.00 g - ----------- ) x 1.0g/mL x 10
for 10 suppositories 1.6g/mL
= 9.813g
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Pharmaceutical Calculations 8. Body Cavity Delivery Systems

Formula for 10 suppositories so far is:

Hydrocortisone 0.300g
Massuppol® 9.813g

10.113g
Step 2: Calculate the weight of 6% Benzocaine.

6% of 10.113 g is the weight of Benzocaine = 0.607g

Step 3: Calculate the final weight of base needed.

Final weight of base = initial amount of base - weight of Benzocaine

= 9.813g - 0.607g =
9.206g

Step 4: Final formulation for 10 suppositories:

Hydrocortisone 0.300g
Benzocaine 0.607g
Massuppol ® 9.206g

10.113g

Quiz Question 8.5

Write the formulation for 15 suppositories containing 1mg Adrenaline and 5% Benzocaine in
PEG Base consisting of PEG 300 (1 part by weight) and PEG 4000 (4 parts by weight).
(Adrenaline is available as a 1 %w/v solution)

Data: DV of aqueous solutions is 1.0

Calibration of mould using Hard Fat = 1.0 g
Density of PEG base = 1.2g/mL

Answer:
Step 1: Do the dose part of the calculation first.
Adrenaline solution: 1000mg : 100mL
or 1mg : 0.1mL (=0.1g of solution, assuming density is 1.00 g/mL)

0.1g
Weight of base = (1.00 g - ................ ) x 1.2g/mL x 15
for 15 suppositories 1.0g/mL
= 16.2g
Formula for 15 suppositories so far is:
Adrenaline Solution (1%w/v)
0.1 mL = 0.1g 1.5 g (of 1%w/v solution)

PEG base 16.2 g

17.7g

Step 2: Calculate the weight of 5% Benzocaine.

5% of 17.7 g is the weight of Benzocaine = 0.885 g = 0.89 g

Step 3: Calculate the final weight of base needed.

Final weight of base = initial amount of base - weight of Benzocaine

= 16.2 g - 0.89 g
= 15.31 g

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Pharmaceutical Calculations 8. Body Cavity Delivery Systems

Step 4: Final formulation for 15 suppositories:

Adrenaline Solution (1%w/v)

0.1mL = 0.1g 1.5 g
Benzocaine 0.89 g
PEG 300 15.31 x 1/5 3.06 g
PEG 4000 15.31 x 4/5 12.25 g

17.70 g
 Pharmaceutical Calculations Module
Tutorial 9: Millimoles, Milliequivalents and
Milliosmoles

About This Tutorial

This tutorial was developed by the Victorian College of Pharmacy, Monash University in
conjunction with the Australian Pharmacy Examining Council Incorporated (APEC Inc)
(now known as the Faculty of Pharmacy and Pharmaceutical Sciences, Monash University
and the Australian Pharmacy Examining Committee respectively).It remains the property of
Monash University. The tutorial cannot be used or copied without prior authorisation.

This tutorial is intended as an aid for students enrolled in Monash University’s Bachelor of
Pharmacy & Pharmacy Internship programs.

• Original tutorial prepared by in1996:

Arthur Pappas Lecturer in Pharmacy Practice
Dr Louis Roller Head, Department of Pharmacy Practice

with the assistance of :

May Admans Senior Assistant-Lecturer in Pharmaceutics

Dr Denis Morgan Reader in Pharmaceutics
Dr Kay Stewart Lecturer in Pharmacy Practice
Prof Peter Stewart Professor of Pharmaceutics

• Original Tutorial Manual produced by Arthur Pappas - December 1996

• Adaptation & updating of the material for online delivery to students of Monash
University was undertaken by Phil Bergen, Assistant Lecturer in Pharmacy Practice -
February 2005

© Copyright 2005
This publication is copyright. Apart from any fair dealing for the purpose of private study, research, criticism or
review as permitted under the Copyright Act, no part may be reproduced by any process or placed in computer
memory without written permission. Any assembled extracts each attract individual copyright and enquiries
about reproduction of this material should be addressed to the appropriate publishers. Enquiries about all other
material should be made to the Faculty named above.
Last amended by EM- November 2008

ii
Pharmaceutical Calculations 9. Millimoles, Milliequivalents and Milliosmoles

9. Millimoles, Milliequivalents and Milliosmoles

Topic Index

Page
9.1 Introduction 73
9.2 Objectives 73
9.3 Moles and Millimoles 73
9.4 Milliequivalents 82
9.5 Milliosmoles 85
9.5.1 Osmotic Pressure 86
9.5.2 Osmolarity and Osmolality 88

Milliequivalents is included in this tutorial only for completeness and interest. Students will
not be expected to be familiar with milliequivalents and will NOT be examined on them.
Students are expected to be familiar with millimoles and milliosmoles.
Pharmaceutical Calculations 9. Millimoles, Milliequivalents and Milliosmoles

9.1 Introduction

"Milliequivalent" and "millimole" are chemical units which denote quantities of ions.
Prescriptions may state the quantities of ions required and it is up to the pharmacist to select
the amount of appropriate salt for delivery. A knowledge of chemical equations and valencies
of atoms is vital.

9.2 Objectives
The aim of this tutorial is to provide an understanding of the concepts of millimole,
milliequivalent and milliosmole.

At the end of this tutorial you should be able to:

a) define millimole, milliequivalent and milliosmole

b) determine the number of millimoles, milliequivalents and milliosmoles of a
substance given its molecular formula and quantity or concentration.

9.3 Moles and Millimoles

Definition of one mole (mol)

One mole (or gram molecular weight) of a substance is defined as the molecular
weight of that substance, expressed in grams.

The formula for determining the number of moles of a substance is:

n= m

----

n = number of moles
m = mass (g)
M = molecular weight (also abbreviated MW)

The number of moles of specific ions produced by dissociation of a salt can be readily
determined by knowing the molecular formula of the salt and the valence of the ions.

Worked Example 9.1

How many moles (mol) result from the dissociation of Sodium Sulphate (Na2SO4)?

Working:

Write the equation first.

Na2S04 → 2Na+ + SO4 2-

1 mol → 2mol 1mol

Answer is: 2 + 1 = 3 mol

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 Pharmaceutical Calculations 9. Mi Hi moles, Milliequivalents and Milliosmoles

Quiz Question 9.1

2+
How many moles of Magnesium Chloride (MgCI2) yield 1 mol of Mg ?

Answer:

Write the equation first.

2+ -
MgCI2 → Mg + 2CI

1 mol → 1mol 2 mol

+
ie: 1 mol of MgCI2 provides 1 mol of Mg

(answer)

Worked Example 9.2

How many grams of NaCI are equivalent to 1 mol?

MW(NaCI) = 58.5

Working:
m
Using: n = —
M

m = 1 x58.5 = 58.5 g

Quiz Question 9.2

How many moles are equivalent to 69.1g of Potassium Carbonate (K2C03) ?

MW(K2C03) = 138.2

Answer:
m
Using: n = —
M
69.1 g
n = --------- = 0.50 mol (answer)
138.2

Quiz Question 9.3

How many grams of Sodium Carbonate Decahydrate (Na2CO3.10H2O) contain 1000mg of
sodium ? MW(Na2CO3.10H2O) = 286.0

Answer:

Write the equation first.

+ 2-
Na2CO3.10H2O → 2Na + CO3 + 10H2O

1000mg of Na+ expressed as mol: n = m/M = 1/23 = 0.043mol

From the equation:

+
1 mole of salt → 2 mol of Na
x → 0.043 mol

74
 Pharmaceutical Calculations 9. Millimoles, Milliequivalents and MilHosmoles

Therefore x = 0.0215mol of salt

Using n = m/M
m = 0.0215 x 286 = 6.15g (answer)

Worked Example 9.3

A formulation of Sodium Fluoride (NaF) has a strength of 0.50% w/v NaF. If a dropper
-
delivers 0.8mL of solution per 40 drops, how many drops will contain 2mg of fluoride (F ) ? MW
(NaF) = 42

AW(F-) = 19

Working:
Write the equation first.

+ - -
NaF → Na + F 1 mol of NaF → 1 mol F

Determine the number of mole of NaF in 0.8mL of

0.50% w/v.

0.50g : 100mL
xg : 0.8mL

x = 0.004g
-5
Using n = m/M = 0.004g/42 = 9.52 x 10 mole

Determine the mole of NaF in one drop.

This is 9.52x10-5
-------------- = 2.38 x 10 -6

40

Determine what weight of F" this is equal to:

m = n x M = 2.38 x 10 -6 x 19 = 4.52 x 10-5 g = 0.0452mg (per drop)

Determine the number of drops per 2mg.

2mg
------------ = 44.2 (44 to the nearest drop)
0.0452mg/drop

Definition of one millimole (mmol)

One millimole is the molecular weight expressed in milligrams Note: this is a

measure of quantity, not concentration.

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Pharmaceutical Calculations 9. Miiiimoles, Milliequivalents and Milliosmoles

The following Tables contain valuable information when dealing with millimole,
milliequivalent and milliosmole calculations.

Table 9.1 Atomic Weight and Valence of Some Elements

Element Atomic Weight (AW) Valence

Calcium 40.0 +2
Carbon 12.0 n/a
Chlorine 35.5 -1
Fluorine 19.0 -1
Hydrogen 1.0 +1
Magnesium 24.3 +2
Oxygen 16.0 -2
Potassium 39.1 +1
Sodium 23.0 +1
Sulphur 32.1 0

Table 9.2 Miiiimoles of commonly used salts.

Ion Salt mg mg of salt containing

per mmol mmol of ion
+
Na 23
Sodium acid phosphate 156
(NaH2PO4.2H2O)
Sodium bicarbonate 84
Sodium chloride 58.5
Sodium citrate 98
(C6H5Na3O7.2H2O)
Sodium hydroxide 40
Sodium lactate 112
Sodium phosphate 179
(Na2HPO4.12H2O)
K+ 39.1
Potassium acid phosphate 136
(KH2PCM)
Potassium bicarbonate 100
Potassium chloride 74.6
Potassium phosphate 87.1
(K2HPO4)
Ca2+ 40.0
Calcium chloride 147
(CaCI2.2H2O)
Calcium gluconate 448
2+
Mg 24.3
Magnesium chloride 203.3
(MgCI2.6H2O)
Magnesium sulphate 246
(MgSO4.7H2O)
NH4* 18.0
Ammonium chloride 53.5

76
Pharmaceutical Calculations 9. Millimoles, Milliequivalents and Milliosmoles

Table 9.2 Millimoles of commonly used salts, (cont)

Ion Salt mg mg of salt containing

per mmol mmol of ion
-
Cl 35.5

Ammonium chloride 53.5

Calcium chloride 73.5
(CaCI2.2H2O)
Magnesium chloride 101.7
(MgCI2.6H2O)
Potassium chloride 74.6
Sodium chloride 58.5
-
HCO3 61.0
Potassium bicarbonate 100
Sodium bicarbonate 84
Sodium lactate* 112
HPO42- 96.0
Potassium phosphate 174.2
(K2HPO4)
Sodium phosphate 358
(Na2HPO4.12H2O)
H2PO4- 97.0
Potassium acid phosphate 136
(KH2PO4)
Sodium acid phosphate 156
(NaH2PO4.2H2O)
Lactate 89.1
Sodium iactate 112

* Sodium lactate is sometimes required in terms of bicarbonate because lactate is

metabolised to bicarbonate.
(Ref APF15 page 448)

Worked Example 9.4

How many mg of NaCI represent 2 mmol ?

MW(NaCI) = 58.5

Working:
Equation:
NaCI →Na + + Cl -

1 mmol NaCI = 58.5 mg

2 mmol NaCI: x

x= 117mg

77
Pharmaceutical Calculations 9. Millimoles, Milliequivalents and Milliosmotes

Quiz Question 9.4

An intravenous solution requires 40 mmol of KCI. What weight of KCI is required ?

MW(KCI) = 74.6

Answer:

By definition:

1 mmol KCI = 74.6mg

40 mmol KCI = x mg

Therefore x = 2984mg = 2.984g

Quiz Question 9.5

How many mmol are there in 4.5g of Magnesium Sulphate (MgSO4.7H2O) ?

MW(MgSO4.7H2O) = 246.4

Answer:

By definition:

1 mmol of MgSO4.7H2O = 246.4mg

x mmol of MgS04.7H2O : 4,500mg

Therefore x = 18.26mmol

Worked Example 9.5

How many grams of NaCI is required to prepare 100mL of a solution of Sodium Chloride
+
containing 1mmol Na per 5ml_ ? MW(NaCI) = 58.5

Working:

Equation:
NaCI → Na + Cl-
1mmol → 1mmol 1 mmol

By definition
1 mmol NaCI = 58.5mg NaCI

Firstly, determine the number of mmol Na+ in 100mL of solution (1mmol/5mL)

+
100mL x 1 mmol/5mL = 20mmol Na

This is equivalent to 20mmol NaCI

Now: 1 mmol NaCI : 58.5mg NaCI

20mmol NaCI : ymg NaCI

Therefore y = 1,170mg = 1.17g NaCI

78
Pharmaceutical Calculations P. Millimoles, Milliequivalents and Milliosmoles

Quiz Question 9.6

How many grams of anhydrous Sodium Sulphate (Na2SO4) are required to prepare 100mL of a
solution of Sodium Sulphate containing 1mmol Na+ per 5mL? MW(Na2SO4) = 142.0

Answer:
Equation:
+ 2
Na2SO4 → 2Na + SO4 -

1 mmol → 2 mmol 1 mmol

By definition:
1mmol Na2SO4 = 142.0mg

Firstly, determine the number of mmol Na* in 100mL of solution (1mmol/5ml_)

+
100mL x 1 mmol/5mL - 20mmol Na This is equivalent to 10mmol Na2SO4

Now: 1 mmol Na2SO4 = 142.0mg Na2SO4

10mmol Na2SO4 = ymg Na2SO4

Therefore y = 1,420mg = 1.42g Na2SO4

Quiz Question 9.7

-
You are required to make 100m of a CaF2 solution which contains 9 ppm of F . How
much CaF2 do you need ? MW(CaF2) = 78.0 AW(F") = 19.0

Answer:
Equation:
2+ -
CaF2 → Ca + 2F
6
By definition: 1 ppm = 1 g per 10 mL
- 6
Therefore 9 ppm = 9g (F ) per 10 mL To
-
determine how much F is in 100mL:
6
9g in 10 mL
xg in 100 mL
-4 -
Therefore x = 9 x 10 g F

To determine the amount of CaF2 required:

From the above equation:
number of mole CaF2 number of mole of F-
1 : 2
-4
x : 9x10 g/19

Therefore x = 2.36 x 10 -5 mole CaF2

mass of CaF2 = 2.36 x 10-5 x 78 = 1.85 x 10 -3 g (answer)

79
 Pharmaceutical Calculations 9, Millimoles, Milliequivalents and Milliosmoles

Worked Example 9.6

How much Potassium Chloride (KCI, MW = 74.6) would be required to prepare 1 litre of an
intravenous solution to be infused into a patient continuously over a 12 hour period at the
rate of 0.05 millimoles K+ per minute?

Working:
+
Firstly, determine the total number of mmol K required over 12 hours:

12 hours = 12 x 60 = 720 minutes

0.05 mmol
------------ x 720 minutes = 36mmol
minute

Equation:
+ -
KCI → K + Cl

+
1 mmol KCI → 1 mmol K = 74.6mg KCI
36 mmol K+ (just cross multiply) = (36 x 74.6)/1 = 2685.6mg KCI (answer)

Worked Example 9.7

You have 60mL of 4.0% w/v CaCI2.2H2O solution. How

-
many millimoles of CI are present ? MW(CaCI2.2H2O)
-
= 147.0 AW(CI ) - 35.5

Working:
Equation:

2+ -
CaCI2.2H2O → Ca + 2CI + 2H2O Firstly determine how

much CaCI2.2H2O is present in 60mL

4g : 100mL
xg : 60mL
Therefore x = 2.4g CaCI2.2H2O

1 mmol of CaCI2.2H2O = 147.0mg y

mmol of CaCI2.2H2O = 2,400mg
Therefore y = 16.33 mmol CaCI2.2H2O
-
This quantity of CaCI2.2H2O will yield twice the mmol of CI ie:
-
16.33 x 2 = 32.66 mmol CI (answer)

80
 Pharmaceutical Calculations 9. Millimoles, Milliequivalents and Milliosmoles

Quiz Question 9.8

How many millimoles of sodium ions are in 10 mL of the following mixture ?

Sodium Citrate 1g (C6H5NaaO72H2O; MW = 294.1)

Sodium Bicarbonate 750 mg (NaHCO3; MW = 84.01)
Orange Syrup 1 mL
Purified Water to 10 mL

Answer:

Equations:
+ 3-
1. C6H5Na3O7.2H2O -> 3 Na + C6H5O7 + 2H2O
+
1 mmol of C6H5Na3O7.2H2O → 3 mmol Na = 294.1 mg C6H5Na3O7.2H2O

To determine number of mmol of Na+ in 1g (1000mg), cross multiply:

+
= 10.2 mmol Na

2. NaHCO3 → Na+ + HCO3"

+
1 mmol NaHCO3 → 1 mmol Na = 84.01 mg NaHCO3

To determine the number of mmol of Na+ in 750mg, cross multiply:

+
= 8.9 mmol Na
+
Total number of mmol Na = 10.2 + 8.9 = 19.1

Quiz Question 9.9

What volume of a sterile Potassium Chloride Injection containing 2.45 g KCI/5 mL would
need to be added to 1 litre of Synthamin® 10% with Electrolytes Solution to give a total of 75
millimoles of potassium?
+
Synthamin® 10% with Electrolytes contains 60 mmol K /litre.
MW(KCI) = 74.6

Answer:
Since Synthamin® 10% with Electrolytes contains 60 mmol K+/litre.
we need to add a further 15 mmol K+ from our KCI injection.

Equation:
+ -
KCI → K + CI

1mmol KCI = 1 mmol K+ → 74.6 mg KCI

+
To determine the amount of KCI needed for 15 mmol K , cross multiply:
= 1119 mg KCI

To determine the volume of KCI injection (2.45g/5mL) that contains 1119mg KCI.

2450 mg KCI : 5mL

1119mgKCI : xmL

Therefore x = 2.28 mL 81
Pharmaceutical Calculations 9. Millimoles, Milliequivalents and Milliosmoles

9.4 Milliequivalents

Milliequivalents is included in this tutorial only for completeness and interest. Students will
not be expected to be familiar with milliequivalents and will NOT be examined on them.
Students are expected to be familiar with millimoles and milliosmoles.

Another unit that is occasionally used in measuring electrolyte quantities is the equivalent.
When a salt compound dissociates, the same number of ' equivalents'of positive and of
negative ions are produced. Similarly when a new compound is formed, one equivalent of a
positively charged ion combines with one equivalent of a negatively charged ion.

The number of equivalents of an ion is determined by multiplying the number of moles by the
absolute value of the valence.

More often used is the milliequivalent.

The number of milliequivalents (mEq) of an ion is determined by multiplying the number of

millimoles by the absolute value of the valence.

Note: the absolute value of 2+ or 2- is two.

Worked Example 9.8

How many equivalents of CI- are produced by the dissociation of 1 mol of NaCI ?

Working:
Equation:
+ -
NaCI → Na + Cl
-
Thus 1 mole of Cl is produced,
equivalent = moles x valence

= 1 x 1 = 1 equivalent of Cl-

Worked Example 9.9

You have a vial of 1.0 g of potassium fluoride.

-
How many mEq of F are present ? MW(KF) = 58.1

Working:

Equation:
+ -
KF→ K + F

1 mmol KF → 1 mmol F - 58.1 mg

-
xmmol F : 1000mg KF

Therefore x = 17.21 mmol

milliequivalent - millimoles x valence =

17.21 x1
-
= 17.21 mEq F

Quiz Question 9.10

A formula for an intravenous solution calls for 25 mEq of Cl-.

-
Given that your source of Cl will be Calcium Chloride (anhydrous), what quantity is
required ? MW(CaCI2.2H2O) = 147.0mg

Answer:
Equation:
2+ -
CaCI2.2H2O → Ca + 2CI + 2H2O82
 Pharmaceutical Calculations 9. Millimoles, Milliequivalents and Milliosmoles

1/2 mmol CaCI2.2H2O → 1 mmol Cl- = 1/2 x 147.0mg = 73.5.5mg CaCI2.2H2O

1 mEq CI- = mmol x valence

= 73.5mg x 1 = 73.5mg CaCI2.2H2O
-
Now for 25mEq CI :

73.5mg x 25 = 1837.5mg CaCI2.2H2O (answer)

Worked Example 9.10

You are required to prepare 200mL of a solution of a Calcium Chloride solution with a
+
concentration of 5mEq of Ca per 5mL How much Calcium Chloride is required ?
2+
MW(CaCI2.2H2O) = 147.0 AW(Ca ) = 40.0

Working:
Equation:
2+ -
CaCI2.2H2O → Ca + 2CI + 2H2O Firstly, determine how

many mEq of Ca2+ are needed in 200mL.

5mEq
-------- x 200mL = 200mEq Ca2+
5mL

Secondly, determine the mass of calcium chloride required:

1 mmol CaCI2.2H2O = 1mmol Ca2+ = 2mEq Ca2+= 147.0mg

Therefore to calculate the mass of 200mEq of Ca2-:

2+
2mEq Ca : 147mg CaCI2.2H2O
2+
200mEq Ca : x mg CaCI2.2H2O

Therefore x = 14.7g CaCI2.2H2O is needed.

Worked Example 9.11

How much NaCI is needed to prepare one litre of the following IV solution ?
MW(NaCI) = 58.45mg
Na+ 154mEq/L
-
Cl 154mEq/L

Working:

Equation:
+ -
NaCI → Na + Cl

+
1mmol NaCI → 1mEq Na = 58.45mg NaCI
To determine what mass of NaCI contains 154 mEq Na+, cross multiply:
= 9,0001.3mg NaCI

Therefore, 9.0 g of NaCI dissolved in a litre of water will produce the desired formulation.

Quiz Question 9.11

How many grams of potassium chloride will contain the same quantity of potassium as 7.5
grams of Potassium Carbonate ?
+
MW(KCI) = 74.6 MW(K2CO3) = 138.2 AW(K ) = 39.1
83
Pharmaceutical Calculations 9. Mitlimoles, Milliequivalents andMilliosmoles

Answer:
Equations:
+ -
1. KCI → K + CI
+ 2-
2. K2CO3 → 2K + CO3

Determine the number of moles of K2CO3:

n = m/M = 7.5/138.2 = 0.0543mole
+
Determine the number of moles of K :
this will be twice the number of moles of K2CO3 = 0.1085

Determine the mass of KCI that yields 0,1085g of K+:

m= n x M = 0.1085 x 74.6 = 8.09g KCI

Quiz Question 9.12

An oral mixture formulation requires 40mEq of Mg 2+

What volume of stock solution of 10% MgCI2 (anhydrous) is required ?
MW (MgCI2) = 95.3

Answer:
Equation:

MgCI2 → Mg2+ + 2CI-

2+ 2+
1 mmol MgCI2 → 1 mmol Mg = 2mEq Mg = 95.3mg MgCI2

Determine the amount of MgCI2 required for 40mEq of Mg2+ :

2mEq Mg2+ : 95.3 mg MgCI2

2+
40mEq Mg : x mg MgCI2

x= 1906mg MgCI2

Determine the volume of 10% w/v MgCI2 solution that contains this:

10gMgCI2 : 100mL

1.906g MgCI2 : y mL

y = 19.1 mL (answer)

Quiz Question 9.13

You are required to prepare 500 mL of Potassium Sulphate solution with a concentration of 2.5
mEq of potassium ion per millilitre. What quantity of potassium sulphate is required ?
MW(K2SO4) = 174.3

Answer:
Equation:
K2SO4 → 2K+ + SO4 2-

Determine the total quantity of mEq of K+ needed in 500mL:

2.5mEq/1mL x 500mL = 1250mEq of K+
From the equation:
1 mmol K2SO4 → 2mEq K+ = 174.3mg K2SO4
+
Determine the amount of K2SO4 needed for 1250mEq of K

2mEqK+ : 174.3 mg K2SO4

+
1250mEqK : y mg K2SO4
84
 Pharmaceutical Calculations 9. Millimoles, Milliequivalents and Milliosmoles

Therefore y = 108.9g of K2SO4 (answer)

Worked Example 9.12

Calculate the quantities of salts required to produce 1 litre of an intravenous injection

containing the following ionic composition:
+
Na 67 mEq MW (NaCI) = 58.5
+
K 6 mEq MW (KCI) = 74.6
2+
Ca 4 mEq MW (CaCI2.2H2O) = 147
-
CI 77 mEq

Working:
milliequivalent = millimoles x valence

Equations:
+
1. NaCI → Na + CI'

+
1mmol NaCI → 1 mmol Na
+
= 1 mEq Na = 58.5mg NaCI
+
To determine, the amount of NaCI required for 67mEq Na , cross multiply:
-
= 3,920mg (Note: this will also provide 67mEq of CI )
+ -
2. KCI → K + CI
+
1 mmol KCI → 1 mmol K
+
= 1 mEq K = 74.6mg KCI To determine, the amount of KCI
+
required for 6mEq K cross multiply:
= 448mg (Note: this will also provide 6mEq of CX)
2+ -
3. CaCI2.2H2O → Ca + 2CI + 2H2O

1 mmol CaCI2.2H2O → 1 mmol Ca2+

= 2mEq Ca2+ = 147mg CaCI2.2H2O
2+
To determine, the amount of CaCI2.2H2O required for4mEq Ca , cross multiply:
-
= 294mg (Note: this will also provide 4mEq of CI )
-
Total mEq of CI = 67 + 6 + 4 = 77

9.5 Milliosmoles

When a solution of a drug comes into contact with a body fluid (eg: blood, or tears) there is
potential for damage to cells if the solution is not isotonic. To achieve isotonicity, there
needs to be balanced osmotic pressure. Differences in osmotic pressure provide the force for
osmosis which is the movement of water from regions of low to high solute concentration. In
various body fluids, the osmotic pressure is generated by the presence of electrolytes,
proteins and other normal constituents.

As an example, if an IV solution (of low osmotic pressure) is injected into the blood, then
there will be a net flow of water into red blood cells (RBC) to decrease the concentration
difference. This will have the effect of making the RBC swell or burst.

On the other hand, if the osmotic pressure of the IV solution is too high, the RBC will lose
water and shrink.

85
 Pharmaceutical Calculations 9. Millimoles, Milliequivalents and Milliosmoles

This movement of water across cell membranes will be minimised greatly if the drug in
solution has the same osmotic pressure as that of the bodily fluid. These solutions are
termed isosmotic with that particular fluid.

Balancing osmotic pressure is a major factor in achieving isotonicity. However there are
some drugs, because of their nature, which can damage cells even though they have the
correct osmotic pressure. We can calculate the theoretical contribution made by solutes
(drugs) to the osmotic pressure of a solution.

9.5.1 Osmotic Pressure

Osmotic pressure depends on the number of particles (molecules or ions) dissolved in a unit
volume of solvent.

a) Non-electrolytes
When an ideally behaving non-electrolyte is dissolved in water, each molecule produces one
particle in solution.

This holds true for real drugs provided that they do not dimerise (two molecules linked
together) or polymerise (many molecules linked together).
Note: The water of hydration present within a crystal becomes part of the solvent when a
drug is dissolved in water. This does not affect the number of osmoles (particles) in solution.

Definition of osmole.
One osmole (Osm) is defined as the weight (g) of a solute osmotically equivalent to one
gram-molecular weight (1 mol) of an ideally behaving non-electrolyte.
A milliosmole (mOsm) is 1/1000 of an osmole.

For an ideal non-electrolyte:

1 mol = 1 osmole

1 mmol = 1 mOsm

1 mEq = 1 mOsm

Worked Example 9.13

How many mOsm in 5g of Sucrose ?

MW (Sucrose) = 342.

Working:
Sucrose is a non-electrolyte.

1mmol = 342mg
1 mmol = 1mOSm = 342 mg
Therefore for 5,000mg of Sucrose,
the number of mOsm = 1mOsm/342mg x 5,000mg = 14.62mOsm.

Worked Example 9.14

You are required to make one litre of a solution containing 200mOsm of Dextrose,
How much Dextrose do you need ? MW (Dextrose) = 180

Working:
Dextrose is a non-electrolyte.

1mmol = 180mg
1 mmol = 1m0sm = 180mg

Therefore, for 200mOsm, the mass of Dextrose needed is:

180mg/1 mOsm x 200 mOsm - 36,000mg = 36g of Dextrose.

86
Pharmaceutical Calculations 9. Millimoles, Milliequivalents and Milliosmoles

b) Electrolytes

It is possible to calculate the theoretical number of mOsm of electrolytes by taking into

account the number of ions formed.
Assuming complete dissociation of the electrolyte, the number of osmoles is the sum of the
number of moles of each ion.

Worked Example 9.15

Calculate the number of mOsm present in 1g of Sodium Chloride.
MW (NaCI) = 58.5

Working:
Equation:
+ -
NaCI →Na +CI

1 mol of NaCI yields 2 mol of ions.

Each mole of ions contributes one osmol.

Therefore:
1 mol NaCI → 2 Osm
or
1 mmol NaCI = 2 mOsm
58.5 mg = 2 mOsm

To calculate the number of mOsm in 1g NaCI:

58.5 mg = 2 mOsm

1000mg = y mOsm y = 34.2 mOsm

NaCI (answer)

Quiz Question 9.14

You are required to produce a solution of Calcium Chloride of 200mOsm strength.

What mass of Calcium Chloride do you need ? MW (CaCI2.2H2O) = 147

Answer:
Equation:
CaCI2.2H2O → Ca2+ + 2 Cl- + 2H2O

147mg of CaCI2.2H2O = 3mmol of ions = 3 mOsm

(Note: the water molecules form part of the solvent and add no further particles)

To determine the mass of CaCI2.2H2O for 200 mOsm:

147 mg of CaCI2.2H2O : 3 mOsm

y mg : 200 mOsm

Therefore y = 9800mg = 9.8g (answer)

87
Pharmaceutical Calculations 9. Millimoles, Milliequivalents and Milliosmoles

9.5.2 Osmolarity and Osmolality

Osmotic pressure is determined by the concentration of osmoles in solution rather than the
absolute number, ie: the number of ions or molecules that are dissolved. Osmotic pressure is
an example of a colligative property (like freezing point depression and boiling point
elevation) since it depends on the number of particles in solution.

Two terms are used for osmole concentration:

1. Osmolarity

1 osmolar solution = 1 Osm/litre of solution

Eg: If 200mOsm are dissolved in a litre , the concentration is 200 milliosmolar.

This can be calculated from measured osmolality (see Note below) or by summing the
particle concentration of each constituent.

2. Osmolality

1 osmolal solution = 1 Osmol/kg of water

(for practical purposes: density of water = 1g/mL)

The osmolality of a solution can be measured using an osmometer which either measures
freezing-point depression or vapour pressure. The instrument is calibrated for a direct
reading of osmolality.

Note: For dilute solutions, the difference between osmolar and osmolal concentrations is very
small. This is because the solute occupies so little space in the solution that the volume of
solvent is virtually the same as the total volume of the solution.

Eg: the osmolality and osmolarity of 0.9% NaCI differ by less than 1%.
When dealing with concentrated solutions osmolarity and osmolality are not similar because

the mass of solute particles becomes significant.

Worked Example 9.16

What is the osmolarity of 30 mOsm dissolved in 100mL of water ?

Working:

1 osmolal = 1 osmol per 1000mL of solution.

We have 30mOsm/100mL or300mOsm/1000mL

ie: Concentration is: 300 milliosmolar

Worked Example 9.17

What is the osmolarity of a solution containing 0.35 mOsm/mL of solution ?

Working:

1 osmolal = 1 osmol per 1000mL of solution

We have 0.35mOsm/mL or 350mOsm/1000mL

ie: Concentration is: 350 milliosmolar 88

Pharmaceutical Calculations 9. Millimoles, Milliequivalents and Milliosmotes

Quiz Question 9.15

What is the osmolarity of the following solution?

45 g of Hydrous Dextrose in 500mL water.

MW (Hydrous Dextrose) = 198

Answer:
Dextrose is a non-electrolyte.

1 mol → 1 mOsm = 198mg

To determine how many mOsm in 45g:

1 mOsm : 198mg

x mOsm : 45,000mg

x = 227.3 mOsm of Dextrose, (that is in 500mL)

To determine the osmolarity: 1 osmolar = 1 osmol/litre

227.3 mOsm : 500mL

y mOsm : 1000mL

y = 454.6 mOsm/L (osmolarity)

Worked Example 9.18

Calculate the osmolarity (mOsm/L) of 0.9% w/v NaCI in water.

MW (NaCI) = 58.5

Working:

Equation:
+ -
NaCI → Na + Cl

1 mmol NaCI → 2 mmol ions = 2 mOsm = 58.5mg

1 osmolar = 1 osmol/L

We have 0.9% w/v = 0.9g/100mL or 9g/1000mL

Determine the number of mOsm in 9g of NaCI.

2 mOsm : 58.5g

x mOsm : 9000mg

x = 307.7 mOsm

ie: osmolarity is: 307.7 mOsm/L

Note: 0.9% NaCI is ' normal saline'. This can be safely instilled into the eye or injected. Any
solution that has an osmolarity of within 10% of 308 mOsm/L is termed to be isosmotic with
body fluids such as blood serum and tears.

Solutions which are isosmotic with body fluids are only considered to be isotonic if:
- membranes in contact with the solution are impermeable to the solute;
- the solute does not alter the permeability of membranes to any other substance present;
- no chemical reaction leads to a change in the total concentration of dissolved ions or
molecule 89
 Pharmaceutical Calculations 9, Millimoles, Miltiequivalents and Milliosmoles

Problems are encountered with solutions of some substances such as boric acid, urea,
ethanol and certain monohydric or polyhydric alcohols, as well as some local anaesthetics.
These solutions cause haemolysis of red blood cells in isosmotic concentrations and hence
are not isotonic with red blood cells.

(Ref APF 15 page 443). See also Tutorial 10: Isotonic Solutions

Quiz Question 9.16

Assuming complete dissociation, calculate the osmoiarity of the following 100mL solution with
the following concentration.

Dextrose (20mmol/100mL)
KCI(4mmol/100mL)
MW (Dextrose) = 180
MW (KCI) = 74.6
Answer;
Equations:
a) Dextrose is a non-electrolyte

Therefore: 20mmol = 20mOsm

b) KCI -> K* + CI"

1 mmol KCI = 2 mmol ions - 2 mOsm

Therefore 4 mmol = 8 mOsm

Total = 20 + 8 = 28 mOsm/100mL = 280 mOsm/L (osmolarity)

Worked Example 9.19

What is the osmolarity of the following solution (Ringer'

s)
0.86% NaCI (MW = 58.5)
0.03% KCI (MW = 74.6)
0.033% CaCI2 (MW =111.0)

Working:

Equations:

1.NaCI → Na + + CI -
0.86% = 860mg/100mL = 8,600mg/1000mL 1mmol
NaCI = 2 mmol ions = 2 mOsm = 58.5mg
How many mOsm in 8,600mg ? (cross multiply)
= 294mOsm
+ -
2. KCI → K + CI
0.03% = 30mg/100mL = 300mg/1000mL 1 mmol
KCI = 2 mmol ions = 2 mOsm = 74.6mg
How many mOsm in 300mg ? (cross multiply)
= 8.04 mOsm
3.
CaCI2 → Ca2+ + 2CI-

0.033% = 33mg/100mL = 330mg/1000ml_

1 mmol CaCI2 = 3 mmol ions = 3 mOsm = 111.0mg
How many mOsm in 330mg ? (cross multiply)
= 8.92 mOsm
Total = 294 + 8.04 + 8.92 = 311 mOsm/L
(This is very close to the osmoiarity concentration for normal saline (308 mOsm/L) ie: they
are osmotically equivalent.
90
Pharmaceutical Calculations 9. Millimoles, Milliequivalents and Milliosmoles

Quiz Question 9.17

If the osmolarity of a NaCI solution is 309 mOsm/L, what is its percentage strength ? MW
(NaCI) = 58.5

Answer:

Equation:
NaCI → Na* + CI -

1 mmol NaCI → 2 mmol ions = 2 mOsm = 58.5mg

To determine the weight of NaCI for 309mOsm, cross multiply.
ie: 309x58.5 / 2 = 9038mg (this is in one litre)

Therefore in 100mL there is 903.8mg = 0.9038g (about 0.9g)

ie: expressed as a percentage: 0.9% w/v

Worked Example 9.20

2+
Prepare 1 L of a solution of CaCI2 containing 40 mEq/L of Ca . Make isotonic with NaCI.
MW(CaCI2.2H2O) = 147

MW (NaCI) = 58.5

Working out:
Equation:

CaCI2.2H2O → Ca2+ + 2CI- + 2H2O

Firstly, determine mass of CaCI2.2H2O required:

2+
1mmol CaCI2.2H2O contains 2mEq Ca = 147mg CaCI2.2H2O

To determine how much CaCI2.2H2O is needed for 40mEq Ca +, cross multiply:

= 2,940mg

Secondly, determine how many mOsm this quantity of CaCI2.2H2O contributes:

1 mmol CaCI2.2H2O → 3 mOsm of ions = 147mg

To determine the number of mOsm in 2,940mg, cross multiply:

= 60 mOsm

Now, an isotonic solution contains 308 mOsm (+/-10%) So we

need 308 - 60 = 248 mOsm (to be added using NaCI)

With NaCI:
+ -
NaCI → Na + CI

1 mmol NaCI -> 2 mOsm ions = 58.5mg NaCI

To determine the amount of NaCI needed for 248 mOsm, cross multiply:
= 7,254 mg NaCI

Final formulation becomes:

CaCI2.2H2O 2,940 mg
NaCI 7,254 mg
Water for Injections to 1000 mL 91
 Pharmaceutical Calculations 9. Millimoles, Milliequivalents and Milliosmoles

Quiz Question 9.18

What quantities of salts are required to prepare 2 litres of a solution of KCI containing 40
+
mEq/L of K and also made isotonic with NaCI ?

MW (KCI) = 74.6
MW (NaCI) = 58.45

Answer:
Equation:
+ -
K CI → K + Cl

1 mmol KCI → 1 mmol K+ = 1mEq K+ = 74.6mg

+
To determine the quantity of KCI needed for 80mEq K , cross multiply:
= 5,968mg

To determine how many mOsm this contributes:

1 mmol KCI → 2 mOsm ions = 74.6mg KCI

Therefore, to determine the number of mOsm in 5,968mg, cross multiply:
= 160mOsm

Remember 308 mOsm/L is isotonic.

We are making 2L of solution here, thus need 308 x 2 = 616mOsm.
The additional amount required is: 616 -160 = 456 mOsm
This will be supplied by NaCI

NaCI → Na+ + Cl-

1mmol NaCI → 2 mOsm ions = 58.45mg
To determine the amount of NaCI needed for 456 mOsm, cross multiply:
= 13,327mg

Final formulation becomes:

KCI 5,968 mg (5.97 g)

NaCI 13,327 mg (13.3 g)
Water for Injections to 2 litres

Quiz Question 9.19

Calculate the number of milliosmoles (mOsm) in Sorensen'

s Phosphate Buffer
Ref: APF15p450(pH6.8)

50 mL of 0.067 M KH2PO4 (0.908%) MW = 136

50 mL of 0.067 M Na2HPO4.12H2O (2.39%) MW = 358

Answer:
Firstly, determine the amount of each salt:

1.KH2PO4

0.908g
-------- x 50 mL = 0.454g = 454mg

100 mL

2. Na2HPO4.12H2O

2.39g
------- x50 mL= 1.195g - 1,195mg
100 mL 92
Pharmaceutical Calculations 9, Millimoles, Milliequivalents and Milliosmoles

Equations:
+

1. KH2PO4 → K + H2PO-4
+

1 mmol KH2PO4 = 2 mOsm ions = 136mg KH2PO4 To determine the

number of mOsm in 454mg, cross multiply:
= 6.68 mOsm
+ 2-
2. Na2HPO4 → 2 Na + HPO4

1 mmol Na2HPO4 = 3 mOsm of ions = 358mg of Na2HPO4

To determine the number of mOsm in 1,195mg, cross multiply:

= 10.01mOsm

Total mOsm = 6.68 + 10.01 = 16.69 mOsm

93
 Pharmaceutical Calculations Module
Tutorial 10: Isosmotic and Isotonic Solutions

About This Tutorial

This tutorial was developed by the Victorian College of Pharmacy, Monash University in
conjunction with the Australian Pharmacy Examining Council Incorporated (APEC Inc)
(now known as the Faculty of Pharmacy and Pharmaceutical Sciences, Monash University
and the Australian Pharmacy Examining Committee respectively).It remains the property of
Monash University. The tutorial cannot be used or copied without prior authorisation.

This tutorial is intended as an aid for students enrolled in Monash University’s Bachelor of
Pharmacy & Pharmacy Internship programs.

• Original tutorial prepared by in1996:

Arthur Pappas Lecturer in Pharmacy Practice
Dr Louis Roller Head, Department of Pharmacy Practice

with the assistance of :

May Admans Senior Assistant-Lecturer in Pharmaceutics

Dr Denis Morgan Reader in Pharmaceutics
Dr Kay Stewart Lecturer in Pharmacy Practice
Prof Peter Stewart Professor of Pharmaceutics

• Original Tutorial Manual produced by Arthur Pappas - December 1996

• Adaptation & updating of the material for online delivery to students of Monash
University was undertaken by Phil Bergen, Assistant Lecturer in Pharmacy Practice -
February 2005

© Copyright 2005
This publication is copyright. Apart from any fair dealing for the purpose of private study, research, criticism or
review as permitted under the Copyright Act, no part may be reproduced by any process or placed in computer
memory without written permission. Any assembled extracts each attract individual copyright and enquiries
about reproduction of this material should be addressed to the appropriate publishers. Enquiries about all other
material should be made to the Faculty named above.
Last amended by EM- November 2008

ii
Pharmaceutical Calculations 10. Isosmotic and Isotonic Solutions

10. Isosmotic and

Isotonic Solutions

Topic Index

Page
10.1 Introduction 95
10.2 Objectives 96
10.3 Types of Calculations 96
10.3.1 Calculations based on
freezing-point depression (FDi%). 96
10.3.2 Calculations based on
Sodium Chloride Equivalents (SCE) 98
10.3.3 Calculations based on
isosmotic concentrations (C|SO) 101
94
 Pharmaceutical Calculations 10. Isosmotic and Isotonic Solutions

10.1 Introduction

When two solutions of different concentration are separated by a semi-permeable membrane

(ie: permeable to the solvent only), the solvent will move from the lower concentration to the
higher concentration solution. The force that causes this movement is called osmotic
pressure.
When there are two solutions with the same osmotic pressure, separated by a semi-
permeable membrane, they will be in osmotic equilibrium (ie: no net movement of solvent
will occur). These solutions are called isosmotic.

What is the difference between isosmotic and isotonic ?

Isosmotic is an absolute term. It implies that two solutions with the same number of particles
will be in osmotic equilibrium when separated by a perfect semi-permeable membrane.
However, in biological systems, the passage of some solute particles does occur. Therefore,
when two solutions are in osmotic equilibrium, they are called isotonic, with respect to that
membrane.

Note: Solutions that are isosmotic can only be considered isotonic if:

1. membranes in contact with the solution are impermeable to the solute;

2. the solute does not alter the permeability of membranes to any other substance
present;
3. no chemical reaction leads to a change in the total concentration of dissolved ions or
molecules.

Some substances even though calculated to be isosmotic with blood serum are not isotonic
because they can pass through the red blood cell (RBC) membrane and cause haemolysis.
Examples are: glycerol, boric acid, procaine HCI and ethanol.

What effect does a hypo-osmotic (hypotonic) solution have on biological cells ?

These solutions have a lower osmotic pressure than blood serum. This is due to a lower
concentration of ions and undissociated molecules. When administered, liquid passes into
the RBC in order to achieve osmotic equilibrium. This may eventually cause the RBC to
burst (haemolysis) which is an irreversible process.

What effect does a hyperosmotic (hypertonic) solution have on biological cells ?

These solutions have a higher osmotic pressure than blood serum. This is due to a higher
concentration of ions and undissociated molecules. When administered, liquid passes out of
the RBC in order to achieve osmotic equilibrium. This eventually causes the RBC to shrink
(crenation) but this can be reversible.

Pharmaceutical preparations, which on administration come into contact with blood cells or
other unprotected tissue cells, need to be made isotonic to prevent tissue damage or pain,
e.g. injections, eye drops, eye lotions, nasal drops, dialysis solutions.

How do you prepare an isosmotic solution ?

There are 2 options.

a) Adjusting a hyperosmotic solution.

The effect on biological cells of a hyperosmotic solution is crenation. This can be reduced by
diluting the solution to make it isosmotic.

b) Adjusting a hypo-osmotic solution.

Since the effect of a hypo-osmotic solution on biological cells can be cell rupture, it is
important to make the solution isosmotic. Dextrose or sodium chloride is added to solutions
for IV use. Boric acid or sodium chloride can be added to solutions for ophthalmic use.

95
 Pharmaceutical Calculations 10. Isosmotic and Isotonic Solutions

Solutions are adjusted so that they are isosmotic with 0.9% w/v NaCI, which is, in most
cases, isotonic with body fluids.

Note: The amount of substance (or dilution factor) required to make a solution isotonic can
not be calculated, but estimates can be made using a variety of methods.

10.2 Objectives
The aim of this tutorial is to give you an appreciation of the need for preparation of isosmotic
solutions which are intended to come into contact with body fluids.

At the end of this tutorial you will be able to perform calculations for making a solution
isosmotic using the following common methods:
- freezing-point depression
- sodium chloride equivalents
- isosmotic concentration of formulation ingredients

10.3 Calculation Types

10.3.1. Calculations based on freezing-point depression (FD1%)

Freezing-point depression is a colligative property that is based on the number of particles in

solution. It can be used as a means of estimating the effect of solutes on osmotic pressure.
Blood serum and lachrymal secretions freeze at -0.52°C. Normal saline (0.9% NaCI) is
isosmotic with these fluids because it also freezes at the same temperature. Therefore, other
solutions (containing one or more solutes) will usually be isosmotic with these body fluids as
long as they freeze at -0.52°C.

Calculation of the isosmotic concentration of a single substance in water.

Formula: 0.52
Ciso --------- %
FD1%

Where:
Cis0 = isosomotic concentration of the substance in water
FD1% = the freezing point depression of that substance.

Worked Example 10.1

Show using the FD1% method that the strength of an isosmotic solution of NaCI is 0.9%w/v.

Working:

FD1%(NaCI) = 0.576°C

0.52
% NaCI = ------- = 0.90%
0.576

Calculation of the amount of adjusting substance to be added to a drug dissolved in

water to make it isosmotic.

Formula:
% adjusting substance = 0.52-[(%A x FD1%A) + (%B x FD1%B) +...]
FD1% adjusting substance

Note: A and B are formulation ingredients.

96
Pharmaceutical Calculations 10. Isosmotic and hotonic Solutions

This method assumes that freezing point depression (FD) is directly proportional to
concentration for dilute solutions. In other words a 2 per cent solution of a drug will have
twice the FD of a 1 per cent solution of that drug; while an 0.25 per cent solution will have
one-quarter of the FD of a 1 per cent solution. This is a close approximation for most drugs
in dilute solution.

A table of FD1% values for a range of drugs can be found in Appendix II APF 15.

Worked Example 10.2

Make the following solution isosmotic with blood serum using Anhydrous Dextrose.

NaCI 1.8g
Water for Injections 1 litre
FD1%(NaCI) = 0.576°C
FD1%(Anhydrous Dextrose) = 0.101°C

Working:
The percent of NaCI in the above solution is 0.18%

0.52-(0.18x0.576)
% Dextrose = ----------------------------- = 4.12%

0.101

ie: 4.12 g Dextrose is needed per 100mL or41.2g Dextrose per 1000mL of solution.

Quiz Question 10.1

How much NaCI is required to render 100 mL Adrenaline Injection BP isosmotic ?

Formulation:
FD1%
Adrenaline Acid Tartrate 0.18% 0.098°C
Sodium Metabisulphite 0.1% 0.386°C
Sodium Chloride qs 0.576°C
W ater for Injections to 100 mL

%NaCl = 0.52 – (%Adrenaline Acid Tartrate x FD1% + %SMBS x FD1%)

FD1% NaCl

= 0.52 - (0.18 x 0.098 + 0.1 x 0.386)

0.576

= 0.805% w/v Sodium Chloride

ie: 805 mg of NaCI is required.

Quiz Question 10.2

Make the following solution isosmotic:

FD1%
Procaine HCI 1% 0.122 °C
NaCI qs 0.576 °C
Water Injections to 250mL
for
 Pharmaceutical Calculations 10. Isosmotic and Isotonic Solutions

Answer:

% NaCI - 0.52 - (%Procaine HCI x FD1%)

FD1% NaCI

= 0.52-(1.0x0.122)
0.576

= 0.691% w/v Sodium Chloride

ie: 0.691 g of NaCI is required per 100mL or 1.728q per 250mL (answer)

10.3.2. Calculations based on Sodium Chloride Equivalents (SCE)

The SCE of a substance is the mass (in grams) of NaCI that has an effect on the freezing-
point depression equivalent to that produced by 1 gram of substance.

In other words, if we start with 1 g of drug, it will be possible to make a certain volume of
isosmotic solution. As a specific example: 14.3mL of isosmotic solution can be prepared by
dissolving 1g of Atropine Sulphate in water. This volume (14.3mL) of normal saline (0.9%
w/v NaCI), would contain 0.13g of NaCI. Therefore, in terms of osmotic pressure, each gram
of Atropine Sulphate can be replaced by 0.13g of NaCI. Hence 0.13g is the SCE of Atropine
Sulphate.

Formula.

0.9
SCE =-------- x FD1%
0.52

where:
0.9 = the percentage strength of an isosmotic solution of NaCI
FD1%= the freezing point depression of a 1% solution of a substance.

Note: SCE values of substances can be found in Appendix II of APF 15.

Worked Example 10.3

What is the SCE of Anhydrous Glucose ?

FD^ (Anhydrous Glucose) =0.101°C

Working:
0.9
SCE (Anhydrous Glucose) = ------- x 0.101 g = 0.175 g
0.52

ie: 0.175 g of Sodium Chloride is osmotically equivalent to 1g of Anhydrous Glucose.

Quiz Question 10.3

Calculate the SCE of Atropine Sulphate.

FD1%(Atropine Sulphate) = 0.074°C

Answer:
0.9
SCE (Atropine Sulphate) = ------- x 0.074 g = 0.128 g
0.52
ie: 0.128 g of Sodium Chloride is osmotically equivalent to 1g of Atropine Sulphate.

98
Pharmaceutical Calculations 10, Isosmotic and Isotonic Solutions

To calculate the isosmotic value of a single substance using SCE:

This value can be read off a table (eg: Appendix II, APF 15) or calculated by the following
methods:

a) using logic:
If the SCE of Atropine Sulphate is 0.128g, that means that 0.128g of Sodium Chloride is
osmotically equivalent to 1g of Atropine Sulphate. We also know that 0.9% w/v NaCI is
isosmotic.
0.128g NaCI : 1 g Atropine Sulphate
0.9 g NaCI : x

x = 7.03 g
ie: 7.0 % of Atropine Sulphate will be isosmotic.

b) using formula:
0.9
Ciso (substance) = ------------------
SCEsubstance

Worked Example 10.4

If the SCE anhydrous glucose = 0.17g, What is its Ciso ?

Working:
0.9
= ------------------------
Ciso (substance)
SCE substance
0.9
Ciso (anhydrous glucose) = ——-—- = 5.29
0.17

To calculate the amount of adjusting substance needed to make a solution isotonic:

Formula:

Percent adjusting substance = 0.9 – [%A x SCEA) + (%B x SCEB)..-]

SCEadjustlng substance

Where A, B, etc are component ingredients of a formulation.

Note if using NaCI as the adjusting substance, its SCE = 1.00

Worked Example 10.5

How much NaCI is required to adjust 100 mL of a 0.5 per cent solution of Methoxamine
Hydrochloride ?
SCE (NaCI) =1.00
SCE (Methoxamine HCI) = 0.26
99
Pharmaceutical Calculations 10. hosmotic and Jsotonic Solutions

Working:

% NaCI required = 0.9 - (% Methoxamine HCI x SCEMethoxamine HCI)

= 0.9 - (0.5 x 0.26)
= 0.9-0.13
= 0.77 per cent

ie: 0.77g of NaCI is required for 100mL of solution.

Quiz Question 10.4

How much Boric Acid is required to render 10mL of the following solution isotonic?

SCE
Streptomycin Sulphate 6.25% 0.06 g
Boric Acid qs 0.5 g
Chlorbutol 0.5% 0.24 g
Water for Injections to 10 mL

Answer:

% Boric Acid = 0.9 - (%Streptomvcin Sulphate x SCE + %Chlorbutol x SCE)

SCEBoric Acid

i.e: % Boric Acid = 0.9 - (6.25 x 0.06 + 0.5 x 0.24)

0.5

0.810% w/v

ie: 81 mg of Boric Acid is required for 10mL of solution.

Quiz Question 10.5

Calculate the amount of Boric Acid required to make 30 mL of the following formulation
isosmotic.
SCE
Atropine Sulphate 1.2% 0.13g
Boric Acid qs 0.5g
Water for Injections to 30mL

Answer:

% adjusting substance = 0.9 – [(%A x SCEA) + (%B x SCEB)...]

SCEacjjusting substance

% Boric Acid = 0.9 - (1.2x0.13)

0.5

- 1.488%

= ie: 1.488g per 100mL or 0.446 q per 30mL (answer)

100
Pharmaceutical Calculations 10. Isosmotic and Isotonic Solutions

10.3.3 Calculations based on isosmotic concentrations (C|$o)

Formula:

% adjusting substance % drug A % drug B

-------------------------------- = 1 - ( ---------------- + ---------------- + ....... )
Ciso adjusting substance Ciso drug A Ciso drug B

Isotonic concentrations of various substances are available in Appendix II of the APF 15.

Worked Example 10.6

How much Sodium Nitrate is required to render 10 mL of the following eye drops isotonic?

Ciso
Silver Nitrate 0.5% 2.74%
Sodium Nitrate qs 1.36%
Water for Injections to 10 mL

Working:

% adjusting substance % drug A % drug B

------------------------------- = 1- ( ----------- + ------------ + … )
Ciso adjusting substance C i s o drug A C i s 0 drug B

% Sodium Nitrate = 0.5

1.36 2.74

0.5
% Sodium Nitrate = (1- ...........) x 1.36 = 1.11
2.74

ie: 1.11g are needed per 100mL or 111 mg per 10mL

Quiz Question 10.6

How many grams of NaCI are required to make the following eye drops isosmotic ?
Ciso
Phenylephrine HCI 0.25% 3.0%
Zinc Sulphate 0.5% 7.65%
Sodium Chloride qs 0.90%
Water for Injections to 60mL

Answer:

Using the formula:

% adjusting substance % drug A % drug B

----------------------------- = 1 - (------------- + ------------)

CiS0 adjusting substance Ciso drug A Ciso drug B

101
Pharmaceutical Calculations 10. Isosmotic and Isotonic Solutions

% NaCI 0.25 0.5

----------= 1 . - ( ----- + --------- )

0.9 3.0 7.65

% NaCI = (1- 0.0833 + 0.0653) x 0.9

= 0.7663

ie: 766.3mg NaCI per 100mL or 459.8mg per60mL = 0.460g per 60mL (answer)

Quiz Question 10.7

How many grams of NaCI are required to make the following solution isosmotic ?

Ephedrine HCI 0.4% 3.2%

Chloramphenicol Sodium Succinate 1.0% 6.83%
NaCI q.s. 0.9%
Water for Injections to 50mL

Answer:

Using the formula:

% adjusting substance % drug A % drug B

------------------------------- = 1- ( ----------- + ------------ + … )
Ciso adjusting substance C i so drug A C i s 0 drug B

% NaCI 0.4 1.0

---------- = 1 - ( ---- + --------- )
0.9 3.2 6.83

% NaCI = (1- 0.125 + 0.146) x 0.9 = 0.656

ie: 0.656g of NaCI per 100mL

or 0.328g per 50mL (answer)

***

102
 Pharmaceutical Calculations Module
Tutorial 12: Drug Stability

About This Tutorial

This tutorial was developed by the Victorian College of Pharmacy, Monash University in
conjunction with the Australian Pharmacy Examining Council Incorporated (APEC Inc)
(now known as the Faculty of Pharmacy and Pharmaceutical Sciences, Monash University
and the Australian Pharmacy Examining Committee respectively).It remains the property of
Monash University. The tutorial cannot be used or copied without prior authorisation.

This tutorial is intended as an aid for students enrolled in Monash University’s Bachelor of
Pharmacy & Pharmacy Internship programs.

• Original tutorial prepared by in1996:

Arthur Pappas Lecturer in Pharmacy Practice
Dr Louis Roller Head, Department of Pharmacy Practice

with the assistance of :

May Admans Senior Assistant-Lecturer in Pharmaceutics

Dr Denis Morgan Reader in Pharmaceutics
Dr Kay Stewart Lecturer in Pharmacy Practice
Prof Peter Stewart Professor of Pharmaceutics

• Original Tutorial Manual produced by Arthur Pappas - December 1996

• Adaptation & updating of the material for online delivery to students of Monash
University was undertaken by Phil Bergen, Assistant Lecturer in Pharmacy Practice -
February 2005

© Copyright 2005
This publication is copyright. Apart from any fair dealing for the purpose of private study, research, criticism or
review as permitted under the Copyright Act, no part may be reproduced by any process or placed in computer
memory without written permission. Any assembled extracts each attract individual copyright and enquiries
about reproduction of this material should be addressed to the appropriate publishers. Enquiries about all other
material should be made to the Faculty named above.
Last amended by EM- November 2008

ii
Pharmaceutical Calculations 12. Drug Stability

12. Drug Stability

Topic Index

Page
12.1 Introduction 114
12.2 Objectives 114
12.3 Rate Laws 114
12.3.1 Zero Order Reactions 114
12.3.2 First Order Reactions 115
12.4 Half-life and Shelf-life 117
12.4.1 Zero-order Reactions 117
12.4.2 First-order Reactions 118
12.5 Relationship between reaction rate and
temperature (Arrhenius Equation) 122
12.5.1 Using Arrhenius Equation to
Extrapolate k2 at T2 122

113
 Pharmaceutical Calculations 12. Drug Stability

12.1 Introduction

The concentration of active ingredients in a formulation can vary with time depending on the
chemical stability of the drug. A drug can therefore degrade to form various byproducts which
maybe inactive therapeutically or even toxic. It is important that we know the likely
degradation pathway of a drug in a particular formulation vehicle and the rate at which it
degrades under specified conditions. Having this information will enable us to ascertain the
storage period and conditions (eg: temperature, pH, presence of light, catalysts) for which we
are confident that the concentration of the drug is within acceptable limits.

12.2 Objectives

The aim of this tutorial is to give you an appreciation of the main issues concerning drug
stability and how a knowledge of degradation rate laws enables us to predict shelf-life of
products.

At the end of this tutorial you will be able to:

- define the term ' order of a reaction’

- state the formula for a zero order and first order reaction
- given appropriate information (eg: reaction order, rate constant (at a specific
temperature), initial concentration, activation energy)
- be able to calculate:
- the half-life of a drug
- the shelf-life of a drug
- the amount of drug remaining at a particular time
- the rate constant at another temperature
- shelf-life at another temperature

12.3 Rate Laws

Drug degradation can be described by the following fundamental rate relationship.

p
rate α C

The rate of degradation is proportional to the concentration of drug (C) raised to

some power (P),
P identifies the order of this equation.

eg: P =0 (zero order)

P = 1 (first order)

P = 2 (second order)

The two commonly used rate laws are zero and first order.

12.3.1 Zero Order

rate α C 0

rate = k0C°
where ko = zero order rate constant

Since any number raised to zero power has a value of unity, this equation can be written as:

rate = k0

'
rate'can be mathematically expressed as - dC/dt

Therefore: -dC/dt = k 0

This expression represents the change in drug concentration with time. 114
 Pharmaceutical Calculations 12. Drug Stability

The negative sign indicates that there is a decrease in concentration with time.
Integrating the above expression yields:

C = Co - k 0 x t

where:
C = concentration at a particular time (units: g/mL, mg/mL, mol/L)
Co = initial concentration (units: g/mL, mg/mL, mol/L)
t = time (units: seconds, minutes, hours)
k0 = zero order rate constant (units: concentration units divided by time units)

When you plot C versus t, there is a straight line with a gradient of -ko

Worked Example 12.1

A 0.50% w/v solution of Drug X is prepared.

It is known to follow a zero order degradation with a rate constant of 0.05mg/mL/year.
What concentration of Drug X will remain after 3 years of storage at 25°C ?

Working:
Using:
C = C0 - k0 . t

since k0 is in units of mg/mL, then concentration will have to be in those units too.
ie: 0.50% w/v = 0.50g/100mL = 500mg/100mL = 5mg/mL

C = 5mg/mL - (0.05mg/mL/year x 3 years)

= 5 mg/mL - 0.15mg/mL

= 4.85mg/mL

12.3.2 First Order

1
rate α C

rate = k1 C1
1
where k1 = first order rate constant (units: time')

Mathematically,

-dC/dt = k1 C

115
Pharmaceutical Calculations 12. Drug Stability

Integrating the above expression yields:

C = Co. e -k1t
or using natural logarithms (to the base e)

In C = In Co – k1t

or using logarithms to the base 10

k1
log C10 = log Co - ..................... t
2.303

(Note: the units of k1 are sec-1, hour-1, day-1 etc.)

When you plot log C versus time, there is a straight line with a gradient of -ki/2.303

Note: If a drug (eg: Drug X) follows first-order degradation, it will have the same rate
constant k1, irrespective of the initial concentration.

Worked Example 12.2

The degradation of Drug Y follows first-order kinetics. The initial concentration was 2.0
mg/mL. It was found that 10% of its activity was lost after 3 months.

How much drug will remain at the end of 6 months ?

Working:

C = Co. e-k1t
Co = 2.0 mg/mL

At the end of 3 months, C = (90% of 2.0mg/mL = 1.8mg/mL)

1.8 = 2 . e -k13

1.8/2 = 0.9 = e -k13

-0.105 = -k1 3
Therefore k1 =
-1
0.035 month
Pharmaceutical Calculations 12. Drug Stability

Now, to determine the concentration after 6 months:

C = Co. e -k1 t
-0.035 x 6
C = 2.e

C = 1.62 mg/mL (answer)

Quiz Question 12.1

Drug K follows first-order kinetics when in solution and loses 20% potency in 25 days at
26°C. What concentration will remain if 0.18M is stored for 80 days at 26°C?

Answer:

C = Co. e -k1t
C o =100%

At the end of 25 days, C = (80% of initial)

80 = 100. e -k1 25 =
-k 25
80/100 = 0.8 = e 1

-0.223 = -k125
Therefore k1 = 0.00893 day-1
Now, to determine the concentration after 80 days. Using Co = 0.18M
-k t
C = Co. e 1

C = 0.18.e-000893 x 80

C = 0.088M (answer)

12.4 Half-life and Shelf-life

'Half-life' is the time required to reduce the concentration of a drug to 50% of its initial value,
ie: C = 0.5 Co
The following symbols are used: t1/2, t50%, t0.5

'Shelf-life' is the time required to reduce the concentration of a drug to 90% of its initial
value, ie: C = 0.9 Co

The following symbols are used; t90%, t0.9

12.4.1 Zero-order Reactions

C = Co - ko . t

For half-life C = 0.5C0

Therefore: 0.5C0 = Co - k 0. t 1/2

- 0.5C0 = - ko . t1/2

0.5C0
ie: t 1/2 =----------- (Half-life Zero-Order Reaction)
ko 117
Pharmaceutical Calculations 12, Drug Stability
For shelf-life C = 0.9C0
Therefore: 0.9C0 = Co - k0. t90%
-0.1 Co = -ko. t 90%
0.1 Co
ie: t90% = ---------- (Shelf-life Zero-Order Reaction)
ko
12.4.2 First-order Reactions
k1
log C = log Co - .................. t
2.303

For half-life

C = 0.5 Co

Therefore:
log 0.5C0 = log Co- k1 t1/2
2.303
log 0.5C0 = 0 - k1 t1/2
2.303
(Note: taking Co as having the value 1, then log10 (1) = 0)
-0.301 - - k1 . t1/2
2.303
t1/2 = -0.301 x 2.303 /-k1

0.693
t1/2 = --------- (Half-life First-Order Reaction)
k1

For shelf-life

C = 0.9C0

Therefore:

log 0.9C0 = log Co -k1 . t90%

2.303
log 0.9C0 = 0 - k1 . t90%
2.303

(Note: taking Co as having the value 1, then log10 (1) = 0)

118
Pharmaceutical Calculations 12. Drug Stability

t90% = log 0.9C0 x 2.303/-k1

t90% = - 0.0458 x 2.303/-k1

0.105
t90% = --------- (Shelf-life First Order Reaction)
k1

Worked Example 12.3

A stability test conducted on a batch of tablets under simulated "patient use" conditions
showed that half of the potency was lost after 27 months. On the basis of this information
and assuming the degradation process is first order what should the shelf-life of the product
be?

Working:

Using t1/2 = 0.693/k,

t1/2 = 27 months = 0.693/k1

k1 = 0.02567 month-1

Now to determine shelf-life t90% = 0.105/ k1

-1
t90% = 0.105/0.02567 month = 4.09 months

Note: The dispensed label should therefore read "Discard 4 months after first opening".

Quiz Question 12.2

The degradation constant of a drug in water is 0.69 hours-1 at 25°C. Degradation is known to
follow first order kinetics.
What is the half-life of this drug ?

Answer:

Using t1/2 = 0.693/k1

-1
t1/2 = 0.693/0.69hr = 1.0 hour

Worked Example 12.4

A solution of Cephalothin Sodium 1g/100 mL retained 90.6% activity in Dextrose Injection

when stored at 5°C for 14 days. What is the shelf-life of the drug under these conditions
(assuming it follows first-order kinetics) ?

119
Pharmaceutical Calculations I2- Dm& Stability

Working:

Using:

k1
log C = log Co - .......... t

2.303

Determine the value of k1:

log 90.6 = log 100 - k1 / 2.303 . 14 days

1.9571 = 2- k1 / 2.303 .14 days

-0.0429 = -k1 . 6.079

-1
k, = 0.00706 day

Determine the value of t90%:

Using t90% = 0.105/ k1

-1
t1/2 = 0.105/0.00706day

t1/2 = 14.87 days

Quiz Question 12.3

A solution formulation of the diuretic Frusemide (10 mg/10 mL) was found to retain 86.2%
potency after 90 days stored at 24°C. Degradation follows first-order kinetics. What would be
the amount of Frusemide remaining in 30 mL of this mixture when stored under these
conditions for one year?

Answer:

Using:

k1
log C = log Co............. t

2.303

Determine the value of k1

log 86.2 = log 100 - k1 / 2.303 . 90 days

1.9355 = 2 - k1 / 2.303 .90 days

-0.0645 = - k1. 39.079 days

k1 = 0.001651 day-1

Determine the % remaining after 365 days:

log C = log C0 - k1_____ . t

2.303 120
 Pharmaceutical Calculations 12. Drug Stability

0.001651day-1
log C = log 100 - ........ . 365 days

2.303

log C = 2 - 0.2617 = 1.7383

C = 54.74%

In 30mL of the original mixture (10mg/10mL) there is 30mg drug.

Therefore 54.75% of 30mg = 16.42mg (answer)

Quiz Question 12.4

A solution containing 0.75g/100mL of Drug P degrades by a first-order process with a rate

constant of 0.0035 day-1 at 20°C. Calculate the shelf-life of this solution.

Answer:

Using:
t90% = 0.105/k1
-1
= 0.105/0.0035day = 30.0 days at 20°C.

Quiz Question 12.5

A new eye drop formulation has an initial drug concentration of 1.6mg/mL It is known that
the half-life of the drug is 850 days. Degradation follows first-order kinetics. What is its shelf-
life ?

Answer:

Firstly, determine the rate constant using:

t1/2 = 0.693/k1

850 days = 0.693/ k 1

k1 = 0.000815day-1

Then, to determine the shelf-life:

t90% = 0.105/k1

= 0.105/0.000815day-1

= 128.8 days (answer)

Quiz Question 12.6

A drug degrades via a zero-order process. It has a k0 value of 2mg/mL/day.

If a solution of concentration 25mg/mL is prepared, what is the shelf-life of this formulation?

121
Pharmaceutical Calculations 12. Drug Stability

Answer:

Using t90% = C0
10k0
= 25mg/ml
10x2mg/mL/day
= 1.25 days

12.5 Relationship between reaction rate and temperature (Arrhenius Equation)

The rate at which a chemical reaction proceeds can depend on several factors, the most
important being pH and temperature.

The Arrhenius Equation shows the relationship between rate constant and temperature.
-(Ea/RT)
k = A.e

k = rate constant
A = constant
Ea = activation energy (calories/mol or joules/mol)
-1 -1 -1 -1
R = gas constant (R = 1.987 cal deg mol or 8.314 J deg mol )
T = absolute temperature (ie: °C + 273)

Logarithm form of the Arrhenius Equation:

Ea
log10 k = log10 A - ....................
2.303 R.T

12.5.1 Using Arrhenius Equation to Extrapolate k2at T2

If k 1 and Ea are known at a particular temperature (T1), the rate constant (k2) at a second
temperature (T2) can be determined using:

Ea (T2 – T1)
logk2 = logk1 + -------------
2.3 R.T1. T2

Worked Example 12.5

1
Drug Y has a k, value of 0.085 hour (35°C and pH6)
What is the k value at 50°C (and pH6) ? What is the half-life ?
[The activation energy Ea = 18kcal/mol]

Working:
Using:
logk2 = logk1 + Ea(T2 -T1)

2.303. R.T1. T2

122
Pharmaceutical Calculations 12. Drug Stability
-1
Ea = 18kcal.mol
T1= 35°C = 308K
T2 = 50°C = 323K
-1 -1
R = 1.987 cal deg mol

18,000 cal.mol-1(323 - 308)

-1
logk2 = log (0.085hour ) + -----------------------------------------------------------
-1 -1
2.303 x 1.987 cal deg mol x 308 x 323

= -1.071 + 0.593 = -0.478

-1
Therefore k2 = 0.333 hour

(Notice that k values are greater at higher temperatures)

(As a practical rule: an increase of 10"C leads to an approximate doubling of the reaction

rate)

Quiz Question 12.7

Drug Y has a k value of 0.085 hour-1 (35°C and pH6)

What is the half-life at refrigeration temperature (4°C) and pH6 ?
Degradation follows first-order kinetics.
-1
[The activation energy Ea = 18kcal.mol ]

Working:
Using:

Ea (T2 – T1)
logk2 = logk1 + —
2.303. R.T1T2

Ea = 18kcal.mol-1
T1 = 35°C = 308K
T2 = 4°C = 277K
-1 -1
R = 1.987 cal deg mol

18,000 cal.mol-1 (277-308)

-1
logk2 = log (0.085hour ) +
-1 -1
2.3 x 1.987 cal.deg .mol x 308 x 277

= -1.071 +-1.429 =-2.50

Therefore k2 = 0.0032 hour-1

To determine the half-life t1/2 at 4°C:

t 1/2 = 0.693/k

= 0.693/0.0032 = 216.6 hours

Quiz Question 12.8

The shelf-life of a new drug is 36 minutes at 36 °C. Degradation follows first-order kinetics.
What is the shelf-life (in hours) of the drug at refrigeration temperature (4 °C) ? The activation
energy is 15.7 kcal/mol.

123
Pharmaceutical Calculations 12. Drug
Stability

Answer:

Firstly determine the k1 value.

At 36°C:

t 90% = 0.105/k1

36 min = 0.105/ki Therefore k1 = 0.00292 min-1

Use the Arrhenius Equation to find k2:

Ea (T2 – T1)
logk2 = logk1 + -----------------
2.303 . R.T1T2

Ea= 15.7kcal/mol

T1 = 36°C = 309K

T2 = 4°C = 277K

-1 -1
R= 1.987 cal deg mol

15,700 cal/mol (277-309)

logk2 = log (0.00292min-1) + ---------------------------------------------------------
2.303 x 1.987 cal deg-1 mol-1 x 309 x 277

logk2 = -2.535 + -1.283 = -3.818

-1
Therefore k2 = 0.000152 min

To determine the shelf- life at 4°C:

t90% = 0.105/k2

= 0.105/0.000152 = 690.8 minutes = 11.5 hours

124
 Pharmaceutical Calculations Module
Tutorial 13: Molecular Manipulations

About This Tutorial

This tutorial was developed by the Victorian College of Pharmacy, Monash University in
conjunction with the Australian Pharmacy Examining Council Incorporated (APEC Inc)
(now known as the Faculty of Pharmacy and Pharmaceutical Sciences, Monash University
and the Australian Pharmacy Examining Committee respectively).It remains the property of
Monash University. The tutorial cannot be used or copied without prior authorisation.

This tutorial is intended as an aid for students enrolled in Monash University’s Bachelor of
Pharmacy & Pharmacy Internship programs.

• Original tutorial prepared by in1996:

Arthur Pappas Lecturer in Pharmacy Practice
Dr Louis Roller Head, Department of Pharmacy Practice

with the assistance of :

May Admans Senior Assistant-Lecturer in Pharmaceutics

Dr Denis Morgan Reader in Pharmaceutics
Dr Kay Stewart Lecturer in Pharmacy Practice
Prof Peter Stewart Professor of Pharmaceutics

• Original Tutorial Manual produced by Arthur Pappas - December 1996

• Adaptation & updating of the material for online delivery to students of Monash
University was undertaken by Phil Bergen, Assistant Lecturer in Pharmacy Practice -
February 2005

© Copyright 2005
This publication is copyright. Apart from any fair dealing for the purpose of private study, research, criticism or
review as permitted under the Copyright Act, no part may be reproduced by any process or placed in computer
memory without written permission. Any assembled extracts each attract individual copyright and enquiries
about reproduction of this material should be addressed to the appropriate publishers. Enquiries about all other
material should be made to the Faculty named above.
Last amended by EM- November 2008

ii
Pharmaceutical Calculations 13. Molecular Manipulations

13. Molecular
Manipulations

Topic Index

Page
13.1 Introduction 126
13.2 Objectives 126
13.3 Types of manipulations 126
13.3.1 Calculating amount of base (or acid)
from the salt 126
13.3.2 Calculating the amount of substance
formed by a chemical reaction 127
13.3.3 Calculating the amount of an element
within a compound 129
125
Pharmaceutical Calculations 13. Molecular Manipulations

13.1 Introduction

A pharmacist must understand basic chemistry in order to be able to provide specific

quantities of drugs from a variety of chemical forms (eg: salt, base, ion etc.)
This requires a knowledge of molecular pathways, mechanism of reaction and stoichiometry.

13.2 Objectives

The aim of this tutorial is to give you an appreciation of the types of molecular manipulations
you may need to undertake in order to provide a specific quantity of a particular drug.

At the end of this tutorial you will be able to calculate:

- the amount of base (or acid) from the salt

- the amount of drug formed by a particular chemical reaction
- the amount of an element in a compound

13.3 Types of manipulations

13.3.1. Calculating amount of base (or acid) from the salt

Sometimes a pharmacist is expected to be able to provide the appropriate amount of drug as

the parent drug utilising the salt.

Worked Example 13.1

How much Ephedrine HCI would be required to provide 300 mg of Ephedrine?

Ephedrine (C10H15NO.1/2H2O; MW= 174.2) Ephedrine

Hydrochloride (C10H15NO.HCI; MW = 201.7)

Working:

Firstly, find the number of moles of Ephedrine:

3
n = m/M =300x10 /174.2 = 0.001722

Now, calculate the mass of Ephedrine HCI that contains this number of moles of
Ephedrine:

m = n.M = 0.001722 x 201.7 = 0.3474g = 347.4mg

Worked Example 13.2

How much of the antibiotic Novobiocin Calcium would be required to prepare a suspension
containing 14 doses, each of 2.5 mg/kg body weight of Novobiocin, for a child weighing 22
kg?

Novobiocin (C 31 H35 N2O11 MW = 612.6)

No vob io cin Cal cium (C31 H35 N 2O11)2 Ca MW = 1263.3)

Working:

Firstly, determine the mass of Novobiocin in 14 doses:

2.5mg
------------x 22 kg x 14 doses = 770mg
kg. dose

126
Pharmaceutical Calculations 13. Molecular Manipulations

Secondly, determine the number of moles of Novobiocin in 770mg:

n = m/M = 0.770/612.6 = 0.001257

Thirdly, determine the number of moles of Novobiocin

Calcium:

From their formulae, 1 mole of Novobiocin Calcium contains 2 moles of Novobiocin

Therefore, the number of moles of Novobiocin Calcium needed is half that of
Novobiocin.

ie: 1/2 x 0.001257 = 0.0006285

mass of Novobiocin Calcium = n.M = 0.0006285 x 1263.3 = 0.7939g = 793.9 mg

Quiz Question 13.1

How much Chlorhexidine (base) is contained in 35g of Chlorhexidine Giuconate ?

Data:
Chlorhexidine Giuconate; C22H30CI2N10.2C6H1207 (MW = 897.8)
Gluconic acid; C6H12O7 (MW = 196.19)

Answer:

Chlorhexidine Giuconate consists of: one Chlorhexidine molecule + two gluconic acid
molecules

Therefore, the molecular weight of chlorhexidine itself = 897.8 - 2(196.19) = 505.42

To determine the amount of Chlorhexidine in 35g of Chlorhexidine Giuconate:

505.42
35g x ----------- = 19.7 g
897.8

13.3.2 Calculating the amount of substance formed by a chemical reaction

This is an example of a substance being formed "in situ" by means of a chemical reaction.

Worked Example 13.3

How many grams of Potassium Bicarbonate (KHCO3; MW = 100) and how many mL of 36%
w/w Acetic Acid (density = 1.045g/mL; MW CH3COOH = 60) are required to prepare 150 g of
Potassium Acetate (MW = 98)?

Working out:

Firstly, write the equation:

CH.COOH + KHCO3 -> CH.COOK + H2O + CO2

Secondly, determine the mass of KHCO3 needed:

a) number of moles of CH3COOK = m/M = 150/98 = 1.531

b) mass of KHCO3 equivalent to this number of moles is:

m = nM = 1.531 x100=153.1g 127

Pharmaceutical Calculations 13. Molecular Manipulations

Thirdly, determine the volume of 36% w/w Acetic Acid required:

a) number of mole of pure CH3COOH required is 1.531

b) mass of CH3COOH required is: m = nM =1.531 x 60 = 91.86g

c) determine the volume of 36% w/w Acetic Acid:

36g Acetic acid : 100g

91.86g Acetic acid : x

x = 255.17g of (36% w/w Acetic Acid) d = 1.045g/mL

d = m/V V = m/d

255.17g
V= -------- = 244.2 mL
1.045g/mL
Final formula:

Acetic Acid (36% w/w) 244.2 mL

Potassium Bicarbonate 153.1 g

Worked Example 13.4

This is another example of an "in situ" reaction, this time showing the formation of a soap
preparation.

i.e: Consider the following formula:

Stearic Acid 200g

Potassium Carbonate qs
Propylene Glycol 100g
Hydrous Wool Fat 50g
Purified Water to 1000g

How many grams of Potassium Carbonate (K2CO31½ H2O; MW = 165.2) should be used to
saponify 25% of the stearic acid (C17H35COOH; MW = 284.5)? Assume Stearic acid to be
100% pure. (C17 H35COOK; MW = 322.6)

Working:

Firstly, write the equation:

2C17H35COOH + K2CO3.11/2H2O → 2C17H35COOK + 2H2O + 2CO2

Calculating for 100% saponification first:

number of moles of Stearic Acid: (n=m/M) n = 200/284.5 = 0.703

number of moles of Potassium Carbonate: n= 1/2 of 0.703 = 0.3515

mass of Potassium Carbonate needed: m - nM = 0.3515 x 165.2 = 58.1 g

Now, for 25% saponification, we only need: 25/100 x 58.1 g = 14.53g Potassium Carbonate.

128
Pharmaceutical Calculations 13. Molecular Manipulations

Quiz Question 13.2

How much p-Amino Benzoic Acid would be needed to prepare 86g of Sodium p-Amino
Benzoate if it were to be reacted with Sodium Bicarbonate?

Data:
(p-Amino Benzoic acid NH2C6H4COOH; MW = 137)
(Sodium Bicarbonate NaHCO3; MW = 84)
(Sodium p-Amino Benzoate NH2C6H4COONa; MW =159)

Answer:

Firstly, write the equation:

NH2C6H4COOH + NaHCO3 → NH2C6H4COONa + H2O + CO2 Secondly,

determine the number of moles contained in 86g of NH2C6H4COONa:

n = m/M n = 86/159 = 0.54088

This would be the same number of mole of NH2C6H4COOH:

To determine the mass of NH2C6H4COOH needed:

m = nM m = 0.54088 x 137 = 74.1g (answer)

13.3.3 Calculating the amount of an element within a compound

This is an example of a calculation that determines the amount of elemental material

contained in a salt.

Worked Example 13.5

Ferrous Sulphate Mixture APF contains 300 mg of Ferrous Sulphate per 10mL dose.
If a person is required to take 10 mL three times a day of the mixture, how much elemental
iron is the patient ingesting daily?
(FeSO4.7H2O; MW = 278; Fe; AW = 55.8)

Working:

Firstly, determine daily intake of Ferrous Sulphate:

300 mg/10mL x 10mL/dose x 3 doses/day = 900mg/day

Secondly, determine amount of Fe in 900mg of FeSO4.7H2O:

AW (Fe)
------------------------- x daily intake = 55.8/278 x 900mg - 180.6 mg Fe
MW (FeSO4.7H2O)

129
Pharmaceutical Calculations 13. Molecular Manipulations

Quiz Question 13.3

How much Sodium Fluoride (NaF, MW = 42, F-, AW = 19) is required to prepare 100 mL of a
-
solution such that when 20 mL is diluted to 1,000 mL with drinking water containing 0.4 ppm of F ,
-
the concentration of F will be raised to 0.8 ppm? (Assume that the NaF available is British
Pharmacopoeia quality (98.5 -100.5% pure)

Answer:

Step1
Amount of F- to be added is 0.8ppm - 0.4ppm = 0.4ppm
1 ppm = 1mg in 1000mL
Therefore 0.4ppm is 0.4mg in 1000mL

Step2.
This 0.4mg F- is to be present in the 20mL concentrate
Therefore in the 100mL concentrate there is 0.4mg/20mL x 100mL = 2mg F"

Step3.
Calculate the amount of NaF containing 2mg of F- :

MW (NaF) 42
ie: 2mg x --------------= 2mg x — = 4.42 mg NaF
-
AW(F ) 19

Step4.
Now taking into account the 99.5% purity (taking the mid-point) the amount of NaF required
is:
100
4.42mg x -------= 4.44mg of 99.5% pure NaF (answer)
99.5

Quiz Question 13.4

Calculate the weight of Lithium (Li+) consumed daily by a patient taking three 250mg Lithium
Carbonate tablets daily. (Li2CO3; MW = 74, Li+ ; AW = 7)

Answer:

Firstly, write the equation:

Li2CO3 → 2 Li+ + CO32-

There are 2 moles of Li per mole of Li2CO3 Secondly,

determine the daily dose of Li2CO3 per day:

The patient is taking 250mg x 3 = 750mg Li2CO3 per day. Finally,

determine the amount of Lithium in 750mg Li2CO3 :

2x7
---------x 750 mg = 141.9 mg Lithium (answer)
74

130