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Pharmacopoeial Standards and Specifications for Pharmaceutical Oral Liquid

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Article · January 2016

DOI: 10.9734/ACRI/2016/22675

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 Archives of Current Research International
3(2): 1-12, 2016, Article no.ACRI.22675
ISSN: 2454-7077

SCIENCEDOMAIN international
www.sciencedomain.org

Pharmacopoeial Standards and Specifications for

Pharmaceutical Oral Liquid Preparations
Md. Sahab Uddin1*, Abdullah Al Mamun1, Nahia Akter2, Md. Shahid Sarwar1,
Mamunur Rashid1 and Md. Shah Amran3
1
Department of Pharmacy, Southeast University, Dhaka-1213, Bangladesh.
2
Department of Pharmacy, University of Asia Pacific, Dhaka-1215, Bangladesh.
3
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Dhaka, Dhaka-1000,
Bangladesh.

Authors’ contributions

This work was carried out in collaboration between all authors. Author MSU designed the study, wrote
the protocol, managed the analyses of the study and prepared the draft of the manuscript. Author
AAM managed the literature searches and helped with author MSU. Authors NA and MSS revised the
final manuscript. Authors MR and MSA reviewed the scientific contents of the manuscript. All the
authors read and approved the final manuscript.

Article Information

DOI: 10.9734/ACRI/2016/22675
Editor(s):
(1) Ravikiran Panakanti, Department of Biopharmaceutical Sciences, College of Pharmacy, Roosevelt University, USA.
Reviewers:
(1) Syed Umer Jan, University of Balochistan, Quetta, Pakistan.
(2) Adriana Passos Oliveira, Federal University of Rio de Janeiro, Brazil.
(3) M. Mohan Varma, Shri Vishnu College of Pharmacy, Andhra Pradesh, India.
Complete Peer review History: http://sciencedomain.org/review-history/13082

Received 19th October 2015

th
Review Article Accepted 26 November 2015
Published 27th January 2016

ABSTRACT

Quality control is an essential operation of the pharmaceutical industry. It is the monitoring process
which encompassing specifications, inspections, analysis and recommendations. The appropriate
design and formulation of a dosage form requires discretion of the physical, chemical and biological
characteristics of active pharmaceutical ingredients (APIs) and inactive pharmaceutical excipients
(IPIs) to be used in formulating the pharmaceutical. The drug and others pharmaceutical materials
utilized must be compatible with one another to produce a drug product that is stable, efficacious,
potent, palatable, easy to administer and well tolerated. The quality of any drug in dosage form
depends on its safety, potency, efficacy, stability, patient acceptability and regulatory compliance. In
order to claim the pharmaceutical oral liquid preparations as quality drugs it must satisfy the
aforementioned criteria. To conform the requirements of pharmaceutical oral liquids during
_____________________________________________________________________________________________________

*Corresponding author: Email: msu-neuropharma@hotmail.com;

 Uddin et al.; ACRI, 3(2): 1-12, 2016; Article no. ACRI.22675

manufacturing, in-process quality control (IPQC) tests are done as per specifications with a view to
remove error or if necessary to adjust the process. The quality of final products depends on finished
product quality controls (FPQC) test. So the quality of pharmaceutical oral liquids is strongly related
to IPQC and FPQC tests. The purpose of this study is to focus on the different in-process and
finished products quality control tests for pharmaceutical oral liquid preparations according to
pharmacopoeias.

Keywords: Pharmacopoeia; standard; specification; pharmaceutical oral liquid preparation, quality

control.

1. INTRODUCTION (FPQC) tests. The whole dealing process (IPQC

and FPQC tests) refers rigorous QC tests to
The pharmaceutical industry is an important make products fully faultless before they are
element of health care systems all over the world delivered into the market. IPQCs are tests that
in order to discover, develop, manufacture and are carried out at regular intervals before the
market medicines for human health [1]. The main manufacturing process is completed. The
goal of the quality control testing process in the function of IPQC includes monitoring and if
pharmaceutical industry is to produce necessary, adaptation of the manufacturing
satisfactory results by investigating and process with a view to consent with the
monitoring the quality of manufacturing products pharmacopoeias [11]. In process materials
to detect problems and prevent their repetition as should be tested for identity, strength, quality and
per comply with pharmacopoeial standards and purity as appropriate and approved or discarded
specifications. Oral liquids are homogeneous by the QC unit during the manufacturing process
liquid preparations, usually consisting of a [12-14]. Discarded in process materials should
solution, an emulsion or a suspension of one or be specified and controlled under a quarantine
more medicaments in a suitable vehicle. Oral system designed to counteract their use in
liquids are intended for oral administration either manufacturing [15]. In the pharmaceutical
undiluted or after dilution [2]. industry standard operating procedures (SOPs)
should be established and followed that mention
The manufacturing process for oral liquid the IPQCs and tests. Specific tests carried out
preparations must meet the requirements of during the manufacturing process, where the
Good Manufacturing Practice (GMP). In the acceptance criterion is identical to or narrower
manufacture of liquid preparations for oral use than the release requirement, (e.g., pH of a
some measures are taken to assure that all solution) which must satisfy requirements when
ingredients are of appropriate quality, minimize the test is included in the specification. Finished
the risk of microbial contamination and diminish product quality controls (FPQC) tests are
the risk of cross-contamination [3]. In addition to performed when the manufacturing process is
this during packaging, storage and distribution of completed with a view to check qualitative and
oral liquids, suitable means should be taken to quantitative characteristics along with test
ensure their best quality. Quality control (QC) procedures and their acceptance limits, by which
refers to the sum of all procedures undertaken to the finished product must comply throughout its
produce a faultless product by a series of valid shelf-life [16]. With a view to determine the
processes requiring a systematized effort by the specifications of the finished product, the quality
QC personnel to prevent or reject errors at every characteristics that are concerned to the
stage in production that ensures the identity and manufacturing process should be taken into
purity of a particular pharmaceutical [4,5]. It account. During the phase of development and
indicates the degree or grade of excellence of a the validation of the manufacturing process, an
product [6,7]. It strengthens testing of products to appropriate specification for each aspect of
prevent errors and asks to assure that the quality should be determined.
finished products consent to the specified
standards of performance, utility and reliability Pharmacopoeias are referred as drugs standard
[8-10]. [17]. They are authentic treatises on drugs and
preparations, their description, formulation,
The total qualities of the pharmaceuticals are analytic composition, physical constants, main
ensured by both In Process Quality Control chemical properties used in identification,
(IPQC) and Finished Product Quality Control standards for strength, purity, and dosage,

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 Uddin et al.; ACRI, 3(2): 1-12, 2016; Article no. ACRI.22675

chemical tests for determining identity and purity and other vehicle properties. Sugarless syrups
of dosage forms etc [18]. Pharmacopeias play an may contain sweetening agents and thickening
important role in the regulatory process and the agents. Syrups may contain ethanol (95%) as a
quality control of active pharmaceutical preservative or as a solvent to incorporate
ingredients (APIs), inactive pharmaceutical flavoring agents. Antimicrobial agents may also
excipients (IPIs) and finished pharmaceutical be added to syrups [24].
products (FPPs) that are used by pharmaceutical
manufacturers and regulatory authorities. 2.2 Elixirs
Pharmacopeias deliver standards, specifications,
and test methods that are expected to be used in Elixirs are clear, flavored oral liquids containing
the pharmaceutical industry to ensure the perfect one or more active ingredients dissolved in a
quality control tests of pharmaceuticals vehicle that usually contains a high proportion of
[19]. There are variant types of pharmacopoeias sucrose or a suitable polyhydric alcohol or
such as British Pharmacopoeia (BP), United alcohols and may also contain ethanol (95
States Pharmacopoeia-National Formulary percent) or a dilute ethanol [25].
(USP-NF), European Pharmacopoeia (PhEur),
International Pharmacopoeia (PhInt), Japanese 2.3 Linctuses
Pharmacopoeia (JP) and Indian Pharmacopoeia
(IP) in different countries of the world and they Linctuses are viscous oral liquids containing one
have contained the specified limits within which or more active ingredients dissolved in a vehicle
the pharmaceuticals should fall in order to be that usually contains a high proportion of
compliant as per the standards. sucrose, other sugars or a suitable polyhydric
alcohol or alcohols. They are intended for use in
the treatment or relief of cough, and are sipped
To further improve the effectiveness and safety
and swallowed slowly without the addition of
of the drug product in the global marketplace,
water [26].
many regulatory agencies such European
Medicines Agency (EMA), Food and Drug
Administration (FDA), Medicines and Healthcare 2.4 Mixtures
products Regulatory Agency (MHRA) and
Therapeutic Good Administration (TGA) are Mixtures are oral liquids containing one or more
continuously developing rules regulation in the active ingredients dissolved, suspended or
Europe, US, UK and Australia respectively [20- dispersed in a suitable vehicle. Suspended solids
22]. FDA assures the quality of pharmaceutical may separate slowly on keeping but are easily
products by carefully monitoring drug redispersed on shaking [26].
manufacturers with the compliance of current
Good Manufacturing Practice (cGMP) regulations 2.5 Oral Solutions
[23]. A drug product that does not consent the
GMP requirements is considerate unacceptable Oral solutions are oral liquids containing one or
according to FDA guidelines [1]. more active ingredients and excipients dissolved
in a suitable vehicle [27]. Water is the most
The objective of this study is to offer the quality common solvent, although organic solvents are
control tests for pharmaceutical oral liquid used in combination with water or on their own.
preparations based on pharmacopoeial All the components of a solution are dispersed as
standards and specifications. molecules or ions, and the solution is optically
clear [28].
2. CLASSIFICATION OF ORAL LIQUID 2.6 Oral Suspensions
PREPARATIONS
Oral suspensions are oral liquids containing one
2.1 Syrups or more active ingredients suspended in a
suitable vehicle. Suspended solids may slowly
Syrups are viscous oral liquids that may contain separate on keeping but are easily redispersed.
one or more active ingredients in solution. The In the manufacture of oral suspensions
vehicle usually contains large amounts of containing dispersed particles, measures shall be
sucrose or other sugars to which certain taken to ensure a suitable and controlled particle
polyhydric alcohols may be added to inhibit size with regard to the intended use of the
crystallization or to modify solubilisation, taste product [29].

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 Uddin et al.; ACRI, 3(2): 1-12, 2016; Article no. ACRI.22675

2.7 Oral Emulsions 3.4 Impurities

Oral emulsions are dispersions of at least two This test determines the presence of any
immiscible or partially miscible liquids. They are component that is not the API or an excipient of
oral liquids containing one or more active pharmaceutical oral liquid preparations. The
ingredients and are stabilized oil-in-water most common type of impurities that are
dispersions, either or both phases of which may measured is related substances, which are
contain dissolved solids. Solids may also be process impurities from the new drug substance
suspended in oral emulsions. Emulsions may synthesis, degradation products of the API, or
exhibit phase separation but are easily reformed both [17,32].
on shaking. The preparation remains sufficiently
stable to permit a homogeneous dose to be 4. QUALITY CONTROL TESTS FOR ORAL
withdrawn [30]. LIQUID PREPARATIONS

2.8 Oral Drops 4.1 Visual Inspection

Oral drops are oral liquids that are intended to be Oral solution and oral drops should be clear and
administered in small volumes with the aid of a free from any precipitate. Discoloration or
suitable measuring device such as a dropper cloudiness of solutions may indicate chemical
[31]. degradation or microbial contamination.
Evidence of physical instability of oral
3. UNIVERSAL TESTS FOR suspension and oral drops that are suspensions
PHARMACEUTICAL ORAL LIQUID is demonstrated by the formation of flocculants or
PREPARATIONS sediments that do not readily disperse on gentle
shaking. In case of oral emulsion and oral drops
The pharmaceutical oral liquid preparations that are emulsions evidence of physical instability
accounts for approximately 20% of all dosage is demonstrated by phase separation that is not
forms on the market. There are four tests that are readily reversed on gentle shaking. Evidence of
generally applicable to pharmaceutical oral liquid physical instability of powders and granules for
preparations and other drug products: oral solutions or oral suspensions and powders
for oral drops is demonstrated by noticeable
changes in physical appearance, including
3.1 Description texture for example, clumping. Discoloration may
indicate chemical degradation or microbial
This test is often called appearance on a contamination of the oral suspension, oral
specification and is a qualitative description of emulsion, powders and granules for oral
the pharmaceutical oral liquid preparations. For solutions or oral suspensions and powders for
example, the description of a syrup on a oral drops [33].
specification may read: red color, slight
characteristic odor, mild taste etc [17,32]. 4.2 pH
3.2 Identification pH of the oral liquid preparations must be
optimum as they are administered. The pH value
The purpose of an identification or identity test is conventionally represents the acidity or alkalinity
to verify the identity of the API in the of an aqueous solution. In the pharmacopoeia,
pharmaceutical oral liquid preparations. This test standards and limits of pH have been provided
should be able to discriminate between for those pharmacopoeial substances in which
compounds of closely related structure that are pH as a measure of the hydrogen ion activity is
likely to be present [17,32]. important from the standpoint of stability or
physiological suitability. The determination is
3.3 Assay carried out at a temperature of 25±2°C, unless
otherwise specified in the individual monograph.
This test determines the strength or content of The pH value of a solution is determined
the API in the pharmaceutical oral liquid potentiometrically by means of a glass electrode,
preparations and is sometimes called a content a reference electrode and a pH meter either of
test [17,32]. the digital or analogue type [31].

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 Uddin et al.; ACRI, 3(2): 1-12, 2016; Article no. ACRI.22675

4.3 Assay 85 percent to 115 percent of the average content

or if one or more individual contents are outside
The assay of oral liquids has to be done to detect the limits of 75 percent to 125 percent of the
API by using suitable analytical method to average content. If 2 or 3 individual contents are
produce good finished pharmaceutical [34]. API outside the limits of 85 percent to 115 percent
is responsible for therapeutic activity of the but within the limits of 75 percent to 125 percent,
pharmaceutical formulations. This test is one of determine the individual contents of another 20
the most important tests that determine the dosage units taken at random. The preparation
strength or content of the API. complies with the test if not more than 3
individual contents of the 30 dosage units are
4.4 Uniformity of Content outside the limits of 85 percent to 115 percent of
the average content and none is outside the
Unless otherwise prescribed or justified and limits of 75 percent to 125 percent of the average
authorized, according to BP this test is applicable content. In accordance with BP and USP-NF
for single-dose preparations that are limits for content uniformity (CU) and mass
suspensions. This test is also applicable for variation (MV) tests of oral pharmaceutical liquids
single-dose powders and granules for syrups, are given in Table 1 [31,33-35].
oral solutions, oral suspensions and single-dose
powders for oral drops, with a content of active Table 1. BP and USP-NF limits for content
substance less than 2 mg or less than 2 percent uniformity (CU) and mass variation (MV) tests
of the total mass. Except single-dose [34,35]
preparations that are suspensions if the
preparation has more than one active substance, Dosage form Dose and ratio
the requirement applies only to those substances of active substance
that correspond to the above conditions. ≥ 25 mg < 25 mg
According to IP unless otherwise specified, and ≥ 25% or < 25%
single dose liquids in suspension form or Solutions MV MV
powders or granules presented in single dose Suspensions CU CU
containers and that contain less than 10 mg or Emulsions CU CU
less than 10 percent of active ingredient also
comply with this test. For this test as per BP According to PhInt this test is applicable for
assay 10 units individually using an appropriate single-dose oral suspensions that contain less
analytical method. Carry out the assay on the than 5 mg of active ingredient per dose or in
amount of well-mixed material that is removed which the active ingredient is less than 5 percent
from an individual container in conditions of of the total weight per dose [33].
normal use. Express the results as delivered
dose. Calculate the acceptance value using the 4.5 Uniformity of Mass
following formula:
According to BP this test is applicable for single-
│M – X │ + KS dose preparations that are solutions or
emulsions; single-dose powders and granules for
Where, syrups, oral solutions, oral suspensions; and
single-dose powders for oral drops. For this test
M = Reference value, X = Mean of individual weigh individually the contents of 20 dosage
content (x1, x2,..., xn) expressed as percentage of units taken at random, emptied as completely as
the label claim, K = Acceptability constant, S = possible, and determine the average mass. As
Sample standard deviation [31,34]. stated by BP, PhEur and PhInt for single-dose
preparations that are solutions or emulsions not
According to IP, BP and PhInt the preparation more than 2 of the individual masses deviate by
complies with the test if not more than one more than 10 percent from the average mass
individual content is outside the limits of 85 and none deviate by more than 20 percent. For
percent to 115 percent of the average content single-dose powders and granules for syrups,
and none is outside the limits of 75 percent to oral solutions, oral suspensions and single-dose
125 percent of the average content. The powders for oral drops according to BP not more
preparation fails to comply with the test if more than 2 of the individual masses deviate from the
than 3 individual contents are outside the limits of average mass by more than the percentage

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 Uddin et al.; ACRI, 3(2): 1-12, 2016; Article no. ACRI.22675

deviation shown in Table 2 and none deviates by contents of each container. For non-viscous and
more than twice that percentage [33,34,36]. free-flowing liquids pour completely the contents
of each container into calibrated volume
Table 2. BP limits for uniformity of mass [34] measures of the appropriate size and determine
the net volume of the contents of the 10
Average mass Percentage deviation containers. Consistent with IP the average net
(mg) (%) volume of the contents of the 10 containers is not
Less than 300 10 less than the labeled amount, and the net volume
300 or more 7.5 of the contents of any single containers is not
less than the percentage deviation as shown in
4.6 Mass Variation Table 3 [31].

According to BP accurately weigh the amount of If this requirement is not met, determine the net
liquid that is removed from each of 10 individual volume of the contents of 10 additional
containers in conditions of normal use. If containers. The average net volume of the
necessary, compute the equivalent volume after contents of the 20 containers is not less than the
determining the density. Calculate the active labeled amount and the net volume of the
substance content in each container from the contents of not more than 1 of the 20 containers
mass of product removed from the individual is less than 91 percent or more than 109 percent
containers and the result of the assay. Calculate of the labeled amount where the labeled amount
the acceptance value using the following formula: is 50 ml or less or less than 95.5 percent or more
than 104.5 percent of the labeled amount where
Xi = W i × A/W the labeled amount is more than 50 ml but not
more than 200 ml or less than 97 percent or
more than 103 percent of the labeled amount
Where, where the labeled amount is more than 200 ml
but not more than 300 ml [31].
x1, x2,..., xn = Individual estimated contents of
the dosage units tested, w1, w2,..., wn = Table 3. IP limits for uniformity of volume [31]
Individual masses of the dosage units tested, A =
Content of active substance (percentage of label Net volume (ml) Percentage deviation
claim) obtained using an appropriate analytical (%)
method (assay), W = Mean of individual weights 50 or less 9
(w1, w2,..., wn) [34]. More than 50 but 4.5
not more than 200
Unless otherwise specified, consistent with BP, More than 200 but 3
the requirement is met if the acceptance value of not more than 300
10 dosage units is less than or equal to 15
percent. If acceptance value is greater than 15 4.8 Uniformity of Weight
percent, test the next 20 dosage units and
calculate the acceptance value. The Consistent with IP this test is suitable for
requirements are met if the final acceptance powders for oral liquids. For this test select a
value of the 30 dosage units is less than or equal sample of 10 filled containers and remove any
to 15 percent and no individual content of the labeling that might be altered in weight while
dosage units is less than (1 – 25 × 0.01)M or removing the contents of the containers. Clean
more than (1 + 25 × 0.01)M in calculation of and dry the outer surfaces of the containers and
acceptance value under mass variation or weigh each container. Remove quantitatively the
content uniformity [34]. contents from each container. If necessary, cut
open the container and wash each empty
4.7 Uniformity of Volume container with a suitable solvent, taking care to
ensure that the closure and other parts of the
According to IP this test is suitable for oral liquids container are retained. Dry and again weigh each
and oral suspensions of viscous preparations. empty container together with its parts which
For this test select a sample of 10 filled may have been removed. The difference
containers and determine the weight of the between the two weights is the net weight of the
contents of each container. Determine the weight contents of the container. As per IP the average
per ml and calculate the net volume of the net weight of the contents of the 10 containers is

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 Uddin et al.; ACRI, 3(2): 1-12, 2016; Article no. ACRI.22675

not less than the labeled amount and the net and PhInt not more than 2 of the individual
weight of the contents of any single containers is masses deviate from the average mass by more
not less than the percentage deviation as shown than 10 percent and none deviates by more than
in Table 4 [31]. 20 percent [33,34].

Table 4. IP limits for uniformity of weight [31] 4.11 Phase Separation

Net weight (g) Percentage deviation This test is applicable for pharmaceutical
(%) emulsion. An approximate estimation of phase
50 or less 9 separation may be obtained visually. In general,
More than 50 but not 4.5 creaming, flocculation, and coalescence have
more than 100 occurred before phase separation is visible, thus
sometimes making quantitative evaluations more
If this requirement is not met, determine the net difficult. The rate and degree of phase separation
weight of the contents of 10 additional in an emulsion can be easily determined by
containers. The average net weight of the keeping a certain amount in a graduated cylinder
contents of the 20 containers is not less than the and measuring the volume of separated phase
labeled amount and the net weight of the after definite time intervals. The phase
contents of not more than 1 of the 20 containers separation may result from creaming or
is less than 91 percent or more than 109 percent coalescence of globules. The phase separation
of the labeled amount where the labeled amount test can be accelerated by centrifugation at low
is 50 g or less than 95 percent or more than or mild rate speeds [37].
104.5 percent of the labeled amount is more than
50 g but not more than 100 g [31]. 4.12 Droplet Size

4.9 Dose and Uniformity of Dose This test is applicable for pharmaceutical
emulsion. Growth in the droplet size after the
According to BP and PhInt this test is applicable preparation of an emulsion is an indication of its
for oral drops. For this test, into a suitable physical instability. The droplet size is measured
graduated cylinder, introduce by means of the by microscopic methods or by electronic devices
dropping device the number of drops usually such as coulter counter. In emulsions containing
prescribed for one dose, or introduce by means droplets greater than 1 µm, optical microscopy is
of the measuring device the usually prescribed particularly useful because it provides a direct
quantity. The dropping speed does not exceed 2 and reassuring measurement of individual
drops per second. Weigh the liquid, repeat the droplet sizes. The tedium of counting droplets to
addition, weigh again and carry on repeating the obtain size distributions is reduced by the use of
addition and weighing until a total of 10 masses image analysis. Indirect methods generally
are obtained. Following BP no single mass involve laser light scattering techniques are used
deviates by more than 10 percent from the extensively with emulsions containing sub-
average mass. The total of 10 masses does not micrometre droplets. In either of these
differ by more than 15 percent from the nominal techniques often the original products has to be
mass of 10 doses. If necessary, measure the suitable diluted before estimation. The dilution
total volume of 10 doses. The volume does not may introduce errors because of incomplete
differ by more than 15 percent from the nominal de-flocculation or new pattern of flocculation
volume of 10 doses [33,34]. [37,38].

4.10 Uniformity of Mass of Delivered 4.13 Thermal Stress

Doses
This test is applicable for pharmaceutical
According to BP and PhInt this test is applicable emulsion. It is usual to evaluate the stability of an
for liquid preparations for oral use supplied in emulsion by subjecting it too high and low
multi-dose containers except oral drops. For this temperatures in alternating cycles. The samples
test, weigh individually 20 doses units taken at are first exposed to 60°C for a few hours and
random from one or more containers with the then to 40°C. Such exposures are repeated a
measuring device provided and determine the number of times and emulsion stability assessed
individual and average masses. As stated by BP after each cycle [39].

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4.14 Sedimentation Volume suspension. ß is more fundamental parameter

than F since it relates the volume of flocculated
This test is applicable for pharmaceutical sediment to that in a deflocculated system
suspension. Sedimentation volume, F of a [37,40].
suspension is expressed by the ratio of the
equilibrium volume of the sediment, Vu to the 4.16 Redispersibility
total volume, Vo of the suspension. The following
formula is used: This test is applicable for pharmaceutical
suspension. If a pharmaceutical suspension
F = Vu/Vo produces sediment upon storage, it is essential
that it should be readily dispersible so that
The value of F normally lies between less than 1 uniformity of dose is assured. The amount of
to 1 or it may exceed 1 for any pharmaceutical shaking required to achieve this end should be
suspension. The larger the value, the better is minimal. Various redispersibility tests have been
the suspendability. The value of F provides a described. For example, the test suspension is
qualitative knowledge about the physical stability placed in a 100 ml graduated cylinder, which,
of the suspension (Table 5). after storage and sedimentation, is rotated
through 360° at 20 rpm. The endpoint is taken
Table 5. Physical stability of the suspension when the inside of the base of the graduated
based on F values [37,40] cylinder is clear of sediment. The ultimate test of
redispersibility is the uniformity of suspended
F values Comments drug dosage delivered from a product, from the
F=1 No sedimentation, no clear first to the last volumetric dose out of the bottle,
supernatant. under one or more standard shaking conditions
F = 0.5 50% of the total volume is [37].
occupied by sediment.
F=>1 Sediment volume is greater than 4.17 Zeta Potential
the original volume due to
formation of floccules which are This test is applicable for pharmaceutical
fluffy and loose. emulsion and suspension. The zeta potential of
emulsion droplets stabilized by a charged
Redispersibility of suspension is also importance. interfacial film is particularly useful or assessing
To help quantitates this parameter to some instability due to flocculation. It can be
extent, a mechanical shaking device may be determined by observing the movement of
used. It simulates human arm motion during the droplets under the influence of an electric current
shaking process and can give reproducible (electrophoretic mobility measurements), often
results when used under controlled conditions in conjunction with photon correlation
[37,40]. spectroscopy [38].

4.15 Degree of Flocculation 4.18 Rheology

This test is applicable for pharmaceutical This test is applicable for pharmaceutical
suspension. Degree of flocculation, ß is the ratio emulsion and suspension. The rheology of an
of the sedimentation volume of the flocculated emulsion is often an important factor in
suspension, F to the sedimentation volume of the determining its stability. Rheological properties of
deflocculated suspension, F∞. The following an emulsion system depend upon globule size,
formula is used: emulsifier and its concentration, phase volume
ratio etc. Any variation in droplet size distribution,
ß = F/F∞ degree of flocculation, or phase separation
ß = (Vu/Vo)/(V∞/Vo) frequently results in viscosity changes. Since
ß = Vu/V∞ most emulsions are non-Newtonian, the cone-
plate type device should be used to determine
The minimum value of ß is 1, this is the case their viscosity rather than the capillary
when the sedimentation volume of the viscometer. A practical approach for the
flocculated suspension is equal to the determination of creaming or sedimentation,
sedimentation volume of deflocculated before it becomes visibly apparent utilizes the

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 Uddin et al.; ACRI, 3(2): 1-12, 2016; Article no. ACRI.22675

Helipath attachment of the Brookfield viscometer must be absent in 1 g or 1 ml of the preparation

[37,39]. [31].

Most of the pharmaceutical suspension 4.20 Antimicrobial Effectiveness Testing

exihibit plastic or pseudoplastic characteristics
along with thixotropic properties. Rheological According to USP-NF the test can be conducted
properties of suspension depend on the either in 5 original containers if sufficient volume
degree of flocculation of the dispersed phase as of product is available in each container.
well as on the type and quantity of the Inoculate each container with one of the
suspending and thickening agent added to the prepared and standardized inoculum, and mix.
system. A practical rheological method involves The volume of the suspension inoculum used is
the use of the Brookfield viscometer mounted between 0.5 percent and 1.0 percent of the
on a Helipath stand. The T-bar spindle is volume of the product. For oral products other
made to descend slowly into the suspension, than antacids, made with aqueous bases or
and the dial reading on the viscometer is then a vehicles, the concentration of test
measure of the resistance the spindle meets at microorganisms that is added to the product are
various levels in a sediment. In this technique, such that the final concentration of the test
the T-bar is continually changing position and 5
preparation after inoculation is between 1 × 10
measures undisturbed samples as it advances 6
and 1 × 10 CFU per ml of the product. For
down into the suspension. This technique antacids made with an aqueous base the final
also indicates in which level of the suspension concentration of the test preparation after
the structure is greater, owing to particle inoculation is between 1 × 103 and 1 × 104 CFU
agglomeration, because the T-bar descends as per ml of the product [35].
it rotates, and the bar is continually
entering new and essentially undisturbed The initial concentration of viable
material. Infact the viscosity of the dispersion microorganisms in each test preparation is
medium of suspension is measured before estimated based on the concentration of
mixing with dispersed phase and also viscosity microorganisms in each of the standardized
after mixing is determined to ensure inoculum as determined by the plate-count
optimum viscosity of the medium so a method. Incubate the inoculated containers at
stable, re-dispersible suspension can be formed 22.5±2.5°C. Sample each container at the
[37,39]. appropriate intervals specified in Table 7. Record
any changes observed in appearance at these
4.19 Microbiological Test intervals. Determine by the plate-count
procedure the number of CFU present in each
Microbial contamination is determined by test preparation for the applicable intervals.
the total viable aerobic count, which is the Incorporate an inactivator (neutralizer) of the
sum of the bacterial count and the fungal specific antimicrobial in the plate count or in the
count. The tests allow quantitative enumeration appropriate dilution prepared for plating. These
of mesophilic bacteria and fungi that may conditions are determined in the validation study
grow under aerobic conditions. Membrane for that sample based upon the conditions of
filtration, plate count methods and most- media and microbial recovery incubation times
probable-number method are used for listed in Table 6. Using the calculated
determination of total viable aerobic count. concentrations of CFU per ml present at the start
According to IP the acceptance limit for this is not of the test, calculate the change in log10 values
more than 103 bacteria and not more than 102 of the concentration of CFU per ml for each
fungi per g or ml of the preparation. Test microorganism at the applicable test intervals,
for specified microorganisms such as and express the changes in terms of log
Escherichia coli contamination is also reductions [35].
determined. Growth of colonies indicates the
possible presence of E. coli. This is confirmed According to USP-NF the requirements for
by identification tests [30]. According to USP-NF antimicrobial effectiveness are met if the criteria
the product complies with the test if no colonies specified under Table 7 are met. No increase is
are present or if the identification tests are defined as not more than 0.5 log10 unit higher
negative [34]. As per IP E. coli contamination than the previous value measured [35].

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Table 6. Culture conditions for inoculum preparation [35]

Organism Suitable medium Incubation Inoculum Microbial recovery

temperature incubation incubation time
(°C) time (hours) (days)
Escherichia coli Soybean–Casein Digest 32.5±2.5 18 to 24 3 to 5
Broth; Soybean–Casein
Digest Agar
Pseudomonas Soybean–Casein Digest 32.5±2.5 18 to 24 3 to 5
aeruginosa Broth; Soybean–Casein
Digest Agar
Staphylococcus Soybean–Casein Digest 32.5±2.5 18 to 24 3 to 5
aureus Broth; Soybean–Casein
Digest Agar
Candida Sabouraud Dextrose 22.5±2.5 44 to 52 3 to 5
albicans Agar;
Sabouraud Dextrose
Broth
Aspergillus Sabouraud Dextrose 22.5±2.5 144 to 240 3 to 7
niger Agar; Sabouraud
Dextrose Broth

Table 7. Criteria for tested microorganisms [35]

Organism Category of products Acceptance limit

Bacteria Oral products other than Not less than 1.0 log reduction from the initial
antacids, made with count at 14 days, and no increase from the 14
aqueous bases or days count at 28 days.
Yeast and Molds vehicles. No increase from the initial calculated count at 14
and 28 days.
Bacteria, Yeast, Antacids made with an No increase from the initial calculated count at 14
and Molds aqueous base and 28 days.

5. CONCLUSION CONSENT

Quality control of pharmaceutical is very It is not applicable.

much important in pharmaceutical industry.
Physicians always need a good quality ETHICAL APPROVAL
pharmaceutical for treatment. Pharmacist and
It is not applicable.
pharmaceutical industry are responsible for
generating superior quality pharmaceutical. All ACKNOWLEDGEMENTS
the factors which contribute either directly or
indirectly to the purity, safety, effectiveness The authors wish to thank the Department of
potency, stability and reliability of the Pharmacy, Southeast University, Dhaka-1213,
pharmaceutical will be includes under the term Bangladesh.
quality. To achieve all these mentioned
characters there is need to undertake quality COMPETING INTERESTS
control from procurement of the raw materials to
the finished product until it gets consumed by the Authors have declared that no competing
patient as per pharmacopoeial standards and interests exist.
specifications. Although various pharmacopoeias
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