Lecture 15

The last thing we have talked about was the tableting process, and we have said there are two
modes of tableting, we have single press machine and the rotary machine and we are operating
with them both similarly in terms of phases of tableting. We have mentioned some of the
differences between them in terms of production rate and potential to have some sticky problems
and we have also mentioned that there are many advances for such machines including the
sensors made for the weight, this is the most important advancement for tableting machine to
have sensors and a mean to make measurements for the weight of the tablet once they are ejected
from filling process.

Some of the problems that can happen during tableting is the segregation tendency and this
happens during the filling stage, flow ability, compression properties and compact ability. How
the material is going to combine with each other, and sometimes there will be a compression
phase but after the ejection the tablet is going to fall apart so this is going to go to the properties
of the powder or the processing parameter. Thus if the tablet falls apart, then we cannot say that
the powder doesn’t have a potential to bind to each other, the powder could have a binding
capacity however, the force that I have applied is not enough or not applied for an enough
amount time. These problems can be evicted by certain sensors or variation by process
parameters.

Friction and adhesion properties also limit the process and powder quality. The powder can have
electrostatic interaction so it can have adhesion towards the punch faces or otherwise friction
from the metal of the punch we are using and this is why we use different grades of stainless
steel to ensure that they are inert and they don’t wear off during compression because there is
internal heat. Usually to avoid this process degrading problems with respect to the friction they
coat the punches with chrome which very efficient to prevent the wearing of the punches.

Sticking of tablets to each other; is not relevant to the process but to the tablet itself, because of
the moisture content and solute migration. If there is sticking of tablets it is called sticking or
picking, if they were two tablets stuck as pairs they refer to it as twinning.

Capping and lamination is relevant to the powder quality

Spray dryer; the cavity of the material will be filled with gaseous material (atmospheric air) and
as a result there is a potential that when compressing the material if there is not enough
compression there will be a chance for capping or lamination due to the entrapment of the air,
however this is less likely with spray dyer granules because they will be very brittle.

Capping and lamination occurs more likely in the filling stage when there archs form due to the
air and the bulk density is high not because of porosity but due to arch formation and this leads
to air entrapment in those powders, as a cavity the volume of the tablet/capsule is going to be
filled but the weight is going to vary.
Erosion is the loss of a certain mass.

Orange peel is for the tablet that has been coated. Orange peel can be the result of poor tablet
composition causing it to become soft.

We have talked about compression when taking place for tablets and there is two types of
compression the classical one and the direct compression. The direct compression is when the
powder that has been used has never been through a unit process of size enlargement. We have
said that direct compression is limited because it depends mainly on the properties of the powder
without needing of the granulation which is an essential unit operation, therefore there are a few
materials eligible for such a process and they are usually expensive.

A direct compression start with expensive raw materials that has guaranteed results with respect
to the binding of the powder, and one of unit processes has been eliminated. (Limited library of
materials that can have direct compression and it is more expensive)

In direct compression if you start with a material eligible for such a process you are going to
invest a high amount of money in the type of the material, but at the same time you have
eliminated the need of granulating step.

There are unit operations where you can have in the same machine drying, mixing and
granulation such as fluidized bed dryer, therefore it is not an issue since the machine is available
either way.

One of properties for tablets that have been produced by direct compression is that drug
dissolution is faster. The key word is that size enlargement is not induced.

When disintegration occurs in tablets produced by granulation their disintegration rate is

somehow slower than those produced by the small particles that are directly compressed.

In general,, even though granules when used alone their dissolution rate is good if they have a
good porosity, tablets that have recruited from powder that is directly compressed has a faster
dissolution rate and this is an added advantage for the drug if it is an immediate release dosage
form.

It is critical in direct compression to be aware of the uniformity of the ingredients present and to
avoid their segregation to ensure that all components are linked with each other; therefore it has a
limited applicability but has a final mass with proper mechanical strength that has been produced
without size enlargement.

Throughout our talk about properties of powder, its flow ability, the mixing and ensuring the
content uniformity and the weight uniformity, we have mentioned that we can have what we
referred to as processing aid. Those processing aid constituents or excipients exist in the table
30.1, those excipients sometimes have more than one property. As a rule, each ingredient that
 you need to include in your formulation, try to
include the ingredient that can have more than
one function for your formulation.

For example if you need a filler and a binder,

pick an excipient that can do both. The most
important thing for any pharmaceutical
preparation is for them to be non-irritating and
non-synthesizing, and this falls in the category
of safety, and in general since excipients are an
ongoing market. There are some excipients that
are generally regarded as a safe material, there is
no safety concern.

However, in according to the application of the

preparation they need to validate the safety
during the clinical study.

Non-synthesizing and non-irritating;

Synthesizing increase awareness, (for example

someone develops a new allergy not since
childhood). Cells in our body have sensors that
are proteins; their function is to transfer the
material that the cell needs and to distinguish
foreign material. If it is a foreign material the
sensors alert the immune system. In accordance
to your body, some people have allergies since
they were born.

Excipients should not cause irritation or

synthesis.

From range of ingredients to select in a

pharmaceutical preparation; it is advised to try
to select the minimum possible ingredients in order to avoid the concern for the irritation or
otherwise the synthesiziation.

Furthermore, when selecting the ingredients compatibility should be evaluated. We need the
excipients to be chemically compatible with other ingredients and they should not cause
degradation with respect to each other, and it has to be biocompatible.
In biocompatibility they study the metabolites as well, sometimes the drug itself is safe but their
metabolites are toxic which the products that result after metabolism are.

When submitting the drug, I need to ensure metabolites are safe and body can excrete them.

The first one of the excipients that is used is the filler or the diluent excipient. Those diluents or
fillers are used to enlarge the size of the final dosage form, and their main purpose is to enhance
the dosage form’s portability. You should be aware that diluent indicates that the concentration
may change, and thus the mixing may change as well. if you use a diluent as a non-functional
excipient and its purpose is to be portable with proper size for the patient to handle or otherwise
for the material to be packed, however this filler could affect mixing efficiency and you have to
investigate the mixing or size distribution after adding the material to your formulation.

What are the kinds of fillers available and what is the need for those fillers?

Fillers are needed for potent or non-potent drug as long as you are going to produce non-less
than 50 mg. if your material is less than 50 mg then it is a must to use the filler, and usually those
fillers are derived from carbohydrates and amongst those carbohydrates we have lactose.

Lactose is non-hydroscopic therefore it will not affect stability, it is readily soluble inside water
thus will immediately dissolute in the human body releasing the constituents, however the main
disadvantage is that some people suffer from lactose intolerance.

In the case of lactose intolerance, they use other excipients such as glucose, mannitol, or sorbitol.
Mannitol has negative latent heat of vaporization, therefore it is going to absorb all heat present
and endothermic action thus it will give a cold sensation. Therefore it is usually used in soreness
of throat, and is used for refreshment.

Minimum we need two components or more in drug, the API and excipient.

Most dangerous thing is to have an acidic material inside a medicine.

Pharmacophore is the one that induces the therapeutic effect.

For each active pharmaceutical ingredient there is one region responsible for binding to target
site and creating this response.

Overage is unethical and is used to maintain certain quantity of drug without affecting
concentration needed.

Overages are nothing but the extra quantity of material taken, which is lost during process stage.
in order to deliver the product with exact quantity(within limit) of API & excipient or Coating
material. It is to make sure to compensate for any expected weight loss as a function of powder
or granule transfer.
 The unethical use is that we know this drug is going to be degraded, and I need to have a certain
therapeutic window to induce a therapeutic response, therefore we need to make sure that for
example 10% of drug is going to be degraded so they increase the concentration of the drug
which is unethical, because they say that even with the metabolites the human body can deal
with those.