Tablet Excipients

• Tablets usually contain materials in addition to the

active ingredient.
• All "nondrug" materials of the formula are called
excipients.
• Excipients are necessary for the following reasons:
1. Some drugs have small doses that cannot be
compressed alone, e.g., Digoxin 0.25 mg.
2. Some drugs have poor compressibility and
flowability that cannot be compressed alone (e.g.
Metformin).
3. If the tablets are compressed alone, è they will
not disintegrate or disintegrate very slowly (è Typical Tablet content
excipients help in disintegration and dissolution).
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MUC- School of Pharmacy- Industrial Pharmacy II - 5th stage. - Fall 2022 Mohammed A. Albarki, PhD

Tablet Ingredients (From Lec. 1)

• Properties of tablet ingredients:
1. Nontoxic and legal in the countries where the product is to be marketed.
2. Must be commercially available.
3. Reasonable cost.
4. Must not be contraindicated by themselves (e.g. sucrose) or because of the
component (e.g. sodium) in any segment of the population.
5. Must be physiologically inert (for excipients)
6. Must be physically and chemically stable themselves or in combination with the
drugs(s) and other tablet component.
7. Free of unacceptable microbiological contaminations.
8. Must be color compatible (must not produce any off-color appearance).
9. Must not alter bioavailability (for excipients)
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MUC- School of Pharmacy- Industrial Pharmacy II - 5th stage. - Fall 2022 Mohammed A. Albarki, PhD
 Types of Excipients
• The main excipients used in tablet
formulation are:
1. Diluents (fillers) such as lactose,
starch, and microcrystalline cellulose.
2. Binders (granulating agents) such as
starch, acacia, and gelatin.
3. Disintegrants such as starch, and super
disintegrant.
4. Lubricant, Antiadherent, Glidants
such as magnesium stearate and
stearic acid.
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MUC- School of Pharmacy- Industrial Pharmacy II - 5th stage. - Fall 2022 Mohammed A. Albarki, PhD

Diluents (Fillers)
• Diluents are materials used to make up the required bulk of the tablet when the drug
itself is inadequate to provide this bulk.
• Occasionally, the active ingredient has a large dose and good compressibility so that it
does not need diluent, e.g., aspirin and some antibiotics.
• However, most tablets need a diluent.
• Round tablets are usually in the size range of 5-13 mm. Tablets below 5mm may be
difficult for the elderly to handle and those larger than 13 mm become difficult to
swallow.
1. Diluents are therefore used to formulate the tablets within the desired size range.
2. Diluent also can have a secondary advantage which is to provide better tablet
properties such as improved cohesion or to promote flow.
• There are large numbers of diluents and the following are examples of them:
• Lactose, Starch, Dextrose, Mannitol, Sucrose, Microcrystalline Cellulose
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MUC- School of Pharmacy- Industrial Pharmacy II - 5th stage. - Fall 2022 Mohammed A. Albarki, PhD
 Lactose
• The most widely used diluent in tablet formulation has no reaction
with most drugs.
• There are three forms of lactose available( anhydrous, hydrous, and
spray-dried).
• Anhydrous lactose has an advantage over the other two types; on
aging, it does not undergo discoloration (brown discoloration,
Maillard reaction) with amines and alkali compounds.
• The anhydrous lactose may pick up moisture from the environment
when exposed to elevated humidity and convert to the hydrous form.
• èThese Tablets should be carefully packaged to prevent moisture
exposure.
• When wet granulation is used for the production of tablets, the
hydrous form is usually used.
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MUC- School of Pharmacy- Industrial Pharmacy II - 5th stage. - Fall 2022 Mohammed A. Albarki, PhD

Lactose
• In general, all lactose types show the following advantages:
1. Good drug release.
2. In granulations, granules are easily dried.
3. The disintegration time of lactose-containing tablets is not very sensitive to
variations in tablet hardness.
4. Low cost.
5. Has no reaction with most drugs.
• Disadvantages: Hydrous form undergoes discoloration when used with alkali or
amine-containing compounds
Note: The other type of lactose is:
• Spray-dried lactose is used for direct compression due to its good
compressibility and flowability.
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MUC- School of Pharmacy- Industrial Pharmacy II - 5th stage. - Fall 2022 Mohammed A. Albarki, PhD
 Starch
• It may be derived from different sources such as corn, wheat, or potatoes.
• Great care should be taken when using starch in the formula because it can be
used as diluent, binder, or disintegrant depending on:
1. Type of starch: the useful type for a particular formula can be known by
experts.
2. The amount used: it is used as a diluent in the ratio of 50-60%, binder in the
ratio of 2-10%, and disintegrant in the ratio of 5-20%.
3. Stage of addition: it is used as a diluent when added in the dry form at the
beginning of the procedure (mixing step), a binder when used as a paste in the
preparation of the wet mass step, and disintegrant when added finally after
granulation as a dry form.
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MUC- School of Pharmacy- Industrial Pharmacy II - 5th stage. - Fall 2022 Mohammed A. Albarki, PhD

Other Diluents
Dextrose: It is available in two forms: hydrous and anhydrous.
• Dextrose is sometimes used in the formulas to replace some of the lactose to
minimize the discoloration (when used with alkaline compounds).
Mannitol:
• It is widely used in chewable and orodispersible tablets because of its sweet taste
(sugar) pleasant feeling in the mouth (due to the negative heat of solution), and slow
solubility.
• It is non-hygroscopic so can be used safely in water-sensitive formulations like
vitamin formulations.
• However, it is somewhat expensive, has poor flow, and requires a high lubricant
level.
Sucrose: It is used sometimes in tablet formulations.
• In general, sucrose and sucrose-based diluents are avoided by some manufacturers
due to their effect on diabetic patients.
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MUC- School of Pharmacy- Industrial Pharmacy II - 5th stage. - Fall 2022 Mohammed A. Albarki, PhD
 Diluents
Microcrystalline cellulose:
• It is often referred to by the trade name Avicel®.
• Different grades of Avicel are available such as PH 101 (powder) and PH 102 (granules).
• It is a multipurpose excipient used as a diluent and disintegrant.
Advantages:
• It is inert and can be used with alkaline or acidic substances (No discoloration).
• Has high purity and low moisture content.
• Avicel is a directly compressible diluent due to its good compressibility and
flowability.
• Avicel-containing tablets are characterized by short disintegration time, high hardness,
low friability, and low weight variation. (Why?)

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MUC- School of Pharmacy- Industrial Pharmacy II - 5th stage. - Fall 2022 Mohammed A. Albarki, PhD

Binders (Granulating agent)

• They are substances that bind the particles together to form granules (in wet and dry
granulation) or to promote the formation of cohesive compacts (in Direct compression).
Below are some examples:
Acacia and tragacanth:
• Natural gums. These materials are more effective when added as a solution than if they
are used as powders.
Disadvantages:
• They are variable in their composition (why?) and performance according to their origin.
• They are also easily contaminated by bacteria.
Gelatin:
• Synthetic protein is preferred over acacia and tragacanth and is also easier to prepare in
solution than the two gums. However, bacterial growth is also troublesome.
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MUC- School of Pharmacy- Industrial Pharmacy II - 5th stage. - Fall 2022 Mohammed A. Albarki, PhD
 Binders
Starch:
• One of the most commonly used granulating agents (binder) and used as a
paste.
• It is prepared by dispersing starch into water which is then heated for a certain
time in order to induce starch hydrolysis into dextrin and glucose.
• A properly made paste is translucent rather than clear (which indicates
complete conversion to glucose).
Modified Natural Polymers:
• Common and important binders. Alginates (e.g., sodium alginates) and
cellulose derivatives (e.g., methylcellulose (MC), ethyl cellulose (EC),
hydroxypropyl cellulose (HPC) and hydroxypropyl methylcellulose
(HPMC)) are examples of these binders.
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MUC- School of Pharmacy- Industrial Pharmacy II - 5th stage. - Fall 2022 Mohammed A. Albarki, PhD

Binders
• Modified Natural Polymers (continue):
• Except for EC, all of the cellulose derivatives can be used as dry powders (in
Direct compression and dry granulation) and as an aqueous solution (in wet
granulation).
• HPC can also be used as an alcoholic solution, thus it is useful for water-sensitive
drugs.
• EC is used only as an alcoholic solution because it is insoluble in water, therefore
it may retard tablet disintegration.

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MUC- School of Pharmacy- Industrial Pharmacy II - 5th stage. - Fall 2022 Mohammed A. Albarki, PhD
 Disintegrants
• A disintegrant is a substance that facilitates the breakdown of the tablet into smaller
fragments upon contact with GI fluids. (https://youtu.be/s5aGmUQIzSs )
• The function of the disintegrant is to oppose the effect of the tablet binder and the
physical force that is applied during the compression process.
• The disintegrants act by drawing water into the tablet, swelling and rupturing the tablet.
• This tablet fragmentation is critical to the subsequent dissolution of the drug and to
achieve satisfactory bioavailability.
• Disintegrants may added at two stages: during the formation of granules (to give
intragranular action) and at the second mixing stage during compaction of granules into
tablets (extragranular).

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MUC- School of Pharmacy- Industrial Pharmacy II - 5th stage. - Fall 2022 Mohammed A. Albarki, PhD

Disintegrants
Starch
• The most commonly used disintegrants because of their low cost. It is used in
the ratio of 5-20% of the tablet weight.
• Starch has the property of rapid water uptake and swelling that leads to the
rupture of the tablet due to the increase in internal pressure.
Super Disintegrant:
• They are so-called due to their powerful disintegrating action. Examples of these
materials are sodium starch glycolate (Explotab®), croscarmellose sodium, and
crospovidone (Kollidon CL).
• They are very potent if compared with the classic disintegrants. For example,
croscarmellose sodium swells to 900% of its original volume in acidic media
while starch swells to 25% only in the same media. They are used when rapid
disintegration is required such as in orodispersible tablets.
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MUC- School of Pharmacy- Industrial Pharmacy II - 5th stage. - Fall 2022 Mohammed A. Albarki, PhD
 Lubricants, Antiadherent, and Glidants
• Lubricants:
• They are materials used to reduce the friction during
tablet ejection between the tablet and the walls of the die
cavity in which the tablet was formed.
• Antiadherents:
• Reduce sticking of tablet granules to the faces of the
bunches or to the die wall
• Glidants:
• They are used to promote the flow of granules or
powders by reducing the friction between the particles
themselves.
• Glidants are thought to work by filling irregularities in
granules making them more round and reducing friction
between granules.
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MUC- School of Pharmacy- Industrial Pharmacy II - 5th stage. - Fall 2022 Mohammed A. Albarki, PhD

Lubricants
• Advantages of lubricants
1. Facilitate tablets’ ejection and prevent their sticking in the die.
2. Prolong the life of the die.
3. Decrease the liberated heat (friction heat). +
• Mechanism of action of the lubricants
1. Fluid lubrication (Hydrodynamic (formation of thin film)): this +-
Die wall

mechanism is used to explain the action of liquid lubricants.

• In general, all liquids (especially oily ones) decrease the friction between +-
two surfaces.
• Example: Mineral oils such as liquid paraffin have been applied on the +-
granules as a fine spray. -
• However, the problem with using this type of lubricant is the production
of oil spots.
• Another problem is that the particle surface will be hydrophobic and the
tablet may have a slower dissolution rate è may alter bioavailability. 18
MUC- School of Pharmacy- Industrial Pharmacy II - 5th stage. - Fall 2022 Mohammed A. Albarki, PhD
• Mechanisms of lubricants (continue):
2. Boundary lubrication: this mechanism is used for solid
lubricants.
• In this type, the polar portion (such as –OH, –NH2) of
the lubricant is attached to the metal and prevents the
tablet from sticking to the die.

• The lubricants should be added in the last step (just before

compression) since they must be present on the surface of
the granules and not between them.

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MUC- School of Pharmacy- Industrial Pharmacy II - 5th stage. - Fall 2022 Mohammed A. Albarki, PhD

Notes About Lubricants

1. The particle size of the lubricants is crucial; they should be 200 mesh
in size or finer.
• As a general rule, as the particle size of the lubricants increases,
their efficacy decreases.
2. The amount of the lubricant in the formula should not exceed 1% (for
most lubricants) and this is due to the following problems that can
happen with increasing lubricant amount:
• These materials are water-insoluble and present on the surface of
the granules, thus retard water penetration and decrease dissolution
rate and may alter bioavailability.
• Adding excess lubricants will result in the hydrocarbon portion
covering the whole surface of the tablet and the interaction between
particles will be replaced by the interaction of hydrocarbons which
is weaker and thus the tablet structure is weakened.
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MUC- School of Pharmacy- Industrial Pharmacy II - 5th stage. - Fall 2022 Mohammed A. Albarki, PhD
 Lubricants
3. The mixing time of the lubricant with the formula should be 2-5 min.
• Over-mixing decreases the lubricant efficacy because it causes the penetration
of the lubricant from the surface to the core of the formula.
4. The mixing rate is also important; a high mixing rate causes the penetration of
the lubricant inside the core of the formula and thus, decreases the lubricant’s
efficacy.
• Examples of the commonly used lubricants:
• Magnesium or calcium stearate are the most widely used lubricants due to
their efficacy. These lubricants should not be used with acidic drugs like
aspirin (due to pH-induced hydrolysis ).
• Stearic acid is less effective than its magnesium and calcium salts. It should
not be used with alkaline drugs.
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MUC- School of Pharmacy- Industrial Pharmacy II - 5th stage. - Fall 2022 Mohammed A. Albarki, PhD

Lubricants and Glidants

• Zinc stearate is inert with good lubricating properties and small particle size. It
is used effectively in direct compression.
• Talc may also be used as a lubricant. Problem: it does contain a trace amount of
iron, so it should be applied carefully in any formulation containing a drug whose
breakdown is catalyzed by the presence of iron.

• Regarding the glidants, they are less commonly used than the lubricants.
Examples of these materials are talc and Aerosil®.

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MUC- School of Pharmacy- Industrial Pharmacy II - 5th stage. - Fall 2022 Mohammed A. Albarki, PhD
 Colorant
• These materials are used for the following reasons:
1. Product identification.
2. The production of more elegant products.
3. To hide undesirable properties. For example, vitamin C undergoes oxidation that
causes brown discoloration, therefore vitamin C tablets are usually colored with
yellow or red color.
• Types of colorants
1. Natural colorants: are not preferred because they are limited (few colors are
available) and unstable.
2. Dyes: are synthetic colorants applied as solution. They are dissolved in the granulating
solution. When using water-soluble dyes, care should be taken to prevent their
migration during the drying process.
3. Lakes: they are powders, insoluble in water mixed with the formula (as powder), and
compressed with the tablet toth give the desired color. 23
MUC- School of Pharmacy- Industrial Pharmacy II - 5 stage. - Fall 2022 Mohammed A. Albarki, PhD

Flavors
• They are usually limited to chewable tablets or other tablets intended to dissolve
in the mouth to mask the undesirable taste.
• It is usually added in the percent of 0.5-0.75%.
• There are different types of flavors:
1. Water soluble flavors: they are not preferred due to their poor stability.
2. Oily flavors: they dissolved in a suitable solvent and mixed with the binder
solution. It is important that such flavors should tolerate the subsequent drying.
3. Dry flavors: these are dry powders blended with the formula.

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MUC- School of Pharmacy- Industrial Pharmacy II - 5th stage. - Fall 2022 Mohammed A. Albarki, PhD
 Sweeteners
• They are also used in mouth tablets.
• Sucrose is not used commonly due to its effect on patients with diabetes.
• Mannitol which is about 72% as sweet as sucrose can be used.
• Synthetic sugars such as saccharine are also used. This material is about 500
times sweeter than sucrose. However, it has the disadvantage of bitter aftertaste
and it is reported to be carcinogenic on large doses.
• Aspartame is another synthetic sugar and is more preferred than saccharine. Its
disadvantage is that it has poor stability in the presence of moisture.

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MUC- School of Pharmacy- Industrial Pharmacy II - 5th stage. - Fall 2022 Mohammed A. Albarki, PhD

Tablet Design and Formulation

• Generally, tablet formulation
consists of the following main
processes:
1. Weighing.
2. Granulation.
3. Milling and mixing.
4. Compression.
• Three types of tablet manufacturing
process:
1. Wet Granulation.
2. Dry Granulation.
3. Direct compression.
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MUC- School of Pharmacy- Industrial Pharmacy II - 5th stage. - Fall 2022 Mohammed A. Albarki, PhD
 Mixing
• A crucial step in the formulation of the pharmaceutical dosage
form.
1. Mixing allows uniform distribution of tablet constituents
throughout the formulation
2. Allows for adequate distribution of lubricants around
tablet granules.
• Undermixing will probably lead to impaired content
uniformity of tablet formulation and poor flow properties
• Over-mixing will lead to other tablet manufacturing problems
such as poor flow properties due to lubricants entering into the
tablet granules instead of staying on the surface. V- Shape Mixer
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MUC- School of Pharmacy- Industrial Pharmacy II - 5th stage. - Fall 2022 Mohammed A. Albarki, PhD

Granulation
• Fine powder drug mostly has poor flow properties.
• Granules have:
1. Better flowability than individual ingredients
2. Better compressibility than individual ingredients.
3. It ensures the consistent spread of API in the formulation.

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MUC- School of Pharmacy- Industrial Pharmacy II - 5th stage. - Fall 2022 Mohammed A. Albarki, PhD
 Wet Granulation (used liquid binder)
• Most common; Contains more steps but
is relatively easier to control and
compress.
• Active ingredients plus excipients are
mixed together then a binder (binding
liquid) is added to a rapid mixer
granulator (machine)
• Granules are then dried and milled to
the required size range
• Then mix with lubricant and compress

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MUC- School of Pharmacy- Industrial Pharmacy II - 5th stage. - Fall 2022 Mohammed A. Albarki, PhD

Dry Granulation
1. Used when there is a limitation for using a
granulating solution such as the interaction
between the active ingredient and the solution
2. Also in cases when the drug is sensitive to heat.
• Drug powder and inactive ingredients are mixed
together and passed through a powder roller
compactor machine to produce slugs.
• This process is called slugging
• Slugs undergo milling and screening to get the
desired particle size
• Examples are vitamin formulations
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MUC- School of Pharmacy- Industrial Pharmacy II - 5th stage. - Fall 2022 Mohammed A. Albarki, PhD
 Direct Compression
• A special case of tablet formulation.
• No granulation step; only mixing ingredients and excipients and compressing
directly.
• It requires certain properties of the active ingredients to be able to produce a good
tablet:
1. Crystalline in nature.
2. Components are easy to compress.
• Sodium chloride, potassium salts of iodide, or chloride tablets can be done using
this method.
• Limitation: Most materials have weak intermolecular interaction attraction that
tends to hinder compaction.
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MUC- School of Pharmacy- Industrial Pharmacy II - 5th stage. - Fall 2022 Mohammed A. Albarki, PhD

Direct Compression
• Advantages of Direct Compression:
1. Simple, low labor input and hence economic.
2. Being a dry process, the risk of deterioration of the active ingredient is
decreased.
3. Tablets will disintegrate onto their primary particles rather than granular
aggregates à the resultant increase in surface area available for dissolution
should result in faster drug release.

• Note: in recent years and due to the development in machine technology and
discovery of new excipients; this method is being used increasingly, especially for
a drug that is effective in a very low dose because this method ensures “better”
content uniformity than others 32
MUC- School of Pharmacy- Industrial Pharmacy II - 5th stage. - Fall 2022 Mohammed A. Albarki, PhD
• Disadvantage or limitation of D.C.:
1. Differences in particle size and bulk density between the drug and diluent may
lead to stratification within the granulation à may result in poor content
uniformity of the drug in the compressed tablet.
2. A large-dose drug may present problems with direct compression if it is not easily
compressible by itself. Because most drugs have low intermolecular forces and
need other materials to increase interaction between molecules.
3. In some instances, the direct compression diluent may interact with the drug à
may lead to problems such as discoloration.
4. Because of the dry nature of direct compression, static charge buildup can occur
on the drug during routine screening and mixing which may prevent a uniform
distribution of the drug in the granulation.
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MUC- School of Pharmacy- Industrial Pharmacy II - 5th stage. - Fall 2022 Mohammed A. Albarki, PhD

Compression
• The final step is tablet formulation.
• Required a set of variables to be evaluated which are beyond the scope of this
class.

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MUC- School of Pharmacy- Industrial Pharmacy II - 5th stage. - Fall 2022 Mohammed A. Albarki, PhD
 Tablet Compression Machine
1. Hopper(s) for holding and feeding tablet components.
2. Dies that define the size and shape of the tablet.
3. Punches for compressing the granulation within the
dies.
4. Cam tracks to guide the movement of the punches.
• Note: there are various auxiliary equipment designed to
aid in tablet production such as automatic feeders,
deduster (beyond the scope of this class)

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MUC- School of Pharmacy- Industrial Pharmacy II - 5th stage. - Fall 2022 Mohammed A. Albarki, PhD