Guidance on Formulating Compressed Solids

There are a few products, such as some of the antihistamine tablets, in which the drug substance is applied during
the coating process. Other products require the active drug
substance to be applied as a dust on tacky tablets as part
of the coating process. For these products, it is particularly
important to apply the drug in the coating solution in many
controlled applications.
Again, it is important as part of the validation of these
processes to demonstrate dose uniformity and dissolution
and control the parameters of the coating process.

XVIII. EXCIPIENTS
Excipients are well defined in the official pharmacopoeia.
No specific pharmaceutical grades are specified in this book,
except where there is a specific reason to do so. However, it is known that different pharmacopoeia may have
different specifications, such as particle size, impurities,
moisture, etc. The harmonization of excipients, a global effort that is underway, would go a long way in making
the choice of excipients. The manufacturer is referred to
http://www.ipecamericas.org/index.html and the Handbook
of Pharmaceutical Excipients for further advice. A large number of proprietary excipients are widely used, such as AcR
R
R
R
R
Di-Sol
, Explotab
, Aerosil
, Ludipress
, Avicel
, etc.,
and many of these are now part of pharmacopoeias. There
is a significant advantage, though the cost is high, in using
these ingredients because they offer additional benefits, often reducing processing time. Additionally, the suppliers of
these ingredients are always willing to provide formulation
support and have large databases, particularly pertaining to
stability of drugs, that may be of great value to manufacturers. The following sections (AF) list the most commonly
used excipients in compressed solids.

A. Coating Agent
Carboxymethylcellulose, sodium cellacefate (formerly cellulose acetate phthalate), cellulose acetate, cellulose acetate phthalate (see cellacefate), ethylcellulose, ethylcellulose
aqueous dispersion gelatin glaze, pharmaceutical hydroxypropyl, cellulose hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate (see hypromellose phthalate), hypromellose phthalate (formerly hydroxypropyl
methylcellulose phthalate), methacrylic acid copolymer,
methacrylic acid copolymer dispersion, methylcellulose PEG,
polyvinyl acetate, phthalate shellac sucrose, titanium dioxide
wax, carnauba wax, microcrystalline zein.

B. Glidant
Calcium silicate, magnesium silicate, silicon dioxide, colloidal talc.

C. Tablet Binder
Acacia alginic acid carboxymethylcellulose, sodium cellulose, microcrystalline dextrin ethylcellulose gelatin glucose,
liquid guar gum hydroxypropyl methylcellulose, methylcellulose polyethylene oxide povidone starch, pregelatinized
syrup.

D. Diluent
Calcium carbonate, calcium phosphate, dibasic calcium phosphate, tribasic calcium sulfate cellulose, microcrystalline
cellulose, powdered dextrates, dextrin, dextrose, excipient,
fructose, kaolin, lactitol, lactose, mannitol, sorbitol, starch,

67

pregelatinized sucrose, sugar, compressible sugar, confectioners sugar.

E. Disintegrant
Alginic acid cellulose, microcrystalline croscarmellose
sodium, crospovidone polacrilin, potassium, sodium starch,
glycolate starch, starch, pregelatinized.

F. Lubricant
Calcium stearate, glyceryl behenate, magnesium stearate,
mineral oil, light PEG, sodium stearyl fumarate stearic acid,
stearic acid, purified talc, vegetable oil, hydrogenated type I
zinc stearate.
The choice of excipients is made based on three distinct
considerations:

r Compatability with the active drugMany excipients

have active functional groups that can interact with the
active drug and enhance its degradation. Even the water
of hydration or moisture in the excipients can create difficulties in solid-state degradation of the active drug; so, it is
not only the selection of the ingredient but also the grade
(such as anhydrous or hydrous) that is important.
r Effect on efficacyExcipients are known to alter the release patterns (e.g., a strong binder would delay break up
of the tablet) and often bind the drug molecules in the gastrointestinal tract. The evaluation should be made in the
full composition of ingredients because the presence of two
ingredients may change their individual characteristics.
r Cost of formulationEven though excipients contribute a
small cost of the total formulation, the declining cost of
APIs makes the selection of excipients based on cost an
important consideration. This is particularly true when
generic manufacturers are filing ANDAs knowing well
that they will compete on a price basis. However, the total cost of formulation should not only be calculated on
the basis of excipients. Often, the use of expensive excipients reduces process time, eliminates certain process
steps, and even allows for the use of a cheaper packaging material. The manufacturer must, therefore, calculate
the overall manufacturing cost. This aspect of formulation
creates unique considerations by the multinational companies doing business worldwide; they are often forced to
develop alternate formulations depending on the availability of excipients, manpower cost, and local environmental
considerations.
The rule of thumb in the selection of excipients
remainskeep it simple and at the bare minimum. The goal
of excipients selection should be clearly definedthe dosage
form yielding to a solution form at a predetermined rate (not
necessarily the fastest in all instances).
The formulations described in this volume provide a
quantitative listing of excipients recommended. An astute
formulator would know the need to alter their quantity based
on the type of equipment used to process them, the size of the
batch processed at one time, and the quality of compressed
product obtained. Therefore, all quantitative listings of excipients must be considered the best starting point, which can
be adjusted and optimized, if necessary. In many instances, a
range of excipients is allowed, such as in the case of a binder
solution, to yield a suitable mass (as it is often described in
the formulation of wet massing).
Where exact quantities of excipients are not available,
but the excipients are identified for an innovators product, this is still a better starting point than establishing
the choice of excipients. Knowledge of the physicochemical

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Handbook of Pharmaceutical Manufacturing Formulations: Compressed Solid Products

characteristics of the API takes a more pivotal role when the

information available is limited. Obviously, one can readily
identify the role of the identified, but not quantified, excipients. Some experimentation is required. However, as provided throughout this volume, significant knowledge can
be gained by benchmarking the formulation. Other similar
drugs or excipients should provide a good clue of the starting quantities. It is noteworthy that in obtaining the copies of
competitor NDAs, through the Freedom of Information Act,
some quantities are often redacted, leaving the formulator to
guess. However, this should not be a difficult step, as long as
the quantities of excipients chosen provide a similar weight,
thickness, and disintegration and dissolution characteristics.
A common practice by innovator companies, as the
NCE gets closer to the patent term expiry, is to patent a variety
R
of formulations; for example, in the case of Aug-mentin
, the
innovator chose to patent a different combination of amoxicillin and clavulanic acid and developed a composition for
pediatric therapy. The purpose of this exercise is to keep
generic competition out; the generic product in some cases
may be the same, but not exact. The patent-end changes may
also include changes in specification, choice of solvent systems used, or other cosmetic changes. However, a generic
manufacturer would do well by just following the original
formulation (for obvious reasons of regulatory compliance)
because this has withstood the test of time. The author recommends that no changes should be made to an otherwise
working formula, albeit this may improve processing, until
such a time that the generic manufacturer has sufficient experience with the product. Most unusual things can happen
when unsuspecting changes, appearing benign at the surface,
are made to proven formulas. Given the cost of bioequivalence study requirements for compressed solids, changes in
formulation should not be made unless essential and, even
then, only for compliance purposes.

XIX. DIRECT COMPRESSION

The technology involved in direct compression assumes great
importance in the tablet formulations, because it is often the
cheapest means, particularly in the production of generics,
that the active substance permits. The limiting factors are the
physical properties of the active substance and its concentration in the tablets. Even substances such as ascorbic acid
that are hardly suitable for direct compression, owing to the
friability of their crystals, can normally be directly pressed
into tablets at concentrations of 30% to 40%. However, this
technique is not as suitable if the content of ascorbic acid is
higher. This limit may be shifted upward by special direct
compression auxiliaries, for example Ludipress. Two important alternatives, viz. Ludipress grades and Kollidon VA 64,
can be found in the BASF line of pharmaceutical excipients
for direct compression.
Ludipress is a speciality derived from lactose, Kollidon
30, and Kollidon CL. It thus combines the properties of a filler,
binder, disintegrant, and flow agent and also often acts as a
release accelerator. By virtue of its versatility, formulations
containing it are usually very simple. It can also be combined
with almost all active substances with the exception of those
that enter into a chemical interaction with lactose (Maillard
reaction).
Active substances, for example many analgetics, behave very differently with Ludipress when the dosage is
extremely high. Acetylsalicylic acid and metamizole can be

pressed when little Ludipress has been added; ibuprofen requires a larger amount; and the fraction of Ludipress required
in the tablets is too large for paracetamol ( = acetaminophen).
An alternative to the Ludipress grades is the outstanding dry binder Kollidon VA 64 together with excipients, for
example calcium phosphate, microcrystalline cellulose, lactose, or starch, and a disintegrant, for example Kollidon CL.
This combination even allows 500 mg of paracetamol to be
pressed into good tablets with a weight of 700 mg.
No other dry binder has a binding power and plasticity
comparable to those of Kollidon VA 64. Plasticity, in particular, is an important parameter in direct compression. This
property of Kollidon VA 64 is not adversely effected by increasing the pressure. The beneficial properties of Kollidon
VA 64 can also be exploited for the production of concentrated
active substance that is subsequently used for direct tabletting. Kollidon VA 64 and Ludipress can also be combined
with one another.

XX. FILL WEIGHTS

Fill weights are provided in all formulations. These may not
coincide with scale for many reasons, as described elsewhere:
differences in the salt forms, hydrates, or overages added
in manufacturing and also to provide the extra margin of
variation in filling during fast compression operations.

XXI. FINAL PACKAGING

A formulation design does not end with assuring that good
tablets are formed; it must allow for handling during packaging, such as sliding into blister sheets or dropping into
bottles. Actual fill runs must be conducted, and then the finished product must be subjected to simulated, and finally,
the actual rigors of shipping before finalizing a formulation.
Know that during shipping, the product may be exposed to
diverse and often harsh weather conditions. Silica gel is often
placed in the finished packs, or cotton is inserted, mainly to
provide moisture or absorb odor (in the case of cotton).

XXII. FINAL TESTING

Finished product testing, particularly assay, content uniformity, and dissolution, is required. In the review of dissolution test results, it is important to eventually see results close
to 100% dissolution. In some cases, manufacturers profile
the dissolution results only to the specification. However, if
lower but still acceptable results are obtained (such as 85%),
it is important to continue the test. This can be performed
by increasing the speed of the apparatus. If a product completely dissolves, yet only results in a value of 85%, it may
indicate some problem with the test. Likewise, high dissolution results (115%) also indicate some problem with the test.
Obviously, unusual or atypical results should be explained in
the validation report.

XXIII. FINES
Solids, when grinded to small particle sizes (as when passing
through sieves or crushing granules), yield a distribution of
various particle sizes. A certain amount of very fine particles,