Formulation
Pharmaceutical formulation is the process in which different chemical substances,
including the active drug, are combined to produce a final medicinal product.
Formulation studies involve developing a preparation of the drug which is both
stable and acceptable to the patient. For orally taken drugs, this usually involves
incorporating the drug into a tablet or a capsule. It is important to appreciate that a
tablet contains a variety of other substances apart from the drug itself, and studies
have to be carried out to ensure that the drug is compatible with these other
substances.
Preformulation involves the characterization of a drug's physical, chemical, and
mechanical properties in order to choose what other ingredients should be used in
the preparation. In dealing with protein pre-formulation, the important aspect is to
understand the solution behavior of a given protein under a variety of stress
conditions such as freeze/thaw, temperature, shear stress among others to identify
mechanisms of degradation and therefore its mitigation.
Formulation studies then consider such factors as particle size, polymorphism, pH,
and solubility, as all of these can influence bioavailability and hence the activity of a
drug. The drug must be combined with inactive additives by a method which ensures
that the quantity of drug present is consistent in each dosage unit e.g. each tablet.
The dosage should have a uniform appearance, with an acceptable taste, tablet
hardness, or capsule disintegration.
It is unlikely that formulation studies will be complete by the time clinical trials
commence. This means that simple preparations are developed initially for use in
phase I clinical trials. These typically consist of hand-filled capsules containing a small
amount of the drug and a diluent. Proof the long-term stability of these formulations
is not required, as they will be used in a matter of days. Consideration has to be
given to what is called the drug load - the ratio of the active drug to the total
contents of the dose. A low drug load may cause homogeneity problems. A high drug
load may pose flow problems or require large capsules if the compound has a low
bulk density.
By the time phase III clinical trials are reached, the formulation of the drug should
have been developed to be close to the preparation that will ultimately be used in
the market. A knowledge of stability is essential by this stage, and conditions must
have been developed to ensure that the drug is stable in the preparation. If the drug
proves unstable, it will invalidate the results from clinical trials since it would be
impossible to know what the administered dose actually was. Stability studies are
carried out to test whether temperature, humidity, oxidation, or photolysis
(ultraviolet light or visible light) have any effect, and the preparation is analysed to
see if any degradation products have been formed.
It is also important to check whether there are any unwanted interactions between
the preparation and the container. If a plastic container is used, tests are carried out
to see whether any of the ingredients become adsorbed on to the plastic, and
whether any plasticizers, lubricants, pigments, or stabilizers leach out of the plastic
into the preparation. Even the adhesives for the container label need to be tested, to
ensure they do not leach through the plastic container into the preparation.
Excipients
An excipient is an inactive substance used as a carrier for the active ingredients of a
medication. In many cases, an "active" substance (such as aspirin) may not be easily
administered and absorbed by the human body; in such cases the substance in
question may be dissolved into or mixed with an excipient. Excipients are also
sometimes used to bulk up formulations with very potent active ingredients, to allow
for convenient and accurate dosage. In addition to their use in the single-dosage
quantity, excipients can be used in the manufacturing process to aid in the handling
of the active substance concerned. Depending on the route of administration, and
form of medication, different excipients may be used. For oral administration tablets
and capsules are used. Suppositories are used for rectal administration.
Often, once an active ingredient has been purified, it cannot stay in purified form for
long. In many cases it will denature, fall out of solution, or stick to the sides of the
container. To stabilize the active ingredient, excipients are added, ensuring that the
active ingredient stays "active", and, just as importantly, stable for a sufficiently long
period of time that the shelf-life of the product makes it competitive with other
products. Thus, the formulation of excipients in many cases is considered a trade
secret.
Pharmaceutical codes require that all ingredients in drugs, as well as their chemical
decomposition products are identified and guaranteed to be safe. For this reason,
excipients are only used when absolutely necessary and in the smallest amounts
possible.
Types of excipients
Antiadherents
Antiadherents are used to reduce the adhesion between the powder (granules) and
the punch faces and thus prevent sticking to tablet punches.
Binders
Binders hold the ingredients in a tablet together. Binders ensure that tablets and
granules can be formed with required mechanical strength, and give volume to low
active dosis tablets. Binders are usually starches, sugars, cellulose or modified
cellulose such as microcrystalline cellulose, hydroxypropyl cellulose, lactose, or sugar
alcohols like xylitol, sorbitol or maltitol.
Binders are classified according to their application:
Solution binders are dissolved in a solvent (for example water or alcohol and used in
wet granulation processes. Examples include gelatin, cellulose, cellulose derivatives,
polyvinylpyrrolidone, starch, sucrose and polyethylene glycol.
Dry binders are added to the powder blend, either after a wet granulation step, or as
part of a direct powder compression (DC) formula. Examples include cellulose,
methyl cellulose, polyvinylpyrrolidone, and polyethylene glycol.
Coatings
Tablet coatings protect tablet ingredients from deterioration by moisture in the air
and make large or unpleasant-tasting tablets easier to swallow. For most coated
tablets, a cellulose (plant fiber) film coating is used which is free of sugar and
potential allergens. Occasionally, other coating materials are used, for example
synthetic polymers, shellac, corn protein zein or other polysaccharides. Capsules are
coated with gelatin.
Changing the dissolution rates of active species
Enteric coatings control the rate of drug release and determines where the drug will
be released in the digestive tract.
Disintegrants
Disintegrants expand and dissolve when wet causing the tablet to break apart in the
digestive tract, releasing the active ingredients for absorption. Examples of
disintegrants include crosslinked polyvinyl pyrrolidone, sodium starch glycolate and
crosslinked sodium carboxymethyl cellulose (crosscarmellose).
Fillers and diluents
Fillers fill out the size of a tablet or capsule, making it practical to produce and
convenient for the consumer to use. By increasing the bulk volume, the fillers make
it possible for the final product to have the proper volume for patient handling.
A good filler must be inert, compatible with the other components of the
formulation, non-hygroscopic, soluble, relatively cheap, compactible, and preferably
tasteless or pleasant tasting.
Plant cellulose (pure plant filler) is a popular filler in tablets or hard gelatin capsules.
Dibasic calcium phosphate is another popular tablet filler. A range of vegetable fats
and oils can be used in soft gelatin capsules.
Other examples of fillers include: lactose, sucrose, glucose, mannitol, sorbitol,
calcium carbonate, and magnesium stearate.
Colours
Colours are added to improve the appearance of a formulation. Colour consistency is
important as it allows easy identification of a medication.
Glidants
Glidants are used to promote powder flow by reducing interparticle friction and
cohesion. These are used in combination with lubricants as they have no ability to
reduce die wall friction. Examples include colloidal silicon dioxide, talc, and etc.
Lubricants
Lubricants prevent ingredients from clumping together and from sticking to the
tablet punches or capsule filling machine. Lubricants also ensure that tablet
formation and ejection can occur with low friction between the solid and die wall.
Common minerals like talc or silica, and fats, e.g. vegetable stearin, magnesium
stearate or stearic acid are the most frequently used lubricants in tablets or hard
gelatin capsules.
Sorbents
Sorbents are used for tablet/capsule moisture-proofing by limited fluid sorbing
(taking up of a liquid or a gas either by adsorption or by absorption) in a dry state.
Freeze-Drying
Freeze-drying (also known as lyophilization or cryodesiccation) is a dehydration
process typically used to preserve a perishable material or make the material more
convenient for transport. Freeze-drying works by freezing the material and then
reducing the surrounding pressure and adding enough heat to allow the frozen
water in the material to sublime directly from the solid phase to gas.
There are three stages in the complete drying process: freezing, primary drying, and
secondary drying.
Freezing
The freezing process consists of freezing the material. In a lab, this is often done by
placing the material in a freeze-drying flask and rotating the flask in a bath, called a
shell freezer, which is cooled by mechanical refrigeration, dry ice and methanol, or
liquid nitrogen. On a larger-scale, freezing is usually done using a freeze-drying
machine. In this step, it is important to cool the material below its eutectic point, the
lowest temperature at which the solid and liquid phases of the material can coexist.
This ensures that sublimation rather than melting will occur in the following steps.
Larger crystals are easier to freeze-dry. To produce larger crystals, the product
should be frozen slowly or can be cycled up and down in temperature. This cycling
process is called annealing. However, in the case of food, or objects with formerly-
living cells, large ice crystals will break the cell walls (discovered by Clarence
Birdseye). Usually, the freezing temperatures are between −50 °C and −80 °C. The
freezing phase is the most critical in the whole freeze-drying process, because the
product can be spoiled if badly done.
Amorphous (glassy) materials do not have a eutectic point, but do have a critical
point, below which the product must be maintained to prevent melt-back or collapse
during primary and secondary drying.
Large objects take a few months to freeze-dry.
Primary drying
During the primary drying phase, the pressure is lowered (to the range of a few
millibars), and enough heat is supplied to the material for the water to sublimate.
The amount of heat necessary can be calculated using the sublimating molecules’
latent heat of sublimation. In this initial drying phase, about 95% of the water in the
material is sublimated. This phase may be slow (can be several days in the industry),
because, if too much heat is added, the material’s structure could be altered.
In this phase, pressure is controlled through the application of partial vacuum. The
vacuum speeds sublimation, making it useful as a deliberate drying process.
Furthermore, a cold condenser chamber and/or condenser plates provide a
surface(s) for the water vapour to re-solidify on. This condenser plays no role in
keeping the material frozen; rather, it prevents water vapor from reaching the
vacuum pump, which could degrade the pump's performance. Condenser
temperatures are typically below −50 °C (−60 °F).
It is important to note that, in this range of pressure, the heat is brought mainly by
conduction or radiation; the convection effect can be considered as insignificant.
Secondary drying
The secondary drying phase aims to remove unfrozen water molecules, since the ice
was removed in the primary drying phase. This part of the freeze-drying process is
governed by the material’s adsorption isotherms. In this phase, the temperature is
raised higher than in the primary drying phase, and can even be above 0 °C, to break
any physico-chemical interactions that have formed between the water molecules
and the frozen material. Usually the pressure is also lowered in this stage to
encourage desorption (typically in the range of microbars, or fractions of a pascal).
However, there are products that benefit from increased pressure as well.
After the freeze-drying process is complete, the vacuum is usually broken with an
inert gas, such as nitrogen, before the material is sealed.
At the end of the operation, the final residual water content in the product is around
1% to 4%, which is extremely low.
Properties of freeze-dried products
If a freeze-dried substance is sealed to prevent the reabsorption of moisture, the
substance may be stored at room temperature without refrigeration, and be
protected against spoilage for many years. Preservation is possible because the
greatly reduced water content inhibits the action of microorganisms and enzymes
that would normally spoil or degrade the substance.
Freeze-drying also causes less damage to the substance than other dehydration
methods using higher temperatures. Freeze-drying does not usually cause shrinkage
or toughening of the material being dried. In addition, flavours and smells generally
remain unchanged, making the process popular for preserving food. However, water
is not the only chemical capable of sublimation, and the loss of other volatile
compounds such as acetic acid (vinegar) and alcohols can yield undesirable results.
Freeze-dried products can be rehydrated (reconstituted) much more quickly and
easily because the process leaves microscopic pores. The pores are created by the
ice crystals that sublimate, leaving gaps or pores in their place. This is especially
important when it comes to pharmaceutical uses. Lyophilization can also be used to
increase the shelf life of some pharmaceuticals for many years.
Freeze-drying protectants and excipients
Similar to cryoprotectants, some molecules protect freeze-dried material. Known as
lyoprotectants, these molecules are typically polyhydroxy compounds such as sugars
(mono-, di-, and polysaccharides), polyalcohols, and their derivatives. Trehalose and
sucrose are natural lyoprotectants. Trehalose is produced by a variety of plant, fungi,
and invertebrate animals that remain in a state of suspended animation during
periods of drought (also known as anhydrobiosis).
Pharmaceutical companies often use freeze-drying to increase the shelf life of
products, such as vaccines and other injectables. By removing the water from the
material and sealing the material in a vial, the material can be easily stored, shipped,
and later reconstituted to its original form for injection.
In bioseparations, freeze-drying can be used also as a late-stage purification
procedure, because it can effectively remove solvents. Furthermore, it is capable of
concentrating substances with low molecular weights that are too small to be
removed by a filtration membrane.
Freeze-drying is a relatively expensive process. The equipment is about three times
as expensive as the equipment used for other separation processes, and the high
energy demands lead to high energy costs. Furthermore, freeze-drying also has a
long process time, because the addition of too much heat to the material can cause
melting or structural deformations. Therefore, freeze-drying is often reserved for
materials that are heat-sensitive, such as proteins, enzymes, microorganisms, and
blood plasma. The low operating temperature of the process leads to minimal
damage of these heat-sensitive products
