Pharmaceutical formulation

Pharmaceutical formulation, in pharmaceutics, is the process in which different chemical substances are combined to a pure drug substance 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.

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.

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Timeline

It is unlikely that these 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 (tested) 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.

Oral formulations

The way a drug is formulated can avoid some of the problems associated with oral administration.

Drugs are normally taken orally as tablets or capsules.

The drug (active substance) itself needs to be soluble in aqueous solution at a controlled rate. Such factors as particle size and crystal form can significantly affect dissolution. Fast dissolution is not always ideal. For example, slow dissolution rates can prolong the duration of action or avoid initial high plasma levels.

Tablet form

A tablet is usually a compressed preparation that contains:

• 5-10% of the drug (active substance);
• 80% of fillers, disintegrants, lubricants, glidants, and binders; and
• 10% of compounds which ensure easy disintegration, disaggregation, and dissolution of the tablet in the stomach or the intestine.

The disintegration time can be modified for a rapid effect or for sustained release.

Special coatings can make the tablet resistant to the stomach acids such that it only disintegrates in the duodenum as a result of enzyme action or alkaline pH.

Pills can be coated with sugar, varnish, or wax to diguise the taste.

Some tablets are designed with an osmotically active core, surrounded by an impermeable membrane with a pore in it. This allows the drug to percolate out from the tablet at a constant rate as the tablet moves through the digestive tract.

Capsule form

A capsule is a gelatinous envelope enclosing the active substance. Capsules can be designed to remain intact for some hours after ingestion in order to delay absorption. They may also contain a mixture of slow- and fast-release particles to produce rapid and sustained absorption in the same dose.

See also

• Medicinal chemistry
  • Drug discovery
  • Drug design
  • Drug development
  • Pharmaceutics
    • Drug delivery
    • Dosage form
      • Excipient
• tablet
• capsule
• pill