Solubility

- If water solubility is low, then the formulator will also examine:

- The effect of solubilising agents on solubility. Selection of the optimum dissolution enhancer for a formulation can improve dissolution rate

- The properties of solid dispersions of the drug. For example Abbott Labs have published information on the properties of ritonavir in solid dispersions²⁸.

Formulation as soft gelatin capsules containing a fatty matrix is an alternative for low dose actives.

pka

pKa indicates how solubility will change with pH.

Polymorphic form

If polymorphs of the active exist, it is important to ensure that batches of the API are always of the optimum polymorphic form. See below for more information and a relevant example.

Stability

- The effect on the API of heat, light, moisture, oxidative conditions, and altered pH
- Compatibility of the API with potential excipients

Polymorphic form

Polymorphism is the ability of a substance to exist as more than one type of crystal, each crystal having a different internal arrangement of molecules. The different types of crystal can have different physicochemical properties such as melting point and, significantly for pharmaceuticals, the rate at which the substance dissolves in a solvent. Because biological environments are aqueous in nature, polymorphism is generally most relevant for drugs that have low water solubility and for which bioavailability may dissolution-limited.

During chemical synthesis, the conditions of final purification (usually recrystallisation or slurrying) largely dictate the final polymorphic form. The nature of the solvent and the rate and temperature of crystallisation are particularly important. Once the most suitable polymorph has been identified, purification conditions can be adjusted so as to produce it more reliably.

Some polymorphs are physically unstable and can metamorphose into another polymorph, thus providing a mechanism by which the dissolution rate of a finished product can change over time.

It is important to know the polymorphic forms in which a substance can exist, the stability of each, and how they can be distinguished during quality control, in order to ensure that the API (the raw material form of the drug) is always presented for use in manufacture in the most suitable polymorphic form.

In 1998, soft gelatin capsules containing ritonavir were found to have a poor dissolution rate and different to earlier batches ^29. Ritonavir has low water solubility and manufacture of capsules involves initial dissolution in ethanol followed by mixing with other excipients. Investigation showed that a hitherto unknown polymorph of even lower solubility than the only one previously known had formed in some batches of the capsule. Insidiously, once detected, polymorph #2 spread to batches of the oral solution, which could no longer be stored in a refrigerator without crystallising. The product was consequently reformulated.