Strategies for Optimizing the Preformulation Process Examined

Preformulation represents an early-stage opportunity to facilitate theeventual movement of a drug substance into a commercial product.Strategies to optimize the preformulation process were outlined byHarry Brittain, institute director for the Center for PharmaceuticalPhysics (Milford, NJ, www.centerpharmphysics.com). He spoke at the PharmTech Annual Event in Somerset,New Jersey this week.

A preformulation program should address five keyelements, outlined Brittain, who also serves as a member of theExcipient General Chapters expert committee of the United StatesPharmacopeia (Rockville, MD, www.usp.org) , and as a member of the Organic andPharmaceutical subcommittee of the International Center for DiffractionData (Newtown Square, PA, www.icdd.com).These include:

• preliminary preformulation;

• assessing whether or not to use a salt form;

• understanding the physical forms of the bulksubstance and their characterization;

• recommending the physical form of the drugsubstance;

• studies of drug-excipient incompatibility.

"During the preliminary preformulation, one may merely know theidentity of the drug candidate," said Brittain. "At this point, it isnecessary to acquire the information necessary to interpret thesolid-state data to be acquired in later stages." He pointed toincreased sophistication of computational programs in being able tocalculate information such as solubility tendencies, pH dependence ofthe partition coefficient, ionization constants, empirical andstructure formulas, and molecular weight.

The preformulation stage also is a critical time tounderstand the polymorphs that may be present. "Unless a program fortheir detection is implemented early in development, polymorphs aremost likely to be uncovered during the later stages of development,"said Brittain. These polymorphs may arise from a different packingarrangement of molecules that have the same conformation or from thealternate assembly of different conformational states of the samemolecule.

A particular problem is the rise ofsolvatomorphism. Solvatomorphismis defined as the ability of a substance to exist in two or morecrystalline phases that differ in their empirical formulae, whicharises from their differences in their solvation states.

"It is entirely possible that solvatomorphs can alsoexhibit polymorphism if the arrangement and/or confirmation of themolecules in the crystal structure can be achieved in different ways,"said Brittain. Solvatomorphs can be characterized by the presence ofwater as in hydrates or as solvates in the crystal structure.

Brittain further outlined the screening protocolused to define the experiments that need to be performed to identifythe possible crystalline states of a drug substance, the analyticaltechniques that should be used to detect and characterize newcrystalline forms, and approaches for enhancing the probability ofdiscovering the most appropriate crystalline form for development.