Preformulation, active solubility

As part of the preformulation activities, investigations include physiochemical character, purity, solubility, stability, and optimal pH studies. In preparation for clinical studies, potential product formulations considering route of administration and solution stability are also studied. Unique to dosage form development studies for lyophilized products, thermal analysis of the drug substance and product formulations are also necessary. Data generated during this phase of product development is useful for future development activities, along with validation. 

Solubility, enzyme activity, chemical and conformational stability of pharmaceutically active proteins under non-aqueous conditions have been well characterized (Zaks and Klibanov, 1988a Zaks and Klibanov 1988b Houen, 1996). Many of the solvents utilized in the literature are not pharmaceutically acceptable, and much of this work has not been directly applied to non-aqueous pharmaceutical formulations. However, the fundamental science and elucidation of concepts important to successfully utilizing non-aqueous conditions are applicable from this literature base. Furthermore, prediction of activity, solubility, chemical and structural stability are not routine, and preformulation work must be done on a targeted basis. 

Hence it is important to study this effect during preformulation by testing the solubility of the salt in the presence and absence of sodium chloride. Although salts do not alter the pharmacological activity of the drug, safety is an important consideration in the selection of salts. From this perspective, salts are treated as a new molecule by the FDA. The safety of the salt is evaluated with respect to its route of administration and dose of the drug [37],... 

By the time an active pharmaceutical ingredient (API) is made available to an analytical chemist in the formulation development group, most or all of the physical characteristics of an API has already been studied and the information should be available in some sort of a report from the drug substance group or preformulation group. Some of the key parameters that an analytical chemist in formulation development requires from such a report are the solubility and solution stability. 

Early preformulation studies are often performed to obtain initial information regarding drug absorption but may be restricted by solubility problems of the active drug. During early... 

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