Drug Substance Modification

Drug substance modification is one of the most straightforward and least expensive approaches to enhancing solubility and bioavailability. However, exploiting the available options requires an understanding of the molecule’s pKa and how it behaves (e.g., solubility and precipitation) in different regions of the GI tract. Understanding these factors clarifies will help developers determine if a particular salt form will enhance properties that lead to an improvement in bioavailability. For molecules with the potential to form stable salts, salt screening studies are the most effective approach for surveying a wide range of acids/bases and crystallization conditions.3

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A drug’s solubility/rate-of-dissolution is often related to its in vivo performance (bioavailability). Therefore, prediction and measurement of these properties becomes critical in characterizing new drug candidates and the formulations in which they are developed. The establishment and understanding of IVIVC’s (in-vitro-in-vivo correlations) of drug candidates formulated into dosage forms begins with measurement of the drug’s solubility and dissolution rate.4

If neither salts nor cocrystal modifications are obtainable, then the free form of the compound may be modified to impart a change in the solubility and dissolution rate and, correspondingly the bioavailability. Two different solid-state forms or modifications of the free-form are usually considered: modifying the packing arrangement of molecules in the unit cell from a highly-ordered crystalline state to a less-ordered form, or producing a material that is either substantially disordered (i.e., a metastable crystalline form) or has no meaningful order (e.g., amorphous). These options can be uncovered through crystallization studies on the free form of the drug substance, such as fast desupersaturation methods. Amorphous materials are often produced by lyophilization, spray-drying, and/or rapid solvent removal (e.g., evaporation). Where modifications of the solid form does not improve bioavailability, particle-size reduction remains a viable option for enhancing the dissolution rate.

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3Stahl, P. H. and Sutter, B. (2006) Salt Selection, in Polymorphism: in the Pharmaceutical Industry (ed R. Hilfiker), Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, FRG.

4Vishweshwar, P., McMahon, J. A., Bis, J. A. and Zaworotko, M. J. (2006), Pharmaceutical co-crystals. J. Pharm. Sci., 95: 499–516.

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