AN INTEGRATED APPROACH TO THE SELECTION OF OPTIMAL SALT FORM FOR A NEW DRUG CANDIDATE

A general method was developed to select the optimal salt form for BMS -180431, a novel HMG-CoA reductase inhibitor and a candidate for oral dosage form development, in an expeditious manner at the onset of the drug development process. The physicochemical properties such as hygro scopicity, physical stability of crystal forms at different humidity c onditions, aqueous solubility, and chemical stability of seven salts, e.g., sodium, potassium, calcium, zinc, magnesium, arginine and lysine , were studied using a multi-tier approach. The progression of studies among different tiers was such that the least time-consuming experime nts were conducted earlier, thus saving time and effort. A 'go/no go' decision was made after each tier of testing the salts, thus avoiding generation of extensive data on all available salt forms. The hygrosco picities of all BMS-180431 salts were evaluated at tier 1 and four sal ts (sodium, potassium, calcium and zinc) were dropped from considerati on due to excessive moisture uptake within the expected humidity range of pharmaceutical manufacturing plants (30-50% R.H. at ambient temper ature). The remaining three salts were subjected to the tier 2 evaluat ion for any change in their crystal structures with respect to humidit y and the determination of their aqueous solubilities in the gastroint estinal pH range. The magnesium salt was dropped from further consider ation due to humidity-dependent changes in its crystal structure and l ow solubility in water (3.7 mg/ml at room temperature). Arginine and l ysine salts, which were resistant to any change in their crystalline s tructures under extremes of humidity conditions (6 and 75% R.H.) and h ad high aqueous solubilities (> 200 mg/ ml), were elevated to tier 3 f or the determination of their chemical stability. Based on solid state stability of these two salts under accelerated conditions (temperatur e, humidity, and presence of excipients), consideration of ease of syn thesis, ease of analysis, potential impurities, etc., and input from t he marketing group with respect to its preference of counter ion speci es, the arginine salt was selected for further development. The number of tiers necessary to reach a decision on the optimal salt form of a compound may depend on the physicochemical properties studied and the number of salts available. This salt selection process can be complete d within 4-6 weeks and be easily adopted in the drug development progr am.