title: Salt Disproportionation in the Solid State: Role of Solubility and Counterion Volatility.
abstract: Disproportionation propensity of salts (HCl, HBr, heminapadisylate) and adipic acid cocrystal of corticotropin releasing hormone receptor-1 antagonist was studied using model free kinetics. Using thermogravimetic weight loss profile or heat flow curves from differential scanning calorimetry, an activation energy plot for salts and cocrystal was generated based on model free kinetics. This activation energy of disproportionation provided qualitative information about the solid state salt stability. To ensure the stability throughout the shelf life, "prototype" formulations of salts and cocrystal in tablet form were stored at 40 °C and several water vapor pressures. Disproportionation kinetics were studied in these prototype tablet formulations using two-dimensional X-ray diffractometry. Formulations containing the adipic acid cocrystal or heminapadisylate salt did not show disproportionation of API when stored at 40 °C/75% RH for 300 days. On the other hand, formulations containing HCl or HBr salt disproportionated. Though isostructural, the disproportionation propensity of HBr and HCl salts was quite different. The HCl salt highlighted the important role that volatility of the counterion plays in the physical stability of the formulations. Solution state stability (i.e., in dissolution medium) of salts and cocrystal was also assessed and compared with solid state stability, by determining their solubility at different pH's, and intrinsic dissolution rate.
authors: Lilly Corporate Center, Eli Lilly and Company , Indianapolis, Indiana 46285, United States.|Department of Pharmaceutics, College of Pharmacy, University of Minnesota , Minneapolis, Minnesota 55455, United States.
authors: Naveen K
authors: NK
authors: Thakral
authors: Lilly Corporate Center, Eli Lilly and Company , Indianapolis, Indiana 46285, United States.
authors: Robert J
authors: RJ
authors: Behme
authors: Lilly Corporate Center, Eli Lilly and Company , Indianapolis, Indiana 46285, United States.
authors: Aktham
authors: A
authors: Aburub
authors: Lilly Corporate Center, Eli Lilly and Company , Indianapolis, Indiana 46285, United States.
authors: Jeffrey A
authors: JA
authors: Peterson
authors: Lilly Corporate Center, Eli Lilly and Company , Indianapolis, Indiana 46285, United States.
authors: Timothy A
authors: TA
authors: Woods
authors: Lilly Corporate Center, Eli Lilly and Company , Indianapolis, Indiana 46285, United States.
authors: Benjamin A
authors: BA
authors: Diseroad
authors: Department of Pharmaceutics, College of Pharmacy, University of Minnesota , Minneapolis, Minnesota 55455, United States.
authors: Raj
authors: R
authors: Suryanarayanan
authors: Lilly Corporate Center, Eli Lilly and Company , Indianapolis, Indiana 46285, United States.
authors: Gregory A
authors: GA
authors: Stephenson
mesh_terms: D004355:Drug Stability; D005079:Excipients / Q000737:chemistry*; D007700:Kinetics; D004364:Pharmaceutical Preparations / Q000737:chemistry*; D012492:Salts / Q000737:chemistry*; D012995:Solubility; D014835:Volatilization; D014867:Water / Q000737:chemistry*
chemical_list: D005079:Excipients; D004364:Pharmaceutical Preparations; D012492:Salts; D014867:Water
keywords: X-ray diffractometry; cocrystal; counterion; disproportionation; intrinsic dissolution; model free kinetics; salt; solubility; volatilization