title: Crystalline solid dispersion-a strategy to slowdown salt disproportionation in solid state formulations during storage and wet granulation.
abstract: Salt disproportionation (a conversion from the ionized to the neutral state) in solid formulations is a potential concern during manufacturing or storage of products containing a salt of the active pharmaceutical ingredient (API) due to the negative ramifications on product performance. However, it is challenging to find an effective approach to prevent or mitigate this undesirable reaction in formulations. Hence, the overall objective of this study is to explore novel formulation strategies to reduce the risk of salt disproportionation in pharmaceutical products. Crystals of pioglitazone hydrochloride salt were dispersed into polymeric matrices as a means of preventing the pharmaceutical salt from direct contact with problematic excipients. It was found that the level of salt disproportionation could be successfully reduced during storage or wet granulation by embedding a crystalline salt into a polymeric carrier. Furthermore, the impact of different polymers on the disproportionation process of a salt of a weakly basic API was investigated herein. Disproportionation of pioglitazone hydrochloride salt was found to be significantly affected by the physicochemical properties of different polymers including hygroscopicity and acidity of substituents. These findings provide an improved understanding of the role of polymeric carriers on the stability of a salt in solid formulations. Moreover, we also found that introducing acidifiers into granulation fluid can bring additional benefits to retard the disproportionation of pioglitazone HCl during the wet granulation process. These interesting discoveries offer new approaches to mitigate disproportionation of API salt during storage or processing, which allow pharmaceutical scientists to develop appropriate formulations with improved drug stability.
authors.affiliation: Department of Industrial and Physical Pharmacy, Purdue University, 575 Stadium Mall Drive, West Lafayette, IN, 47907, United States; Formulation Sciences, Teva Pharmaceuticals, 145 Brandywine Parkway, West Chester, PA, 19380, United States.
authors.forename: Haichen
authors.initials: H
authors.lastname: Nie
authors.affiliation: Preformulation Sciences, Merck & Co., Inc., 770 Sumneytown Pike, West Point, PA, 19486, United States. Electronic address: wei_xu@merck.com.
authors.forename: Wei
authors.initials: W
authors.lastname: Xu
authors.affiliation: Department of Industrial and Physical Pharmacy, Purdue University, 575 Stadium Mall Drive, West Lafayette, IN, 47907, United States.
authors.forename: Lynne S
authors.initials: LS
authors.lastname: Taylor
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 789 South Limestone Street, Lexington, KY, 40536, United States.
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Marsac
authors.affiliation: Department of Industrial and Physical Pharmacy, Purdue University, 575 Stadium Mall Drive, West Lafayette, IN, 47907, United States. Electronic address: sbyrn@purdue.edu.
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Byrn
mesh_terms: D004339:Drug Compounding / Q000379:methods*; D004355:Drug Stability; D005079:Excipients / Q000737:chemistry; D006863:Hydrogen-Ion Concentration; D000077205:Pioglitazone; D011108:Polymers / Q000737:chemistry*; D012492:Salts / Q000737:chemistry*; D045162:Thiazolidinediones / Q000737:chemistry*; D017155:Wettability
chemical_list: D005079:Excipients; D011108:Polymers; D012492:Salts; D045162:Thiazolidinediones; D000077205:Pioglitazone
keywords: Acid-base interaction; Hygroscopicity; Microenvironmental pH; Pioglitazone hydrochloride salt; Salt stability; Wet granulation; pH modifier