title: Impact of Metallic Stearates on Disproportionation of Hydrochloride Salts of Weak Bases in Solid-State Formulations.
abstract: Excipient-induced salt disproportionation (conversion from salt form to free form) in the solid state during storage or manufacturing is a severe formulation issue that can negatively influence product performance. However, the role of excipient properties on salt disproportionation and mechanisms of proton transfer between salt and excipients are still unclear. Moreover, knowledge about the formation of disproportionation products and the consequent impact of these reactions products on the disproportionation process is still inadequate. In the present study, three commonly used lubricants (sodium stearate, calcium stearate, and magnesium stearate) were mixed with a hydrochloride salt as binary mixtures to examine their different capabilities for inducing salt disproportionation at a stressed storage condition (40 °C/65% RH). The overall objective of this research is to explore factors influencing the kinetics and extent of disproportionation including surface area, alkalinity, hygroscopicity, formation of new species, etc. In addition, we also aim to clarify the reaction mechanism and proton transfer between the model salt and stearates to provide insight into the in situ formed reaction products. We found that the properties of stearates significantly affect the disproportionation process in the initial stage of storage, while properties of the reaction products negatively affect the hygroscopicity of the powder mixture promoting disproportionation during longer-term storage. In addition, lubrication difference among three stearates was evaluated by performing compaction studies. The findings of this study provide an improved understanding of the proton transfer mechanism between the ionized form of an active pharmaceutical ingredient and excipients in solid dosage forms. It also provides pragmatic information for formulation scientists to select appropriate lubricants and other excipients, and to design robust formulations.
authors.affiliation: Department of Industrial and Physical Pharmacy, Purdue University , 575 Stadium Mall Drive, West Lafayette, Indiana 47907, United States.
authors.forename: Haichen
authors.initials: H
authors.lastname: Nie
authors.affiliation: Preformulation Sciences, Merck & Co., Inc. , 770 Sumneytown Pike, West Point, Pennsylvania 19486, United States.
authors.forename: Wei
authors.initials: W
authors.lastname: Xu
authors.affiliation: Oral Formulation Science, Merck & Co., Inc. , 770 Sumneytown Pike, West Point, Pennsylvania 19486, United States.
authors.forename: Jie
authors.initials: J
authors.lastname: Ren
authors.affiliation: Department of Industrial and Physical Pharmacy, Purdue University , 575 Stadium Mall Drive, West Lafayette, Indiana 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, Kentucky 40536, United States.
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Marsac
authors.affiliation: Discovery Pharmaceutical Science, Merck & Co., Inc. , 770 Sumneytown Pike, West Point, Pennsylvania 19486, United States.
authors.forename: Christopher T
authors.initials: CT
authors.lastname: John
authors.affiliation: Department of Industrial and Physical Pharmacy, Purdue University , 575 Stadium Mall Drive, West Lafayette, Indiana 47907, United States.
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Byrn
mesh_terms: D004339:Drug Compounding / Q000379:methods*; D004355:Drug Stability; D005079:Excipients / Q000737:chemistry; D012492:Salts / Q000737:chemistry; D012995:Solubility; D013228:Stearates / Q000737:chemistry*; D013229:Stearic Acids / Q000737:chemistry
chemical_list: D005079:Excipients; D012492:Salts; D013228:Stearates; D013229:Stearic Acids; C031183:stearic acid
keywords: deliquescence; form conversion; hygroscopicity; lubricants; proton transfer; salt stability; solid state acid−base reaction; surface area