title: Dehydration and Stabilization of a Reactive Tertiary Hydroxyl Group in Solid Oral Dosage Forms of BMS-779788.
abstract: BMS-779788 contains a reactive tertiary hydroxyl attached to a weakly basic imidazole ring. Propensity of the carbinol toward dehydration to yield the corresponding alkene, BMS-779788-ALK, was evaluated. Elevated levels of BMS-779788-ALK were observed in excipient compatibility samples. Stability studies revealed that BMS-779788 degrades to BMS-779788-ALK in capsules and tablets prepared by both dry and wet granulation processes. An acid-catalyzed dehydration mechanism, in which the heterocyclic core contributes resonance stability to the cationic intermediate via charge transfer to the imidazole ring, was proposed. Therefore, neutralization via a buffered (pH 7.0) granulating solution was used to mitigate dehydration. Solution studies revealed degradation of BMS-779788 to BMS-779788-ALK over the pH range of 1-7.5. Reversibility was confirmed by initiating reactions with BMS-779788-ALK over the same pH range. Accordingly, a simple reversible scheme can be used to describe reactions initiated with either BMS-779788 or BMS-779788-ALK. To eliminate potential for charge delocalization across the heterocycle and probe the degradation mechanism, the imidazole ring of BMS-779788 was methylated (BMS-779788-Me). The propensity for acid-catalyzed dehydration was then evaluated. The acid stability of BMS-779788-Me confirmed that the heterocyclic core contributes to reactivity liability of the tertiary hydroxyl.
authors.affiliation: Drug Product Science and Technology, Bristol-Myers Squibb Company, New Brunswick, New Jersey 08903. Electronic address: monica.adams@bms.com.
authors.forename: Monica L
authors.initials: ML
authors.lastname: Adams
authors.affiliation: Drug Product Science and Technology, Bristol-Myers Squibb Company, New Brunswick, New Jersey 08903.
authors.forename: Vijayata
authors.initials: V
authors.lastname: Sharma
authors.affiliation: Drug Product Science and Technology, Bristol-Myers Squibb Company, New Brunswick, New Jersey 08903.
authors.forename: Madhushree
authors.initials: M
authors.lastname: Gokhale
authors.affiliation: Analytical and Bioanalytical Development, Bristol-Myers Squibb Company, New Brunswick, New Jersey 08903.
authors.forename: Yande
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Company, Lawrenceville, New Jersey 08648.
authors.forename: Kevin
authors.initials: K
authors.lastname: Stefanski
authors.affiliation: Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Company, Lawrenceville, New Jersey 08648.
authors.forename: Ching
authors.initials: C
authors.lastname: Su
authors.affiliation: Drug Product Science and Technology, Bristol-Myers Squibb Company, New Brunswick, New Jersey 08903.
authors.forename: Munir A
authors.initials: MA
authors.lastname: Hussain
mesh_terms: D002214:Capsules; D003681:Dehydration; D004339:Drug Compounding; D004355:Drug Stability; D005079:Excipients / Q000737:chemistry; D006863:Hydrogen-Ion Concentration; D007093:Imidazoles / Q000737:chemistry*; D007700:Kinetics; D012995:Solubility; D013450:Sulfones / Q000737:chemistry*; D013607:Tablets
chemical_list: C000596177:2-(2-(1-(2-chlorophenyl)-1-methylethyl)-1-(3'-(methylsulfonyl)-4-biphenylyl)-1H-imidazol-4-yl)-2-propanol; D002214:Capsules; D005079:Excipients; D007093:Imidazoles; D013450:Sulfones; D013607:Tablets
keywords: chemical stability; kinetics; pH; preformulation; solid dosage form; stability; stabilization