Degradation of a Fluoropyridinyl Drug in capsule Formulation: Degradant Identification, Proposed Degradation Mechanism, and Formulation Optimization

The purpose of this paper was to investigate the degradation chemistry of a fluoropyridinyl drug candidate in capsule formulation and to optimize the formulation based on a proposed degradation mechanism. Small developmental batches of capsules were made by tituration of drug substance and excipient...

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Bibliographic Details
Published in:	Pharmaceutical development and technology Vol. 5; no. 4; pp. 561 - 570
Main Authors:	Chen, Jian-Ge, Chen, Jian-Ge (James), Markovitz, Debbie A., Yang, Amy Y., Rabel, Shelley R., Pang, Josephine, Dolinsky, Olga, Wu, Lei-Shu, Alasandro, Mark
Format:	Journal Article
Language:	English
Published:	New York, NY Informa UK Ltd 2000 Taylor & Francis Informa Healthcare
Subjects:	Anthracenes - administration & dosage Anthracenes - chemistry Biological and medical sciences Capsules Chemistry, Pharmaceutical Chromatography, Liquid Degradation chemistry DMP 543 Drug Stability Excipients Fluoropyridinyl drug Formulation development General pharmacology Hydrogen-Ion Concentration Mass Spectrometry Medical sciences Neuropharmacology Nootropic Agents - chemistry Pharmaceutical technology. Pharmaceutical industry Pharmacology. Drug treatments Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease) Psychology. Psychoanalysis. Psychiatry Psychopharmacology Temperature Temperature Pharmaceutical technology Psychotropic Fluoropyrimidine derivatives Chemical stability Vehicle(excipient) Chemical degradation Antialzheimer agent Lactose Formulation Acid digestion Dosage form pH Hard capsule Chemical properties Nucleophilic substitution Degradation product Physicochemical properties
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Summary:	The purpose of this paper was to investigate the degradation chemistry of a fluoropyridinyl drug candidate in capsule formulation and to optimize the formulation based on a proposed degradation mechanism. Small developmental batches of capsules were made by tituration of drug substance and excipients using a mortar and pestle, followed by manual encapsulation. Degradants were identified by LC-MS MS and LC-photodiode array detector (PDA) and were monitored by LC-ultraviolet detector (UVD) during stability studies. It was found that the drug could undergo a nucleophilic substitution reaction in which hydroxyl groups replace the fluorine substituents on the pyridine rings. The initial degradation rate is independent of the drug concentration but dependent on the temperature, the pH of the microenvironment, and the excipient type. On the basis of these experimental results, a nucleophilic substitution reaction mechanism for the degradation was proposed and a successful capsule formulation was developed.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1083-7450 1097-9867
DOI:	10.1081/PDT-100102039