title: Understanding the degradation pathway of a poorly water-soluble drug formulated in PEG-400.
abstract: VX-497 is a poorly water-soluble compound. It is formulated in PEG-400 and encapsulated in softgel capsules. Although the drug product is stable at refrigerated conditions, many degradation peaks have been observed at accelerated storage conditions. An investigation utilizing high performance liquid chromatography-mass spectrometry (HPLC-MS) was conducted to understand the degradation mechanism of the active pharmaceutical ingredient (VX-497) in PEG-400 formulation. Results revealed that the degradation was mainly caused by the reaction between VX-497 with moisture (hydrolysis) and PEG-400 (PEGylation). The numerous degradation peaks observed in the samples stored at accelerated conditions were PEG adducts covalently attached to portions of the VX-497 molecule, which were confirmed by comparison with synthetic markers. Investigation also found that an impurity, which was present in the VX-497 drug substance, reacted with PEG-400 following the same reaction mechanism, and generated additional impurities in the VX-497 drug product. By changing the process for drug substance synthesis, pure batches of VX-497 were obtained. Furthermore, it was found that the reaction between VX-497 and PEG-400 was temperature and time dependent. When the drug product was manufactured at 45 degrees C and the processing time was controlled, the PEG degradants and by-products were reduced to non-detectable levels, resulting in greatly improved drug product quality. This paper presents an integrated effort among analytical, process, and formulation scientists on how to develop a better drug product by understanding the fundamental issues of the drug product, namely the degradation mechanism.
authors.affiliation: Analytical Development Department, Vertex Pharmaceuticals, Inc, 130 Waverly Street, Cambridge, MA 02139, United States. Jianmei_Kochling@vrtx.com
authors.forename: Jianmei D
authors.initials: JD
authors.lastname: Kochling
authors.forename: Hai
authors.initials: H
authors.lastname: Miao
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Young
authors.forename: Adam R
authors.initials: AR
authors.lastname: Looker
authors.forename: Michael
authors.initials: M
authors.lastname: Shannon
authors.forename: Eda Ross
authors.initials: ER
authors.lastname: Montgomery
mesh_terms: D002214:Capsules; D002219:Carbamates / Q000032:analysis / Q000138:chemical synthesis / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism*; D002626:Chemistry, Pharmaceutical; D002851:Chromatography, High Pressure Liquid; D004340:Drug Contamination; D006868:Hydrolysis; D013058:Mass Spectrometry; D015394:Molecular Structure; D004364:Pharmaceutical Preparations / Q000032:analysis / Q000138:chemical synthesis / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism*; D010671:Phenylurea Compounds / Q000032:analysis / Q000138:chemical synthesis / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism*; D011092:Polyethylene Glycols / Q000737:chemistry*; D012995:Solubility; D012996:Solutions / Q000737:chemistry; D013696:Temperature; D013997:Time Factors; D014867:Water / Q000737:chemistry*
chemical_list: D002214:Capsules; D002219:Carbamates; C407002:N-3-(3-(3-methoxy-4-oxazol-5-ylphenyl)ureido)benzylcarbamic acid tetrahydrofuran-3-yl ester; D004364:Pharmaceutical Preparations; D010671:Phenylurea Compounds; D012996:Solutions; D014867:Water; D011092:Polyethylene Glycols