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Degradation of BMS-753493, a novel epothilone folate conjugate anticancer agent

Madhushree Gokhale1, Ajit Thakur, Frank Rinaldi

  • 1Exploratory Pharmaceutical Sciences, Bristol Myers Squibb Company, New Brunswick, New Jersey 08903, USA. madhushree.gokhale@bms.com

Drug Development and Industrial Pharmacy
|October 9, 2012
PubMed

Insights

BMS-753493, a cancer drug candidate, undergoes degradation via macrolactone and aziridine ring hydrolysis. Optimal pH for injectable drug product development is between 6-7, ensuring stability.

Area of Science:

  • Pharmaceutical Chemistry
  • Drug Degradation Studies
  • Preformulation Science

Background:

  • BMS-753493 is a novel folate-targeted therapeutic candidate for cancer treatment.
  • Understanding drug degradation pathways is crucial for successful preformulation and drug product development.
  • The epothilone moiety, BMS-748285, served as a model compound due to the complexity of BMS-753493 degradation.

Purpose of the Study:

  • To elucidate the primary degradation pathways of BMS-753493.
  • To investigate the kinetics of BMS-753493 degradation.
  • To inform the development of a stable injectable drug product formulation.

Main Methods:

  • Hydrolysis studies of BMS-753493 across a pH range of 1.5-9.4 at varying temperatures (5-40°C).
  • Utilized BMS-748285 as a model compound to study macrolactone versus aziridine ring hydrolysis.
  • Employed Liquid Chromatography-Mass Spectrometry (LC-MS) and Liquid Chromatography-Solid Phase Extraction-Nuclear Magnetic Resonance (LC-SPE-NMR) for product characterization.

Main Results:

  • Identified three major degradation pathways for BMS-753493, including carbonate ester and aziridine/macrolactone ring hydrolysis, yielding products with m/z = 794 in the pH 5-7.5 range.
  • Characterized two addition products (D1 and D2, m/z = 555) from BMS-748285 hydrolysis under neutral conditions, identified as an isomeric hydroxy acid pair from alkyl oxygen cleavage.
  • Established a U-shaped pH-stability profile for BMS-753493, with maximum stability observed at pH 7.

Conclusions:

  • BMS-753493 undergoes degradation primarily through macrolactone ring opening via alkyl-oxygen cleavage, analogous to BMS-748285.
  • The optimal pH range for developing an injectable formulation of BMS-753493 is 6-7, balancing stability and solubility.
  • These findings provide critical data for the preformulation and development of BMS-753493 as a cancer therapeutic.

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