Influence of pH, Alcohol Structure, and Temperature on Lenalidomide Alcoholysis with Implications for Pharmaceutical Quality Control
Abstract
Artifacts generated during sample preparation or analysis can compromise impurity evaluation in pharmaceutical quality control. Lenalidomide, a thalidomide derivative used for multiple myeloma treatment and as a cereblon ligand in a proteolysis-targeting chimera (PROTAC), undergoes methanolysis through ring opening of its glutarimide moiety, forming constitutional isomers. This study systematically evaluated the alcoholysis of lenalidomide under various pH, methanol (MeOH) concentration, temperature, and alcohol conditions to clarify key factors affecting artifact formation. Stress studies showed that the total amount of methanolysis products exhibited linear relationships with pH, MeOH concentration, and temperature after log transformation. Kinetic modeling indicated that pH had the strongest effect on degradation, followed by MeOH concentration and temperature. The reaction was markedly accelerated under basic conditions, likely due to nucleophilic attack by methoxide ions. Evaluation of monohydric alcohols revealed that MeOH produced the greatest amount of alcoholysis products, whereas longer-chain and branched alcohols showed lower reactivity. In particular, 2-propanol effectively suppressed product formation, probably because of steric hindrance. These results demonstrate the importance of controlling pH and solvent composition during analysis to minimize artifact formation. The findings provide practical strategies for improving impurity assessment methods for lenalidomide and related thalidomide derivatives, including cereblon-recruiting PROTACs.
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BibTeX
@article{miyazaki2026influence,
title = {{Influence of pH, Alcohol Structure, and Temperature on Lenalidomide Alcoholysis with Implications for Pharmaceutical Quality Control}},
author = {Keisuke Miyazaki and Kousuke Tamura and Eiji Obara and Nobuyuki Suzuki},
journal = {Chemical and Pharmaceutical Bulletin},
year = {2026},
month = aug,
doi = {10.1248/cpb.c26-00244},
url = {https://www.jstage.jst.go.jp/article/cpb/74/8/74_c26-00244/_article},
note = {CC BY-NC},
}
RIS
TY - JOUR
TI - Influence of pH, Alcohol Structure, and Temperature on Lenalidomide Alcoholysis with Implications for Pharmaceutical Quality Control
AU - Keisuke Miyazaki
AU - Kousuke Tamura
AU - Eiji Obara
AU - Nobuyuki Suzuki
PY - 2026
DA - 2026/08/25
JO - Chemical and Pharmaceutical Bulletin
DO - 10.1248/cpb.c26-00244
UR - https://www.jstage.jst.go.jp/article/cpb/74/8/74_c26-00244/_article
AB - Artifacts generated during sample preparation or analysis can compromise impurity evaluation in pharmaceutical quality control. Lenalidomide, a thalidomide derivative used for multiple myeloma treatment and as a cereblon ligand in a proteolysis-targeting chimera (PROTAC), undergoes methanolysis through ring opening of its glutarimide moiety, forming constitutional isomers. This study systematically evaluated the alcoholysis of lenalidomide under various pH, methanol (MeOH) concentration, temperature, and alcohol conditions to clarify key factors affecting artifact formation. Stress studies showed that the total amount of methanolysis products exhibited linear relationships with pH, MeOH concentration, and temperature after log transformation. Kinetic modeling indicated that pH had the strongest effect on degradation, followed by MeOH concentration and temperature. The reaction was markedly accelerated under basic conditions, likely due to nucleophilic attack by methoxide ions. Evaluation of monohydric alcohols revealed that MeOH produced the greatest amount of alcoholysis products, whereas longer-chain and branched alcohols showed lower reactivity. In particular, 2-propanol effectively suppressed product formation, probably because of steric hindrance. These results demonstrate the importance of controlling pH and solvent composition during analysis to minimize artifact formation. The findings provide practical strategies for improving impurity assessment methods for lenalidomide and related thalidomide derivatives, including cereblon-recruiting PROTACs.
SN - 1347-5223
SN - 0009-2363
ER -