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Published on: December 7, 2014
Ruxolitinib photodegradation mechanisms by theoretical and experimental chemistry
Philippe-Henri Secretan1, Joel Schlatter2, Salvatore Cisternino3
1Paris Cardiovascular Research Centre, INSERM U970, Paris, France; Université Paris-Saclay, Matériaux et santé, 92296, Châtenay-Malabry, France.
Abstract:
Ruxolitinib is a Janus Kinase inhibitor currently approved for the treatment of myelofibrosis. It is also a promising drug for the treatment of skin and infectious diseases. In terms of pharmaceutical stability, although ruxolitinib has been established as being sensitive to light, no data on photodegradation processes are available to date, while these may be useful for quality risk management and any potential development of other pharmaceutical forms for other routes of administration. One way to partially fill this gap was to carry out a study that combines a consistent determination of the most sensitive sites of the molecule to photolysis through theoretical calculations based on functional density, with the identification of the main photodegradation products obtained after forced degradation. This integrated approach has shown converging results describing the mechanisms based on photo-oxidation that can lead to the opening of the pyrrole ring. Having access to the structure of the degradation products and intermediates then made it possible to carry out an in silico evaluation of their potential mutagenicity and it appears that some of them feature alert structures.
Insights
Ruxolitinib, a Janus Kinase inhibitor, undergoes photodegradation via photo-oxidation, potentially opening its pyrrole ring. Some resulting degradation products show mutagenic potential, highlighting risks for pharmaceutical development.
Area of Science:
- Pharmaceutical chemistry
- Photochemistry
- Computational chemistry
Background:
- Ruxolitinib is a Janus Kinase (JAK) inhibitor approved for myelofibrosis and investigated for other conditions.
- Ruxolitinib's photosensitivity is known, but photodegradation pathways and products remain uncharacterized.
- Understanding photodegradation is crucial for quality risk management and developing new drug formulations.
Purpose of the Study:
- To elucidate the photodegradation mechanisms of ruxolitinib.
- To identify key photodegradation products and their potential mutagenicity.
- To provide data for pharmaceutical quality control and formulation development.
Main Methods:
- Theoretical calculations using density functional theory (DFT) to identify photosensitive molecular sites.
- Forced degradation studies to induce and isolate photodegradation products.
- In silico evaluation of the mutagenicity of identified degradation products.
Main Results:
- DFT calculations indicated specific sites on the ruxolitinib molecule are susceptible to photolysis.
- Forced degradation experiments identified major photodegradation products resulting from photo-oxidation.
- The pyrrole ring was identified as a vulnerable site susceptible to opening during photodegradation.
- In silico analysis revealed potential mutagenic alerts in some degradation products.
Conclusions:
- Ruxolitinib photodegradation primarily involves photo-oxidation, leading to pyrrole ring opening.
- Identified degradation products may pose mutagenic risks, necessitating careful consideration in pharmaceutical development.
- This study provides essential data for managing ruxolitinib's stability and guiding future formulation strategies.
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