Structural studies of impurities of risperidone by hyphenated techniques

Area of Science:

• Analytical Chemistry
• Organic Chemistry
• Pharmaceutical Sciences

Background:

• Understanding the impurity profile of pharmaceutical compounds is crucial for drug safety and efficacy.
• Risperidone (RSP) is an antipsychotic medication with a well-established therapeutic use.
• Identifying and characterizing impurities ensures compliance with regulatory standards.

Purpose of the Study:

• To identify and characterize unknown impurities detected during risperidone (RSP) analysis.
• To elucidate the chemical structures of these risperidone-related impurities.
• To rationalize the formation pathways of the identified impurities.

Main Methods:

• Liquid Chromatography-Mass Spectrometry (LC-MS) for impurity detection and initial separation.
• Isolation and enrichment techniques for obtaining pure impurity samples.
• Nuclear Magnetic Resonance (NMR) and Mass Spectrometry for structural elucidation.
• Single Crystal X-ray Diffraction (XRD) for unambiguous structural confirmation.

Main Results:

• Two impurities, RSP-1 (more polar) and RSP-2 (more non-polar), were detected and isolated.
• RSP-1 was characterized as risperidone N-oxide.
• RSP-2 was characterized as 9-methylene risperidone.
• The formation mechanisms for both impurities were proposed.
• Single crystal XRD confirmed the proposed structures of both impurities.

Conclusions:

• The impurity profile of risperidone includes risperidone N-oxide and 9-methylene risperidone.
• Established analytical methods allowed for the isolation and definitive structural characterization of these impurities.
• Understanding impurity formation aids in optimizing synthesis and storage conditions for risperidone.