Study On Impurity Analysis In THP Drug Substance

THP is a muscarinic acetylcholine receptor antagonist which can suppress the acetylcholine hyperactivity and relieve tremor.Owing to its significant efficacy and low price,THP has been widely used in China for the treatment of Parkinson’s disease and extrapyramidal disorders caused by central nervous system drugs.THP tablets are included in national essential medicines list as an anti-tremor paralysis drug for the neurological system.In order to ensure the drug quality and safety,it is necessary to establish appropriate evaluation standards and analytical methods for THP quality control.Impurity research plays an important role in drug quality control,among which developing effective analytical methods for impurity determination is a priority to assure drug safety and quality.Therefore,this article aimed to conduct a comprehensive impurity profiling of THP drug substance and develop practical impurity analysis methods for its routine quality control,consisting of the following two parts.Part one The study on genotoxic impurities in THP drugs.Chlorocyclohexane was identified as a synthesis-related genotoxic impurity during the evaluation of THP preparation process.Based on the threshold of toxicological concern and medication instruction of dosage,the acceptable limit of chlorocyclohexane exposure in THP could be calculated as75 ppm.Considering the stringent requirements on method sensitivity,gas chromatography mass spectrometry was utilized in this method.With the screening of internal standard,solvent,temperature program and qualifier ion,a specific approach was obtained for chlorocyclohexane quantitation.Then,the detector voltage,interface temperature and column temperature in GC-MS conditions were optimized,oriented to the maximum determination sensitivity.Consequently,the method was established with a low detection limit of 17.92 ng/ml and verified to be applicable and reliable for trace-level analysis of chlorocyclohexane.As was applied to a series of bulk drug batches,results showed that the residues of genotoxic impurity in THP were well below the acceptable limits.Part two The study on related substances in THP drugs.We first reviewed and summarized the developing requirements for the analytical method of THP and its related substances according to pharmacopeial standards.Next,we investigated and improved the separation between the impurity and other components via modulating the elution gradient.Subsequently,sample preparation was optimized to solve the problems of matrix interference and solvent effect.The method was fully validated in terms of system suitability,specificity,linearity,accuracy,precision and robustness.No related substance over the reporting threshold was detected in multiple THP batches,indicating the fact that the current drug products fulfilled the quality control requirements of impurity management.In conclusion,this article focused on the THP impurity profiling and put forward GCMS and HPLC methods for the determination of the genotoxic impurity and related substances in THP drugs,respectively.The proposed analytical methods and formulated limits for impurity control could be further adopted as convenient tools in quality assessment and stability study of THP drug substance.