Abstract

LASMIDITAN HEMISUCCINATE: IDENTIFICATION, SYNTHESIS AND CHARACTERIZATION OF PROCESS RELATED IMPURITIES, STRESS-TESTING STUDIES AND HPLC METHOD VALIDATIONS

Ponnoju Vijay Bhaskar*, Edhara Venkata Reddy, Mandem Maheswar Reddy, Awari Raghavendra, Ambala Varun Kumar, Shaik Anil Kapoor, Nukapanugu Tejasri, Dubbaka Yakaiah, Vegiraju Bala Surya Varma, Thandavamurthy Karthikeyan, Aambala Nanda Kishore Kumar Reddy

ABSTRACT

Lasmiditan Hemisuccinate (LDT), used as an antimigraine drug and it is synthesized for commercial use as an active pharmaceutical ingredient (API) in highly pure form. In LDT synthetic process development, the LDT-amine intermediate is treated with 2,4,6 trifluoro benzoyl chloride through acid-amine coupling reaction to give LDT-amide intermediate. During this conversion, 2,6 di fluro and 2,4 difluro amide intermediates are formed as impurities, i.e., LDT- Impurity-C and LDT-Impurity-D. Further, these impurities converted to their derivatives in consecutive synthetic steps of LDT. These derivatives had shown gigantic impact on the quality and yield of LDT. Hence, these impurities identified, synthesized, characterized and controlled in API to improve the quality and yield. The mechanisms of their formation were discussed in brief. After all standardization procedures, they used as reference standards for analytical studies. In addition, a separate related substances (RS) by HPLC method was developed and validated for detection, quantitation of process related impurities. These impurities detected at 260 nm with limit of quantitation (LOQ) up to 0.45 μg mL-1 in RS by HPLC. As a complementary of this work, stress-testing studies of LDT were carried out under specified conditions. Long term and accelerated stability studies are continued. The HPLC assay method was developed with determination co-efficient 0.999 and validated. Both the methods used in analysis of the stability studies of LDT.

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