CHROMATOGRAPHIC DEVELOPMENT & VALIDATION OF 2-CHLOROMETHYL-4-METHYL QUINAZOLINE FOR QUANTIFICATION OF QUALITY

Dipra Dastider*, Dr. Sudip Kumar Mandal and Dr. Dhrubo Jyoti Sen

ABSTRACT

Linagliptin is a DPP‒4 inhibitor[dipeptidyl peptidase‒4 inhibitor] used as antidiabetic drug which is made of three subordinate units (4‒methyl quinazoline, purine‒2,6‒dione and 3R‒piperidine‒3‒amine) which has one chiral point [8‒[(3R)‒3‒Aminopiperidin‒1‒yl]‒7‒(but‒2‒yn‒1‒yl)‒3‒methyl‒1‒[(4‒methylquinazolin‒2‒yl)methyl]‒3,7‒dihydro‒1H‒purine‒2,6‒dione] at amino piperidine unit. The quality of starting material 2‒(chloromethyl)‒4‒methylquinazoline has been examined for purity to avoid the unwanted impurities, safety and efficacy by which the active pharmaceutical ingredient (API) linagliptin has to be synthesized. A host of impurities in pharmaceutical ingredients do occur that may be partially responsible for toxicity, chemical interference and general instability. In order to ensure that drugs reaching consumers are effective, safe of good quality regulatory requirement now demand to use standard pure API. Purity of API depends on the synthetic process involving chemical reactions using different reagents under different conditions. Therefore, estimation of purity along with impurity profile is necessary to get the pure API. These can only be achieved by thorough analysis of the precursor (Starting Material) used. Here, the anti‒diabetic drug, linagliptin is to be synthesized from 2‒(chloromethyl)‒4‒methyl quinazoline (CMQ). Its standardization i.e. purity and impurity profile has been developed and validated as required by the regulatory authorities. There is no such existing literature reports available for the estimation of CMQ.A key component of the quality of pharmaceutical drugs is the control of impurities. The pharmaceutical analytical chemistry is concerned with new analytical techniques. The main objective of our research work is to develop a RP‒HPLC validated method for estimation of the purity of CMQ (KSM) along with the impurities level (known & unknown). Here, linagliptin (API) has the structural similarity with CMQ (2‒chloromethyl‒4‒methyl‒quinazoline). The method has been developed & validated should have the related impurities level <0.1% (unknown impurities) and <0.15% (known impurities) as per ICHguidelines6,27. This has been carried out in two steps:1.RP‒HPLC Method Development.2.RP‒HPLC Method Validation.

Keywords: CMQ, Linagliptin, API, TLC, UV, RP?HPLC, Rf, Rt, Validation, LOD, LOQ, Robustness, Accuracy, Stability.