| DOI: 10.29090/psa.2026.03.26.9720 | Pharm Sci Asia 2026; 53(3), 309-320 |
Efficient synthesis, characterization, and establishment of reference standards of major candesartan cilexetil impurities for pharmaceutical quality controlNguyen Thi Huynh Trang1,2, Vo Thi Kim Khuyen1, Dam To Uyen2, Nguyen Ai Vy1, Pham Van Son2, Truong Ngoc Tuyen1, Nguyen Duc Tuan1*
1 School of Pharmacy, University of Medicine and Pharmacy at Ho Chi Minh City, 41-43 ?inh Tien Hoang Street, Sai Gon Ward, Ho Chi Minh City, Viet Nam
2 HCMC centre for the quality control of Food, Drug and Cosmetics, 45 Nguyen Van Trang Street, Ben Thanh Ward, Ho Chi Minh City, Viet Nam
Process- and degradation-related impurities of candesartan cilexetil present significant challenges in pharmaceutical quality control due to their structural similarity to the parent drug and the limited availability of certified reference standards. This study aimed to develop efficient and cost-effective synthetic routes for five important impurities of candesartan cilexetil (A, B, D, F, and G), followed by structural characterization and establishment of reference standards suitable for pharmaceutical analysis. Controlled acidic and alkaline hydrolysis of candesartan cilexetil produced impurities B and G in high yields (88% and 95%, respectively). Impurities F and D were obtained from candesartan cilexetil and impurity B, respectively via alkylation reactions with average yields of approximately 40%, while impurity A was synthesized via a one-step esterification of impurity G with a yield of up to 70%. Structural identities were confirmed using nuclear magnetic resonance and high-resolution mass spectrometry. A validated reverse-phase high-performance liquid chromatography method demonstrated excellent specificity, linearity (R2 > 0.998), precision (RSD < 0.52%), and accuracy (98.0–101.9%). Homogeneity testing and assigned value determination were conducted in accordance with ISO and ICH guidelines through interlaboratory comparison. The certified purity values ranged from 98.2% to 99.1% with low uncertainty. The developed workflow provides a practical, scalable, and economically feasible approach for producing impurity reference standards, supporting impurity profiling, stability testing, and routine pharmaceutical quality control of candesartan cilexetil and related formulations.
Keyword:
Synthesis; Candesartan; Impurities; Reference standard
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