Olmesartan medoxomil
Drugs have become an important part of human life to combat various deceases. Unlike ancient days, most of the drugs in recent years are purely synthetically made. Unambiguously, the synthetic drugs certainly contain various impurities such as either chemical or microbial. But of course most of the impurities are chemical only.
The process-related impurities in an active pharmaceutical ingredient (API) can have a significant impact on the quality and safety of the drug products. The impurity levels in any drug substance are described as per its biological or toxicological data. It is quite important for “regulatory” aspect of drug approval also to provide limitation of “related impurities.” Therefore, it is necessary to study the impurity profile of any API and control it during the manufacturing of a drug product. As per the ICH guidelines, any impurities which are forming at a level of ≥0.10% with respect to the API should be identified, synthesized, and characterized thoroughly [
Among the various health problems, high blood pressure is one of the critical one, and of course most of the times itself does not harm much, but it leads to various chronic and panic health disorders such as cardiodeceases, cerebral hemorrhage, and others. Olmesartan medoxomil
Synthesis of olmesartan medoxomil
All reagents and solvents employed were of commercial grade and were used as such, unless otherwise specified. Reaction flasks were oven-dried at 200°C, flame-dried, and flushed with dry nitrogen prior to use. All moisture and air-sensitive reactions were carried out under an atmosphere of dry nitrogen. TLC was performed on Kieselgel 60 F254 silica-coated aluminium plates (Merck) and visualized by UV light (
To a solution of 4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5-ethyl carboxylate
To a solution of
Formic acid (50 mL) was added to a solution of
IR: (KBr, cm−1) 3409 (NH); 1664 (C=O); 1219 (Ar C–N); 1384, 1459 (Ar C=C); 1055.7, 957.7 (Ar C–H). 1H NMR: (DMSO-d6) 0.96 (t, 3H,
To a solution of
Formic acid (50 mL) was added to a solution of
IR: (KBr, cm−1) 3404.9 (N–H); 1717.8 (C=O); 1099 (O–H); 1143.9 (Ar C–N); 1531–1610.2 (Ar C–C); 2874–2967.8 (C–H). 1H NMR (CDCl3) 0.96 (t, 3H, CH3); 1.54 (s, 6H, 2CH3): 1.66 (m, 2H, CH2); 2.55 (t, 2H, CH2); 4.65 (s, 2H, –O–CH2); 5.23 (s, 2H, –N–CH2); 7.05-7.20 (m, 2H, Ar–H), 7.20–7.35 (m, 6H, Ar–H); 7.42–7.50 (m, 4H, Ar–H); 7.60–7.77 (m, 4H, Ar-H). ESI-MS: (m/z): 679.5, mp: 78–82°C, Elemental analysis: calculated for C38H36N10O3: C, 67.04; H, 5.33; N, 20.58; O, 7.05; found: C, 67.17; H, 5.47; N, 20.62; O, 7.12.
To a solution of
To a solution of 1-((2′-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl)-4-(2-hydroxypropan-2-yl)-2-propyl-1H-imidazole-5-carboxylic acid
IR (KBr, cm−1) 3385 (O–H); 2931 (C–H); 2875 (Ar C–H); 1816.4 (Carbonate C=O); 1741.9 (Ester C=O); 1531 (Ar C=C); 1531 (Ar C–N). 1H NMR (CDCl3) 0.96 (t, 3H, CH3); 1.54 (s, 6H, 2CH3); 1.66 (m, 2H, CH2); 1.7–1.98 (s, 6H, 2CH3); 2.55 (t, 2H, CH2); 4.40 (s, 2H, CH2); 4.92 (s, 2H, CH2); 5.19 (s, 2H, CH2); 6.98 (d, 2H, Ar–H); 7.28 (dd, 2H Ar–H); 7.45–7.80 (m, 4H, Ar–H). Mass (m/e): 671.4, mp: 126–130°C, Elemental analysis: calculated for C34H34N6O9: C, 60.89; H, 5.11; N, 12.53; O, 21.47; found: C, 60.91; H, 5.23; N, 12.62; O, 21.52.
During the API process development of olmesartan medoxomil
HPLC chromatogram of olmesartan medoxomil.
The two known impurities were prepared by Schemes
Synthesis of olmesartan medoxomil known impurity
Synthesis of olmesartan medoxomil known impurity
A comprehensive study was undertaken to identify the unknown impurities by LC-MS followed by confirming through synthesis of respective unknown impurities, followed by characterization based on spectroscopic techniques such as 1H NMR and IR mass spectroscopy.
Presence of these unknown impurities was detected by HPLC in synthesized olmesartan medoxomil
The identified impurities present at nonpolar end of the chromatogram compared to required product. The RRT of unknown impurities 12, 17, and 19 are 1.09, 1.40, 1.63, respectively, each of the impurities contaminating the product with 0.2 to 0.5% (area by HPLC). Being researchers of organic chemistry, we intended to identify the possible structures by considering the molecular weights (by LC-MS), followed by their synthesis and confirming through correlating these with the impurities forming in the reaction (by HPLC) (Figures
Unknown impurity RRT.
Entry number | RRT by HPLC | Mass (m/z) value by LC-MS |
| ||
1 | 1.09 | 488.58 |
2 | 1.40 | 680.76 |
3 | 1.63 | 670.67 |
LC-MS chromatogram of unknown impurity
LC-MS chromatogram of unknown impurity
LC-MS chromatogram of unknown impurity
Proposed structures of “unknown impurity
Proposed structures of “unknown impurity
The relevant chemical structures of the impurities were predicted by considering the mass details (m/z value) by LC-MS. While reviewing the mechanistic aspects of the possibilities of these impurities formation, the most probable structures were identified first and started synthesizing the same to confirm through structural elucidation followed by employing the chromatographic techniques (HPLC).
The unknown impurity
Synthesis of olmesartan medoxomil unknown impurity
The unknown impurity
The proposed impurity was synthesized by following Scheme
Synthesis of olmesartan medoxomil unknown impurity
Synthesis of olmesartan medoxomil unknown impurity
Since the impurity is identified and mechanistic possibility of expected, the formation of the respective contaminant (impurity
The unknown impurity
Since the impurity is identified and mechanistic possibility of expected, the formation of the respective contaminant (Impurity
Chromatographic studies (HPLC) with varying the concentration and coinjection of impurity were also conducted and concluded that the same impurities were existed in targeted entity olmesartan medoxomil. The reason for formation is also discussed, and preventive studies were also carried out and process has been modified such that the formation of mentioned impurities is subsidized.
The possible process-related impurities of olmesartan medoxomil are identified by LC-MS data followed by confirmation by chemical synthesis and characterization using analytical tools such as HPLC,1HNMR, IR, mass, and melting point.
The authors thank Inogent Laboratories Private Limited (a GVK BIO Company) for the financial support and encouragement.