Trimetazidine Impurity D_Industrial Additive

[Background and Overview]^[1][2][3]

As clinicians’ understanding of coronary atherosclerotic heart disease (coronary heart disease) gradually deepens, its treatment methods are also constantly improving. Conservative drug treatments (such as antiplatelet, thrombolysis, beta-blocker agents, calcium antagonists, nitrate preparations, lipid-lowering therapy) and interventional therapy have become the main methods for the current treatment of coronary heart disease. However, the above-mentioned drugs mainly exert myocardial protection effect indirectly by improving the oxygen supply and demand balance of ischemic myocardium. Therefore, patients still have symptoms or signs of heart failure after treatment, and the clinical efficacy is limited.

Trimetazidine is a piperazine derivative and a new type of anti-myocardial ischemia drug. It mainly inhibits myocardial fatty acid β-oxidation by inhibiting 3-ketoacyl-CoA thiolase, increases glucose oxidation, and improves glucose metabolism. Glycolysis is coupled with glucose oxidation to optimize energy metabolism of cardiomyocytes. A large number of basic studies have confirmed that trimetazidine hydrochloride can reduce the overload of intracellular H⁺, Na⁺, and Ca²⁺ and inhibit oxygen freedom. It generates base, stabilizes the functional status of mitochondrial membrane, has various cell protective effects such as antioxidant and anti-apoptosis, and does not affect hemodynamics and has no side inotropic effects. Its good pharmacological effects are increasingly favored by clinicians. Trimetazidine hydrochloride is a new drug that improves myocardial energy metabolism. Its therapeutic effect in heart failure has been confirmed. It has no obvious side effects, has good treatment tolerance, is safe and reliable, and is worthy of clinical promotion and application. However, there is little clinical data on treating patients’ arrhythmia, improving patient mortality, and adverse effects of long-term use, and further research is needed. There are currently 8 main types of trimetazidine impurities detected, including trimetazidine impurity A, trimetazidine impurity B, trimetazidine impurity C, trimetazidine impurity D, trimetazidine impurity E, Trimetazidine Impurity F, Trimetazidine Impurity G, Trimetazidine Impurity H, Trimetazidine Impurity I, may originate from process impurities, reaction by-products and unreacted starting materials and intermediates in the raw materials. bodies and reagents, etc. With the improvement of the quality of life, people pay more and more attention to drug safety, and impurities in drugs are directly related to the quality of drugs. The “Technical Guiding Principles for Research on Impurities in Chemical Drugs” systematically stipulates the analysis of impurities and the rapid characterization of impurities. It has good guiding significance for quality control and process optimization of the R&D process.

[Structure]^[4]

Trimetazidine impurity D, chemical name 2,3,4-trimethoxybenzyl alcohol, CAS number 71989-96-3, molecular formula C10H14O4, molecular weight 198.21600, density 1.151 g/mL at 25 ℃ (lit.) , boiling point 105℃ 25 mm Hg(lit.), flash point >230 °F, refractive index n20/D 1.532(lit.), structural formula is as follows:

【Synthesis】^[5]

The preparation of trimetazidine impurity D is as follows: using 2,3,4-trimethoxybenzaldehyde as raw material, a reduction reaction is performed to generate 2,3,4-trimethoxybenzyl alcohol, which is trimetazidine impurity D. , the yield can reach 99%, the reaction equation is as follows:

[Application]^[1][5]

The study of impurities is an important part of drug research and development. It includes selecting appropriate analytical methods, accurately identifying and measuring the content of impurities, and determining reasonable limits of impurities based on the results of pharmaceutical, toxicological and clinical studies. This research occurs throughout the entire process of drug development. Adverse reactions caused by drugs in clinical use are not only related to the pharmacological activity of the drug itself, but also related to impurities in the drug. For example, polymer impurities such as polymers in antibiotics such as penicillin are the main cause of allergies. Therefore, conducting impurity research in a standardized manner and controlling impurities within a safe and reasonable range will be directly related to the quality and safety of marketed drugs. Impurity D of trimetazidine can be used in the formulation of standards during the research and development of trimetazidine. During the development of generic trimetazidine, it is necessary to conduct a detailed study on the quality of products of the same type that have been launched and analyze the types of impurities. Including trimetazidine impurity D and its content, and a comprehensive quality comparison with the product under development, based on which the impurity limits of the product under development are formulated, including the limit of impurity D in trimetazidine.

[References]

[1] Zhang Ying, Shi Dazhuo. Research progress on trimetazidine optimizing myocardial metabolism[J]. Medical Review, 2015, 21(13): 2313-2316.

[2] Xia Mingwei, Ma Likun. Progress in the clinical application of trimetazidine in cardiovascular diseases[D]. , 2008.

[3] Jiang Zhoutian. Research progress on clinical application of trimetazidine in heart failure[J]. Internal Medicine, 2013, 8(5): 523-525.

[4]Baruah, Robindra N. Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, 1994, vol. 33, # 2 p. 182 – 183

[5] Technical guiding principles for chemical drug impurity research