Sulfonates belong to the class of detergents and dispersants. They have high alkalinity and calcium content and have a good cleaning effect on sludge. Sulfonate raw materials are easily available, cheap, have good high-temperature detergency, strong acid neutralization ability, and good rust resistance, and have a certain dispersing and solubilizing ability. It is used in combination with other additives for internal combustion engine oil and rust prevention oil. Among them, its disadvantage is that it has the effect of promoting oxidation during use.
Genotoxicity refers to the degree to which pollutants can directly or indirectly damage cell DNA and produce mutagenic and carcinogenic effects. Certain pollutants in the environment are genotoxic. For example, benzopyrene in polycyclic aromatic hydrocarbons can cause mutations and alter proto-oncogenes and tumor suppressor genes. Many chemotherapeutics are also genotoxic, and their adverse reactions are caused by the genotoxicity of chemotherapeutics to normal cells, such as cisplatin, carboplatin, and fluorouracil.
In recent years, drug review departments have become more stringent and demanding in their review of genotoxic substances. Are genotoxic substances detected? What is the potential risk? To what extent? It is directly related to the life and death of the project. However, the author believes that the "high standards and strict requirements" of the problem of gene toxicity must not give up because of choking when it comes to drug development!
For the "sulfonate drugs" we are going to talk about today, the "sulfonic acids" required for salt formation are themselves potential hazards of genotoxic substances, but they have not affected their tremendous help to the successful marketing of the improved drug properties, and until Today, this method of salt formation is still in use no matter at home or abroad. Friends who are worthy of drug research and development will study and learn from it!
1. The fuse of sulfonate gene toxicity-"Nelfinavir mesylate"
Nelfinavir mesylate is an HIV-1 protease inhibitor for the treatment of HIV-1 infection; developed by Agouron, approved by the US FDA in 1997, approved by the European EMA in 1998, and approved by the Japanese PMDA in 1998, Jointly sold by Agouron and ViiV Healthcare in the US market under the trade name Viracept®.
On June 6, 2007, the European EMA discovered that some batches of anti-AIDS drug Viracept, that is, nelfinavir mesylate containing high doses of genotoxic impurity ~ ethyl methanesulfonate, decided to recall the drug produced by Roche Pharmaceuticals Viracept. The ethyl methanesulfonate in medicine is a potential carcinogen. When the drug dose is 2.5g/d, up to 2.75mg of ethyl methanesulfonate may be ingested by the patient and affect the patient’s body. health.
2. What are the specific varieties of sulfonate esters?
Methanesulfonic acid, benzene methanesulfonic acid, and other sulfonate substances and a small amount of lower alcohols generate alkyl sulfonates in the synthesis reaction, such as methyl methanesulfonate (MMS), ethyl methanesulfonate (EMS), isopropyl Methanesulfonate (IMS), n-butyl methanesulfonate (NBMS), and arylsulfonate such as methyl benzenesulfonate (MBS), ethyl benzenesulfonate (EBS), p-toluenesulfonate (MP -TS), these substances can undergo alkylation reactions with DNA, which may become the cause of cancer. Therefore, it is very important to control the threshold of toxicological concern (TTC) level of such impurities in drugs. The European EMA has issued a report on genotoxic impurities The maximum intake is 1.5 μg/d.
3. Related important indicators-TTC
Both the European EMA and the US FDA propose to adopt the "threshold of toxicological concern" (TTC) as the acceptable limit for genotoxic impurities. In the clinical development stage, the staged TTC is used as the limit of genotoxic impurities in the short-term medication period, as shown in the following table. The maximum limit of genotoxic impurities is the ratio of TTC to the maximum daily dose of the drug. At the same time, most genotoxic impurities are chemically active and have poor stability, which places high demands on analytical methods.
4. Control & specific analysis methods
When the solubility and stability of the sample are good, and the response is strong, the sample can be injected directly, and then gas chromatography (GC), liquid chromatography (LC), and their combined techniques are used for analysis.
When the sample cannot meet the conditions of direct injection analysis, the sample needs to be pre-processed. The usual sample pre-processing methods mainly include various extraction techniques, derivatization methods, etc., to separate, purify, enrich and concentrate the sample, To meet the requirements of analytical methods.
The GC method is mainly used for the determination of volatile components. The method has high sensitivity and strong specificity. For example, the trace detection of mesylate compounds can use the GC method and its combined technology. The GC method can be divided into direct injection GC method and headspace injection GC method according to different sampling methods. The types of detectors include FID, ECD, NPD, MS, etc.
Compared with the GC method, the LC method can analyze the non-volatile components, and the sample load is also larger, and the method is simple and feasible. The main methods are the high-performance liquid chromatography (HPLC) method; HPLC-MS method; extraction technology and derivatization method combined with HPLC-MS; ion pair chromatography (IPC) method.
5. How to avoid the production process?
Genotoxic impurities mainly come from the starting materials, intermediates, reagents, and reaction by-products in the synthesis of APIs. Besides, drugs may also be degraded to produce genotoxic impurities during synthesis, storage, or formulation. As potential genotoxic impurities, acid ester compounds should be avoided as much as possible. Studies have reported the formation of sulfonate esters and various factors that affect their degradation, including temperature, alcohols, moisture, acids, alkalis, salts, etc. The results show that in neutral or trace amounts of alkali excess (such as 2,6-dimethyl The formation of these impurities can be avoided under the conditions of base pyridine), anhydrous, low-concentration alcohol, acids weaker than methanesulfonic acid (such as phosphoric acid), and salts (such as sodium perchlorate). There is currently no report indicating that sulfonate compounds are produced by degradation in other drugs.
6. Global "sulfonate drugs"
Through the drug crossing data query, 72 sulfonate drugs have been marketed, 3 NDA varieties, 14 clinical phases III, 17 clinical phases II, and 12 clinical phases I; in terms of treatment, they are mainly distributed in tumors and heart Cerebrovascular, nervous system, infection, respiratory system, endocrine, etc.; for some drugs, see the table below for details (readers can make inquiries for specific information).
7. Domestic "sulfonate drugs"
For further inquiries, domestically developed/under-study drugs, "sulfonate drugs", have 1 approved marketed product, 2 NDA products, 5 clinical phase III products, 4 clinical phase II products, and 11 clinical phase I products.
8. Summary
Be cautious of sulfonate drugs, this is right, after all, there are potential risks! But sometimes, sulfonate drugs do have better data support in the pharmacy! Therefore, how to design and control this process is very necessary!
What I want to say here is that gene toxic substances are annoying, but we can't stay away from them one-sidedly. In the process, it is good to be able to avoid nature. If it cannot be avoided, then we will control + study it! In short, don't give up eating because of choking, and in-depth research in the process, to further feel the importance of technology, there will still be a lot of fun!
Comments
Post a Comment