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NDMA is N-nitrosodimethylamine, It belongs to a class of chemicals commonly called nitrosamines and many of those are found to be cancerogenic.Valsartan has a tetrazole ring in his structure (highlighted in blue)The traditional way to make a tetrazole involves azide chemistry. More, in particular, a [2 + 3] cycloaddition between an organic azide (R-N3) and an organic nitrile (R-CN). However, this cycloaddition is too slow to be synthetically useful unless you add catalysts or use special reagents.Novartis (the company that developed the molecule) uses tributyltin azide. Or to be correct, based on the information in their patents and info online we assume they do.Tributyltin azide is a nasty chemical and you most likely gonna make it in situ (from tributyltin chloride and sodium azide.)One extra reason why we assume Novartis is using this route is that it was the method of choice when Novartis developed the process of Valsartan (or Diovan). Most pharmaceutical companies tend to stick with one commercial route of synthesis and are not willing to change this route unless there is a very good reason to do so. But in the meantime Valsartan is a generic product. So besides Novartis, there are many other manufacturers on the market.The generic market is a bit special. Most medicines are protected by patents. The main patent is describing the molecule itself. But most of the time there are patents protecting the route of synthesis as well. The patent describing the molecule will be older and consequently will expire sooner. Meaning that in many cases the synthesis patent is still valid at the time the molecule is becoming generic. The generic manufacturer will need to use a route of synthesis that is different than the patented one (i.e. the one of Novartis). In addition, the generic manufacturer has the advantage that they can use more recent reactions and in order to be competitive generic manufacturers will have much more emphasis on costs.In this specific case, one of the Chinese generic producers (Zhejiang Huahai Pharmaceutical) uses a cheaper process involving sodium azide and zinc chloride. [1]This general method for producing tetrazoles is developed by Demko and Sharpless in 2001 so it wasn’t available at the time Novartis launched the molecule in 1997.Again, this newer and cheaper route on itself does not produce NMDA, but apparently, the solvent they used was DMF and they destroyed the excess of sodium azide at the end of the reaction with sodium nitrite.There is nothing strange about using sodium nitrite to destroy excess azides. (In fact, it is the most common way to destroy azides.)But nitrites in acidic circumstances will also form some nitrous acid and in combination with (dimethyl)amine this nitrous acid will form NMDA.(Dimethyl)amine on his turn is coming from the solvent DMF. Either as an impurity in this solvent but most likely it will be formed during the reaction as well.Apparently, this route of synthesis was introduced by the Chinese manufacturer in 2012.The contamination was only discovered in 2018 causing several recalls of Valsartan. During the course of the investigation, it was discovered that another manufacturer used diethylformamide as solvent causing a similar nitrosamine impurity (N-nitrosodiethylamine). (I’m guessing here, but possibly that other manufacturer used this atypical solvent not because it has a real advantage but chiefly to circumvent the patent of Zhejiang Huahai.)And because Valsartan is not the only molecule in the Sartan family with a tetrazole ring other (generic) API’s were involved as well.Based on the values published by FDA[2] the maximum contamination was in the order of 60 ppm or 20µg in one tablet (of 320 mg, the largest daily dose).0.1 µg of NDMA per day is considered reasonably safe for human ingestion based on lifetime exposure. So some patients did get 200 times this dose.The whole incident is obviously bad publicity for the pharmaceutical industry and it raises some concern about how changes in chemical processes are introduced and checked for potential genotoxic impurities.I work in a manufacturer of APIs, it wouldn't surprise me that the guidelines will become more stringent because of this incident.Footnotes[1] CN104045602A - Improved method for preparing tetrazole for valsartan - Google Patents[2] Laboratory analysis of valsartan products

Oxo-octyl acetate is a colorless, clear, and oily liquid used in cosmetic products such as sunscreen and skin creams. Oxo-octyl acetate is produced by the reaction between ethylene oxide and phenol at elevated pressure and temperature. It has intermediate water solubility and exhibits moderate evaporation rate. Oxo-octyl acetate is a used as a solvent in pesticides. It is also used simultaneously with ammonium compounds as substitute for sodium azide due to its less toxic properties. Additionally, oxo-octyl acetate is non-reactive with lead and copper. It is used in numerous applications such as vaccines, cosmetics, and pharmaceutical products as preservative. Oxo-octyl acetate is necessary to enhance the shelf life of cosmetics and personal care products. It can also be used as an alternative to potentially harmful formaldehyde-releasing preservatives. The activity of the preservative oxo-octyl acetate is effective in inactivating gram-positive and gram-negative microorganisms and yeast.Oxo-octyl acetate is used in biological active agents such as bactericides, preservatives, fungicides, germicides, and insect repellents. It is also used as an anesthetic agent. Oxo-octyl acetate is employed in paints and coatings to improve fluidity, intensity, and luster; and reduce film forming temperature. Additionally, oxo-octyl acetate is used in perfumes as a fixative. It is also used as a solvent for inks, resins, dyes, and pharmaceuticals. It is also employed in organic synthesis. Oxo-octyl acetate is listed as an ingredient for vaccines in the U.S., the EU, and Japan. Furthermore, it is used as a solvent for nitrocellulose, waxes, oils, and some resins.Expansion of the cosmetics industry is expected to increase the consumption of oxo-octyl acetate. Increase in standard of living, rapid urbanization, and rise in per capita income in emerging economies of Asia Pacific and Latin America are expected to boost spending on cosmetics and personal care products. Oxo-octyl acetate is popular as it is less toxic and offers an extensive spectrum of antimicrobial activity. It is approved by the FDA for use in the cosmetics industry. However, availability of substitutes and stringent government regulations could hamper market growth. The future of preservatives in the cosmetic industry is anticipated to be shaped by regulatory issues and consumer perception.Asia Pacific is projected to a rapidly growing market for oxo-octyl acetate due to the increasing demand for cosmetics and personal care products in the region. India and China are likely to be the key consumers of oxo-octyl acetate due to the presence of an established cosmetics industry in these countries. The Republic of Korea, Japan, Taiwan, Malaysia, and Indonesia are other prominent consumers of oxo-octyl acetate in Asia Pacific. Furthermore, the market in emerging economies in Latin America and the Middle East is anticipated to exhibit incremental growth in the near future. Europe and North America are mature markets; hence, the market for oxo-octyl acetate in these regions is anticipated to expand at a moderate pace during the forecast period.The oxo-octyl acetate market is dominated by large and medium chemical and materials companies. Key players operating in the market include BASF, The Dow Chemical Company, E. I. du Pont de Nemours and Company, N V Organics Pvt. Ltd, Triveni Interchem Private Limited, Hangzhou Uniwise International Co., Ltd, Zhejiang WeishiBiotechnology Co., Ltd., Liaoning Kelong Fine Chemical Co., Ltd., Yingkou Tanyun Chemical Research Institute Corporation, Eastman Chemical Company, Chemsynth Corporation, and Mitsubishi Chemical.Full Report Analysis@ Oxo-octyl Acetate Market - Global Industry Analysis and Forecast 2016 - 2024