A new method for refining antihypertensive raw material valsartan, pharmaceutical grade filtration, washing and drying three-in-one


Valsartan is a new generation of angiotensin Ⅱ receptor antagonist, with high selectivity and special direct action, can effectively antagonize AT1 receptor, its half-life is about 9 hours, and the antihypertensive effect can be maintained for more than 24 hours, and has Better valley-to-peak ratio, with a wide range of therapeutic effects, and good patient tolerance. The general dosage of valsartan is 80 mg/day, which can effectively lower blood pressure in patients with mild and moderate hypertension.

Since valsartan is a drug for chronic diseases, patients need to take it for a long time. In order to prevent the side effects caused by the accumulation of impurities in the product in the patient's body, the 2010 Chinese Pharmacopoeia requires that the total content of impurities in the valsartan raw material should not exceed 0.30%, and The content of a single unknown impurity shall not exceed 0.10%.

The impurity content in the valsartan crude drug is greatly affected by the quality of the raw materials used in its preparation process, especially the quality of the raw material n-valeryl chloride. The detection of raw material n-valeryl chloride generally needs to be derivatized and then carried out by chromatography, which often results in the impurity in it not being fully and effectively detected, which may be transferred to the final product. Once the valsartan impurity content exceeds the specified limit of the quality standard, it is required to be purified.

Therefore, it is crucial to determine an economical and efficient purification method for valsartan.

The structure of valsartan has a chiral center. During the refining and purification process, when valsartan is heated and dissolved in a solvent, its chiral center is easily racemized to generate D-type valsartan isomer (EP Pharmacopoeia impurity A) , leading to a decrease in the optical purity of refined valsartan. At present, regarding the removal of D-type valsartan isomers, most of the existing patent reports use simple ester solvents or mixed alcohol ester solvents to repeatedly refine valsartan. The disadvantage of using this type of refining method is that after production and amplification, valsartan With the prolongation of refining, purification and drying process time, the D-valsartan isomer is constantly increasing, which is unfavorable for removing the D-valsartan isomer, and the drying time is long, and the residual solvent is relatively high, so it is not suitable for high Industrial production of standard valsartan.

Pharmaceutical-grade filtration, washing and drying three-in-one new method for refining antihypertensive raw material valsartan, working principle In the cyclization process of the common purification method of antihypertensive raw material valsartan, the racemization of the product is obvious, and there is no separation and purification step for the intermediate of valsartan methyl ester, resulting in the final product valsartan requiring multiple recrystallizations. The chemical purity and optical purity can reach the Pharmacopoeia standard, the operation is complicated, the yield is low, and the cost is high. The medical-grade filtration, washing and drying three-in-one developed by Changzhou Baide has solved the problem of low chemical purity and low optical purity of valsartan produced by existing technology, and requires multiple recrystallizations to meet the pharmacopoeia standard. The valsartan cyclization reaction solution is stirred and reacted in a pharmaceutical-grade filter, washing and drying three-in-one, and then filtered, washed, and dried to obtain the pure alkali metal salt of valsartan methyl ester; then the alkali metal valsartan methyl ester The pure salt is mixed with inorganic alkali aqueous solution II, heated and hydrolyzed, then acidified, extracted, recrystallized once, and dried to obtain valsartan.

Pharmaceutical-grade filtration, washing and drying three-in-one new method for refining antihypertensive raw material valsartan (1) stirring reaction of valsartan crude product The cyclization reaction solution for preparing valsartan methyl ester is mixed with the inorganic alkali aqueous solution I, and stirred for reaction; (2) Preparation of valsartan crude product: After the reaction was completed, separate layers and cool the water layer to 10°C, adjust the pH to 1 with hydrochloric acid, filter and wash to obtain crude valsartan. (3) Refined dissolution of valsartan Add the obtained valsartan crude product into ethyl acetate, and heat until completely dissolved; (4) Primary refining of valsartan After cooling to room temperature, continue cooling to 10°C and store for 3 hours, filter, wash the filter cake with a small amount of cold ethyl acetate; dry to obtain the primary crystallization product of valsartan; (5) Secondary refining of valsartan Heat the primary crystallization product of valsartan in ethyl acetate until dissolved, stir and cool to room temperature, filter, wash the filter cake with a small amount of ethyl acetate, and dry it to obtain the secondary crystallization product of valsartan, that is, refined valsartan . The impurities in the refined valsartan were detected by HPLC method, and the relevant impurities were not detected, the valsartan impurity K was not detected, and the chiral isomers were not detected.

Compared with the traditional refining method, the three-in-one refining method of pharmaceutical grade filtration, washing and drying can not only reduce the isomer content of valsartan from 0.1 to 1.0% to N.D, but the chromatographic purity of the obtained valsartan is higher than 99.9%, and all solvents The residue can be dried to below the detection limit in a relatively short period of time. The amplification process is stable, the process is highly repeatable, the operation is simple, and the cost is low. It is very suitable for industrial production.


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