[Shenzhen Business Daily News] (Reporter Tu Jingyu Wen/photo) "We cooperated with Tianjin University and other institutions to carry out collaborative innovation and R&D from the molecular level to the implementation of industrialization, breaking the foreign technological monopoly, and meeting the national requirement of" overcoming a number of key common technologies that restrict industrial development "through innovation drive." Yang Zhanju, general manager of Shenzhen Huarun Jiuxin Pharmaceutical Co., Ltd., said in an interview with the reporter of Shenzhen Business Daily. Recently, the project of "R&D and industrialization of refined crystallization technology of high-end pharmaceutical products", which was participated by Shenzhen China Resources Jiuxin Pharmaceutical Co., Ltd., won the second prize of National Science and Technology Progress Award.

● One product of the company has won two national invention patents

As one of the largest manufacturers of cephalosporin sterile APIs and preparations in China, China Resources Jiuxin Pharmaceutical Co., Ltd. specializes in the research, development, production and sales of anti infective drugs. It is the first batch of "national high-tech enterprises" in Shenzhen and the first drug manufacturer in China that has passed the EU GMP certification in the whole system of sterile preparations and sterile APIs. The company's product "Xintailin" has won two national invention patents, and has been granted patent protection for 20 years.

● Use modern crystallization technology to manufacture high-end products

According to the reporter, although China is the largest country in pharmaceutical production, export and use, the pharmaceutical products are still low-end because the crystal form of chemical APIs is blocked by international patents and the refined crystallization technology is backward, and the product quality leads to frequent drug use incidents. The current situation of "price for quantity" in the export of APIs and the drug market of key tertiary hospitals is almost monopolized by foreign enterprises has emerged. According to relevant statistics, more than 85% of China's pharmaceutical products are crystalline products, and industrial crystallization technology is a key common technology in the R&D and production of APIs. However, the complexity of industrial crystallization process and the unclear mechanism make industrial crystallization technology and device R&D still difficult in the world. There are no advanced industrial crystallization modules and design calculation cases in major design manuals and commercial software at home and abroad.

"Due to the existence of technical and commercial barriers to the internationally advanced industrial crystallization technology and devices, most high-end pharmaceutical products are in the stage of crystal patent protection. The weak international competitiveness of enterprises has restricted the transformation and upgrading of China's pharmaceutical industry." Yang Zhanju told reporters, "We use cefazolin sodium pentahydrate (trade name 'Xintailin') Nine kinds of pharmaceutical products are the specific research objects. Starting from the basic research in the laboratory, through systematic data and mechanism analysis, combined with computer aided process simulation, engineering amplification research and development has been carried out until industrial application, realizing the large-scale crystallization production of high-end drugs with specific crystal forms. At the same time, the crystal form identification standards and detection and analysis platform of drugs have been established. "

Yang Zhanao said that the technical research of the project implemented the research strategy from molecular level to industrialization, focused on breaking through the key complete set of technologies such as drug crystal design and screening, process quality control, coupling crystallization, etc., developed and formed crystallization equipment with intelligent and information-based characteristics, and broke the foreign technology monopoly.

● The invention of coupling refining crystallization technology is the first in the world

"In terms of the technical research of the project, we first constructed a research method for the engineering of polymorphic drug crystals, which revealed the law of the molecular assembly process of drug crystals, broke through the patent barrier of drug crystals, and laid a theoretical foundation for the research and development of high-end pharmaceutical products." Yang Zhanao said about the independent innovation of technical research, "Secondly, the green refined crystallization process set we have developed has provided technical support for the industrialization of high-end pharmaceutical products. Among them, the drug crystal form high-throughput screening technology has proved the structure-activity relationship of polycrystalline drugs, developed online quality control technology, and the coupling crystallization technology has solved the preparation problem of specific target crystal form drugs. In addition, we have integrated and innovated the refined crystallization production line of high-end pharmaceutical products, developed an intelligent crystallization device and an automatic control system for crystallization process, and realized industrial application. "

There are many refining and crystallization processes for pharmaceutical products, with long process and low efficiency. The R&D and innovation of the project is an arduous process. Yang Zhanao gave the reporter an example that drug crystal form screening is a huge challenge facing this field in the world. The new drug crystal form high-throughput rapid screening technology developed by CR IX successfully screened five new drug crystal forms, and established crystal form identification standards and quantitative analysis methods. The new coupling crystallization technology is specifically aimed at the problems in the refining process of pharmaceutical products at the current stage, and has invented the coupling refining crystallization technology of nine high-end products, including cefazolin sodium pentahydrate, which is the first at home and abroad.

It is understood that the patented product of China Resources Jiuxin Pharmaceutical, Wushui Cefazolin Sodium, has solved the problem of unstable quality of ordinary Cefazolin Sodium with its new and unique coupling structure, and the product validity is 6 months longer than ordinary Cefazolin Sodium. At present, it has obtained two Chinese patents and three international patent authorizations in Europe, the United States, India and other countries, and won the 11th and 16th "China Patent Excellence Awards". At present, the product occupies more than 95% of the domestic market, and the annual market consumption exceeds 2 billion yuan.