Fang Hanmin did not take Lao Liang's self-blame to heart. He knew very well that although the deputies in the team did not blatantly oppose him like Deputy Director Wang, who was in charge of production, they all had their own reasons. They make small calculations and muddle along at work. One more thing is worse than one less thing. When problems arise, they are pushed out and no one wants to take responsibility.
Fang Hanmin focused mainly on scientific research and production. He had neither the interest nor the energy to think about people. He saw what his deputies did and never argued with them as long as it was justified. After all, there was Deputy Factory Wang Being old is enough to annoy him. As long as it doesn't violate the general principle, everyone can live in peace, so as not to add to the troubles, but it will also lead to peace and quiet.
However, Fang Hanmin could also see that Deputy Factory Director Liang's self-blame was indeed from the bottom of his heart. Out of mutual respect, he comforted him a few words, and Lao Liang went back to his office.
...
According to the exploration direction pointed out by Fang Hanmin, the generic drug research team investigated the effectiveness of alkaline resolving agents. After two or three months of testing, they compared the resolving effects of seven or eight alkaloids and found that the two separation effects were very good. Good resolving agents, one is called (-)-strychnine and the other is called (+)-α-phenylethylamine.
Guo Peng and other scientific and technical personnel have not been exposed to optical splitting technology for a long time, and their understanding of this technology is still superficial. After the test was completed, they presented the test records and test results to Fang Hanmin, waiting for his analysis and judgment.
Judging from the test results and testing data, the resolving effect of strychnine and phenylethylamine is significantly better than that of acid resolving agents, and they are indistinguishable from each other. There is no doubt that these two alkaloids have become the most popular. A good candidate for resolving agent.
However, before determining the final splitting process, one must choose one of the two splitting agents and select the most reasonable one as the process shaping raw material.
In the case of the same splitting effect, other factors need to be considered, such as the price of the splitting agent, whether it is easy to purchase, its own toxicity, whether it is easy to separate from the target product, and the ease of recycling, etc. Only for each Only after careful analysis of the situation and comprehensive comparison can we determine which splitting agent is finally used.
Strychnine was first extracted from plants, but it was synthesized abroad in 1954. Scientific and technological personnel in related domestic industries also mastered the synthesis technology of this substance. By the late 1980s and early 1990s, , there is no shortage of this product in the domestic market. Phenylethylamine is a compound secreted in the human brain. However, all commercially available phenylethylamines are artificially synthesized.
In terms of price, because the raw material routes and technological processes for producing the two resolving agents are very different, the production cost of strychnine is relatively low, while the cost of phenylethylamine is high, resulting in the commercialization of strychnine. The price is about 20% lower than phenylethylamine.
Of course, both splitting agents are readily available on the market.
In the optical resolution process, the resolving agent forms a racemic compound with the active ingredient or trans-isomer of the generic drug, because strychnine and the active ingredient or trans-isomer of the drug are both solid crystal particles. It is difficult to achieve the ideal state of separation. In comparison, the separation of phenylethylamine and the anti-or isomer of the active ingredient of the drug is more complete.
Based on the physical and chemical properties of the two compounds, it can be judged that strychnine is more convenient to recycle after separation from the active ingredient of the drug or the trans isomer; while phenylethylamine, as a high-boiling liquid substance, is more troublesome to recycle.
After listening to Fang Hanmin's analysis and comparison, the scientific and technical personnel of the research team agreed that strychnine should be selected as the resolving agent in the setting process.
Because the toxicological data of strychnine could not be found in the relevant books at that time, but the time traveler had some knowledge of the complete data of this compound in his previous life, he vaguely remembered that strychnine was highly toxic. Fang Hanmin reminded a few Assistant, don't ignore the toxicity of the splitting agent.
"Strychnine is well separated from the two components of the drug. Even if the splitting agent is a bit toxic, it shouldn't have any impact on the final drug quality, right?" Because the phenylethylamine recycling process is troublesome, Guo Peng et al. tended to choose strychnine as the optical resolving agent.
"I hope everyone will never forget that drugs are used to treat diseases and save lives. The reason why generic drugs are optically separated is because the trans isomers in them are not only ineffective, but also toxic. We cannot eliminate the trans isomers. While removing the human body, introducing another toxic substance into the medicine is not only a fool’s errand, but also an irresponsible act! Although this possibility is very small.”
"Director Fang, if you choose phenylethylamine as the splitting agent, not only will the price be higher, it will inevitably push up the production cost, but also the troublesome recycling process will also lead to an increase in operating costs. The final total cost must also be considered. factors!"
It is not that Fang Hanmin has not considered the issue of production costs, but he believes that as drugs that treat diseases and save lives, among the many factors that need to be considered, the efficacy and safety of the drugs are the first factors that must be considered. “For the conscience of practitioners, Ma No matter how much cost advantage it has, it must be excluded because of its toxicity. Phenylethylamine is a secretion in the human brain and is absolutely safe for the human body. Even if it is used as a resolving agent, it will High production costs can also be reduced through technological advancement, but this is the work to be done next.”
Fang Hanmin's goal is very clear. He wants to provide patients with a pharmaceutical product that has high efficacy, extremely low side effects, and is significantly cheaper than similar imported drugs. Through accounting, under the current technological conditions, if phenylethylamine is used as the resolving agent, the final cost will increase by 10%. Although the first two goals of this generic drug have been achieved, the production cost is still high, which still This was not the result Fang Hanmin wanted.
In order to achieve the goal of high efficiency and low toxicity of generic drugs, the raw material route cannot be changed. The remaining work is to reduce production costs by optimizing process technology, and ultimately make this drug a high-quality and low-cost pharmaceutical product.
Faced with Fang Hanmin's persistence, although Guo Peng and other technical staff said they obeyed his decision, they were helpless, "Director Fang, we feel that it is a bit unrealistic to reduce costs by optimizing process technology. Judging from the test process in 2017, we don’t know which process links can be further optimized.”
No matter how advanced the process technology is, even if it achieves industrialization, Fang Hanmin will not think that it has reached the ultimate level of technology, let alone a process that is still in the experimental stage. He believes that there is more than one process link that can be optimized. This is what Guo Peng and others The gap in technical level between him and Fang Hanmin!
Guo Peng and others believe that they worked at the test site from beginning to end, operating every step with their own hands, and doing all aspects of the process technology carefully enough that they could no longer find any areas for improvement.
Fang Hanmin has no doubts about the professionalism of all the scientific and technical personnel and experimental workers in the research team, but that has nothing to do with technological progress and process optimization. He believes that there must be more reasonable process technology, and it is entirely possible to reduce the final cost through technological progress.
Fang Hanmin decided to find a breakthrough from the completed tests. He carefully reviewed the test records from beginning to end, recorded the technical nodes that he thought needed further study, and then proposed targeted improvement measures.
After screening, Fang Hanmin believes that the following three nodes require further research: First, during the process of synthesizing APIs, can the formation of trans isomers be better suppressed by changing the temperature, pressure and material ratio?
Second, when performing optical resolution of trans isomers, is it possible to achieve higher resolution efficiency by changing the process conditions? If this can be achieved, not only can the amount of splitting agent be reduced, directly reducing costs, but also operating costs can be saved.
Third, look for better splitting agent recycling technology to make the recycling process easier, which can also reduce costs.
After receiving the task, Guo Peng and other technical staff looked at each other in confusion. Fang Hanmin knew that they wanted to end the project as soon as possible, but in order to provide patients with a safe, effective, high-quality and affordable medicine, he believed that these studies must be carried out in depth and the project should be concluded. Sooner or later it doesn't matter.
Back in the laboratory, Guo Peng and others followed Fang Hanmin's instructions to conduct further investigations and tests on the first node problem. Based on the previous experiments, the research team investigated dozens of material ratios and found that in Under certain temperature and pressure conditions, the material composition of the system has almost no impact on the production of isomers.
Subsequent experiments demonstrated that temperature has minimal effect on the isomers.
After listening to Guo Peng's disheartened situation report, Fang Hanmin didn't care. "Previous experiments were all conducted under normal pressure. Why not see what happens under pressurized conditions?"
"You mean pressure test? However, the current test equipment can only be used under normal pressure conditions. Moreover, if the equipment is under pressure, will it be dangerous?"
"Yes, I am talking about the pressure test. Under a certain pressure, the form and reaction mechanism of certain substances will change. I think it is worth a try. As for the equipment, you can ask the relevant manufacturers to see if they have ready-made equipment. , hurry up and buy it back. As for the danger of pressure test, it is definitely there, but it is not terrible. As long as you operate it carefully and observe at any time, you can be safe. When you are ready, I will go to the laboratory to demonstrate to you. Operate under pressure.”…
After filing with the regulatory agency and obtaining registration approval, Hongxing Pharmaceutical Factory is preparing for the industrial production of this generic drug. The first thing to do in the early stage is to contact the relevant pharmaceutical design institutions to carry out the basic design of the industrial device. Because there were too many things to do, Fang Hanmin was really too busy. He planned to leave this matter to the chief engineer Lao Xia. After all, Mr. Xia had dealt with the Medical Design Institute before and was familiar with the processes and routines.
After listening to the task given by Fang Hanmin, despite some rejection in his heart, Lao Xia still agreed verbally, but he didn't seem so happy, "Director Fang, the production of generic drugs is the top priority of Red Star Pharmaceutical Factory since its establishment. Let me be responsible for the design and design. Logically speaking, this is my honor, but as you know, at my age, I will retire in more than a year. Now I am on a business trip. If I sit in the car for a long time, I feel very tired. I can’t even keep up with young people when walking. pace, I’m afraid that I won’t be able to complete the task well and live up to your expectations!”
Except for Mr. Xia and Deputy Director Wang in the team, no one at all levels of the factory dared to shirk the work assigned by Fang Hanmin himself. However, Lao Xia was one of the main veterans of the Red Star Pharmaceutical Factory. He relied on his seniority to actually After politely rejecting the task assigned to him by Fang Hanmin, Lao Xia doesn't want to worry about anything now. He doesn't want to do any specific work. He just wants to dawdle. He hopes to stay in the position of chief engineer until he retires.
