Fang Hanmin did not take Lao Liang's self-blame to heart, he knew very well in his heart that several deputies in the team, although they were not like Deputy Director Wang, who was in charge of production, blatantly opposed him, but they all had their own small calculations, and they were able to get by at work, and it was better to have more than one thing.

Fang Hanmin focuses on scientific research and production, he has neither interest nor energy to ponder people, for what the deputies do, he sees in his eyes, as long as it is reasonable, never bother with them, after all, there is a deputy director Wang is enough for him to annoy, without violating the general principle, everyone is safe, so as not to increase the troubles, but also to be quiet.

However, Fang Hanmin could also see that Deputy Director Liang's self-blame this time was indeed from the heart, out of mutual respect, he comforted 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 group investigated the effectiveness of alkaline fractionants, and compared the separation effects of seven or eight alkaloids through two or three months of experiments, and found two fractionants with good separation effects, one is called (-)-strychnine, and the other is called (+)-α-phenylethylamine.

Guo Peng and other scientific and technological personnel have not been in contact with optical splitting technology for a long time, and their understanding of this technology is still on the surface, and after the test is completed, they submit the test records and test results to Fang Hanmin, waiting for his analysis and judgment.

Judging from the test results and test data, the separation effect of strychnine and phenylethylamine is significantly better than that of acid fractionants, and it is difficult to distinguish between them, and there is no doubt that these two alkaloids have become the best candidate resolutions.

However, before determining the final splitting process, it is necessary to choose one of the two splitting agents that makes the most reasonable one as the raw material for process finalization.

In the case of the same splitting effect, it is necessary to consider the influence of other factors, such as the price of the splitter, whether it is easy to buy, its own toxicity, whether it is easy to separate from the target product, and the ease of recovery, etc., only after careful analysis of all aspects of the situation, and after comprehensive comparison, can determine which fractionant to use in the end.

Nux strychnine was first extracted from plants, but in 1954 it was artificially synthesized abroad, and the scientific and technological personnel of related industries in China also mastered the synthesis technology of this substance, and in the late eighties and early nineties, there was no shortage of this product in the domestic market. Phenethylamine is a compound secreted in the human brain, but commercially available phenethylamine is synthesized.

In terms of price, because the raw material routes and technological processes for the production of the two splitting agents are very different, the production cost of strychnine is relatively low, while the cost of phenylethylamine is higher, resulting in the market price of strychnine being about 20% lower than that of phenylethylamine.

Of course, both dispensers are readily available in the market.

In the optical fractionation process, the fractionant 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 solid crystalline particles, and the separation of the two is difficult to achieve an ideal state.

According to the physical and chemical properties of the two compounds, it can be judged that strychnine is more convenient to recover after separation from the active ingredients of the drug or trans isomers; As a liquid substance with a high boiling point, phenylethylamine is more troublesome to recycle.

After listening to Fang Hanmin's analysis and comparison, the scientific and technological personnel of the research group agreed that strychnine should be selected as the splitting agent in the shaping process.

Because the toxicological data of strychnine could not be found in the relevant books at that time, but the traveler had some understanding of the complete data of this compound in his previous life, he vaguely remembered that strychnine was very toxic, and Fang Hanmin reminded several assistants not to ignore the toxicity of the splitting agent.

"Strychnine has a good separation from the two components of the drug, even if the fractionant is a little toxic, it should not have any effect on the final quality of the drug, right?" Because the phenylethylamine recovery process is more troublesome, Guo Peng et al. tend to choose strychnine as an optical resolving agent.

"I hope you never forget that drugs are used to treat diseases and save people, the reason why the optical separation of generic drugs is because the trans isomers are not only ineffective, but also toxic, we can't eliminate the trans isomers at the same time, and introduce another toxic substance into the drug, which is not only a blind toss, but also an irresponsible behavior! Although this is very unlikely. ”

"Director Fang, if you choose phenylethylamine as a splitting agent, in addition to the high price itself, it will inevitably push up the production cost, and the more troublesome recovery process will also lead to an increase in operating costs, and the final total cost is also a factor that must be considered!"

Fang Hanmin has not considered the issue of production cost, but he believes that as a drug that treats diseases and saves people, among the many factors that need to be considered, the efficacy and the safety of the drug are the first elements that must be considered, "For the conscience of practitioners, strychnine should be excluded even if it has a great cost advantage because of its toxicity." Phenethylamine is a secretion in the human brain, which is absolutely safe for the human body, even if using it as a decomposition agent will push up the cost of production, and the final cost can be reduced through technological progress, but this is the next work to be done. ”

Fang Hanmin's goal is very clear, he wants to provide patients with a pharmaceutical product with high efficacy, very low toxicity and side effects, and significantly lower price than similar imported drugs. Through accounting, under the current process technology conditions, if phenylethylamine is used as a splitting agent, the final cost will increase by 10%, although the first two goals of this generic drug have been achieved, but the production cost is high, which is still not the result that Fang Hanmin wants.

In order to achieve the goal of high efficiency and low toxicity of generic drugs, the raw material route has been irreversible, and the remaining work is to reduce the production cost by optimizing the process technology, and finally make the drug a high-quality and low-cost pharmaceutical product.

In the face of Fang Hanmin's persistence, although Guo Peng and other technicians expressed their obedience to his decision, they were also helpless, "Director Fang, we feel that it is a bit unrealistic to achieve the purpose of reducing costs by optimizing process technology. ”

No matter how advanced the technology is, even if it is industrialized, Fang Hanmin will not think that it has reached the extreme of technology, not to mention a process that is still in the experimental stage, he believes that there is more than one process link that can be optimized, which is the gap between Guo Peng and others and Fang Hanmin in terms of technical level!

Guo Peng and others believe that they have been working at the test site from beginning to end, operating each step by hand, and all aspects of the process technology have been done carefully enough that they can no longer find the places that need to be improved.

Fang Hanmin has no doubt about the professionalism of all the scientific and technological personnel and test workers in the research group, but it has nothing to do with technological progress and process optimization, he believes that there must be a 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 experiments, he carefully looked at the test records from beginning to end, recorded the technical nodes that he thought needed in-depth research, and then proposed targeted improvement measures.

After screening, Fang Hanmin believes that the following three nodes need to be further studied: first, in the process of synthesizing APIs, can the formation of trans isomers be better inhibited by changing the temperature, pressure and material ratio?

Second, is it possible to achieve higher resolution efficiency by changing the process conditions when optically resolving trans isomers? If this can be achieved, not only can the amount of dispensant be reduced, which will directly reduce the cost, but also save operating costs.

Third, find a better technology for the recovery of dissociants to make the recycling process easier and reduce costs.

After receiving the task, Guo Peng and other technicians looked at each other, 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 low-cost conscience medicine, he believed that these studies must be carried out in depth, and it does not matter whether the topic is concluded sooner or later.

Back in the laboratory, Guo Peng and others carried out further investigation and testing on the first node problem according to Fang Hanmin's instructions, and on the basis of the previous experiments, the research team investigated the ratio of dozens of materials, and found that under certain temperature and pressure conditions, the material composition of the system has almost no effect on the production of isomers.

Subsequent experiments proved that the effect of temperature on the isomer was negligible.

After listening to Guo Peng's disheartened report, Fang Hanmin didn't care, "The previous tests were all atmospheric pressure operations, why not see what happens under pressurized conditions?" ”

"You mean a compression test? However, the current test equipment can only be used under normal pressure conditions, and the equipment is under pressure, will it be dangerous? ”

"Yes, I'm talking about the pressure test, under a certain pressure, the form and reaction mechanism of certain substances will change, I think it's worth trying. Equipment, you ask the relevant manufacturers to see if they have ready-made ones, and hurry up to buy them back. As for the danger of pressurization test, there must be, but it is not terrible, as long as it is carefully operated and observed at any time, it can be foolproof. When you're ready, I'll go to the lab and show you how to operate under pressure. ”......

After the regulatory agency filed and obtained the registration approval, Red Star Pharmaceutical Factory is preparing for the industrial production of this generic drug, and 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 are too many things, Fang Hanmin is really too busy, and he is ready to hand over this matter to the chief engineer Lao Xia to do, after all, Mr. Xia has dealt with the medical design institute before and is familiar with the process and routine.

After listening to Fang Hanmin's task, although he refused a little in his heart, Lao Xia still verbally agreed, but he didn't seem so happy, "Director Fang, the production of generic drugs is the top priority since the establishment of the Red Star Pharmaceutical Factory, let me be responsible for liaising with the design institute, it stands to reason that this is my honor, but you also know that at my age, I will retire in more than a year, and now I am on a business trip, and I feel very tired when I sit in the car for a little longer, and I can't even walk to keep up with the pace of young people, I'm afraid that I can't complete the task well and live up to your hopes!" ”

Except for Mr. Xia and Deputy Director Wang in the team, other leaders at all levels of the factory, no one dared to shirk the work assigned by Fang Hanmin personally, but Lao Xia was one of the main veterans of the Red Star Pharmaceutical Factory, he relied on his old qualifications, and actually declined the task given to him by Fang Hanmin.