Through an in-depth analysis of the process route and technical conditions of the original patent, Fang Hanmin believed that according to the method given in the patent specification, the product obtained must be a racemate, and it is impossible to eliminate the enantiomers by changing the reaction conditions. The purpose of the structure.
The patent protection of generic drugs is about to expire. Because this drug has significant efficacy and high market expectations, Red Star Pharmaceuticals is not the only domestic pharmaceutical company that is interested in this drug.
In order to be the first to develop this kind of drug in China and take advantage of the time, Fang Hanmin believes that it is no longer possible to start from scratch in terms of technical solutions. Now he can only continue to move forward according to the original patented process route.
In order to find out which isomer is the active ingredient of the drug, Fang Hanmin decided to use the "disassembly" method to split the racemate sample obtained from the experiment, completely separate the two enantiomers, and then Their biological activities were measured respectively.
Fang Hanmin reported his ideas to the scientific and technical personnel of the generic drug research group. Guo Peng and others expressed their understanding of the next scientific research path, but when it came to the specific methods, they were at a loss, "Dismantle, you mean to separate these two Can the isomers be separated? Their physical and chemical properties are almost identical, how can they be separated?"
Because it involves brand-new concepts and advanced technology, Fang Hanmin has to do some popular science for these scientific and technical personnel before carrying out the split test. “In order to find out which optically active substance is the active ingredient of the drug, it is necessary to combine the two opposite substances. Enantiomers are separated because the two isomers have almost identical physical and chemical properties. Of course, using known conventional methods cannot achieve the purpose. Generally speaking, the main methods for resolving enantiomers are mechanical resolution, Microbial resolution method, selective adsorption resolution method, induced crystallization resolution method and chemical resolution method.”
"Director Fang, which method are we going to use?"
“I haven’t made a final decision yet, but based on the molecular structure of this drug, I think both the selective adsorption method and the induced crystallization method are suitable, but there are many trade-offs that need to be made, such as the difficulty of operation, the raw materials involved, cost and efficiency. Factors such as this all need to be considered comprehensively.”
"What is the next task of the research team?"
"Continue to improve and optimize the current test conditions. Even if the racemate of the enantiomer is obtained, the yield should be increased as much as possible and the material consumption should be reduced."...
When the time traveler was an undergraduate student at 985 University in his previous life, he was exposed to the optical resolution technology of chiral compounds in the laboratory. In his subsequent study and work, this technology was even used as a tool and was often used in scientific research experiments. Therefore, Fang Hanmin is very familiar with this technology.
The current problem is to choose the most appropriate method among the two methods. Fang Hanmin must comprehensively consider various factors such as the operating process of each method, the required auxiliary raw materials, energy consumption, cost and environmental impact.
Through analysis and comparison, Fang Hanmin believes that the adsorption method has a longer operating cycle, slightly lower production efficiency, and more complicated equipment, but its biggest advantage is that it has good separation effect and can obtain highly pure optically active substances after separation.
The induced crystallization method saves time, is relatively simple to operate, has high efficiency, and has relatively simple equipment, but the purity of the optically active substance obtained by separation is difficult to exceed 95%.
For special commodities such as drugs, the higher the purity of the original drug, the fewer impurities, the better the efficacy of the drug, and the smaller the toxic and side effects, and vice versa.
After comparison and weighing, even though the operation was relatively complicated and the efficiency was lower, Fang Hanmin finally decided to choose the adsorption method.
The key to the adsorption separation method is the selection of solid adsorbent, the determination of adsorption conditions, such as temperature and solution concentration, and the determination of temperature and pressure during the desorption process.
Because the original patent did not disclose any information about this operation, a large amount of work needs to be started from scratch to separate and purify the two optical isomers of the generic drug.
Fang Hanmin formulated the test method for adsorption and separation and explained the next test plan to Guo Peng and others, "Through the test, we will first find an adsorption material with the highest efficiency and best selectivity among several solid adsorbents. On this basis, we will then examine the process conditions of the adsorption and desorption processes.”
"Director Fang, according to your statement, the adsorption splitting test may be more difficult than drug synthesis. This test may take more time. No one can say what technical difficulties may be encountered during the test." Guo Peng was a little afraid of the experimental task.
"Although optical splitting technology has already appeared, after all, not only have you never seen this technology before, but you have not even heard of it. Therefore, for you, this experiment is an exploration of an unknown world, and of course it will not be strictly limited in time. . You can carry out your work with confidence and boldness. There will inevitably be twists and turns in the test process, but it is not scary to encounter difficulties. I believe there are no difficulties that cannot be overcome. I can discuss technical issues with you at any time."
Fang Hanmin's encouragement strengthened the confidence of Guo Peng and other technical staff. They believed that with the support of factory director Fang, there would be no technical problem that could not be solved.
...
In early May, at about 10 o'clock in the morning on a Tuesday, Fang Hanmin had just returned to his office from the technical center. A staff member from the factory office sent him a letter. He took it and saw that it was from his hometown.
The content of the letter was not long. It was written by his brother Fang Hanwen. The main message was that he had received the last letter to his family. Knowing that he was getting married in the city, his parents were very unhappy, especially the old father who was furious.
At the end of the letter, Fang Hanwen wrote: "Brother, please take some time to take your sister-in-law back to your hometown recently. Listen to your father. If you don't come back, he will go to the city to find you. What's your father's temper?" You know, if he really comes to find you, he will come to your workplace to make a fuss with you and let outsiders laugh, which will do you no good, right?"
"Hi!" After reading the letter, Fang Hanmin leaned on his chair and sighed helplessly.
At dinner, Fang Hanmin took out the letter and handed it to Song Yuping, "Look at this."
"What is this?" Song Yuping put down her chopsticks, "Hey, why do you want me to read the letter from your hometown?"
"It has something to do with you, you'd better take a look."
Hearing that it had something to do with her, Song Yuping pushed the bowl and chopsticks aside, read it from beginning to end, and then returned the letter to Fang Hanmin, "The problem is very serious! Let us go back to our hometown. If we don't go back, the old man will arrive I'm looking for you here. If it's on Sunday, I don't care. The important thing is do you have time?"
"They do things completely regardless of other people's feelings. I don't understand what they think!" Fang Hanmin didn't understand his parents' actions.
"Needless to say, our parents were very angry because we didn't go back to our hometown to get married. If your father insists on letting us go back, he will definitely charge you with it."
"Hey, call for punishment? What did I do wrong?" Both the time traveler and the host believe that where to get married is entirely their own business. Fang Hanmin got married and started a family. Not only did he not ask his parents to pay a penny, he also continued to support his hometown. What's wrong with providing financial assistance?
"It's a pity that they don't understand this! You are their son, and your parents think that they should arrange your marriage no matter what. Otherwise, they will lose face in front of relatives, friends and villagers. It is treason for you to do this. .”
"What age are you in? You still pay attention to these meaningless things. The customs and habits in your hometown are really unbearable! How much is face worth in such a poor place?" Fang Hanmin had strong resistance to his parents' demands.
Song Yuping looked extra calm, "Whether you can bear it or not, you have to take your parents' requests seriously. Otherwise, if your old father comes to the city to settle a score with you, how will you face it? Although this is a private matter in your own family, But your current position is different from that of ordinary employees, so you have to consider the impact!"
These words made Fang Hanmin completely lose his temper. Song Yuping was right. Even if it was a private matter, it had nothing to do with work. If it caused a stir in the city, it would at least give the outside world a bad impression. As the director of Red Star Pharmaceutical Factory, even herself If you can't handle your family affairs well, how can you manage a business with seven or eight thousand people?
Although everyone knows that Fang Hanmin can sit in the position of factory director entirely based on his own strength and contribution, he cannot be careless in other aspects.
Thinking of this, Fang Hanmin asked: "How about taking some time to go back? It can be considered as a way to appease them."
Song Yuping looked indifferent, "Whatever, as long as you have time."
Fang Hanmin shook his head helplessly, "How can I have time! But I have to face it."
Song Yuping understood her husband's situation very well, "Yes, I know you are in a difficult situation, but I can't replace you in this matter, so you should take time to go back during your busy schedule."
After some discussion, the two decided to use this weekend to go back to their hometown and wrote a letter to inform their parents in advance.
The production department of the Red Star Pharmaceutical Factory operates continuously regardless of day, night and holidays. Even the administrative and logistics organizations are always on duty. Therefore, even though Fang Hanmin is the head of the factory, even if he goes out for personal matters, he must report to the relevant factory officials according to regulations. The department said hello in case something happened in the factory and they couldn't find him.
On Friday afternoon, Fang Hanmin told the factory office that he was going back to his hometown on the weekend, and the director of the factory office would send a car to take him there. "Director Fang, this is not very far from your hometown. It can be reached in more than two hours by car. I Make arrangements and ask the minibus driver to take you there tomorrow."
Fang Hanmin immediately refused, "Absolutely not! It's also very convenient for us to take long-distance buses. If you start this way, team members and even middle-level cadres may ask you for a car to do private things in the future, and then the small buses will not be enough." "
Private use of official vehicles is a common disadvantage of all units, but Red Star Pharmaceutical Factory has done relatively well in this regard. When Director Yuan was in office, he imposed strict restrictions on the use of vehicles. Fang Hanmin did not pay attention to pomp and circumstance. After he took over, he even more He had plugged all the previous loopholes in vehicle management. In order to return to his hometown, he could not break the rules he had set.
This weekend coincided with the weekend break. Fang Hanmin and Song Yuping got up early on Saturday, had breakfast at home, freshened up, brought the gifts they bought for the elderly, and took the first train to their hometown at the long-distance station. Shuttle bus.
At around nine o'clock in the morning, the bus arrived at the stop. When they got off the bus, they found that the sky was gray and a bit hot. Song Yuping said casually: "I didn't bring an umbrella. Is it going to rain?"
Fang Hanmin looked up at the sky, "It's just cloudy, it doesn't look like it's going to rain."
It takes about an hour to walk from the long-distance bus station to Shuangshu Village. When Fang Hanmin and his wife appeared at the head of the village, there were many villagers working in the fields on both sides of the road. Villagers he knew greeted him, "Hanmin, come back." La?"
Fang Hanmin responded to the other party and walked forward. There were discussions behind him, "He hasn't been back for several years, has he?"
"How beautiful that girl is! Are they married?"
"He's over thirty, right? He should have gotten married long ago."
"Who knows whether Yue is married or not? I haven't heard from his parents."...
