API synthesis is of great importance for chemical synthesis companies. What is it? API (active pharmaceutical ingredients) is the active ingredient used in the manufacture of pharmaceutical preparations. It is usually obtained by chemical synthesis, semi-synthesis, and microbial fermentation or separation of natural products, and is made through one or more chemical unit reactions and operations. The research on the API synthesis process is the basis of drug research and production. Today, Hawach will share with you three elements of the synthesis of active pharmaceutical ingredients.
Key elements of API synthesis — element 1
First, the selection and design of the synthetic route of API synthesis must be based and reasonable.
(1) The general procedures for the design and selection of synthetic routes include:
a. Conduct literature research on the target compound to be synthesized, and design or select a reasonable synthetic route;
b. Carry out a preliminary analysis of the selected route, and have an overall understanding of the domestic and foreign research status and intellectual property rights of the compound;
c. Conduct a preliminary evaluation of the process used and provides a reliable basis for drug evaluation through the above research.
(2) For new chemical entities
According to its structural characteristics, comprehensively consider the following:
a. Degree of difficulty in obtaining starting materials;
b. The length of the synthesis step;
c. The level of yield;
d. Whether the post-treatment and conditions of the reaction meet the requirements of industrial production and environmental protection.
(3)For drugs with known structure
Based on literature research, a comprehensive understanding of the research situation of the drug preparation should be obtained, which includes:
a. Feasibility (whether raw materials are easily available and whether the reaction conditions can be industrialized);
b. Controllability (whether the reaction conditions are mild and easy to control);
c. Stability (whether the quality of the intermediate is controllable, the quality of the final product, and the yield are stable);
c. Reasonability (cost, price, and toxicity of raw materials, reagents, solvents, etc.).
Key elements of API synthesis — element 2
Secondly, the starting materials, reagents, and organic solvents must have standards and emphasize standardization. For the control of starting materials, GMP requires to control the quality of products from the source.
(1) There are the following requirements for synthetic products:
a. List of materials: List the names of materials (such as raw materials, starting materials, solvents, reagents, and catalysts) used in the synthesis of active pharmaceutical ingredients, explain their respective use procedures, and identify key materials;
b. Testing methods of materials: clarify the quality control information of these materials;
(2) The selection principle of starting materials:
a. The quality is stable and controllable, and the source, standard, and supplier’s inspection report should be available. If necessary, internal control standards should be established according to the requirements of the process of the API synthesis.
b. For special intermediates, it is even more important to provide relevant process routes and internal control quality standards.
c. There should be a certain understanding of the impurities that may be introduced by the starting materials during the preparation process, especially for the impurities and isomers introduced by the starting materials, relevant studies should be carried out and quality control methods should be provided.
(3) The selection principle of solvents and reagents:
Reagents with lower toxicity should be selected; the choice of organic solvents should generally avoid the use of class 1 solvents and control the use of class 2 solvents; the toxicity of the reagents and solvents used should be explained to facilitate control in the production process.
Key elements of API synthesis — element 3
Finally, the middle process of the API synthesis should be controlled. The control of the intermediate process is divided into the quality control of the preparation intermediates and the selection, optimization, and control of the process conditions and process parameters.
(1) Quality control of preparation intermediates
The information provided should be able to show how to determine the key intermediates and general intermediates through research, and how to achieve process control through different control of the intermediates, so as to better guarantee the quality of the final product.
(2) Selection, optimization, and control of process conditions and process parameters
Process conditions, such as reaction device, temperature, pressure, time, solvent, pH value, light, etc. should be strictly controlled; the end of the reaction (the degree of conversion of raw materials into target products, the generation of impurities, etc.) should be clearly determined.
The research on the process of synthesis of active pharmaceutical ingredients is the starting point of drug development, and it also runs through the entire process of drug development. In the research of the API synthesis process, special emphasis is placed on the importance of the control of the whole process, the accumulation of data, the analysis of impurities, and the control of the starting materials and reagents, thus determining a feasible, controllable, and stable production process.