An API is an active ingredient used in the manufacture of pharmaceutical preparations, usually made from a drug substance obtained through chemical synthesis, semi-synthesis, and microbial fermentation or natural product isolation, through the reaction of one or more chemical units and their manipulation. The study of drug synthesis process of API is an important part of drug research and production, which is the basis of drug research and development and an important link in the formation of drug quality. The following is a brief introduction to the key elements involved in the study of the synthesis process of the following APIs.

Drug synthesis is the center of medicinal chemistry, is the key to drug modification and verification of drug design, and occupies a very important position in the pharmaceutical industry. Medussy is a comprehensive biomedical R & D services company with a unique "customized" process development model that allows customers to access APIs as early as possible for clinical research.

Usually good drug synthesis process has the following characteristics:

(1) Feasibility-Whether the target compound can be prepared using the declared process route.

(2) Controllability-good reproducibility, to ensure the consistency of product quality between different batches, and meet the requirements of quality standards.

(3) Rationality-the feasibility of industrialization, the requirements of the process route for raw materials, equipment, reaction conditions, etc.

1. First of all, the selection and design of synthetic routes should be based and reasonable.

(1) The general procedures for the design and selection of synthetic routes include:

a. Conduct literature research on the target compounds to be synthesized, and design or select reasonable synthetic routes;

B. Make a preliminary analysis of the selected route and have an overall understanding of the domestic and foreign research and intellectual property status of the compound;

c. Have a preliminary evaluation of the process used, and provide a reliable basis for the evaluation of drugs through the above research.

(2) For new chemical entities

① According to its structural characteristics, comprehensive consideration:

a. The ease of obtaining the starting materials;

B. Length of the synthesis step;

c. the level of yield;

d. Whether the post-treatment of the reaction and the reaction conditions meet the requirements of industrial production and environmental protection; determine the reasonable synthesis route.

② According to the literature reports of similar structure compounds at home and abroad, a comprehensive analysis was carried out to determine the appropriate synthesis method.

(3) For drugs with known structure

Through literature research, the research on the preparation of the drug has a comprehensive understanding, focusing on:

A. feasibility (whether the raw materials are readily available and the reaction conditions can be industrialized);

B. Controllability (whether the reaction conditions are mild and easy to control);

c. Stability (whether the quality of intermediates is controllable, and whether the quality and yield of final products are stable);

d. Advanced nature (the advanced nature of the adopted route compared with the literature route);

e. Reasonableness (cost and price and toxicity of raw materials, reagents, solvents, etc.).

Secondly, the starting materials, reagents and organic solvents should have standards, emphasizing standardization. For the control of starting materials, GMP requirements from the source to control the quality of the product.

(1) The requirements for synthetic products are as follows:

a. List of materials: list the names of the materials used in the production process of the API (e. g. raw materials, starting materials, solvents, reagents, catalysts), describe the respective processes of use, and identify key materials;

B. Material testing methods: clarify the quality control information of these materials;

C. COA of key material suppliers: quality standards and inspection reports; For raw materials such as animal, plant or its tissues and organs-provide raw material families, genera, origin, collection season, storage conditions of collected materials, etc. and provide their quality requirements. Biosynthetic antibiotics shall provide species genera and composition of culture medium.

(2) the principle of selection of starting materials:

a. The quality is stable and controllable, and the inspection report of the source, standard and supplier shall be provided. If necessary, the internal control standard shall be established according to the requirements of the synthesis process.

B. For special-purpose intermediates, it is emphasized to provide relevant process routes and internal control quality standards.

C. the starting material in the preparation process may be introduced impurities should have a certain understanding, especially for the introduction of impurities, isomers from the starting material, should be related to the study and provide quality control methods; with chiral center of the starting material, should be formulated as impurities of enantiomers or diastereomers of the limit.

For the length of the synthetic route of the API, FDA believes that the determination of the starting material in the preparation process, the proposed starting material should be separated from the final intermediate of the API in multiple steps. This can effectively reduce the negative impact on the quality of the drug substance due to the change of the preparation process before the starting material. It should be noted that a reaction may include multiple purification steps, but should be considered a one-step reaction.

If the final intermediate is isolated and purified in the process, the reaction of synthesizing the final intermediate can be regarded as a one-step reaction, while the mutual conversion between free acid (or free base) and salt should not be regarded as a one-step reaction. And to determine a key raw material in the starting material, the raw material should also be in line with GMP conditions of the workshop production.

(3) Selection principle of solvent and reagent:

Should choose less toxic reagents; organic solvent selection should generally avoid the use of a class of solvents, control the use of two types of solvents; should be used to explain the toxicity of reagents, solvents, in order to control in the production process.

3. Finally, the synthesis intermediate process should be controlled, emphasizing controllability. The control of the intermediate process is divided into the quality control of the preparation of intermediates and the selection, optimization and control of 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 realize process control through different control of intermediates, so as to better ensure the quality of the final product, including the purification method of intermediates, internal control quality standards, test results, and analysis of impurity spectrum.

FDA's summary of major intermediates is divided:

a. Hub intermediates: intermediates that can be synthesized by different methods;

B. Key Intermediates: Intermediates that are usually formed for the first time in an important part of the molecule. Such as: the first time with the introduction of stereomeric molecules chiral atoms intermediate.

c. Final intermediate: The previous step in the final reaction of the synthesis of the drug substance.

(2) The selection, optimization and control of process conditions and process parameters.

① The description of process operation steps shall be detailed;

The process conditions, such as: reaction device, temperature, pressure, time, solvent, p H value, light and other control should be strict; the end of the reaction (indicating the degree of conversion of raw materials into target products, the generation of impurities, etc.) should be clear.

The research of API preparation process is the starting point of drug development, and also runs through the whole process of drug development. In the study of API preparation process, special emphasis is placed on the importance of whole process control, data accumulation, impurity analysis and control of starting materials and reagents, in order to determine a feasible, controllable and stable production process, and also to provide a basis for quality research.

At the same time, the evaluation of the preparation process of API is not isolated, and should be combined with the evaluation of quality control, safety and effectiveness. From the perspective of drug evaluation, it is hoped that the real process can be evaluated in order to achieve the purpose of reasonable and comprehensive evaluation of drugs.