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Analysis of the critical elements of the API synthesis process

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API is the active ingredient used in the manufacture of pharmaceutical preparations, usually obtained by chemical synthesis, semi-synthesis, and microbial fermentation or natural product isolation of APIs after one or more chemical unit reactions and their operations. API research is an integral part of drug research and production, at the foundation of drug development, and is an essential part of drug quality formation. The following is a brief description of the critical elements involved in the research of API synthesis processes.

Drug synthesis is the center of medicinal chemistry, the key to drug modification and validation of designed drugs, and plays a vital role in the pharmaceutical industry. Medicilon is an integrated biopharmaceutical R&D services company with a unique "custom" process development model that allows customers to get APIs for clinical studies as early as possible.


Good drug synthesis processes are usually characterized by the following.

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

(2) Controllability - Good reproducibility, consistency of product quality from batch to batch, and compliance with quality standards.

(3) Reasonableness - the feasibility of industrialization, the requirements of the process route for raw materials, equipment, reaction conditions, etc.; preferably low toxicity solvents, reagents, environmental protection, and labor protection; cost accounting.

One, First of all, the selection and design of the synthetic route should be based on rationality.

(1) The general procedure for designing and selecting synthetic routes includes the following.

a. Conduct literature research on the target compound to be synthesized and design or select a reasonable synthetic route.

b.Conduct a preliminary analysis of the chosen route and have a general understanding of the compound's domestic and foreign research and intellectual property status.

c. Have a preliminary evaluation of the process used, and provide a reliable basis for assessing the drug through the above studies.

(2) For new chemical entities

① Based on their structural characteristics, careful consideration of

a. The ease of obtaining the starting material.

b. The length of the synthesis steps.

c. The level of yield.

d. Post-treatment of the reaction, whether the reaction conditions meet the requirements of industrial production and environmental protection; determine a reasonable synthetic route.

② Conduct a comprehensive analysis to determine the appropriate synthesis method based on domestic and foreign literature reports on compounds with similar structures.

(3) For drugs with known structures

A comprehensive understanding of the research on the preparation of the drug is obtained through literature research, focusing on

a. Feasibility (whether raw materials are readily available and whether 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 end products are stable).

d. Advancedness (the advancedness of the adopted route compared with the literature route).

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

Secondly, starting materials, reagents, and organic solvents should be standardized, emphasizing normality.

For the control of starting materials, the requirements of GMP control the quality of the product from the source.

(1) For synthetic products have the following requirements.

a. List of materials: list the materials used in the API production process (such as raw materials, starting materials, solvents, reagents, and catalysts) name, and explain the respective use of processes to confirm the essential materials.

b. Testing methods for materials: clarify the quality control information for these materials.

c. Key materials supplier COA: quality standards and inspection reports; to animals, plants or their tissues and organs as raw materials - to provide raw materials family species, origin, collection season, collection preservation conditions, etc., and to provide their quality requirements biosynthetic antibiotics to provide strains of family species and the composition of the culture medium.

(2) The selection principles of starting materials:

a. Stable and controllable quality, sources, standards, and supplier inspection reports, if necessary, should be based on the requirements of the synthesis process to establish internal control standards.

b. For particular intermediates, more emphasis should be placed on providing the relevant process route and internal control quality standards.

c. The starting material in the preparation process may introduce impurities should have a thorough understanding, especially the impurities introduced by the starting material, isomers, should be related to the study and provide quality control methods; on the starting material with the chiral center, should be developed as impurities of the enantiomeric isomers or diastereoisomers limits.

For the length of the API synthesis route, the FDA believes that the starting material is determined in the preparation process; the proposed starting material should be interspersed with the final intermediate of the API multi-step reaction; and, in the interval of the reaction should have separated purified intermediates, this can effectively reduce the negative impact on the quality of the API due to changes in the preparation process before the starting material may bring. It is noted that a reaction may include multiple purification steps but should be considered a one-step reaction.

If the final intermediate is separated and purified, synthesizing the last intermediate can be regarded as a one-step reaction. At the same time, the interconversion between free acid (or free base) and salt should not be viewed as a one-step reaction. And to identify a critical raw material in the starting material, producing the raw material should also be made in the workshop in line with GMP conditions.

(3) Solvent and reagent selection principles:

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

Finally, the intermediate synthesis process should be controlled, emphasizing Controllability.

The control of the medium cycle is divided into the quality control of the preparation of intermediates and the selection, optimization, and management of the process conditions and parameters.

(1) The quality control of the preparation of intermediates

The information provided should be able to show how the study identified essential intermediates and general mediators, how to achieve process control through different controls on intermediaries to ensure better the quality of the final product, including the purification method of intermediates, internal control quality standards, test results, analysis of impurity profiles.

FDA for the central intermediates are summarized as follows

a. Pivotal intermediates: intermediates that different methods can synthesize;

b. Key intermediates are usually intermediates where important molecule parts are formed for the first time. For example, the molecule with stereoisomerism for the first time introduces chiral atoms intermediates.

c. Final intermediates: API synthesis of the final reaction of the previous step.

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

① The description of the process operation steps should be detailed.

② process conditions, such as reaction device, temperature, pressure, time, solvent, p H value, light, etc. control should be strict; reaction endpoint (suggesting the degree of conversion of raw materials into the target product, the generation of impurities, etc.) judgment should be clear.

API preparation process research is the starting point of drug development, but also throughout the entire process of drug development. In the study of the API preparation process, particular emphasis is placed on the importance of the complete process control, data accumulation, impurity analysis, and control of starting materials and reagents to determine a feasible, controllable and stable production process, but also to provide the basis for quality research.

At the same time, the evaluation of the API preparation process is not isolated but should be carried out in conjunction with the assessment of quality control, safety, and efficacy. From the perspective of drug review, it is hoped that evaluating natural processes can be assessed to achieve a rational and comprehensive evaluation of the drug.

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