Types and Analysis of Residual Solvents in the R&D and Production of APIs

Residual solvents in drugs are defined in Q3C as organic volatile compounds produced or used in the production of bulk drugs or excipients, and during the preparation of the formulations, and they cannot be completely eliminated in the process. In the process of drug substance impurity analysis, the study of residual solvents has attracted much attention from drug synthesis workers, because the residue of organic solvents not only brings about the safety problems of residual solvents, but is also closely related to the quality of the drug substance.

In the R&D and production process of APIs, impurities can be divided into organic or inorganic liquids (that is, residual solvents) used in the preparation of solutions or suspensions during the synthesis of APIs according to their physical and chemical properties, which originate from the production process ( Usually known or identified inorganic impurities) and organic impurities that may increase during the production process or storage of the API. The analysis of these three types of impurities is very important for the quality control of APIs.

Residual solvents in the R&D and production of APIs may be harmful to the human body

The guidelines for residual solvents formulated by ICH are divided into the following 4 categories according to the hazards they may cause to the human body:

(1) The first category of solvents: solvents to be avoided are human carcinogens, suspected human carcinogens or environmental hazards;

(2) The second category of solvents: solvents that should be restricted, which are carcinogenic to non-genotoxic animals or may cause other irreversible toxicity to test neurotoxicity or teratogenicity reagents;

(3) The third category of solvents: low-toxicity solvents, which are harmless to humans when they exist in drugs in general amounts, and the residual amount is generally not higher than 0.5%;

(4) The fourth category of solvents: solvents without sufficient toxicity data, the manufacturer should provide a rationale demonstration report of the residual levels of these solvents in the preparation when using them.

Since residual solvents have no curative effect, all residual solvents should be removed as much as possible to meet product specifications, GMP or other basic quality requirements. The level of residual solvents contained in the formulation should not be higher than the safe value. Some solvents are known to cause unacceptable toxicity. Unless proven to be particularly reasonable, their use in the production of APIs, excipients and formulations should be avoided. Some solvents are not too toxic and should be restricted to prevent potential adverse reactions from patients. It is ideal to use low-toxic solvents.

Analysis method of residual solvent

The analysis method of residual solvent impurities should generally be determined before putting it in the laboratory. Analytical method development work should not be carried out prematurely. The types of solvents involved in the process cannot be basically determined. Too many changes in the types of solvents will cause duplication of work and waste resources; therefore, it is best to start this process when the process is basically mature and the types of solvents involved are not greatly changed. Work and optimize methods in conjunction with process requirements. The analytical chemistry and purification separation team of Medicilon, a pre-clinical CRO company, provides customers with high-quality analysis and purification and separation services, such as the use of various technologies such as HPLC to separate and supervise impurities in starting materials, intermediates, APIs and pharmaceutical products.

The residual solvent impurity analysis technology usually uses chromatography, such as the GC method. If possible, a unified determination method should be used for the residual solvents specified in the Pharmacopoeia to be tested. The manufacturer can also choose a more appropriate and proven method for determination. If only the third type of solvent exists; use non-specific methods such as loss on drying to check. In the impurity analysis in the drug residual solvent test, GC-MS is effective for the confirmation of unknown peaks (impurities) detected in the test. Choosing an appropriate solvent in the synthetic raw material can increase the yield or determine the properties of the drug, such as crystal form, purity and solubility. Therefore, sometimes the solvent is a very critical factor in the synthesis. The organic or inorganic liquids used to prepare solutions or suspensions during the synthesis of raw materials are easier to choose control methods due to their generally known toxicity.

For the impurity analysis of APIs, all materials involved in the entire synthesis step should be found, including starting materials, solvents, reagents and additives added in the process, etc., and then the physical and chemical properties of these materials should be analyzed.