The key technology of pharmaceutical process - What are the advances of crystallization technology?

Crystallization is the process by which a solid substance is removed from a vapor, solution or melt in a crystal state.

According to the different crystallization methods, crystallization can be divided into evaporative crystallization, cooling crystallization, salting crystallization, melting crystallization and sublimation crystallization.

Because the crystallization process can effectively remove other impurities in the system and the whole process has low energy consumption and is environmentally friendly, in addition, the formed solid products have a specific crystal structure and shape, and the nature is stable, so crystallization has become an important part of the production process of many drugs and intermediates, and is an effective method to prepare pure substances. It has gradually become one of the important means of purification and separation in the pharmaceutical industry.

In addition to being widely used in the impurity control of intermediates and raw materials, the crystallization process can also effectively control the crystal shape, crystal habit, particle science properties, solvent residues, humidification, etc., thus affecting downstream processes such as filtration, drying, grinding and storage and transportation. Due to the widespread existence of polycrystalline phenomenon in organic compounds, different crystalline forms have completely different physical and chemical properties such as solubility, stability, etc., which directly affect the subsequent production process and the chemochemistry of the compound, and the crystallization process is the only means to control the polycrystalline form, its importance is self-evident.

However, due to the differences in drug crystallization processes, important indicators such as crystal size, purity and crystal type are affected, which have an important impact on drug druggability, stability, safety, quality control, clinical efficacy and safety. Therefore, it is particularly important to master the influencing factors, crystallization technology and control strategy of drug crystallization.

Common problems in the development of the crystallization process of apis and intermediates:

1) Residual solvent: In the preparation process due to inappropriate crystallization conditions or improper proportion of mixed solvents may lead to the formation of solvent inclusions or solvates, resulting in sufficient drying can not remove the residual solvent;

2) Impurity problem: The choice of recrystallization solvent and crystallization process is crucial, if the choice is not appropriate, it will lead to impurities and products precipitation together and difficult to remove;

3) Material filtration problem: if the crystallization process is too fast, it will cause the material to be too fine and difficult to filter, and if the product contains too many impurities, the product viscosity will become larger, which will also lead to difficult filtration;

4) Quality of crystallized products: in the production process, there will be unqualified product quality after recrystallization, and it needs to be recrystallized several times to reach the standard, which is an unfavorable factor for both efficiency and benefit;

5) Crystallization process control: under the same crystallization conditions, the obtained crystalline products are not the same, that is, the quality of the product is unstable, which is related to the control of the reaction conditions during the crystallization process, so the influencing factors in the crystallization process should be fully considered and strictly controlled;

6) Insufficient understanding and application of emerging technologies: Due to insufficient understanding of emerging technologies, inadequate application in the process of drug crystallization has limited the development of crystallization process.

At present, although crystallization is widely used, the application of crystallization technology in the pharmaceutical industry is still challenging due to the conservative state of the overall pharmaceutical environment and the strict supervision of the pharmaceutical process.

Fortunately, the current business environment (such as increased competition, diversification of production methods, strong support for innovation) and the rapid development of related innovative technologies have provided a strong impetus for the pharmaceutical industry to adopt drug crystallization technology.

Therefore, fully understanding the progress of existing drug crystallization technology is of great significance for the application and improvement of related production methods, and it is also conducive to grasping the development and opportunities of drug crystallization technology.

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Spherical crystallization technique

Spherical crystallization is a technology that obtains large spherical drug particles by controlling the mutual polymerization of drug molecules in the process of recrystallization. As a new particle design method, this technology can improve the relevant properties of powders (including fluidity, compressibility, bioavailability, etc.). The spherical particles with ideal particle size distribution can be obtained by controlling the process parameters (temperature, stirring rate, type and amount of solvent, type of auxiliary materials, etc.).