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

The common preparation methods of spherical crystallization include spherical aggregation method and emulsion-like solvent diffusion method. Ammonia diffusion method and crystallization coaggregation method are the improved methods of spherical crystallization, which are used for the main drugs which are not suitable for the classical preparation method.

(1) Spherical aggregation method (FIG. 1) : four components of main drug, good solvent, bad solvent and bridging agent are required. First, the main drug is pre-dissolved in a good solvent, and then the resulting main drug solution is poured into a bad solvent that can be miscible with the good solvent. Because the affinity between the two solvents is stronger than that between the main drug and the good solvent, drug crystallization can be produced. Finally, bridging agent is also needed to act as a bridge between precipitated particles in this process to promote the continuous process of particle aggregation.

(2) Emulsion-like solvent diffusion method (FIG. 2) : three components of main drug, good solvent and bad solvent are required. The prerequisite is that the interaction between the good solvent and the bad solvent is weaker than that between the main drug and the good solvent. In this case, even if the good solvent and the bad solvent are miscible, the solution of the good solvent of the main drug into the bad solvent will still form an emulsion-like solution rather than a suspension. Under this condition, the good solvent present in the droplet of the good solvent of the main drug slowly diffuses into the external bad solvent, while the external bad solvent penetrates into the droplet, the solubility of the main drug decreases, local susaturated droplets are generated, and crystallization occurs. The remaining good solvent in the droplet can act as a bridging agent to promote the precipitation of precipitated particles.

(3) Ammonia diffusion method: Because amphoteric substances are insoluble in neutral media and organic solvents, the above two methods are not applicable, and ammonia diffusion method can be considered at this time. This method requires four components: main drug, ammonia water, bad solvent and solvent to induce ammonia release. First, ammonia was used as a good solvent for the main drug and as a bridging agent, and then a solvent with low solubility but which could be miscible with ammonia was selected as a bad solvent. Finally, water-immiscible solvents, such as hydrocarbons, are added to the system to promote the release of ammonia. The principle is that when the ammonia solution of the main drug is poured into the mixed solution composed of an undesirable solvent and a water-immiscible solvent, the undesirable solvent molecules enter the drops of the ammonia solution, and the ammonia molecules diffuse into the organic solvent of the external phase, which eventually leads to the crystallization and no ammonium salt is produced.

(4) Crystallization copolymerization method: It is a new method of spherical crystallization preparation, breaking through the limitations that spherical crystallization technology is only applicable to dosage forms with high main drug dosage and can not be applied to compound preparations, and can precipitate excipients of drugs or other drug molecules with the main drug at the same time. This method is similar to the spherical aggregation method, the substance that needs to be crystallized is dissolved with good solvent, and the bad solvent and bridging agent are added to precipitate the crystallization and aggregate.

Spherical crystallization technology is widely used in other industrial fields, but it is less used in the pharmaceutical field, which is generally used to improve the powder properties of drugs, make the main drug suitable for direct tablet pressing or adjust the dissolution curve of the main drug, so as to achieve slow release and controlled release. Compared with the traditional granulation process, the ball crystallization process is simpler and lower in cost, which is suitable for expanding production.

02

Co-refining of raw materials and excipients

Co-refining of apis and excipients is a relatively new technology in the field of particle engineering, which can make the combination of excipients and active ingredients of drugs more uniform and stable. This method mixes two or more materials together in a specific way to obtain a composite material with better physical or chemical properties to facilitate the crystallization or separation process of the bulk drug, thereby solving some common problems associated with the production of solid preparations, such as material fluidity, stability, formability, dissolution rate, bioavailability, content uniformity, etc.

03

Continuous crystallization

At present, most of the crystallization processes in the pharmaceutical industry are intermittent operations, and the problems of batch difference and low process efficiency are obvious.

In order to solve the above problems, continuous crystallization technology came into being, with its constant operating conditions and high production efficiency in the steady state has received high attention. Continuous crystallization is a unit operation in which the mother liquid continues to flow and the slurry continues to flow. According to the analysis of relevant scholars, continuous crystallization can reduce the production cost by 9% ~ 40%.