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When the drug is crystallized, if different solvents and processes are used, the arrangement form and number of drug molecules in the crystal cell are different, thus forming different crystal structures. Different crystal structure in the solubility, stability, efficacy and other properties of the performance are different. In the production process of APIs, crystallization is the last key step of solid APIs. An excellent crystallization process can make APIs with specific purity, particle size and crystallinity, i.e. higher quality drug crystals. Therefore, crystallization process development and optimization is an essential step in the pharmaceutical production process.
1. Crystallization method
There are three main crystallization methods in common use: cooling crystallization, solution crystallization, and reaction crystallization. Other crystallization methods include: spherical crystallization technique, ultrasonic crystallization, micro recrystallization, etc. Each crystallization method has various parameters that need to be adjusted, such as solvent type, temperature, humidity, etc. In the actual crystallization operation, different crystallization methods need to be selected according to the solubility characteristics of drugs in different solvents.
2. Crystal nucleation
Nucleation occurs when the solute molecules reach a critical size in a supersaturated solution. The size and dimensions of the nuclei, as well as the nucleation rate, directly affect the particle size and size distribution. These parameters are important for product separation, filtration and downstream processes. The rate of nucleation depends on the molecule of crystallization and can also be changed by adjusting the solvent type, controlling supersaturation, etc. The addition of crystalline seeds is a common strategy used to control initial nucleation. Effective addition of crystalline seeds can initiate nucleation at a consistent point, therefore, the crystallization strategy (i.e., seed type, timing of seed addition, seed aging time, and amount of seeds) is an important determinant of crystal nucleation quality.
3. Crystal growth
Crystal growth can be classified into four major categories according to the type of its parent phase: melt growth, solution growth, gas phase growth and solid phase growth. Crystal growth is a complex process and so far there is no sound scientific theory to guide the control of crystal growth, and a great deal of it still depends on experience. The preparation of high quality intact crystals requires control of supersaturation release (rate of cooling, rate of antisolvent addition, etc.) to prevent local overcooling or overheating, as well as to ensure uniform crystal growth without concentration gradients.