Crystallization Process Development

The research on drug solid state is the nexus between the chemical synthesis and formulation development of APIs. Its quality and effectiveness directly affect how an API is transformed into a drug product. The study of solid form can be divided into two parts based on its focus: one is materials science, which focuses on the structure-property relationship, i.e., the research on salt form and crystal form, which aims to optimize the properties of drugs; the other is chemical engineering, which focuses on reproducible and scalable production. Based on the specific crystal form and its crystal habit, a scientific and reasonable crystallization process can improve the crystallization operation yield. It can also significantly optimize the solvent residue, particle size and particle size distribution, bulk density, and other powder properties of API products to improve the overall quality and added value of products.

Process Development for Specific Polymorph

Based on their mechanism, pharmaceutical crystallization methods can be divided into two types: free assembly after dissolution (kinetic control) and solution-mediated transformation (thermodynamic control). It is generally preferred to generate the metastable crystalline form by free assembly after dissolution. The metastable form is generated by controlling the degree of supersaturation of solution in a short period. Then crystalline products are quickly separated from the solvent system and isolated from sensitive factors. The preparation of stable crystalline form is generally combining the two methods, which ensure the purity of crystal form and improve the crystallization yield.

Case in point：A client wanted to develop a drug and preferred the metastable form S2 over the stable form S1 due to property limitations. Preliminary experimental studies showed that metastable crystal S2 would quickly transform into crystal form S1 in the solution. After the product was filtered and dried, the transformation would be induced due to the presence of moisture in the air.

Through a systematic search, we first selected a solvent system with a higher saturated gradient to guarantee the initial yield of metastable crystal form S2 through rapid crystallization. After further study, we discovered that S2 would be trans-crystallized after extended exposure to the air. It was necessary to reduce the surface area of the product to inhibit trans-crystallization. Since the metastable crystal in a solution system couldn't be acquired by crystal growth, we used spherical crystallization technique to reduce the particle’s specific surface area. This approach not only successfully solved the crystal form S2 transformation problems, but also increased the product particle size and reduced the difficulty of the suction filter.

The key technologies

  • The composite solvent system with a higher saturated gradient of metastable crystal form was screened for crystallization
  • The influence of sensitive factors on the trans-crystallization process was investigated and quantified
  • Spherical crystallization technique was used to inhibit the trans-crystallization process

Crystallization Process Optimization

The crystallization process is a crucial link in the refining of API products. It directly affects the final product yield and controls the quality of the product. The crystal habit and particle size of powder products are the primary technical indicators. In the process of drug crystallization production, usually, needle-shaped crystals need to be avoided in the process of agitation and filtration as they break easily under in agitated crystallization conditions, and a secondary nucleation will occur, which directly affects the final control of product size and crystal form. Particle size and particle size distribution are another concern in the refining of API products. Uneven product size distribution affects the final product dissolution and cause quality fluctuations. Therefore, the development of the crystallization process based on optimized particle size and particle size distribution is an important way to guarantee the API’s powder properties.

Case in point：A client wants to refine and optimize an API product. The product, with the its crystallization process at the time, had problems with uncontrollable and broad particle size distribution. At the same time, small crystals would block the feeding port and increase the pressure on the filter cake during filtration.

In this typical case, we found that the root cause to the problems lied in the needle-like crystal’s habit and stirring conditions. Through systematic research, we selected the composite solvent system conditions to change the growth rate in a desired direction so as to adjust the length-diameter ratio of the crystal in the crystallization process. In this way, the crystal was not easy to break and the overall particle size was increased. At the same time, the mixing mode was changed from paddle-type to anchor-type to reduce the impact strength of fluid on the crystal. Combined with the adjustment of crystallization conditions, the crystal grows slowly and we successfully optimized the crystal habit and particle size.

The key technologies

  • Screen the composite solvent that directionally controla crystal growth
  • Qualitative optimization of stirring mode
  • The product particle optimized by crystallization conditions