In any process of manufacturing an active pharmaceutical ingredient (API), the final step can make all the difference between a perfect product and a useless one. Steps like salt formation and crystal form isolation need to be optimized prior to the first round of good manufacturing practices (GMP) development.
A well-planned GMP for the final crystallization stage will ensure that the process’s solid-state guidelines, engineering practices and chemical techniques are all standardized. A high level of standardization will enable teams to consistently create product with the right purity profile, particle characteristics and overall form; even at the scale of metric tons.
Still, the challenge of engineering and maintaining stringent control over a crystallization system is a significant one. Here are some of the most critical concerns in the crystallization of an API.
Variations in crystal forms
Throughout the final stages of the production process, minor variations in crystallization can have major impacts on the crystals’ particle-size distribution, as well as their shape. Inadequate crystallization can even lead to the agglomeration and inclusion of solvent in the crystals, or can trigger the conversion of one polymorph into another. Any or all of these changes can significantly damage the purity of a batch, and may lead to the complete loss of expensive product.
Solvents and solubility
In the earlier stages of development, researchers assess the utility of various solvents and growth inhibitors. Some solvents will contribute to the creation of the ideal polymorphs of the API, while others will not. In some cases, the necessary solvent may have to be created by desolving an intermediate hydrate or solvate formation, or by some other process. Growth inhibitors, meanwhile, can help guide and set limits on crystal growth, and can impact the shape of the final polymorph.
Mixing, temperature and humidity
Polymorphic transformations take place in a complex environment, and are shaped by the temperature, humidity and other mixing conditions within the reactor. Inaccurate mixing can lead to undesirable variations in supersaturation zones, which will affect agglomeration and nucleation. An excessive amount of agitation in the mixing process, meanwhile, can break up particles and cause secondary nucleation. This makes it crucial to pinpoint the kinetic limits between the nucleation point and the solubility curve, so environmental conditions can be kept within these limits.
Control over supersaturation
The amount of supersaturation that takes place within the reactor will directly impact the particle-size distribution of the final product. An inadequate level of control over supersaturation can lead to excessively large crystals, or undesirably fine ones. Techniques like antisolvent addition, evaporation, cooling, and direct chemical reactions can all help maintain supersaturation within the necessary parameters.
Growth, nucleation and metastability
Once a crystal reaches its metastable form, the system often traps or isolates this polymorph, which loses the ability to convert to the desired stable form. A clear understanding of the thermodynamic interplay among all polymorphs in the system is necessary for preventing (or at least controlling) polymorph isolation. It’s crucial to prevent generation or nucleation of metastable forms as much as possible, to prevent them from becoming kinetically hindered from conversion into the stable form.
Consistency and performance at scale
Above the level of actual chemistry and engineering, a detailed understanding of the process as a whole is vital for optimization and long-term consistency. Supervisors need to gather a steady stream of analytics on the behavior of each chemical product at small scales. The better they’re able to study and characterize this behavior , the better they’ll be able to predict and design processes and strategies that will continue to work at larger scales as well.
In short, a well-designed API crystallization stage should include a detailed understanding of variability in crystal forms; precisely measured solvents, temperatures and mixing; tight control over supersaturation, growth, nucleation and metastability; and clear optics on the process as a whole.
When all the above factors are carefully monitored throughout the production of an API, the process is far more likely to result in a product with the intended attributes. Bulk density, purity and crystal size distribution are all directly impacted by these factors; as are performance properties of the end crystalline product, such as solubility, dissolution rate, flowability, hydrogscopicity and color stability. Consistency across batches results in tremendous cost savings, in a market where “getting it right the first time” is more essential than ever.
In addition to being an author and speaker, Susan Thompson serves as the Technical Director of Indianapolis based VxP Pharma.