Crystallization
Tackling the challenges of batch-produced crystalline API substances during the transition to drug products
Today, API crystallization in batch processes remains complex and inefficient. Even when the correct polymorph is obtained through seeded batch crystallization, the drug substance often requires additional processing to achieve the desired particle size and shape. This typically means extra steps such as grinding, milling or sieving on top of seeding, growth, filtration and drying.
At Secoya, we have developed a unique crystallization process that minimises these steps. Starting from a solution, we directly generate the final critical material attributes of the drug product in a single process step, followed only by filtration and drying. No seed optimisation, no post-processing, just a streamlined path from drug substance to drug product.
Rapid screening and development cycle
Experienced crystallization scientists will be surprised by the speed at which crystallization experiments can be conducted using the Secoya Crystallization Technology. Even more, parameter testing is further streamlined by simply inputting the desired temperatures, flow rates, and volumes, allowing the instrument to stabilize quickly. The intuitive software then facilitates swift and efficient test execution. Vast amounts of process data are generated in very short periods of time.
Precise control of spontaneous nucleation:
By the adaptation of reactor size to the speed of nucleation events, Secoya Crystallization Technology precisely controls spontaneous nucleation events occurring for solutes in solution. These designed reactors permit very precise changes of any important parameter to generate a stable stream of nuclei like temperature, shear rate and mixing.
Controlled Crystallization process
Unlike any alternative process, the Secoya crystallization technology is based on the precise control of spontaneous nucleation through the use of millifluidic tubular reactors upon cooling and different antisolvent addition possibilities. Using such capillaries, any parameter influencing the nucleation is ideally optimized and controlled.
Secoya’s crystallization technology is unique, enabling crystallization of molecules in a single process step avoiding difficult work-up when performed with conventional batch systems.
List of publications:
Nandi, S. et al., Continuous Microfluidic Antisolvent Crystallization as a Bottom-Up Solution for the Development of Long-Acting Injectable Formulations. Pharmaceutics 2024, 16, 376. https://doi.org/10.3390/ pharmaceutics16030376
Rimez et al., Cryst. Growth Des., 2018, 11, 6431-6439, https://doi.org/10.1021/acs.cgd.8b00928
Rimez et al., Cryst. Growth Des., 2018, 11, 6440-6447, https://doi.org/10.1021/acs.cgd.8b00930
Rimez et al., React. Chem. Eng., 2019, 4, 516-522, https://doi.org/10.1039/C8RE00313K
Rimez et al., J. Flow. Chem., 2019, https://doi.org/10.1007/s41981-019-00042-z
Versatile equipment for multiple crystallization modes
The Secoya Crystallization Technology is engineered to support various crystallization processes, including cooling crystallization, co-flow antisolvent crystallization, and frontal antisolvent crystallization. These differences enable for one single molecule different types of applications, whether as an oral dosage form, inhalation medicine, injectable, gene delivery and others.
Development a complete process cycle
Once the process parameters are set at the laboratory scale, pilot unit testing can be conducted using the complete process chain from liquid state to dried product while working together with our expertise and help from industrial filtration and drying partners to enable full scale dimensioning of the final process conditions and process unit configuration.
Seamless scale-up from lab to production
The Secoya Crystallization Technology allows for a smooth transition from laboratory to manufacturing scale by maintaining the same process parameter settings in our devices, utilizing exactly identical reactor and insert combination from lab to production without any bad surprises.
Frequently Asked Questions
It transforms the active pharmaceutical ingredient from solution into a solid crystalline form. As the final step of drug substance manufacturing, it directly governs purity, stability and reproducibility. The crystal form and size is determined by its administration route and influences solubility, uptake and overall effectiveness.
Crystal size, size distribution and shape, which is a large share of a drug product’s critical material attributes (CMA). These drive dissolution rate and bioavailability, dose uniformity, processability, polymorphism control and product stability.
Batch crystallization relies on extensive trial and error and usually needs grinding, milling or sieving afterwards to reach the target particle size. Secoya’s continuous-flow technology controls spontaneous nucleation directly, producing crystals at the target size and cutting the process down to its essential steps: crystallization, filtration and drying.
The reactor size is matched to the speed of nucleation events. This is allowed by the very precise control of temperature, shear rate and mixing. These parameters generate a stable, steady stream of nuclei rather than random nucleation bursts.
From 0.1 to 1,000 µm: from large crystals for oral dosage forms down to very small, light particles for pulmonary and injectable applications.
Cooling and antisolvent crystallization. Both use the same key principles – nucleation control, particle size control, and the samereactor setup from lab to production. The right mode depends on the API’s BCS class and solubility profile and is selected during the feasibility study.
Yes. Polymorphism control is one of the parameters affected by poor crystallization control. Secoya’s precise control of reached supersaturation levels, temperature and intense mixing drives the nucleation of only the wanted polymorphic form consistently.
The same reactor design is used at every stage, so conditions found in the lab transfer directly:
Unit | Stage | Typical quantity per test/production scale |
|---|---|---|
SCT-LAB 1 mL | Discovery phase | ~100 mg |
SCT-LAB 20 mL | Formulation development | 0.5-2 g |
SCT-PILOT | Process validation | <10 kg |
SCT-Production | Commercial production | >1,000 kg |
The SCT-LAB 1 mL unit works at around 100 mg scale, so early screening can start with discovery-phase quantities of API, as from roughly 1 g of API. For the SCT-LAB validation of the process at 20 mL, about 20-100 g is required, all depending on the used concentration of product
That is the aim. Direct size control reduces trial-and-error experiments, fewer downstream steps simplify the process, and a single reactor design avoids re-development at each scale-up – all of which shorten time-to-market.
1 mL of solution. Screening runs on the SCT-LAB 1 mL unit, so early crystallization trials can start with as little as 1 mL.
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