Abstract
Application of ultrasound during crystallization can efficiently inhibit agglomeration. However, the mechanism is unclear and sonication is usually enabled throughout the entire process, which increases the energy demand. Additionally, improper operation results in significant crystal damage. Therefore, the present work addresses these issues by identifying the stage in which sonication impacts agglomeration without eroding the crystals. This study was performed using a commercially available API that showed a high tendency to agglomerate during seeded crystallization. The crystallization progress was monitored using process analytical tools (PAT), including focus beam reflectance measurements (FBRM) to track to crystal size and number and Fourier transform infrared spectroscopy (FTIR) to quantify the supersaturation level. These tools provided insight in the mechanism by which ultrasound inhibits agglomeration. A combination of improved micromixing, fast crystal formation which accelerates depletion of the supersaturation and a higher collision frequency prevent crystal cementation to occur. The use of ultrasound as a post-treatment can break some of the agglomerates, but resulted in fractured crystals. Alternatively, sonication during the initial seeding stage could assist in generating nuclei and prevent agglomeration, provided that ultrasound was enabled until complete desupersaturation at the seeding temperature. FTIR and FBRM can be used to determine this end point.
Highlights
Crystallization is one of the most important processes during the manufacturing of active pharmaceutical ingredients (APIs)
Sonication during the initial seeding stage could assist in generating nuclei and prevent agglomeration, provided that ultrasound was enabled until complete desupersaturation at the seeding temperature
This study aims to evaluate the potential of ultrasound for agglomeration control during the recrystallization of a commercially available API produced by Johnson & Johnson
Summary
Crystallization is one of the most important processes during the manufacturing of active pharmaceutical ingredients (APIs). Precise process control allows tuning the final physical properties of the crystals such as purity, size distribution and polymorphic form. These properties should be controlled to facilitate processing during filtration, drying and formulation. These characteristics provide the opportunity to control the drug release profile after intake into the human body. Particle formation during crystallization in agitated vessels is governed by two primary processes: crystal nucleation and growth. Secondary mechanisms such as breakage, Ostwald ripening and agglomeration can have a substantial influence on the obtained crystal polymorph, shape and particle size distribution (PSD) [7,8].
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