Agglomeration Control during Ultrasonic Crystallization of an Active Pharmaceutical Ingredient

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.

Reducing the Induction Time Using Ultrasound and High-Shear Mixing in a Continuous Crystallization Process

“…The higher degree of macromixing increases the collision frequency which, in turn, increases agglomeration and aggregation. When the ultrasound probe was inserted, the macromixing was mainly due to acoustic streaming, which was significantly less than the macromixing that resulted from the high rotational speeds obtained using the rotor-stator mixer [36].…”

Formation of Spherical Agglomerates in Cooling Crystallization of Hexahydro‐1,3,5‐trinitro‐1,3,5‐triazine

“…In terms of flowability, filterability, and compaction properties, agglomerated particles exhibit a clear benefit over single primary particles depending on the final morphology. The agglomeration mechanism involves three consecutive steps: (i) individual particles collide due to hydrodynamic condition in agitated vessels, (ii) stabilization of adhered particles due to attractive force, (iii) cementation of liquid bridges . However, if the particle‐particle adhesion is insufficient, the agglomerates are disintegrated.…”

Discrimination between Single Crystals and Agglomerates during the Crystallization Process

“…Agglomerates are favorable when making crystalline products consisting of small particles easier to handle , they result in different flowability and filterability , , or can lead to a decrease in purity by entrapment of mother liquor between bigger crystals , , . The agglomeration process itself can be divided into three steps: (i) collision of particles within the slurry, (ii) formation of aggregates, i.e., loosely bound particles that can disintegrate easily, and (iii) actual agglomeration through the merging growth of aggregated particles , . Moreover, the size of agglomerates is limited by particle breakage due to shear forces .…”