API Continuous Cooling and Antisolvent Crystallization for Kinetic Impurity Rejection in cGMP Manufacturing

Abstract

Crystallization of 204 kg of final active pharmaceutical ingredient was accomplished continuously using a cascade of mixed suspension mixed product removal crystallizers in cGMP manufacturing. This article describes the journey taken to transform a set of technical to final batch crystallizations into a continuous, combined cooling and antisolvent crystallization using three stirred tank crystallizers in series. Conversion of the batch process to a continuous process was beneficial to kinetically purge a key impurity. The conversion also allowed for the direct integration of the crystallization process with upstream continuous chemistry sections. A robust control strategy was developed from early research scale all the way to cGMP manufacturing. The authors will share the tools, techniques, modeling, and equipment used and challenges overcome to ensure a safe and reliable manufacturing process. A new intermittent flow technique transferred hot solution from a continuous evaporator into the first crystallizer with no solids bearding at the end of the inlet tubing. The continuous distillation, crystallization, and slurry-off filters were a key part of a broader continuous process and new building that won an International Society for Pharmaceutical Engineering 2019 Facility of the Year Award for Innovation.

Process Intensification Enabling Continuous Manufacturing Processes Using Modular Continuous Vacuum Screw Filter

“…Thereby, a strategy of switching filter plates is realized for a quasi-continuous filter cake discharge. Since their work focused on end-to-end manufacturing, the individual effect of the filter on product quality was not investigated in detail …”

“…Since their work focused on end-to-end manufacturing, the individual effect of the filter on product quality was not investigated in detail. 23 To overcome the stated open issues, we developed and patented the small-scale continuous vacuum screw filter (CVSF) for continuous particle isolation from suspensions in small-scale for volume flow rates between 10−100 mL min −1 . 24 Our first study showed that the PSD was entirely maintained during filtration, and a narrow residence time distribution of solid phase (RTD S ) is ensured.…”

Correlation of Solubility Thermodynamics of Glibenclamide with Recrystallization and In Vitro Release Profile

“…The probable cause of reduced dissolution in DMSOte and NMPate might be due to the impurities formed upon degradation (DMSO boiling point 462.15 K, NMP boiling point 475.15 K) compared to dioxanate and THPate, as those GLN solvates decomposed at 473.74 K and 469.53 K respectively which were close to the Form I decomposition peak (489.15 K) [4]. Even a small amount of impurity in the slurry could impede polymorphic stability [42]; however, the degradation of the solvates kept at 40 • C and 75% RH for 30-day, had less than 1.5% impurity, indicating a high degree of purity of the GLN solids with respect to impurities and degradation products [43]. Previously, GLN binary mixture gave more hydrophilic structure of the crystal surface compared to GLN reference (dissolution of X G = 0.3, 0.5 or 0.7 > dissolution of X G = 1) which increased its wettability and contributed to improved dissolution [7].…”

Towards 4th industrial revolution efficient and sustainable continuous flow manufacturing of active pharmaceutical ingredients

“…However, this can be achieved by final-product purification using techniques such as multicolumn chromatography catch-and-release chromatography, simulated moving bed (SMB), crystallisation, recrystallisation and centrifugal partition chromatography (CPC). 51,54–59 Adding to scalability concerns of some of these purification methodologies, these techniques have their drawbacks; crystallization and recrystallisation usually requires semi-batch processing, catch-and-release chromatography needs automated multiple columns switching and the SMB chromatography operation is technically complex and it uses expensive absorbents. 12,51,60 The application of various downstream continuous flow processing strategies examples are reviewed herein.…”