Process Analytical Tools To Control Polymorphism and Particle Size in Batch Crystallization Processes

Abstract

In this work, process analytical technology (PAT) based approaches for controlling the polymorphism and crystal size of a nonsteroidal anti-inflammatory drug (piroxicam) during batch cooling crystallization has been investigated. Previously obtained results regarding the crystallization behavior of the different polymorphs of piroxicam in a small-scale (100 mL) crystallizer have been used to design and to initiate the control approach described in this paper. The results of the present work demonstrated the challenge of reproducing the crystallization process with respect to the product polymorphism at different scales. The solute concentration has been proved to be a critical parameter in determining the polymorphism of piroxicam in the small-scale crystallization experiments; however, the same operation parameters could not yield the same polymorph in the crystallization in 2 L crystallizers. Both direct nucleation control (DNC) and supersaturation control (SSC) have been proven to be effective at controlling the polymorphism of piroxicam in seeded cooling crystallization; furthermore, applying DNC also improved the particulate properties (larger crystal size).

Cooling Crystallization of Indomethacin: Effect of Supersaturation, Temperature, and Seeding on Polymorphism and Crystal Size Distribution

“…), operating temperature, solvent, impurities, agitation etc. 3,[7][8][9][10][11] Therefore, a thorough understanding of crystallization process parameters and their impact on critical quality attributes of APIs is required in order to produce consistent and desired quality APIs. The objective of this work is twofold: firstly, to investigate the interplay between crystallization process parameters and quality attributes of APIs; secondly, to understand the mechanisms involved in the crystallization process.…”

Antisolvent Crystallization of Indomethacin from a Ternary Solvent System with High Productivity, Better Polymorphism, and Particle Size Control

“…Temperature cycling is a widely used strategy to tune the particle size and shape through the dissolution and growth cycles during crystallization of APIs. 26 In this work, we have investigated the feasibility of solvent-antisolvent addition cycles to effect the dissolution-growth cycles to Having enough crystals formed in the crystallizer after min into the crystallization, 10 g solvent i.e., a binary mixture of acetone-methanol (66.5-33.5 wt%) was added to the suspension. After stabilization of IR signal, 4 g antisolvent i.e., water was added to the suspension.…”

Process Analytical Technology for Crystallization of Active Pharmaceutical Ingredients

“…Table 3. [107] Progesterone in wateracetone mixture Raman spectroscopy, multivariate MLR calibration [108] Flufenamic acid in water-ethanol mixture Raman spectroscopy, FBRM, univariate calibration [109] Carbamazepine in ethanol-water mixture Raman spectroscopy, univariate calibration [110] MK-A in isopropyl acetate Raman spectroscopy, multivariate PLS calibration [111] Piroxicam in acetone Raman spectroscopy, PVM, FBRM, ATR-UV/Vis, multivariate calibration [68] Buspirone in isopropyl alcohol Raman spectroscopy, univariate calibration [112] Isonicotinamide in five organic solvents…”

“…Particle size distribution of piroxicam during DNC controlled cooling crystallization, modified from[68].…”