Evaluation of focused beam reflectance measurement (FBRM) for monitoring and predicting the crystal size of carbamazepine in crystallization processes

Abstract

Pharmaceutical crystallization affects the properties of APIs as it determines the purity and crystal size distribution, among other attributes. This work presents two CLD–CSD models, theoretical and empirical, for a model compound.

Rapid, Automated Measurement of Dynamic Size Distributions and Size-Dependent Growth Rates of Crystal Ensembles within Microfluidic Flow Cells

“…The ability to make direct crystal size measurements circumvents the need for indirect inference methods for CSDs from CLDs, as is the case in FBRM measurements. 22,46 These indirect methods involve transformation matrices that are dependent on parameters such as shape and aspect ratios of the crystals under study that are typically assumed to be constant throughout the crystal growth, which may not be generally valid. 46,47 Furthermore, from a mathematical standpoint, the inversion of CLD to CSD has been reported to be an ill-conditioned problem.…”

“…22,46 These indirect methods involve transformation matrices that are dependent on parameters such as shape and aspect ratios of the crystals under study that are typically assumed to be constant throughout the crystal growth, which may not be generally valid. 46,47 Furthermore, from a mathematical standpoint, the inversion of CLD to CSD has been reported to be an ill-conditioned problem. 46 The extracted CSDs over time allows the acquisition of the growth rate function G(L(t)) (as shown in eqs 1−3), which can then be applied in population balance models.…”

Enantioselective synthesis of (−)-tetrabenazine via continuous crystallization-induced diastereomer transformation

“…A variety of process analytical technologies (PATs) are available to make such real-time measurements on continuously crystallizing systems, as outlined by a recent review. 8 Techniques such as online powder x-ray diffraction (PXRD), 9 focused beam reflectance measurement (FBRM), 10,11 particle vision and measurement (PVM) 12,13 and in situ Raman spectroscopy 14,15 allow for real-time solid phase characterization. Additionally, in situ Infrared (IR) 16,17 and Raman spectroscopy can provide solution-phase concentration data, with the latter also giving solid-phase composition information.…”

Process Analytical Technology for the Production of Parenteral Lipid Emulsions According to Good Manufacturing Practices

“…Models are used to predict the effects of process variables on inline measurements using FBRM technology. Two quantitative crystal size/chord length distribution (CSD/CLD) models (one theoretical, the other empirical) have been developed and validated for the continuous crystallization of carbamazepine (CBZ) during cooling [94]. The precision and robustness of FBRM, as well as the influence of process variables on the method, were evaluated using CBZ crystal sand ideal spherical bodies with a uniform distribution.…”

“…It is ideal for monitoring during the fine emulsification of the product in the lower particle size range. However, the measurement can be influenced by many properties of the sample, including the particle shape (or a mixture of different particle shapes), the number of phases, the particle orientation, the particle concentration, the refractive indices of the continuous and dispersed phases, and the particle surface [94]. These influences are limited in emulsions due to the spherical particle shape, but must be considered for successful integration.…”