A continuously operated single stage mixedsuspension, mixed-product-removal (MSMPR) crystallizer using intermittent withdrawal via a dip pipe with combined pressure/vacuum was successfully developed for the manufacture of active pharmaceutical ingredients. Approximately 5.8% of the total operating volume was intermittently removed at a high velocity using vacuum. The transfer line was also periodically purged with nitrogen to ensure complete removal of residual solids. In situ process analytical technologies (focused beam reflective measurement (FBRM) and process video microscopy (PVM)) were successfully applied to monitor and characterize the MSMPR crystallization process. In this study, a cooling crystallization of paracetamol from an aqueous isopropyl alcohol solution was investigated. Experimental results indicate that the crystallization system was able to operate without any clogging issues for over 10 residence times, before which the system had approached steady state. Three different start-up strategies for continuous crystallization were investigated, and the results indicate that the chord length distributions at steady state were the same for all cases. Also, starting the continuous operation from a saturated solution that was seeded with product from a previous MSMPR run offered the quickest route to steady state. To better control and scale up the crystallization process, the nucleation and crystal growth kinetics of the model compound were also determined through use of the newly developed process. The growth rates were found to be size dependent, and an exponential three-parameter model was employed to characterize the size-dependent growth. It was seen that the crystal growth rate was extremely low and increased linearly with particle size when the particle size was below 10 μm. However, the growth rate increased dramatically with particle size when the particle size was between 10 and 1000 μm. The nucleation kinetics was correlated by the semiempirical equation B TOT = 1.11 × 10 15 M T 0.98 G avg 1.12 . The orders of the total nucleation rate with respect to the magma density and average growth rate were 0.98 and 1.12, respectively. Therefore, the effect of supersaturation (or residence time) and magma density on the steady state crystal size was investigated.
The use of in situ tools to monitor the transformation of a polymorphic material has the potential to provide unique information about the mechanism and rate of transformation of the polymorphs. In this paper, the solution mediated transformation between α and β form p-aminobenzoic acid (PABA) was investigated in detail. Solubility of α and β form PABA in pure ethanol was also reported for the first time, allowing the accurate determination of the transition temperature of 13.8 °C. For the transformation experiments, Raman spectroscopy and Attenuated Total Reflectance Fourier Transform Infrared (ATR-FTIR) spectroscopy were used to in situ monitor the solid phase concentration and liquid concentration, respectively; Focused Beam Reflectance Measurement (FBRM) was used to in situ track the changes in the size and morphology of the particles. The observed changes were confirmed using PVM in-process imaging. It was proved by solubility data and transformation experiments that the relationship between α and β form is enantiotropic.
d-Mannitol is a typical polymorphic crystalline compound. In this paper, this polymorphic transformation from the α to the β form of mannitol is monitored by in situ Raman spectroscopy, focused beam reflectance measurement (FBRM) and particle vision measurement (PVM). The standard Raman spectra of the two polymorphs of mannitol were determined and the characteristic peaks for the different polymorphs were chosen to track the transformation process. By combining Raman with FBRM and PVM, relationships between fine particles and metastable form dissolution and also between coarse particles and stable form crystallization could be defined. The solution-mediated polymorphic transformation mechanism was confirmed by these in situ tools. The effect of temperature, solvent and substrate mass on the transformation time was also investigated. It was noted that operating temperature and solvent composition have a significant influence on the transformation time.
Nucleation and growth kinetics of benzoic acid crystallized by cooling from 1.5:1 (w/w) water/ethanol solutions were determined using a 500 mL continuous mixed suspension, mixed product removal (MSMPR) crystallizer and a mathematical model of the MSMPR process. The developed model solves the population, moment, and mass balance relationships with the kinetic expressions for the system and is coupled with a nonlinear optimization routine for kinetic parameter estimation. Comprehensive experimental data for model fitting and parameter estimation was obtained by varying crystallizer operating conditions to induce changes in the rate-affecting variables for growth and nucleation (temperature, supersaturation, and suspension density). The size distribution was monitored in real-time using focused beam reflectance measurement (FBRM) to identify steady-state and hence to enable on-demand adjustment of the operating conditions to transition multiple steady-states for rapid acquisition of kinetic data. A Malvern Mastersizer was used to quantify the crystal size distribution (CSD) at steady-state, whereas concentration was determined gravimetrically. Six kinetic parameters for crystal growth and nucleation were estimated from the model fitting procedure, which enabled accurate prediction of CSD and concentration results at steady-state.
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