Polymorph dynamics of L-glutamic acid were examined during continuous mixed suspension mixed product removal (MSMPR) crystallization as a function of residence time and temperature. Results indicate that it is possible to selectively produce metastable or stable polymorphs via a kinetically controlled crystallization in an MSMPR crystallizer by manipulating the crystallizer temperature and residence time. Additionally, on the basis of experimental and modeling studies, it was found that seeding is not necessarily sufficient to alter polymorphism at a given steady state, indicating that this traditional polymorph control strategy may not be applicable in MSMPR systems. The competition between nucleation and growth kinetics of the metastable α form and the stable β form is the major factor in determining the polymorphic outcome at particular steady state conditions. A metastable steady state with a population of the stable β polymorphic was experimentally obtained at 25 °C and 120 min residence time where a small perturbation from the α form could induce a change in the steady state polymorphism. This "polymorphic transformation", unlike the traditional solvent-mediated transformation, is a result of the interplay of kinetic driving forces. In addition, our dynamic simulation suggests that long residence times (>17.4 h) are required to obtain a steady state of the stable β form when operating at temperatures of 25 °C. Our studies indicate one challenge for designing a MSMPR crystallization will be the interplay of growth and nucleation kinetics of the various forms at conditions which produce the desired yield and polymorph.
Control of polymorphism of the enantiotropic p-aminobenzoic acid at either the α or β polymorph while maintaining high yield was achieved by mixed suspension mixed product removal (MSMPR) cascade design. A systematic approach was developed to identify the operational window of the process variables, stage temperature and residence time, in which the stringent polymorph purity criterion (>95 wt %) and high yield were met. The comprehensive understanding of the polymorphism of the model compound, p-aminobenzoic acid, was the key for the identification of the operational window. On the basis of single-stage MSMPR experiments, three temperature regimes thermodynamic control, energy barrier control, and kinetic competitionwere identified, and the interplay between the crystallization kinetics and the thermodynamics in each regime was elucidated. Experimental studies also demonstrated the first polymorph specific MSMPR for enantiotropic systems. Single-stage MSMPRs at low temperature, e.g., 5°C, were found to be β polymorph-specific at steady states across multiple operating conditions. Two-stage MSMPR was designed to alter the polymorphism at the 5°C stage from β polymorph-specific to α polymorph-specific. The first stage temperature was selected in the thermodynamic control regime (30°C) at which the steady state polymorphism was α-specific. Feeding continuously to the second stage, the α crystals generated at the first stage increased the total surface area and thereby the secondary nucleation and mass deposition rates of the α polymorph in the 5°C stage. This in turn increased the α polymorph from 0 wt % to at least 75 wt %, proving that it is feasible to control the polymorphism via design of the MSMPR cascade.
If continuous processing is to be
employed in pharmaceutical production,
it is essential that continuous crystallization techniques can meet
the purity and yield achievable in current batch crystallization processes.
Recycling of mother liquor in steady state MSMPR crystallizations
allows the yield in the equivalent equilibrium batch process to be
met or exceeded. However, the extent to which yield can be increased
is limited by the buildup of impurities within the system. In this
study, an organic solvent nanofiltration membrane was used to preferentially
concentrate an API (deferasirox, M.W. = 373 Da) and purge the limiting
impurity 4-hydrazinobenzoic acid (MW = 152 Da) from the mother liquor
recycle stream in a mixed solvent (THF:ethanol) antisolvent (water)
system. Incorporation of the membrane recycle allowed yields of 98.0%
and 98.7% to be achieved. This compares to the following: a control
MSMPR run without a membrane (70.3%), an equivalent batch process
(89.2%), and the current commercial batch process (92%). Comparable
product impurity levels were measured for the following: the MSMPR
membrane recycle experiments (0.15 ppm and 0.22 ppm), the MSMPR control
(0.13 ppm), and batch (0.32 ppm) control experiments. All processes
met the regulatory specifications of a maximum of 3 ppm of the impurity
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.
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.
Microfluidic technology provides a unique environment for the investigation of crystallization processes at the nano or meso scale. The convenient operation and precise control of process parameters, at these scales of operation enabled by microfluidic devices, are attracting significant and increasing attention in the field of crystallization. In this paper, developments and applications of microfluidics in crystallization research including: crystal nucleation and growth, polymorph and cocrystal screening, preparation of nanocrystals, solubility and metastable zone determination, are summarized and discussed. The materials used in the construction and the structure of these microfluidic devices are also summarized and methods for measuring and modelling crystal nucleation and growth process as well as the enabling analytical methods are also briefly introduced. The low material consumption, high efficiency and precision of microfluidic crystallizations are of particular significance for active pharmaceutical ingredients, proteins, fine chemicals, and nanocrystals. Therefore, it is increasingly adopted as a mainstream technology in crystallization research and development.
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