Antisolvent crystallization

Depolymerization, e.g., polyethylene terephthalate and cellulose hydrolysis Hydrothermal oxidation of organic wastes in water Crystallization, particle formation, and coatings Antisolvent crystallization, rapid expansion from supercritical fluid solution (RESS)... 

Dixon, J. and Johnston, K. (1991) Molecular thermodynamics of solubilities in gas antisolvent crystallization. AIChE Journal, 37 (10), 1441-1449. 

Fig. 10 Schematics for automatically collecting the IR spectra for constructing the calibration model for cooling and antisolvent crystallizations.

Rather, the batch time varies from batch to batch depending on the kinetics of the crystallization. As shown below, the direct design approach for antisolvent crystallization is implemented in a very similar manner. 

There are different approaches to implementing the feedback concentration control for the direct design. Various schemes to implement the concentration control for direct design are described in the literature for cooling and antisolvent crystallizations. " The basic steps are as follows (i) the solution concentration is estimated from IR absorbances and temperature or solvent-antisolvent ratio using the calibration model that relates IR spectra to concentration and (ii) the temperature or antisolvent flow rate setpoint is calculated from the concentration, solubility curve, and the user-specified supersaturation setpoint. 

Fig. 15 shows an example of the direct design approach implemented for the isothermal antisolvent crystallization of acetaminophen (paracetamol) from acetone-water mixture. A constant relative supersaturation (Ac/c ) setpoint profile was followed. The flow rate setpoint of the antisolvent was calculated every minute based on the solution concentration measured using the IR spectra so that a setpoint supersaturation profile was followed. The change in solution concentration and antisolvent flow rate during the batch is shown in Fig. 16. After an initial start-up...

Fig. 15 Direct design approach using concentration measurement for seeded antisolvent crystallization of paracetamol (acetaminophen) from acetone-water mixture. The concentration-% solvent profile of the batch, the setpoint profile, and the solubility curve are shown. The setpoint followed is that of a constant relative supersaturation Ac/c = 0.04 g/mLsolvent+antisolvent"...

Fig. 16 Change in solution concentration and antisolvent flow rate during the seeded antisolvent crystallization of paracetamol following a constant relative supersaturation.

Fig. 17 FBRM counts during seeded batch antisolvent crystallizations of paracetamol from water/acetone with secondary nucleation and with minimum secondary nucleation.

The supercritical fluid mefhod is a relafively new method, which can minimize the use of organic solvents and harsh manufacturing conditions taking advantage of two distinctive properties of supercritical fluids (i.e., high compressibility and liquid-like density). This method can be broadly divided into two parts rapid expansion of supercritical solutions (RESS), which utilizes the supercritical fluid (e.g., carbon dioxide) as a solvent for the polymer, " and supercritical antisolvent crystallization (SAS), using the fluid as an antisolvent that causes polymer precipitation. Recent reviews of the supercritical technology for particle production are available in the literature. ... 

Woo, X.Y., R.B.H. Tan, P.S. Chow, and R.D. Braatz (2006). Simulation of mixing effects in antisolvent crystallization using a coupled CFD-PDF-PBE approach. Crystal Growth Design 6, 1291-1303. 

The relatively high molecular weight of proteins coupled with their flexibility make normal antisolvent crystallization difficult. In a situation where crystallization is achieved, the large particle size and wide size distribution means these particles are not favourable towards pulmonary delivery. Although milling has been applied... 

Badilla et al. as the criterion for characterizing the antisolvent crystallization process (46). 

Equation (46) implies that the fraction of solute crystallized is proportional to the reduction in the partial molar volume of the solvent. Accordingly, the characteristic parameter for the antisolvent crystallization is the relative partial molar volume reduction (RPMVR), which is defined as... 

Solvent selection for the micronization of drugs is crucial because the molecules may be multifunctional and polar with a tendency toward hydrogen bonding, resulting in specific solute-solvent interactions (61). However, it is generally believed that the solute-antisolvent interaction is negligible compared with the solvent-antisolvent interaction for the S-F-V equilibrium in antisolvent crystallization systems. Thus the solvent-C02 interaction is solely responsible for the reduction of solvent power of the mixed solvent. Accordingly, the PMVF of solvent in a binary (solvent-antisolvent) mixture depicts the solute mole fraction in the ternary (solute-solvent-antisolvent) liquid phase. 

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