Investigation of crystallization mechanisms for polymorphic and habit control from the Supercritical AntiSolvent process

Abstract

In this work, the Supercritical AntiSolvent (SAS) process has been used to generate micronized crystals of Sulfathiazole (STZ) from different organic solutions, namely acetone, acetonitrile, tetrahydrofuran and acetic acid. The flow rates of CO 2 (2-21 g min −1) and of the organic solution (0.19-6 mL min −1), as well as STZ concentration in the organic solution (20-70% under the saturation), have been varied to identify the conditions leading to powders exhibiting only one polymorphic form. Pressure (10 MPa) and temperature (313 K) have been kept constant. In this paper, thermodynamic and hydrodynamic aspects are discussed so as to rationalize the obtained crystal characteristics and provide a new way to control the SAS process applied to drug preformulation. The influence of the organic solvent nature on both the polymorphic form and the habit of generated crystals, has been particularly discussed.

Prediction of Crystal–Solvent Interactions in a Supercritical Medium: A Possible Way to Control Crystal Habit at High Supersaturations with Molecular Modeling

“…The proposed analysis was based on the qualitative approach from Pèpe et al The simple E att model is exploited, coupled with a solvent adsorption simulation so as to identify face hindering. In vacuo crystals, which are used as a theoretical basis to further investigate crystal face–solvent interactions, do not allow for reliable habit prediction: many limitations of the habit prediction ability of the E at t model were underlined in the literature. ,, As suggested by Bennema and van der Eerden and last by Nguyen et al, the Jackson α factor (eq ) was calculated. where Δ H fus (J mol –1 ) is the heat of fusion (taken from and equal to 24.9 kJ mol –1 ), R (8.314 J.K –1 ·mol –1 ) is the ideal gas constant, T (313 K) is the absolute temperature, X s is the mole fraction of the solute, calculated for the global volume of the autoclave, and ξ hkl is the anisotropy factor as defined below: In the experimental part of this work, supersaturations were ranging from 800 to 3000, and with ξ hkl < 0.6 for every one of the faces our experimental conditions clearly lead to α < 2 in all cases. This suggests a roughened face growth and therefore a continuous monomer-by-monomer addition (MMA) crystallization mechanism rather than screw dislocation or birth and spread.…”

“…The second part of this work consists of comparing the results of the modeling study with the characteristics of experimentally grown crystals. The comparison was made on experiments performed by the SAS process applied to the recrystallization of sulfathiazole with acetonitrile, acetone, tetrahydrofuran, and acetic acid previously published by Clercq et al A screening of the operating conditions has led to the generation of powders with a 100% polymorphic purity in either STZ FIV or STZ FI, crystalline powder being analyzed by nuclear magnetic resonance following the methodology of Apperley et al To minimize the effect of thermodynamics, the experiments were carried out under fixed conditions of pressure and temperature (respectively 10 MPa and 313 K). The screening of operating conditions was operated on the flow rate of both phases and on the initial concentration of STZ in the organic solution (β OS ).…”

“…Referring to the different contributions reported in the literature, − it is now possible to determine operating conditions which allow intense mixing conditions to form fine particles with homogeneous characteristics. However, in many cases when it comes to drugs, the objective is to form the most stable polymorph and to obtain it pure.…”

“…However, in many cases when it comes to drugs, the objective is to form the most stable polymorph and to obtain it pure. Previous works have shown that when intense mixing conditions are used, the kinetically favored form (i.e., less stable form) is obtained . A compromise must therefore be reached, and unfortunately, it is mandatory to perform experiments to determine which operating conditions will lead to the formation of the most stable polymorphic form with homogeneous characteristics in terms of size and particle size distribution.…”

“…As for conventional crystallization in solution, the crystallization in supercritical media can lead to the formation of a powder composed either of single crystals or of larger structures resulting from crystal aggregation . Moreover, the crystal aggregates can form spherical particles that may result from a droplet drying …”