Abstract
A route to the accelerated nucleation of α-para-aminobenzoic acid in ethanol/water (EtOH/H2O) mixed solvent solutions, using antisolvent crystallization, is presented. An isothermal by design approach is adopted, whereby the exothermic enthalpy of mixing associated with antisolvent addition is offset by the control of the temperature of the antisolvent added. Induction times (τ) are found to be reduced by 4 orders of magnitude using this methodology, consistent with the use of this approach as a nucleation acceleration technique. Calculation of the nucleation kinetic parameters for a range of solution concentrations, compositions, and supersaturations (S) reveal that effective interfacial tensions (γeff) vary from 8.4 to 2.3 mJ m–2 from solutions in H2O solvent and EtOH solvent, respectively, in line with the trend in solubility. The critical nucleus radius (r*) decreases from 1.98 to 0.40 nm associated with a decrease in the number of molecules in the critical nucleus (i*) from 196 to 2 molecules. A change in nucleation mechanism from heterogeneous nucleation to homogeneous nucleation is observed to take place at S ≈ 1.5. Limitations, particularly with focus toward larger-scale operation, are highlighted together with potential solutions to overcome such aspects.
Highlights
Crystallization is a highly energy-efficient key unit operation for isolation and purification in the manufacture of drugs, pigments, agrochemicals, confectionary, and other fine chemicals.[1]
Because of the dynamics of heat transfer, regulation of reactor temperature is not really a feasible option for processscale reactions given the difficulties associated with the homogeneity of solution temperatures in large-scale vessels, especially with fast changes in solution temperature, given the conductive heating control of reactor jackets.[2,31−34] An alternative approach is to offset the temperature of the antisolvent that is added to the solution in a manner so as to affect a heat balance associated with the enthalpy of mixing, ensuring both isothermal conditions and high supersaturations
Solubility data obtained for varying solution compositions (Figure 3) fit a linear regression model; this along with visual inspection of the crystals and no previous finding of other p-aminobenzoic acid (pABA) polymorphs than the alpha form crystallizing from ethanolic solutions indicated that there was no difference in the solid-state form of pABA over the range of temperatures used
Summary
Crystallization is a highly energy-efficient key unit operation for isolation and purification in the manufacture of drugs, pigments, agrochemicals, confectionary, and other fine chemicals.[1]. Nucleation can occur in an infinitesimally short time frame or it can take a period of years This uncertainty means that tests are currently performed to screen crystalline products, which might undergo nucleation events with significant impact upon product performance, such as polymorphic screening,[5] which includes solution crystallization using an array of solvents as well as relatively high supersaturation conditions. Because of the dynamics of heat transfer, regulation of reactor temperature is not really a feasible option for processscale reactions given the difficulties associated with the homogeneity of solution temperatures in large-scale vessels, especially with fast changes in solution temperature, given the conductive heating control of reactor jackets.[2,31−34] An alternative approach is to offset the temperature of the antisolvent that is added to the solution in a manner so as to affect a heat balance associated with the enthalpy of mixing, ensuring both isothermal conditions and high supersaturations This approach is described through the nomenclature “isothermal by design” (IbD). The structure of the paper is as follows: After this introduction, the methodology workflow is presented, followed by results, discussion and conclusions
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