Isothermal by Design: Comparison with an Established Isothermal Nucleation Kinetics Analysis Method

Abstract

The nucleation kinetics of the alpha form of p‐aminobenzoic acid from ethanolic and aqueous solutions is examined through a comparative examination of temperature‐jump and anti‐solvent drown‐out isothermal crystallization methodologies. Analysis of the data reveals the measured induction times, and the calculated effective interfacial tensions as a function of the supersaturation show broadly equivalent behavior for the aqueous‐ethanol mixed‐solvent drown‐out and temperature‐jump ethanol solution systems, confirming the comparability of the two methodologies. The results also demonstrate poorer agreement with the temperature‐jump pure aqueous system, highlighting the importance of the strength of solvation/desolvation as the key rate‐limiting process for the overall nucleation behavior.

Influence of solution chemistry on the solubility, crystallisability and nucleation behaviour of eicosane in toluene : acetone mixed-solvents

“…A previous study demonstrated that, in solubility mismatched mixed-solvent solutions, such as the system studied here, the local solvation environment of a nucleating solute would be likely to be dominated by the strongest solvating solvent, due to the much higher intermolecular interaction strengths. 17 Therefore, for the current procedure the interactions of toluene molecules with eicosane were calculated first, followed by the acetone molecules. Whilst this molecular modelling technique provides an attractive and representative molecular-scale assessment as to likely solute : solvent ordering within the solution, it is clearly limited by the fixed interaction procedure imposed by the chosen grid size that neither directly allows for the effects of molecular conformational flexibility nor deals with the random solute : solvent interactions, which might be expected within a mixed-solvent/antisolvent system, as studied here.…”

“…[13][14][15] Crystallisation from mixed-solvent solution systems can be directed, either through cooling of an initial solvent blend 7,16 or through antisolvent crystallisation. 15,17 Both routes require miscible solvents, with the latter requiring significant differences in the solubility of the solute between the solvent and antisolvent, the addition of which lowers solute solubility and hence generates supersaturated conditions. In the design of mixed-solvent crystallisation processes, it is helpful to have developed workflows for the characterisation of the solubility and solution properties over the full range of compositions used and, through this, optimise the process parameters to ensure the desired crystal product characteristics.…”

“…18,19 For the design of antisolvent crystallisation processes knowledge of the solubility-temperature relationship as a function of the composition of solvent mixture is important for control of the solution supersaturation generated by the addition of the lower solubility solvent. Depending upon the magnitude and sign of the enthalpy of mixing, the addition of a second solvent can change the solution temperature 15,17 and hence a detailed knowledge of a solution's mixed-solvent thermodynamics is also needed.…”

“…Variation in mixed-solvent composition can also change the nature of the intermolecular interactions associated with solute desolvation and clustering, which can directly affect the ability of the solute to nucleate, impacting, in turn, on the nucleation kinetics and associated mechanism. 15,17,20 In the latter respect, polynuclear nucleation can occur either through instantaneous (IN) or progressive (PN) nucleation mechanisms, 21 whereby IN describes the process in which all nuclei form instantly and subsequently undergo crystal growth, whereas in PN the nuclei continuously form in the presence of growing crystals. Such mechanistic changes can impact on the crystal product properties, e.g.…”

Crystal Agglomeration and Microscopic Molecular Exchange Mechanism in Antisolvent Crystallization

“…The crystals prepared by this method are relatively tiny, and their dimensions do not increase significantly during AC . Compared to traditional cooling or evaporative crystallization methods, the precipitation process is typically quick, and the induction period is much shorter . The purification effect is typically poor, and the impurities are challenging to separate .…”