Abstract
Recently we showed how crystallization in microemulsions could lead directly to the most stable polymorph, thereby leapfrogging Ostwald’s rule of stages. Here we consider in more details the crystallization of mefenamic acid from dimethylformamide microemulsions. Crystallization of mefenamic acid from bulk DMF has previously been shown to produce only the metastable Form II irrespective of the supersaturation or temperature. In contrast, we show that stable Form I can be produced from DMF microemulsions provided the lowest supersaturations that can achieve crystallization are used; these correspond to initial supersaturations that are significantly higher than those commonly used in bulk solution crystallizations, owing to the large decrease in supersaturation that occurs when a nuclei grows in a 3D-nanoconfined droplet. Increasing the supersaturation above the minimum required for crystallization leads to increasing proportions of metastable Form II crystals. In compositions crystallizing a mixture of Form I and Form II crystals, the Form I crystals can nevertheless be obtained exclusively by slowly heating the microemulsions.
Highlights
Crystallization within microemulsions differs fundamentally from bulk crystallization because the limited amount of material within a droplet results in the solution supersaturation decreasing substantially as the nucleus grows
In contrast to the lack of Form I crystallization in bulk dimethyl formamide (DMF), Form I nanocrystals, along with a minority of Form II nanocrystals, were evident from transmission electron microscopy (TEM) analysis of DMF-in-heptane microemulsions containing 3% by mass of AOT in heptane and 70 to 90 mg/mL mefenamic acid in DMF on cooling from 50 C to 8 C over 12 h and leaving at 8 C for 12–24 h, see Table 1. These conditions corresponded to the lowest supersaturations at which crystallization was still possible in the microemulsions, with the mean initial supersaturation ratios, c csat
(>90%†) Form I nanocrystals after 24 h, with a minority of
Summary
Crystallization within microemulsions differs fundamentally from bulk crystallization because the limited amount of material within a droplet results in the solution supersaturation decreasing substantially as the nucleus grows. This larger nuclei size, compared to all other polymorphs, and the stable polymorph’s intrinsic greater bulk stability, would typically result in Fmin having the lowest value It is, possible, that surface effects could result in a metastable form becoming lower in energy, and crystallizing out under conditions where crystallization is only just possible. Note that thermodynamic control requires supersaturations for which crystallization is only just possible in the microemulsions, these correspond to initial supersaturations that are typically much higher than would occur in bulk solution crystallizations This is because the substantial supersaturation decrease in the droplets as the nuclei grow necessitates using very high initial supersaturations to enable (near) stable nuclei to form. This suggests that the nucleation barrier, F*, for stable Form I is significantly higher than that of Form II in DMF
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