Crystallization of Mefenamic Acid from Dimethylformamide Microemulsions: Obtaining Thermodynamic Control through 3D Nanoconfinement

Abstract

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.

Crystallization in Confinement

“…Form I crystals could be exclusively obtained from compositions that initially yielded a mixture of Form I and Form II crystals by gently heating the microemulsions to preferentially dissolve Form II. [196] Gylcine, in turn, forms as α, β, and γ polymorphs under ambient conditions where the γ-polymorph is the stable form. is not favored and the system is stabilized due to confinement.…”

“…An elegant demonstration of the potential of achieving thermodynamic control over crystallization in small, finite volumes has been provided by experiments utilizing microemulsions, where the extreme confinement provided by these environments was used to select crystal polymorph. [87,196,197] As described in Section 5.1, crystallization within highly constrained, isolated environments leads to a substantial depletion in the supersaturation as the nucleus grows, leading to a minimum in the free energy with respect to the nucleus size.…”

Nucleation of quartz under ambient conditions

“…Previous studies have demonstrated the ability of microemulsions to elicit thermodynamic control over crystallization for organic molecular crystals [12][13][14][15][16] but this is the first time thermodynamic control has been achieved for a 3D giant covalent structure. The theory underlying this thermodynamic control has been detailed previously 12,13 .…”

“…Recently it has been shown that microemulsions can induce thermodynamic control of crystallization in organic crystals [12][13][14][15][16] . We show here that microemulsions can elicit the same thermodynamic control in crystallizing silica, a giant covalent structure, even though this requires the creation and breaking of much stronger covalent bonds compared to the intermolecular bonds in organic crystals.…”

Nonclassical Crystallization of Dipicolinic Acid in Microemulsions

“…1 This methodology has been successfully adopted to produce the stable polymorphs of glycine, mefenamic acid and 5-methyl-2-[(2-nitrophenyl) amino]-3-thiophenecarbonitrile (commonly known as ROY because of its red, orange and yellow polymorphs) under conditions that would produce metastable forms in bulk solution. [1][2][3] However, the crystallisation of organic hydrates has yet to be studied using this methodology. Dipicolinic acid (DPA, pyridine-2,6-dicarboxylic acid), which is known to exist as an anhydrous form, 4 a monohydrate form 5 and a dihydrate form 6 under ambient conditions, was chosen as a model compound for such a study.…”