Eun Hee Lee

Additive-Induced Metastable Single Crystal of Mefenamic Acid

PurposeTo utilize additives to develop a strategy and a method to grow single crystals that allow structure determination of a metastable form of a drug.Materials and MethodsThe metastable form of mefenamic acid (MFA) was grown in the presence of various amounts of the structurally similar additive flufenamic acid (FFA) in ethanol. Single crystal X-ray analysis was performed on the single crystals of MFA II that were formed. The solubility of MFA in the presence of FFA was measured to elucidate the mechanism of MFA II formation.ResultsA supersaturated solution of MFA in ethanol produced the metastable form using FFA as an additive. Ethanol–water mixtures and toluene were also used to investigate the relationships between form produced and solvent since these two solvent systems do not produce MFA II.ConclusionsAdditives can be used to obtain the metastable form of pharmaceutical compounds, and the relationships between molecules and solvent as well as between host and guest molecules are critical to obtaining the desired form.

Organic vapor sorption method of isostructural solvates and polymorph of tenofovir disoproxil fumarate

Tenofovir disoproxil fumarate (TDF) is a prodrug of tenofovir that belongs to a class of antiretroviral drugs, a nucleotide reverse transcriptase inhibitor. An acetonitrile solvate of TDF I, another new solvated form of TDF, was prepared and solid state characterization of its form was conducted using powder X-ray diffraction, FT-IR spectroscopy, and organic vapor sorption isotherm. During the characterization work, it was discovered that (1) TDF I can form solvates and polymorph with a wide variety of organic solvents as well as water and (2) to different extents, these solvates undergoes anisotropic lattice contraction/expansion during desolvation/solvation process suggesting the formation of isostructural solvates of TDF. Solvents used in this study include ethanol, isopropyl alcohol, acetonitrile, cyclohexane, toluene, and water. Four new solvates using ethanol, isopropyl alcohol, acetonitrile, and toluene vapor and one polymorph using water vapor were discovered. Their solid state characterizations were conducted using powder X-ray diffraction, differential scanning calorimetry, thermogravimetric analysis, and Fourier transform infrared spectroscopy. A variety of isostructural solvates and a polymorph of TDF was produced by an organic vapor sorption method, showing varying physicochemical properties. This study demonstrates an alternative crystallization method to obtain isostructural solvates.

The solution properties of mefenamic acid and a closely related analogue are indistinguishable in polar solvents but significantly different in nonpolar environments

This study investigates the cosolute effects of mefenamic acid (XA) and flufenamic acid (FA). These compounds serve as model of a drug discovery lead compound and a structural analogue. The activity coefficients of XA and FA in different solvents were obtained from solubility measurements at 25°C. The effect of varying concentrations of FA on the solubility of XA in four different solvents, including toluene, cyclohexane, ethanol, and an ethanol-water mixture (80:20, v/v), was investigated. The magnitude of change in the activity coefficient of XA in the presence of FA in different solvents was used to elucidate the thermodynamic effect of FA on the solubility of XA. Nuclear magnetic resonance and Fourier-transform infrared spectroscopy were used to obtain molecular level information about the interactions of the compounds in solution. The presence of FA increases XA solubility in toluene and in cyclohexane as much as seven-fold. Conversely, in ethanol and the ethanol-water mixture, similar levels of FA have essentially no effect on the solubility of XA. The solution properties investigated show that despite the close structural similarity between XA and FA, the two compounds are strongly distinguishable in nonpolar solvents. Conversely, the solution properties of the same two solutes are indistinguishable in polar solvents. A solubilization model based on solute-cosolute interactions is presented.

Stabilization of Metastable Flufenamic Acid by Inclusion of Mefenamic Acid: Solid Solution or Epilayer?

The physical stability of metastable form I of flufenamic acid (FFA) increased by using mefenamic acid (MFA) as an inclusion compound. We studied the extent of this effect and explained the mechanism by investigating the effect of the presence of MFA on nucleation and crystal growth of the mixed crystals and the effects it has on the surface morphology. We conclude that the polymorphic transformation of FFA was inhibited in the presence of MFA both by lowering the difference in free energy of the MFA/FFA I and MFA/FFA III solid solution crystals, and also by forming an epilayer, thus affecting the kinetics of the polymorphic transformation.