Demonstration of the Terms Enantiotropy and Monotropy in Polymorphism Research Exemplified by Flurbiprofen

Abstract

The thermodynamic terms enantiotropy and monotropy are demonstrated by means of solid-state analytical results of polymorphous flurbiprofen (FBP). Vibrational spectra, differential scanning calorimetry (DSC), and thermomicroscopy investigations as well as X-ray powder patterns for three modifications of FBP are described. The melting points are mod. I 113-114 degreesC (enthalpy of fusion 27.9 +/- 0.2 kJ mol-1) for modification I (mod. I), 92 degreesC for mod. II, and 87 degreesC for mod. III. The true densities of mod. I (1.279 +/- 0.001 g cm-3) and mod. II (1.231 +/- 0.002 g cm-3) were measured at 25 degreesC. Modification I (commercial product) is the thermodynamically stable crystal form from absolute zero to its melting point. Modification II was crystallized on a gram scale from a warm saturated solution of FBP in n-heptane and rapid cooling of the solution to -18 degreesC. Modification I is monotropically related to mod. II and mod. III, due to application of the density rule and the entropy-of-fusion rule. The thermodynamic relationships between the three modifications are demonstrated by a semischematic energy/temperature diagram. Theoretical vapor pressure/temperature diagrams and energy/temperature diagrams are compared and briefly discussed.

Structural relationships, thermal properties, and physicochemical characterization of anhydrous and solvated crystalline forms of tetroxoprim

“…In addition to a similar endothermal effect at 159.1 AE 0.38C (n 3) with an enthalpy change of 142 AE 7 J g À1 , for TXP form II (from acetone) there is a smaller and broader endothermal effect between 113±1248C (T peak 118.3 AE 0.58C, enthalpy change 12.7 AE 1.4 J g À1 ; n 3) attributable to a solid-state phase transition from polymorph II to polymorph I. 23 TGA of TXP form II revealed no weight loss from the samples over the 110±1308C temperature range, indicating that the ®rst endotherm in the DSC trace cannot be attributed to any inclusion of solvent in the crystal. Attempts to record melting of polymorph II by increasing the DSC scanning rate up to 100 K min À1 for possible application of the Heat of Fusion Rule 23,24 were unsuccessful.…”

“…23 TGA of TXP form II revealed no weight loss from the samples over the 110±1308C temperature range, indicating that the ®rst endotherm in the DSC trace cannot be attributed to any inclusion of solvent in the crystal. Attempts to record melting of polymorph II by increasing the DSC scanning rate up to 100 K min À1 for possible application of the Heat of Fusion Rule 23,24 were unsuccessful. By stopping a DSC run on TXP form II at 1508C and cooling to 308C, however, a broad exothermic region in the range 105±658C was recorded (see inset of Fig.…”

“…This effect may be attributed to a solid-state phase transition from form I to form II, which substantiates the enantiotropic relationship between them. 23 TXP forms I and II were examined visually by HSM to assist in the interpretation of the DSC results. No change in the physical appearance of the I-form and II-form crystals was observed up to the melting point, which was 157±1588C for both forms.…”

Diversity in Single- and Multiple-Component Crystals. The Search for and Prevalence of Polymorphs and Cocrystals

“…Also be aware of enantiotropism. 48 For systems that are enantiotropic with a transition temperature near ambient, it is common to obtain mixtures no matter what technique is used, including long-term slurrying in hopes of converting all to the stable form. Since enantiotropic forms have the same free energy at the transition temperature, there is little or no driving force to interconvert near or at that temperature.…”

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“…The plotting of Gibb's free energy difference, ∆G, against the absolute temperature, T, given the most complete and quantitative information on the stability relationship of polymorphs with the most stable polymorph having the lowest Gibbs free energy 16 . ∆G between the polymorphs may be obtained using several techniques operating at different temperatures such as solubility and intrinsic dissolution rates 17 .…”