Measuring Free-Energy Difference between Crystal Polymorphs through Eutectic Melting

Abstract

We describe a method to measure the free-energy difference, DeltaG, between crystal polymorphs from their calorimetric data of eutectic melting with a common additive. The use of different additives yields DeltaG as a function of temperature. The method is suitable for crystals that chemically decompose or physically transform before melting. It applies to not only true polymorphs but also pairs of racemate and conglomerate of resolvable enantiomers. We illustrate the method with the polymorphs of glycine, d-mannitol, and tazofelone and report a new value (123 degrees C) for the enantiotropic transition temperature of alpha and gamma glycine. We show how different additives (including a liquid additive, water) can be used for different compounds. The DeltaG data thus obtained are important for structure-stability studies and controlling crystallization in polymorphic systems.

Dynamics and Thermodynamics of Crystalline Polymorphs. 3. γ-Glycine, Analysis of Variable-Temperature Atomic Displacement Parameters, and Comparison of Polymorph Stabilities

“…5b for the temperature range 10-300 K, including the putative β-glycine transition at 252 K, 51 but not the α-γ transition at 396 K. 52 For both techniques, the ΔC p 's are small, the largest difference being < 1.2 cal mol -1 K -1 . The negative ΔC p 's at 50 < T < 200 K from ADP analysis are probably due to shortcomings of the ADP analysis for γ-glycine at low temperatures; see difference curve in Fig.…”

“…Open : ADP analysis K. 52 The putative phase transition at 252 K of β-glycine observed from calorimetry is marked with an arrow. 51 The enthalpic difference ΔΔH vib are small, but tend to increase the differences between polymorphs.…”

Capturing the Role of Temperature and Entropy in Crystal Polymorphs Through Molecular Simulations

“…Properties than can change between polymorphs include density [11,20,31], compressibility [32], hardness [33,34], gel strength [35], flexibility [36], conductivity [26][27][28][29][30][37][38][39], explosivity [20,[22][23][24], catalytic activity [40,41], transparency [42,43], weather resistance [25,44], heat capacity [20], melting point [32,45,46], vapor pressure [46], stability [25,29], solubility [14,[47][48][49], bioavailability [14,33,48,[50][51][52][53][54], and dissolution rate [47,55,56].…”

“…Structures that can be isolated at one temperature may become kinetically unstable at higher temperatures. Furthermore, the thermodynamically most stable structure can also change with the temperature [18,46,[92][93][94][95][96][97][98][99][100][101][102][103] or pressure [76][77][78][79][80][81] leading to new observable forms.…”

“…Structures that can be isolated at one temperature may become kinetically unstable at higher temperatures. Furthermore, the thermodynamically most stable structure can also change with the temperature [18,46,[92][93][94][95][96][97][98][99][100][101][102][103] or pressure [76][77][78][79][80][81] leading to new observable forms.The complete set of all 'observable polymorphs' for a given material therefore consists of all structures that can be produced from any crystallization method in any thermodynamic state of practical interest to the material. The challenge for experimental polymorph screening procedures is to cover a large enough range within this multidimensional space to achieve high confidence that another undiscovered form, which could compromise the performance of the product, will not be observed.…”