Thermodynamic vs. Kinetic Basis for Polymorph Selection

Abstract

Ratios of equilibrium solubilities rarely exceed two-fold for polymorph pairs. A model has been developed based on two intrinsic properties of polymorph pairs, namely the ratio of equilibrium solubilities of the individual pairs (C*me/C*st) and the ratio of interfacial energies (γst/γme) and one applied experimental condition, namely the supersaturation identifies which one of a pair of polymorphs nucleates first. A domain diagram has been developed, which identifies the point where the critical free energy of nucleation for the polymorph pair are identical. Essentially, for a system supersaturated with respect to both polymorphs, the model identifies that low supersaturation with respect to the stable polymorph (Sst) leads to an extremely small supersaturation with respect to the metastable polymorph (Sme), radically driving up the critical free energy with respect to the metastable polymorph. Generally, high supersaturations sometimes much higher than the upper limit of the metastable zone, are required to kinetically favour the metastable polymorph.

Axial vs equatorial: Capturing the intramolecular charge transfer state geometry in conformational polymorphic crystals of a donor–bridge–acceptor dyad in nanosecond-time-scale

“…3(a) ]. The PES results show that the axial conformation between the two π-rings of pyrene and DMA, in PyCHDMA1, is close to a global minimum with respect to the optimized energy values, thus considering the polymorph as representing the stable thermodynamic form, 83 whereas the equatorial conformation between pyrene and DMA in PyCHDMA20 was close to a local minimum [ Fig. 3(a) ] and can be considered as the polymorphic representation of the metastable kinetic form.…”

“…3(a) ] and can be considered as the polymorphic representation of the metastable kinetic form. 83 Figure 3(a) shows that in order to go from the molecular conformation of PyCHDMA1 to the conformation of PyCHDMA20, a potential barrier of height >2 kcal/mol needs to be crossed by rotation about a single bond, suggesting that the nature of the polymorphs is conformational. 31 …”

Crystallization of para-aminobenzoic acid forms from specific solvents

“…10 In such compounds, for example, o-ABA, D-mannitol, eflucimibe, L-histidine, stavudine, BPT propyl ester, L-glutamic acid, famotidine etc., the kinetically favored meta-stable form nucleates at high supersaturation and the thermodynamically favored stable form nucleates at low supersaturation. 11 A contrary behavior is observed in the case of p-ABA polymorphs.…”

“…, the kinetically favored meta-stable form nucleates at high supersaturation and the thermodynamically favored stable form nucleates at low supersaturation. 11 A contrary behavior is observed in the case of p -ABA polymorphs.…”

Application of Selective Crystallization Methods To Isolate the Metastable Polymorphs of Paracetamol: A Review

“…Let us consider a pair of polymorphs, one stable and another one metastable. The classical nucleation theory (CNT) can help us to predict which polymorph crystallizes first as a function of the experimental conditions. , The CNT describes the nucleation rate as where Δ G c * is the critical nucleation free energy, A is a pre-exponential constant, T is the temperature (in Kelvin), and R is the ideal gas constant. So, the polymorph that will nucleate first is the one with the highest nucleation rate or, in other words, the one with the lowest critical nucleation free energy.…”