Partial Miscibility of Organic Compounds in the Solid State – The Case of Two Epimers of a Diastereoisomer

Abstract

The purification that can be attained via crystallization is on the one hand governed by kinetic factors, such as the growth rate, and can on the other hand be limited by thermodynamic factors, such as the formation of a solid solution of the impurity with the product. For organic substances, these solid solubilities are difficult to establish, especially for low partial solubilities in the solid state. For the case of the crystallization of two epimers of a diastereoisomer, the formation of partial solid solutions with a respective solubility limited to approximately 5 % and 3 % has been shown using both DSC and XRPD measurements. The enthalpies of fusion of the solids are a strong function of the content of the opposite epimer. This can be interpreted with a disruption of bonds in the lattice, a disruption index of ∼ 8 is found. First determinations of the crystal structure of one of the epimers suggest the formation of a solid solution, which occurs via the replacement of dimers of molecules that are bound by two hydrogen bonds involving the epimeric hydroxyl group and a vicinal phenoxy group. By replacing dimers, the lattice distortion might be limited.

Effect of Headgroup Chirality in Nanoassemblies. 2. Thermal Behavior of Vitamin C-Based Surfactants

“…In some cases, partial miscibility has been observed. 18 The melting temperature and enthalpy change are different for the two epimers, as would be expected for diastereoisomers.…”

A Structured Approach To Cope with Impurities during Industrial Crystallization Development

“… 34 Partial miscibility between a pair of α- and β-epimers (2.6% for α in β and 4.4% for the reverse) was revealed by construction of binary phase diagrams and subsequent Tammann triangle plots. 35 When considering the purity required for crystalline API compounds, such low levels of miscibility could pose an issue to the purification process. When considering the extent of impurity incorporation is a function of crystallization driving force, i.e.…”

Impurity incorporation in solution crystallization: diagnosis, prevention, and control

“…Alternative methods have been used where the suspension is carefully sampled directly from the crystallizer, and diluted in a large amount of saturated solution to simultaneously quench crystallization and dilute the solids concentration to a level that facilitates imaging. 10 Analysis of powder mixtures by X-ray powder diffraction (XRPD) can also reveal information on crystallizing impurities, seen as the appearance of a new pattern revealing a mixture of crystalline phases, [79][80][81][82][83][84] or the formation of a cocrystal. 85 In addition, solid solutions have been shown to affect the diffraction peak positions by expansion or contraction of the lattice, 86 as well as a reduction in peak intensities due to the loss of crystallinity.…”

“…43 Differential scanning calorimetry (DSC) analysis of crystallized powders can also be used to detect the incorporation of impurities. The lattice incorporation of impurities can have a small effect on the observed melting point and enthalpy of fusion, 53,84,87 and the co-precipitation of impurities can be seen as peak doubling. 88 However, due to the possibility of peak doubling by melting and recrystallization of the solute crystals, care should be taken when interpreting DSC data on systems potentially presenting impurity co-precipitation and polymorphism.…”

“…Analysis of powder mixtures by X-ray powder diffraction (XRPD) can also reveal information on crystallizing impurities, seen as the appearance of a new pattern revealing a mixture of crystalline phases, 79–84 or the formation of a co-crystal. 85 In addition, solid solutions have been shown to affect the diffraction peak positions by expansion or contraction of the lattice, 86 as well as a reduction in peak intensities due to the loss of crystallinity.…”