Characterization of Racemic Species of Chiral Drugs Using Thermal Analysis, Thermodynamic Calculation, and Structural Studies

Abstract

The identification of the racemic species, as a racemic compound, a racemic conglomerate, or a racemic solid solution (pseudoracemate), is crucial for rationalizing the potential for resolution of racemates by crystallization. The melting points and enthalpies of fusion of a number of chiral drugs and their salts were measured by differential scanning calorimetry. Based on a thermodynamic cycle involving the solid and liquid phases of the enantiomers and racemic species, the enthalpy, entropy and Gibbs free energy of the racemic species were derived from the thermal data. The Gibbs free energy of formation, is always negative for a racemic compound, if it can exist, and the contribution from the entropy of mixing in the liquid state to the free energy of formation is the driving force for the process. For a racemic conglomerate, the entropy of mixing in the liquid state is close to the ideal value of R ln 2 (1.38 cal.mol-1. K-1). Pseudoracemates behave differently from the other two types of racemic species. When the melting points of the racemic species is about 30 K below that of the homochiral species, is approximately zero, indicating that the racemic compound and racemic conglomerate possess similar relative stabilities. The powder X-ray diffraction patterns and 13C solid-state nuclear magnetic resonance spectra are valuable for revealing structural differences between a racemic compound and a racemic conglomerate. Thermodynamic prediction, thermal analysis, and structural study are in excellent agreement for identifying the nature of the racemic species.

Solubility, metastable zone width, and racemic characterization of propranolol hydrochloride

“…; the formula for enthalpy of formation and entropy of formation of racemate by using the thermodynamic cycle involves solid phase enantiomers and racemate D S , L S , R S and liquid phase enantiomers and racemate D L , L L , R L has been derived as 14,15 : Enthalpy of formation:…”

“…15 Although this observation is not conclusive for all compounds (as indicated before, the melting point phase diagram is not an adequate criterion for identifying the nature of the racemic species), for example, ephedrine á HCl 15 is a racemic compound even though it has DT f of )28.3 K, large differences in the melting points (DT f approaching )30 K) between the homochiral and racemic species have been widely utilized to examine the nature of chiral drugs due to its easy application. In addition, the entropy of mixing of (R)-and (S)-PN á Cl in the liquid state was calculated according to Eq.…”

Effect of the chiral discrimination on the vibrational properties of (R)-, (S)- and (R,S)-ibuprofen/methyl-β-cyclodextrin inclusion complexes

“…Structural properties of IBP enantiomers and racemate have been widely characterized, by different experimental techniques and simulation [3][4][5][6][7][8][9][10][11]. In particular, it was observed that in crystal lattices of both (S)-and (R, S)-IBP two molecules are arranged to form a cyclic dimer through hydrogen bonds between their carboxylic groups COOH.…”

“…In particular, it was observed that in crystal lattices of both (S)-and (R, S)-IBP two molecules are arranged to form a cyclic dimer through hydrogen bonds between their carboxylic groups COOH. Thermodynamics of sublimation, crystal lattice energies, and crystal structures of racemate and enantiomers of IBP have been also characterized [4,5] in order to understand the differences of drug-drug intermolecular interactions in the two cases. This information is the basic knowledge needed for a rational development of the appropriate method for the resolution of racemate.…”

Verfahren zur Enantiomerentrennung

“…B. Lit. [141]) und Klussmann. [142,143] Unseres Wissens gibt es bislang keine Monographie, die im Schwerpunkt Phasengleichgewichte organischer Verbindungen behandelt.…”