An Examination of the Phase Transition Thermodynamics of ( S )- and ( RS )-Naproxen as a Basis for the Design of Enantioselective Crystallization Processes

Abstract

A detailed experimental analysis of the phase transition thermodynamics of (S)-naproxen and (RS)-naproxen is reported. Vapor pressures were determined experimentally via the transpiration method. Sublimation enthalpies were obtained from the vapor pressures and from independent TGA measurements. Thermodynamics of fusion which have been well-studied in the literature were systematically remeasured by DSC. Both sublimation and fusion enthalpies were adjusted to one reference temperature, T = 298 K, using measured heat capacities of the solid and the melt phase by DSC. Average values from the measurements and from literature data were suggested for the sublimation and fusion enthalpies. In order to prove consistency of the proposed values the vaporization enthalpies obtained by combination of both were compared to vaporization enthalpies obtained by the group-additivity method and the correlation-gas chromatography method. The importance of reliable and precise phase transition data for thermochemical calculations such as the prediction of solid/liquid phase behaviour of chiral compounds is highlighted.

Structure and Glass Transition Temperature of Amorphous Dispersions of Model Pharmaceuticals with Nucleobases from Molecular Dynamics

“…While no such data exist for the nucleobases, carbamzepin, and indomethacin to our knowledge, we can illustrate the computational accuracy for naproxen and racemic ibuprofen. Based on the sublimation pressure measurements, calorimetric enthalpy of fusion and qualified estimates of the difference in heat capacities of gas and condensed phases, experimental vaporization enthalpy of naproxen at 410 K can be evaluated as 106.9 ± 3.0 kJ mol −1 [ 44 ]. Assuming the ideal behavior of the vapor, our simulations predict the corresponding value at 108.2 ± 1.0 kJ mol −1 , which can be accepted as a very close agreement of theory with experiment, with the actual difference of 1.3 kJ mol −1 well within the chemical accuracy threshold (~4 kJ mol −1 ).…”

Accurate lattice energies of organic molecular crystals from periodic turbomole calculations

“…[ ] where DMACRYS and HF‐3c were used to calculate absolute lattice energies and their differences. As reference data experimental lattice energies, E latt,exp , have been extracted from experimental sublimation enthalpies for lactide and naproxen using the suggested thermal and zero‐point corrections from ref. [ ] For 3ClMA, experimental sublimation data are not available since the compound decomposes before evaporation but absolute and relative energies can be estimated from experimental solubilities instead …”

Thermochemistry of Racemic and Enantiopure Organic Crystals for Predicting Enantiomer Separation

“…Direct use of the sublimation cycle when sublimation data are available gives very similar estimates of x eu (Figure 9). The combination of electronic structure calculations and experimental solubilities "exp/theory" (black bar in Figure 9) to yield Δ RS-S ΔG subl,exp/theory , gives the best estimate of x eu and correlates well with experimental sublimation free energies 27,65 when using the ψ crys model. The observed temperature dependence of x eu (Supporting Information, Table S28) cannot be accounted for by the calculations, but can be estimated by numerically integrating the measured heat capacity differences between 298 and 318 K. There is a small temperature effect on the Gibbs free energy of sublimation differences Δ T1-T2 Δ RS-S ΔG subl which slightly shifts the eutectic composition: for lactide and naproxen, x eu decreases by −0.4 and −0.9 mol % and increases by 0.6 mol % for 3ClMA.…”

“…26 Naproxen is marketed in the enantiopure form as a nonsteroidal anti-inflammatory drug, although the racemic form is more stable. 27,28 3-Chloromandelic acid (3ClMA) is used as an intermediate for pharmaceutical products and represents the mandelic acid family of prototypical chiral molecules. 29 It has complex polymorphic crystallization behavior that defies many current assumptions.…”

“…Both the racemic molecular compound and the ( S )-enantiomer are used in the preparation of polylactide, , a biologically decomposable polymer with many complex properties that make it ideal for medical applications . Naproxen is marketed in the enantiopure form as a nonsteroidal anti-inflammatory drug, although the racemic form is more stable. , 3-Chloromandelic acid (3ClMA) is used as an intermediate for pharmaceutical products and represents the mandelic acid family of prototypical chiral molecules . It has complex polymorphic crystallization behavior that defies many current assumptions. , …”