Racemic Naproxen: A Multidisciplinary Structural and Thermodynamic Comparison with the Enantiopure Form

Abstract

Following the computational prediction that (<i>RS</i>)-naproxen would be more stable than the therapeutically used and more studied homochiral (<i>S</i>)-naproxen, we performed an interdisciplinary study contrasting the two compounds. The crystal structure of the racemic compound was solved from powder X-ray diffraction data (<i>Pbca</i>) and showed no packing similarity with the homochiral structure (<i>P</i>2₁). The binary melting point phase diagram was constructed to confirm the nature of the racemic species, and differential scanning calorimetric and solubility measurements were used to estimate the enthalpy difference between the crystals (Δ<i>H</i>_{<i>R</i>+<i>S</i>→<i>RS</i>}^cry) to be −1.5 ± 0.3 kJ·mol^–1 at <i>T</i> ∼ 156 °C and −2.4 ± 1.0 kJ·mol^–1 in the range 10–40 °C. A comparison of the different approximations involved in estimating Δ<i>H</i>_{<i>R</i>+<i>S</i>→<i>RS</i>}^cry implied that the difference in the lattice energies overestimated the stability of the (<i>RS</i>) crystal. The naproxen lattice energy landscape confirmed that all the practically important crystal structures have been found and characterized and provided insights into the crystal growth problems of the racemic form. This highlights the complementarity of computational modeling in investigating chiral crystallization