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

Following the computational prediction that (RS)-naproxen would be more stable than the therapeutically used and more studied homochiral (S)-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 (Pbca) and showed no packing similarity with the homochiral structure (P21). 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 (ΔHR+S→RScry) to be −1.5 ± 0.3 kJ·mol–1 at T ∼ 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 ΔHR+S→RScry implied that the difference in the lattice energies overestimated the stability of the (RS) 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.

基于计算预测，(RS)-萘普生((RS)-naproxen)的稳定性将优于临床应用中研究更为广泛的手性纯(S)-萘普生((S)-naproxen)，本研究开展了对比两种化合物的跨学科研究。通过粉末X射线衍射（powder X-ray diffraction）数据解析得到该外消旋化合物的晶体结构（空间群Pbca），结果显示其堆积特性与手性纯(S)-萘普生的晶体结构（空间群P2₁）无相似性。本研究构建了二元熔点相图以确认该外消旋体的性质，并结合差示扫描量热法与溶解度测定，估算得到晶态下(R+S→RS)的焓差ΔH_(R+S→RS)cry：在约156℃时为−1.5 ± 0.3 kJ·mol⁻¹，在10~40℃范围内为−2.4 ± 1.0 kJ·mol⁻¹。对估算ΔH_(R+S→RS)cry所涉及的不同近似方法的对比分析表明，晶格能差异高估了(RS)-萘普生晶态的稳定性。萘普生的晶格能量图谱证实，所有具有实际意义的晶体结构均已被发现并完成表征，同时为外消旋形式的晶体生长难题提供了研究视角。该研究凸显了计算建模在手性结晶研究中的互补价值。