Benmore Chris J, Edwards Angela, Alderman Oliver L G, Cherry Brian R, Smith Pamela, Smith Daniel, Byrn Stephen, Weber Richard, Yarger Jeffery L
Advanced Photon Source, Argonne National Laboratory, Argonne, IL 60439, USA.
School of Molecular Sciences, Arizona State University, Tempe, AZ 85281, USA.
Quantum Beam Sci. 2022 Dec;6(4). doi: 10.3390/qubs6040031. Epub 2022 Nov 15.
To enhance the solubility of orally administered pharmaceuticals, liquid capsules or amorphous tablets are often preferred over crystalline drug products. However, little is known regarding the variation in bonding mechanisms between pharmaceutical molecules in their different disordered forms. In this study, liquid and melt-quenched glassy carbamazepine have been studied using high energy X-ray diffraction and modeled using Empirical Potential Structure Refinement. The results show significant structural differences between the liquid and glassy states. The liquid shows a wide range of structures; from isolated molecules, to aromatic ring correlations and NH-O hydrogen bonding. Upon quenching from the liquid to the glass the number of hydrogen bonds per molecule increases by ~50% at the expense of a ~30% decrease in the close contact (non-bonded) carbon-carbon interactions between aromatic rings. During the cooling process, there is an increase in both singly and doubly hydrogen-bonded adjacent molecules. Although hydrogen-bonded dimers found in the crystalline states persist in the glassy state, the absence of a crystalline lattice also allows small, hydrogen-bonded NH-O trimers and tetramers to form. This proposed model for the structure of glassy carbamazepine is consistent with the results from vibrational spectroscopy and nuclear magnetic resonance.
为提高口服药物的溶解度，液囊或无定形片剂通常比结晶药物产品更受青睐。然而，对于药物分子在不同无序形式下键合机制的变化却知之甚少。在本研究中，利用高能X射线衍射对液态和熔融骤冷玻璃态卡马西平进行了研究，并使用经验势能结构精修法进行建模。结果表明，液态和玻璃态之间存在显著的结构差异。液态呈现出广泛的结构；从孤立分子到芳环相关性以及NH - O氢键。从液态骤冷至玻璃态时，每个分子的氢键数量增加约50%，代价是芳环之间紧密接触（非键合）的碳 - 碳相互作用减少约30%。在冷却过程中，单氢键和双氢键相邻分子均有所增加。虽然在结晶态中发现的氢键二聚体在玻璃态中依然存在，但晶格的缺失也使得小的氢键NH - O三聚体和四聚体得以形成。所提出的玻璃态卡马西平结构模型与振动光谱和核磁共振的结果一致。
