Thai T H Nguyen, Cai Y Ma, Ioanna D Styliari, Parmesh Gajjar, Robert B Hammond, Philip J Withers, Darragh Murnane, Kevin J Roberts
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引用次数: 0
Abstract
The particulate properties of α-lactose monohydrate (αLMH), an excipient and carrier for pharmaceuticals, is important for the design, formulation and performance of a wide range of drug products. Here an integrated multi-scale workflow provides a detailed molecular and inter-molecular (synthonic) analysis of its crystal morphology, surface chemistry and surface energy. Predicted morphologies are validated in 3D through X-ray diffraction contrast tomography. Interestingly, from aqueous solution fastest growth is found to lie along the b-axis, i.e. the longest unit cell dimension of the αLMH crystal structure reflecting the greater opportunities for solvation on the prism compared to the capping faces leading to their slower relative growth rates. The tomahawk morphology reflects the presence of β-lactose which asymmetrically binds to the capping surfaces creating a polar morphology. The crystal lattice energy is dominated by van der Waals interactions (between lactose molecules) with electrostatic interactions contributing the remainder. Predicted total surface energies are in good agreement with those measured at high surface coverage by inverse gas chromatography, albeit their dispersive contributions are found to be higher than those measured. The calculated surface energies of crystal habit surfaces are not found to be significantly different between different crystal surfaces, consistent with αLMH's known homogeneous binding to drug molecules when formulated. Surface energies for different morphologies reveals crystals with the elongated crystal morphologies have lower surface energies compared to those with a triangular or tomahawk morphologies, correlating well with literature data that the surface energies of the lactose carriers are inversely proportional to their aerosol dispersion performance.
一水α-乳糖(αLMH)是一种药用辅料和载体,其微粒特性对多种药物产品的设计、配制和性能非常重要。这里的多尺度综合工作流程对其晶体形态、表面化学和表面能进行了详细的分子和分子间(合成)分析。预测的形态通过 X 射线衍射对比断层扫描进行三维验证。有趣的是,从水溶液中发现沿着 b 轴(即 αLMH 晶体结构的最长单胞尺寸)生长最快,这反映出棱柱上的溶解机会比盖面更多,导致其相对生长速度较慢。战斧状形态反映了 β-乳糖的存在,它不对称地与封盖面结合,形成了极性形态。范德华相互作用(乳糖分子之间)在晶格能中占主导地位,静电作用占其余部分。预测的总表面能与反气相色谱法在高表面覆盖率下测得的总表面能十分吻合,但发现它们的分散贡献比测得的要高。不同晶型表面的计算表面能差异不大,这与已知的 αLMH 在配制时与药物分子的均匀结合是一致的。不同形态的表面能显示,与三角形或战斧形形态的晶体相比,细长晶体形态的晶体表面能较低,这与乳糖载体的表面能与其气溶胶分散性能成反比的文献数据十分吻合。
期刊介绍:
The Journal of Pharmaceutical Sciences will publish original research papers, original research notes, invited topical reviews (including Minireviews), and editorial commentary and news. The area of focus shall be concepts in basic pharmaceutical science and such topics as chemical processing of pharmaceuticals, including crystallization, lyophilization, chemical stability of drugs, pharmacokinetics, biopharmaceutics, pharmacodynamics, pro-drug developments, metabolic disposition of bioactive agents, dosage form design, protein-peptide chemistry and biotechnology specifically as these relate to pharmaceutical technology, and targeted drug delivery.