Purpose

Application of multi-scale modelling workflows to characterise polymorphism in ritonavir with regard to its stability, bioavailability and processing.

Methods

Molecular conformation, polarizability and stability are examined using quantum mechanics (QM). Intermolecular synthons, hydrogen bonding, crystal morphology and surface chemistry are modelled using empirical force fields.

Results

The form I conformation is more stable and polarized with more efficient intermolecular packing, lower void space and higher density, however its shielded hydroxyl is only a hydrogen bond donor. In contrast, the hydroxyl in the more open but less stable and polarized form II conformation is both a donor and acceptor resulting in stronger hydrogen bonding and a more stable crystal structure but one that is less dense. Both forms have strong 1D networks of hydrogen bonds and the differences in packing energies are partially offset in form II by its conformational deformation energy difference with respect to form I. The lattice energies converge at shorter distances for form I, consistent with its preferential crystallization at high supersaturation. Both forms exhibit a needle/lath-like crystal habit with slower growing hydrophobic side and faster growing hydrophilic capping habit faces with aspect ratios increasing from polar-protic, polar-aprotic and non-polar solvents, respectively. Surface energies are higher for form II than form I and increase with solvent polarity. The higher deformation, lattice and surface energies of form II are consistent with its lower solubility and hence bioavailability.

Conclusion

Inter-relationship between molecular, solid-state and surface structures of the polymorphic forms of ritonavir are quantified in relation to their physical-chemical properties.

中文翻译：

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与理化性质相关的利托那韦构象多晶型的分子、固态和表面结构

目的

应用多尺度建模工作流程来表征利托那韦在稳定性、生物利用度和加工方面的多态性。

方法

使用量子力学 (QM) 检查分子构象、极化率和稳定性。分子间合成子、氢键、晶体形态和表面化学使用经验力场建模。

结果

I型构象更稳定和极化，具有更有效的分子间堆积、更低的空隙空间和更高的密度，但其被屏蔽的羟基只是一个氢键供体。相比之下，更开放但不太稳定和极化的 II 型构象中的羟基既是供体又是受体，导致更强的氢键和更稳定的晶体结构，但密度较低。两种形式都具有强大的一维氢键网络，并且形式 II 中的堆积能差异被其相对于形式 I 的构象变形能差异部分抵消。对于形式 I，晶格能量会聚在较短的距离处，与其优先结晶在高过饱和度。两种形式都表现出针状/板条状晶体习性，疏水侧增长较慢，亲水性封端习性面增长较快，纵横比分别从极性质子、极性非质子和非极性溶剂增加。II 型的表面能高于 I 型，并随着溶剂极性的增加而增加。形式 II 的较高变形、晶格和表面能与其较低的溶解度和生物利用度一致。

结论

利托那韦多晶型的分子、固态和表面结构之间的相互关系根据其物理化学性质进行量化。