Mechanistic Multiscale Co-crystal Dissolution Modelling

口服给药的药物制品（如片剂和胶囊）中活性药物成分（api）的溶解是在人体内吸收的先决条件，因为只有溶解的药物分子才能通过活组织扩散。低溶性药物可导致低溶出率和较差的生物利用度。因此，需要较少传统固体形式的制备和更多创新的配方策略。在这项工作中，我们的目标是利用共晶来提高难溶性药物的口服生物利用度，共晶的定义是将原料药和一种或多种其他分子物种（称为共成体）以化学计量量形成晶格。共晶的优点是提高原料药的溶解度、溶解速率、物理化学稳定性和力学性能。因此，原料药的共结晶可以提供一种改善难溶性药物的口服生物利用度而不影响其药理活性的方法。对于单组分结晶化合物，当达到药物的溶解度极限时，溶解瞬态通常终止，只要系统热力学不受干扰，溶液浓度就保持不变。在这种情况下，溶解和沉淀的速率处于动态平衡状态。然而，对多组分共晶的溶解机理的认识非常有限。已经观察到，共晶的溶解可以导致溶液介导的相变（SMPT），其中由于“弹簧”效应，当母体药物溶液浓度超过晶体浓度时，母体药物可以在溶解的共晶表面和/或在体溶液中析出。这两个过程的速率，在相反的方向上工作，定义了溶解度增强的“降落伞”的大小和持续时间，这可以直接影响药物的生物利用度。因此，表征共晶的再结晶动力学对预测共晶的体内和体外性能具有重要意义。此外，稳定（成核和生长抑制）聚合物通常存在于制剂或溶解介质中，以延迟药物沉淀，从而最大化共晶的益处。溶液去过饱和事件的动力学通常要复杂得多，而且很难理解。由于这个原因，通过模拟这种行为，我们可以显著减少表征“弹簧”和“降落伞”效应所需的实验负担。此外，通过我们的共晶溶解机制建模，我们将促进临床相关溶解规范（CRS）的开发和利用，并在基于生理的药代动力学（PBPK）模型中成功预测体内清除方面发挥关键作用。

Dissolution of active pharmaceutical ingredients (APIs) in orally administrated drug products (such as tablets and capsules) is a pre-requisite for absorption within the human body because only dissolved drug molecules are able to diffuse through living tissues. Poorly soluble drugs can lead to a low dissolution rate and poor bioavailability. Therefore, the preparation of less conventional solid forms and more innovative formulation strategies are needed. In this work we aim to address improving the oral bioavailability of poorly soluble drugs using co-crystals, which are defined as bringing an API and one or more other molecular species (called co-formers) in stoichiometric amounts to form a crystal lattice. The advantage of co-crystals is to improve the API solubility, dissolution rate, physical and chemical stability as well as in mechanical properties. Therefore, co-crystallisation of APIs can offer a means of improving the oral bioavailability of poorly soluble drugs without compromising their pharmacological activity. For a single component crystalline compound, the dissolution transient typically terminates when the solubility limit of the drug is reached, with the solution concentration being maintained as long as the system thermodynamics remain unperturbed. In this situation, the rates of dissolution and precipitation are in dynamic equilibrium. However, the understanding of dissolution mechanisms of multi-component co-crystals is very limited. It has been observed that the dissolution of co-crystals can lead to solution-mediated phase transformation (SMPT) where precipitation of the parent drug could take place on the surface of the dissolving co-crystal and/or in the bulk solution due to the "spring" effect where the parent drug solution concentration exceeds that of the crystal. The rates of these two processes, working in opposing directions, define the magnitude and duration of the solubility-enhanced "parachute", that can have direct implications on the drug bioavailability. Therefore, characterizing the recrystallization kinetics is of importance for predicting in vitro and in vivo performance of co-crystals. Additionally, stabilizing (nucleation and growth inhibiting) polymers are normally present within a formulation or in the dissolution medium to delay drug precipitation for maximising the benefits of co-crystals. The kinetics of the solution de-supersaturation event are often much more complex and less well understood. For this reason, through modelling such behaviour we can significantly reduce the experimental burden required to characterize the "spring" and "parachute" effects. Furthermore, through our mechanistic modelling of co-crystal dissolution we will facilitate the development and leverage of clinically relevant dissolution specifications (CRS) and play a key role in the successful prediction of clearance in vivo within physiologically-based pharmacokinetic (PBPK) modelling.