Mechanistic Multiscale Co-crystal Dissolution Modelling

口服药物产品（如片剂和胶囊）中活性药物成分（API）的溶解是人体吸收的先决条件，因为只有溶解的药物分子才能通过活组织扩散。难溶性药物可导致低溶出速率和差的生物利用度。因此，需要制备不太常规的固体形式和更创新的制剂策略。在这项工作中，我们的目标是解决使用共晶体改善难溶性药物的口服生物利用度，共晶体被定义为使API和一种或多种其他分子种类（称为共形成物）以化学计量的量形成晶格。共晶的优点是改善了API的溶解度、溶出速率、物理和化学稳定性以及机械性能。因此，API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损害其药理活性的方法。对于单组分结晶化合物，溶解瞬态通常在达到药物的溶解度极限时终止，只要系统热力学保持不受干扰，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。然而，对多组分共晶的溶解机理的理解非常有限。已经观察到，共晶体的溶解可以导致溶液介导的相转化（SMPT），其中由于“弹簧”效应，母体药物溶液的浓度超过晶体的浓度，母体药物的沉淀可以发生在溶解的共晶体的表面上和/或本体溶液中。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，这可能对药物生物利用度有直接的影响。因此，表征共晶的重结晶动力学对于预测共晶的体内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中或溶出介质中以延迟药物沉淀，从而使共晶的益处最大化。溶液去过饱和事件的动力学通常要复杂得多，也不太清楚。由于这个原因，通过模拟这种行为，我们可以显着减少所需的实验负担，以表征“弹簧”和“降落伞”的影响。此外，通过我们对共晶溶出的机制建模，我们将促进临床相关溶出质量标准（CRS）的开发和利用，并在基于生理学的药代动力学（PBPK）建模中成功预测体内清除率方面发挥关键作用。

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.