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Modeling Recrystallization Kinetics Following the Dissolution of Amorphous Drugs.
Molecular Pharmaceutics ( IF 4.9 ) Pub Date : 2019-12-18 , DOI: 10.1021/acs.molpharmaceut.9b00940
Peter J Skrdla 1 , Philip D Floyd 1 , Philip C Dell'Orco 1
Affiliation  

Amorphous phases are frequently employed to overcome the solubility limitation that is nowadays commonplace in developmental small-molecule drugs intended for oral administration. However, since the solubility enhancement has finite longevity (it is a "kinetic solubility" effect), characterizing its duration (i.e., the so-called "parachute" effect) can be important for optimizing a formulation with regard to its in vivo exposure. Two semiempirical models, based on dispersive kinetics theory, are evaluated for their ability to precisely describe experimental transients depicting a loss in supersaturation (initially generated by the dissolution of the amorphous phase) over time, as the solubilized drug recrystallizes. It is found that in cases where the drug solubility significantly exceeds that of the crystal at longer times, the mechanism has substantial "denucleation" (dissolution) character. On the other hand, "nucleation and growth" (recrystallization) kinetics best describe systems in which the recrystallization goes to completion within the experimental time frame. Kinetic solubility profiles taken from the recent literature are modeled for the following drugs: glibenclamide, indomethacin, loratadine, and terfenadine. In the last case, a combination of three different kinetic models, two classical ones plus the dispersive model, are used together in describing the entire dissolution-recrystallization transient of the drug, obtaining a fit of R2 = 0.993. By precisely characterizing the duration of the "parachute" in vitro (e.g., under biorelevant conditions), the proposed models can be useful in predicting trends and thereby guiding formulation development and optimization.

中文翻译:

溶解无定形药物后的重结晶动力学建模。

非晶态相经常被用来克服溶解度的限制,而溶解度的限制在当今旨在口服的发展中的小分子药物中是很普遍的。但是,由于溶解度提高具有有限的寿命(这是“运动溶解度”效应),表征其持续时间(即所谓的“降落伞”效应)对于优化制剂的体内暴露量可能是重要的。对基于分散动力学理论的两个半经验模型进行了评估,以精确描述实验瞬态的能力,这些瞬态描述了随着溶解的药物重结晶而随着时间的流逝而发生的过饱和损失(最初由无定形相的溶解产生)。发现在较长时间药物溶解度明显超过晶体溶解度的情况下,该机制具有实质性的“去核”(溶解)特性。另一方面,“成核和生长”(重结晶)动力学最能描述其中重结晶在实验时间内完成的系统。对于以下药物,对从最近文献中获得的动力学溶解度进行了建模:格列本脲,消炎痛,氯雷他定和特非那定。在最后一种情况下,结合使用三种不同的动力学模型,两种经典的动力学模型和分散模型,来描述药物的整个溶解-重结晶瞬变,拟合度为R2 = 0.993。通过精确描述体外“降落伞”的持续时间(例如在生物相关条件下),
更新日期:2019-12-19
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