Molecular simulation of size-dependent crystal stability and water solubility of carbamazepine polymorphs: Guides to tailor drug formulation

IF 3.8 3区 医学 Q2 CHEMISTRY, MEDICINAL
Moritz Macht, Dirk Zahn
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引用次数: 0

Abstract

While molecular simulations are by now well-established for predicting bulk crystal structures and their lattice energy, here we present an approach to predicting the stability of finite precipitates in different solvent scenarios. Mimicking carbamazepine formulation from apolar solution, we outline size-dependent energy profiles for crystallites of polymorphs I-III and amorphous particles, respectively. In particular, crystal nucleation barriers are computed as functions of supersaturation and contrasted to the size-dependent stability profiles of the competing polymorphs. On this basis, we argue that carbamazepine follows a two-step nucleation process starting from amorphous precipitates of spherical shape. These indeed reflect the thermodynamically preferred state of aggregates counting up to ∼100 carbamazepine molecules. In turn, larger aggregates experience thermodynamic driving to self-organization into crystalline arrangements. Crystallites of up to ∼1000 molecules showed an energetic preference of form II, whilst thermodynamic stability of form III applies to larger crystals. Tailoring critical nucleus size and energy from different degrees of supersaturation, our models suggest routes to promote nucleation of carbamazepine form II from apolar solution. In turn, immersing our series of crystallite/precipitate models in water, we re-evaluate size-dependent polymorph stability – and predict relative solubility in water. On this basis, boosts in relative solubility by 100 and 200 % are suggested for 50 and 25 nm scale spatial confinements (e.g. solid dispersion in polymer solutions), respectively.
卡马西平多晶型的大小依赖性晶体稳定性和水溶性分子模拟:定制药物配方指南。
虽然分子模拟现在已经建立了预测大块晶体结构及其晶格能量的方法,但在这里,我们提出了一种在不同溶剂情况下预测有限沉淀稳定性的方法。模拟极性溶液中的卡马西平配方,我们分别概述了多晶I-III和非晶颗粒晶体的尺寸依赖性能量分布。特别是,晶体成核屏障被计算为过饱和的函数,并与竞争多晶的尺寸依赖的稳定性曲线进行对比。在此基础上,我们认为卡马西平遵循两步成核过程,从球形无定形沉淀开始。这些确实反映了计算到~ 100个卡马西平分子的聚集体的热力学首选状态。反过来,更大的聚集体经历热力学驱动自组织成晶体排列。高达1000个分子的晶体表现出对形式II的能量偏好,而形式III的热力学稳定性适用于更大的晶体。根据不同过饱和程度来调整临界核的大小和能量,我们的模型提出了从极性溶液中促进卡马西平II型成核的途径。反过来,将我们的一系列结晶/沉淀模型浸入水中,我们重新评估尺寸依赖性多晶型稳定性,并预测在水中的相对溶解度。在此基础上,对于50 nm和25 nm尺度的空间限制(如聚合物溶液中的固体分散),相对溶解度分别提高了100%和200%。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
CiteScore
7.30
自引率
13.20%
发文量
367
审稿时长
33 days
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.
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