{"title":"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。","authors":"Moritz Macht, Dirk Zahn","doi":"10.1016/j.xphs.2025.103923","DOIUrl":null,"url":null,"abstract":"<div><div>While molecular simulations are by now well-established for predicting <em>bulk</em> crystal structures and their lattice energy, here we present an approach to predicting the stability of <em>finite</em> 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.</div></div>","PeriodicalId":16741,"journal":{"name":"Journal of pharmaceutical sciences","volume":"114 9","pages":"Article 103923"},"PeriodicalIF":3.8000,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Molecular simulation of size-dependent crystal stability and water solubility of carbamazepine polymorphs: Guides to tailor drug formulation\",\"authors\":\"Moritz Macht, Dirk Zahn\",\"doi\":\"10.1016/j.xphs.2025.103923\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><div>While molecular simulations are by now well-established for predicting <em>bulk</em> crystal structures and their lattice energy, here we present an approach to predicting the stability of <em>finite</em> 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.</div></div>\",\"PeriodicalId\":16741,\"journal\":{\"name\":\"Journal of pharmaceutical sciences\",\"volume\":\"114 9\",\"pages\":\"Article 103923\"},\"PeriodicalIF\":3.8000,\"publicationDate\":\"2025-07-24\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of pharmaceutical sciences\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S0022354925003752\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"CHEMISTRY, MEDICINAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of pharmaceutical sciences","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0022354925003752","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}
Molecular simulation of size-dependent crystal stability and water solubility of carbamazepine polymorphs: Guides to tailor drug formulation
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.
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.