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Presenting the Lynne S. Taylor dedicated issue of JPharmSci®. 推出 Lynne S. Taylor 专刊《JPharmSci®》。
IF 3.7 3区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2024-11-12 DOI: 10.1016/j.xphs.2024.11.001
Kenneth L Audus
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引用次数: 0
Discovery of the Most Stable Form of an Adenosine Receptor Antagonist through Virtual Polymorph Screening and Targeted Crystallization. 通过虚拟多态性筛选和定向结晶发现腺苷受体拮抗剂的最稳定形式。
IF 3.7 3区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2024-11-12 DOI: 10.1016/j.xphs.2024.10.027
Dedong Wu, Emma S E Eriksson, Sten O Nilsson Lill, James F McCabe, Christoph Bauer, Michelle L Lamb

An innovative approach was developed to identify the optimal crystalline form, usually the thermodynamically most stable form. This method involves using virtual polymorph screening and targeted crystallization based on in silico solid-state modeling. By utilizing advanced crystal structure prediction (CSP) technology, the virtual polymorph screening method helps confirm whether the most stable crystalline form has been identified in actual crystallization experiments. If the predicted most stable form is not observed in experiments, predictions based on the method of COnductor like Screening MOdel for Real Solvents (COSMO-RS) are used to highlight solvent systems that can increase the likelihood of experimentally obtaining the desired form through a targeted crystallization process. In this work, such an approach has enabled the rapid discovery of the most stable polymorphic form and the development of a crystallization process of an adenosine receptor antagonist using minimal amounts of the sample within a shortened timeframe. Additionally, it provides a scientific rationale for ensuring the selection of the most stable form in the early stages of drug discovery, thereby reducing risks in future pharmaceutical development.

我们开发了一种创新方法来确定最佳结晶形态,通常是热力学上最稳定的形态。这种方法包括利用虚拟多晶体筛选和基于硅学固态建模的定向结晶。通过利用先进的晶体结构预测(CSP)技术,虚拟多晶体筛选方法有助于确认是否已在实际结晶实验中确定了最稳定的结晶形式。如果在实验中没有观察到预测的最稳定形式,则会使用基于 COnductor like Screening MOdel for Real Solvents(COSMO-RS)方法的预测来突出溶剂系统,以增加通过有针对性的结晶过程在实验中获得所需形式的可能性。在这项工作中,这种方法能够快速发现最稳定的多态形式,并在更短的时间内使用最少的样品量开发出腺苷受体拮抗剂的结晶过程。此外,它还为确保在药物发现的早期阶段选择最稳定的形式提供了科学依据,从而降低了未来药物开发的风险。
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引用次数: 0
Effect of material properties and extrusion process parameters on permeability of etonogestrel in ethylene vinyl acetate copolymer (EVA) films. 材料特性和挤压工艺参数对乙烯-醋酸乙烯共聚物(EVA)薄膜中依诺孕酮渗透性的影响。
IF 3.7 3区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2024-11-11 DOI: 10.1016/j.xphs.2024.10.057
Ziyue Zhong, Angela Ren, Lance Arbilo, Qiangnan Zhang, William Smith, Bin Qin, Yan Wang, Feng Zhang

Ethylene vinyl acetate copolymers (EVA) have been extensively used in controlled drug delivery systems due to its good biocompatibility and tunable applicability based on simple variations in vinyl acetate (VA) content. We investigated impacts of material properties of EVA, including VA content and molecular weight, as well as extrusion process parameters, including draw down ratio and cooling rate, on permeability of etonogestrel in EVA films. Among all factors studied, the VA content was the most dominant factor that controls drug permeability by affecting crystallinity of EVA. MW, DDR, and cooling rate exhibited less significant effects. The impacts of these factors on crystallinity, crystallite size, and degree of crystalline orientation of EVA were characterized using polarized light microscope, differential scanning calorimetry (DSC) and wide-angle X-ray scattering (WAXS). Based on the solution-diffusion model, the mechanisms by which the crystalline properties controlled drug solubility and diffusivity in EVA were discussed. These results can be applied to investigate the effects of material properties of EVA and manufacturing process conditions on drug release properties of reservoir-type EVA-based drug delivery systems with a rate-controlling membrane.

乙烯-醋酸乙烯共聚物(EVA)具有良好的生物相容性,且可根据醋酸乙烯(VA)含量的简单变化进行调整,因此已被广泛应用于可控给药系统。我们研究了 EVA 的材料特性(包括 VA 含量和分子量)以及挤出工艺参数(包括拉伸比和冷却速度)对 EVA 薄膜中依托孕烯渗透性的影响。在所有研究因素中,VA 含量是通过影响 EVA 的结晶度来控制药物渗透性的最主要因素。MW、DDR 和冷却速率的影响较小。利用偏光显微镜、差示扫描量热仪(DSC)和广角 X 射线散射(WAXS)分析了这些因素对 EVA 的结晶度、晶粒尺寸和结晶取向度的影响。根据溶液扩散模型,讨论了结晶特性控制药物在 EVA 中的溶解度和扩散性的机制。这些结果可用于研究 EVA 的材料特性和生产工艺条件对带有速率控制膜的储层型 EVA 给药系统的药物释放特性的影响。
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引用次数: 0
Combating Pharmaceutical Folklore: No Alkyl-Sulfonate Impurities Formed During the Synthesis of Sulfonate Salts. 打击制药业的民间传说:磺酸盐合成过程中不会产生烷基磺酸盐杂质。
IF 3.7 3区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2024-11-09 DOI: 10.1016/j.xphs.2024.11.002
David J Snodin

Whilst an alcohol can be forced to react with a sulfonic acid, this reaction produces minimal ester conversion even under extreme conditions (anhydrous, very low pH) that bear no resemblance to the mild synthetic procedures typically used for the formation of sulfonate salts of basic drugs. The latter involve the addition of a molar equivalent of pharma-grade sulfonic acid to the base form of a drug substance (pKa ≥3.5), dissolved or suspended in an alcohol solvent, normally ethanol (pKa -2). All added acid is neutralized, and so there is no potential for ester formation. Many drug-substance base forms are polyamines, thus preventing the generation of acidic reaction conditions even in the presence of excess of sulfonic acid. Despite the experimental evidence, the perception that short-chain mutagenic alkyl sulfonates are "potential impurities" in sulfonate salts is widely held within regulatory bodies. This stance implies that a mechanistically-impossible reaction can occur: nucleophilic displacement by sulfonate anion of the hydroxyl group from a short-chain alcohol under non-acidic conditions. The European Pharmacopoeia (Ph.Eur.) and the British Pharmacopoeia (BP) include "production statements" in monographs for sulfonate-salt drug substances requiring a "risk assessment" of the production process. Neither body has provided supporting evidence. Information obtained from the BP via Freedom of Information requests showed that expert-group discussions were characterised by a range of ad-hoc opinions rather than an evidence-based evaluation of mechanism, kinetics and experimental data. Alternative sources of alkyl-sulfonate impurities such as methyl methanesulfonate (MMS) arising from the use of impure, reagent-grade methanesulfonic acid (MSA) were not considered. Both BP and Ph.Eur. production statements appear to be based on policy rather than scientific evidence and so should be discontinued.

虽然可以强迫酒精与磺酸发生反应,但即使在极端条件下(无水、pH 值极低),这种反应也只能产生极少的酯转化,与通常用于形成碱性药物磺酸盐的温和合成程序毫无相似之处。后者是在溶解或悬浮于醇溶剂(通常为乙醇,pKa -2)中的药物物质(pKa ≥3.5)的基础形式中加入摩尔当量的医药级磺酸。所有添加的酸都会被中和,因此没有形成酯的可能性。许多药物物质的碱基形式是多胺,因此即使在磺酸过量的情况下也不会产生酸性反应条件。尽管有实验证据,但监管机构普遍认为短链致突变烷基磺酸盐是磺酸盐中的 "潜在杂质"。这种立场意味着可能会发生一种机械上不可能发生的反应:在非酸性条件下,磺酸盐阴离子对短链醇羟基的亲核置换。欧洲药典》(Ph.Eur.)和《英国药典》(BP)在磺酸盐盐类药物的各论中列入了 "生产说明",要求对生产过程进行 "风险评估"。这两个机构都没有提供支持证据。通过 "信息自由 "申请从英国药典获得的信息显示,专家组讨论的特点是提出一系列临时意见,而不是对机理、动力学和实验数据进行循证评估。没有考虑烷基磺酸盐杂质的其他来源,如使用不纯的试剂级甲磺酸 (MSA) 而产生的甲磺酸甲酯 (MMS)。英国石油公司和欧洲博士公司的生产声明似乎都是基于政策而非科学证据,因此应予停止。
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引用次数: 0
Counteracting the loss of release for indomethacin-copovidone ASDs. 抵消吲哚美辛-科波维酮 ASD 的释放损失。
IF 3.7 3区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2024-11-06 DOI: 10.1016/j.xphs.2024.10.022
Dominik Borrmann, Pascal Friedrich, Justin Smuda, Gabriele Sadowski

This work revisits the changing release behavior of indomethacin(IND)-copovidone amorphous solid dispersions (ASDs) when increasing their drug load (DL). While showing congruent release behavior at DL 0.1, ASDs with DLs of 0.3 and higher show incongruent release finally resulting in a complete loss of release. To study and explain this phenomenon, we modeled the release kinetics of these ASDs and looked into their phase behavior both experimentally and theoretically. We applied a diffusion model to accurately describe experimental release profiles for congruent release, incongruent release as well as for loss of release. Predicted concentration profiles for IND, copovidone, and water within the ASD revealed the formation of an ASD layer that almost exclusively contains amorphous IND. Our phase-diagram predictions and experimental data explain this phenomenon by water-induced phase separation in those parts of the ASD which did absorb water from the dissolution medium. Whereas the evolving copovidone-rich phase dissolved, the IND-rich phase remained undissolved and formed a super-hydrophobic cover of the remaining inner core of the ASD, thus finally completely preventing its dissolution. Higher DLs promote phase separation. This leads to the counterintuitive effect that the higher the DL, the lower the absolute amount of IND released. While the ASD containing 6 mg IND (DL 0.1) released 6 mg IND, the one containing 42 mg IND (DL 0.7) released only 1 mg IND. The theoretical approach applied in this work is for the first time able to quantitatively predict that reducing DL or tablet size could be used to overcome this problem.

这项研究重新审视了吲哚美辛(IND)-科波维酮无定形固体分散体(ASD)在增加药物载量(DL)时的释放行为变化。DL 为 0.1 的 ASD 表现出一致的释放行为,而 DL 为 0.3 或更高的 ASD 则表现出不一致的释放行为,最终导致完全丧失释放。为了研究和解释这一现象,我们对这些 ASD 的释放动力学进行了建模,并从实验和理论两方面研究了它们的相行为。我们应用扩散模型准确地描述了一致释放、不一致释放以及释放损失的实验释放曲线。IND、共聚维酮和水在ASD中的预测浓度曲线显示,ASD层的形成几乎完全包含无定形IND。我们的相图预测和实验数据解释了这一现象,即在 ASD 从溶解介质中吸水的部分,由水引起的相分离。不断演变的富含聚维酮的相溶解了,而富含 IND 的相却没有溶解,并在 ASD 的剩余内核上形成了超疏水性覆盖层,从而最终完全阻止了其溶解。较高的 DL 会促进相分离。这导致了一种反直觉效果,即 DL 越高,释放的 IND 绝对量越低。含有 6 毫克 IND(DL 0.1)的 ASD 释放出 6 毫克 IND,而含有 42 毫克 IND(DL 0.7)的 ASD 仅释放出 1 毫克 IND。本研究采用的理论方法首次能够定量预测减少 DL 或药片大小可用于克服这一问题。
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引用次数: 0
Understanding the effect of plasticizers in film coat materials on the physical stability of amorphous solid dispersions. 了解薄膜涂层材料中的增塑剂对无定形固体分散体物理稳定性的影响。
IF 3.7 3区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2024-11-04 DOI: 10.1016/j.xphs.2024.10.024
Kaustav Chatterjee, Ashish Punia, Alex M Confer, Matthew S Lamm

Amorphous solid dispersions (ASDs) have been extensively utilized to improve the bioavailability of drugs that have low aqueous solubility. The influence of different excipients on the conversion of amorphous drugs into their crystalline forms in ASDs has been extensively researched. However, there is limited knowledge examining the impact of film coating materials on the physical stability of oral tablet formulations containing ASDs. In this study, we demonstrate that plasticizers present in film coats can have a detrimental impact on the physical stability of ASDs. We systematically compared two frequently used plasticizers in film coats: triacetin and polyethylene glycol 3350 (PEG 3350). To gain mechanistic insights into the detrimental effects of plasticizers on the physical stability of ASDs, plasticizer leaching studies and physical stability studies of solvent-evaporated and spray-dried intermediates (SDI) using two BCS class II drugs were conducted. Triacetin was found to leach into the tablet core within one week when stressed at 40 °C/75 % RH, whereas no leaching was observed for PEG 3350, as discerned from spectroscopic studies. We also found that triacetin-containing ASDs exhibited greater amorphous to crystalline form conversion of the drug compared to PEG 3350-containing ASDs after stability testing. Moreover, the incorporation of triacetin into polymers was found to cause a significant depression of glass transition temperature and upon equilibration with moisture, a drop below room temperature. Overall, these observations underscore the importance of carefully selecting plasticizers to be present in film coatings when developing ASD pharmaceutical products.

无定形固体分散体(ASD)已被广泛用于提高水溶性低的药物的生物利用度。不同辅料对无定形药物在 ASDs 中转化为结晶形式的影响已得到广泛研究。然而,关于薄膜包衣材料对含有 ASD 的口服片剂物理稳定性的影响的研究还很有限。在本研究中,我们证明了薄膜包衣中的增塑剂会对 ASD 的物理稳定性产生不利影响。我们系统地比较了薄膜衣中常用的两种增塑剂:三醋精和聚乙二醇 3350(PEG 3350)。为了从机理上深入了解增塑剂对 ASD 物理稳定性的不利影响,我们使用两种 BCS II 类药物对溶剂蒸发和喷雾干燥中间体 (SDI) 进行了增塑剂浸出研究和物理稳定性研究。研究发现,在 40°C/75% 相对湿度条件下,三醋精会在一周内浸出到片剂芯中,而根据光谱研究,PEG 3350 没有浸出。我们还发现,在稳定性测试后,与含 PEG 3350 的 ASD 相比,含三醋精的 ASD 表现出更大的药物无定形到结晶形式的转化。此外,我们还发现,将三醋精掺入聚合物中会显著降低玻璃化转变温度,并且在与水分平衡后,玻璃化转变温度会降至室温以下。总之,这些观察结果表明,在开发 ASD 药物产品时,仔细选择薄膜包衣中的增塑剂非常重要。
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引用次数: 0
Insights into pharmaceutical co-crystallization using coherent Raman microscopy. 利用相干拉曼显微镜深入了解药物共结晶。
IF 3.7 3区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2024-11-02 DOI: 10.1016/j.xphs.2024.10.054
Alba M Arbiol Enguita, Elina Harju, Lea Wurr, Teemu Tomberg, Oona Auvinen, Leena Peltonen, Clare Strachan, Jukka Saarinen

Formulating active pharmaceutical ingredients (APIs) as co-crystals requires a thorough understanding of co-crystallization behavior under different process conditions. This study employs two forms of coherent Raman microscopy, narrowband coherent anti-Stokes Raman scattering (CARS) and stimulated Raman scattering (SRS) with spectral focusing, to study co-crystallization via liquid-assisted ball milling. Indomethacin and nicotinamide served as the model API and co-former, and the results were compared with established analytical methods. Narrowband CARS, with univariate peak position analysis, was useful to visualize co-crystal formation, but suffered some degree of signal mixing that affected component identification. Hyperspectral SRS imaging, combined with classical least squares multivariate analysis, separated the different components with high confidence and proved to be a robust and rapid tool to qualitatively and quantitatively image co-crystallization. The coherent Raman imaging results explained divergent co-crystallization endpoints obtained with the conventional solid-state analysis methods. CARS and SRS microscopies also revealed the presence of otherwise undetected trace forms. Finally, we also demonstrated the dramatic reversal of partial co-crystal formation during milling, depending on ethanol content. Overall, the study demonstrates the added value coherent Raman microscopy can provide for analysis of co-crystallization processes.

将活性药物成分(API)配制成共晶需要全面了解不同工艺条件下的共晶行为。本研究采用窄带相干反斯托克斯拉曼散射(CARS)和带光谱聚焦的受激拉曼散射(SRS)这两种相干拉曼显微镜形式来研究通过液体辅助球磨进行的共结晶。吲哚美辛和烟酰胺分别作为模型原料药和共成体,研究结果与已有的分析方法进行了比较。采用单变量峰位分析的窄带 CARS 有助于观察共晶体的形成,但存在一定程度的信号混合,影响了成分的识别。高光谱 SRS 成像与经典的最小二乘法多元分析相结合,以较高的置信度分离出了不同的成分,并证明是定性和定量成像共晶体的可靠而快速的工具。相干拉曼成像结果解释了传统固态分析方法得出的不同共晶终点。CARS 和 SRS 显微镜还揭示了原本未检测到的痕量形式的存在。最后,我们还展示了研磨过程中部分共晶体形成的急剧逆转,这取决于乙醇含量。总之,这项研究证明了相干拉曼显微镜在分析共晶体形成过程中所能提供的附加价值。
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引用次数: 0
A survey of solid form landscape: Trends in occurrence and distribution of various solid forms and challenges in solid form selection. 固体形式现状调查:各种固体形态的出现和分布趋势以及固体形态选择方面的挑战。
IF 3.7 3区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2024-11-02 DOI: 10.1016/j.xphs.2024.10.045
Z Jane Li, Yue Lu, Ruiping Wang, Xiaomei Dong, Pengyuan Chen, Jie Duan, Meiting Shi, Liyu Wang, Yuan Liu

This survey provides a comprehensive analysis of solid form screens for 476 new chemical entities (NCEs) conducted at Pharmaron from 2016 to 2023. The findings from this survey reveal notable trends in polymorphism, salt formation, crystallization behavior and molecular weight (MW) distribution of the NCEs evaluated. Most solid form screens were conducted to select the preferred solid form for Investigational New Drug (IND) enabling projects, others were for candidate selection or late-stage development. Comparison to published historical data was made to show changes in occurrence of counterions/co-formers for salts/co-crystals, polymorphs, and the distribution of MWs over time. Increased complexity in the solid-form landscape and selection of the development form are discussed, including challenges in crystallization and selection of lead forms. The distribution of types of crystal forms and the observation of emerging and disappearing polymorphs are presented. These results highlight the evolving challenges and considerations in solid form screening and form selection and offer insights for future pharmaceutical development and crystallization strategies.

本调查全面分析了Pharmaron从2016年到2023年对476种新化学实体(NCE)进行的固型筛选。调查结果揭示了所评估的新化学实体在多态性、成盐性、结晶行为和分子量(MW)分布方面的显著趋势。大多数固态筛选是为新药研究 (IND) 启动项目选择首选固态,其他则用于候选药物选择或后期开发。通过与已公布的历史数据进行比较,可以看出随着时间的推移,盐类/共晶体、多晶型的反离子/共形物发生的变化以及截留分子量的分布。讨论了固态形式的复杂性增加和开发形式的选择,包括结晶和铅形式选择方面的挑战。介绍了晶体形态类型的分布以及对新出现和消失的多晶型的观察。这些结果突显了在固态形式筛选和形式选择方面不断变化的挑战和考虑因素,并为未来的药物开发和结晶策略提供了启示。
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引用次数: 0
β-Cyclodextrin derivatives bind aromatic side chains of the cyclic peptide lanreotide. β-环糊精衍生物结合环肽兰瑞奥肽的芳香族侧链
IF 4.3 3区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2024-11-02 DOI: 10.1016/j.xphs.2024.10.042
Negar Jafari, Justin T Douglas, Sarah A Neuenswander, Payam Kelich, Michael J Hageman

Cyclodextrin complexation has a potential to modulate the physicochemical properties of peptide drugs. The ability of peptides to form an inclusion complex can be influenced by factors such as size, amino acid sequence of peptide, and the size and charge of the cyclodextrin cavity. In this study, the inclusion complexes of the cyclic peptide drug lanreotide acetate with two common β-cyclodextrin derivatives, Sulfobutyl ether β-CD (SBEβ-CD) and hydroxypropyl β-CD (HPβ-CD) were investigated. NMR spectroscopy was used to examine the interaction between β-cyclodextrin derivatives and specific residues of lanreotide. It was observed that the hydrophobic side chain of aromatic residues in the lanreotide sequence can fit into the cavities of both β-cyclodextrin derivatives. Additionally, NMR revealed a lower diffusion coefficient and higher hydrodynamic radius of complex, indicative of binding to the cavities. Each aromatic residue was individually studied by substituting alanine in lanreotide to measure its association binding with both β-cyclodextrin derivatives. The alanine-substitute study indicated a stronger binding of SBEβ-CD to Lanreotide compared to HPβ-CD. Docking studies suggested that the 1:1 inclusion complex is more favorable than higher-order complexes due to the steric hindrance and size considerations. Docking analysis indicated the stable conformation of all three aromatic side chains with both β-cyclodextrin derivatives, SBEβ-CD and HPβ-CD.

环糊精复合物具有调节多肽药物理化性质的潜力。肽形成包合物的能力受多种因素的影响,如肽的大小、氨基酸序列以及环糊精空腔的大小和电荷。本研究考察了环肽药物醋酸兰瑞奥肽与两种常见的β-环糊精衍生物--磺丁醚β-CD(SBEβ-CD)和羟丙基β-CD(HPβ-CD)的包合复合物。核磁共振光谱用于研究β-环糊精衍生物与兰瑞奥肽特定残基之间的相互作用。结果表明,兰瑞奥肽序列中芳香残基的疏水侧链可与两种 β-环糊精衍生物的空腔相匹配。此外,核磁共振显示,复合物的扩散系数较低,流体力学半径较大,表明与空腔结合。通过取代兰瑞奥肽中的丙氨酸,对每个芳香族残基进行了单独研究,以测量其与β-环糊精衍生物的结合情况。丙氨酸替代物研究表明,与 HPβ-CD 相比,SBEβ-CD 与兰瑞奥肽的结合力更强。对接研究表明,由于立体阻碍和尺寸因素,1:1 包合复合物比高阶复合物更有利。对接分析表明,所有三个芳香族侧链都与β-环糊精衍生物 SBEβ-CD 和 HPβ-CD 形成了稳定的构象。
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引用次数: 0
Impact of surfactants on solution behavior and membrane transport of amorphous solid dispersions. 表面活性剂对无定形固体分散体的溶液行为和膜传输的影响
IF 4.3 3区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2024-11-02 DOI: 10.1016/j.xphs.2024.10.023
Amjad Alhalaweh, Mira El Sayed, Lucia Kovac, Christel A S Bergström

The purpose of the study was to develop an amorphous solid dispersion (ASD) of a poorly soluble compound (AK100) and investigate the impact of different surfactants on its dissolution, supersaturation and membrane transport. The solubility of the AK100 was determined in crystalline and amorphous form in the absence and presence of three surfactants at different concentrations: sodium dodecyl sulphate (SDS), polysorbate 80 (PS80) and D-α-tocopherol polyethylene glycol succinate (TPGS). The relation between solubility and surfactant solubilization was evaluated using a computational model. The ASD powder was prepared by solvent evaporation for non-sink dissolution experiments with and without the pre-dissolved surfactants. A transport study with Caco-2 cells was conducted to evaluate the impact of surfactants-based formulation on membrane transport. Both the corresponding crystalline and amorphous solubility of AK100 increased linearly as a function of the surfactant concentrations. The supersaturation was maintained for at least three hours in absence of surfactant and in presence of TPGS, whereas supersaturation declined with SDS and PS80. As expected, the membrane flux of the AK100 was higher for the ASD than for the crystalline powder, and further increased with increased concentration of TPGS. The supersaturation ratio based on the activity-based calculation from Caco-2 cells study was always higher than that of the concentration-based one for the amorphous and crystalline forms of AK100. This study shows how additional solubilizing excipients during formulation development can improve the resulting dissolution and phase behavior of supersaturated drug solution.

本研究的目的是开发一种难溶性化合物(AK100)的无定形固体分散体(ASD),并研究不同表面活性剂对其溶解、过饱和及膜传输的影响。在没有和有三种不同浓度的表面活性剂(十二烷基硫酸钠(SDS)、聚山梨醇酯 80(PS80)和 D-α-生育酚聚乙二醇琥珀酸酯(TPGS))的情况下,测定了 AK100 的晶体和无定形溶解度。利用计算模型评估了溶解度与表面活性剂溶解度之间的关系。通过溶剂蒸发法制备了 ASD 粉末,进行了含有和不含预溶解表面活性剂的非沉降溶解实验。用 Caco-2 细胞进行了运输研究,以评估基于表面活性剂的配方对膜运输的影响。随着表面活性剂浓度的增加,AK100 的相应结晶溶解度和无定形溶解度均呈线性增加。在无表面活性剂和有 TPGS 的情况下,过饱和度至少能维持三小时,而在有 SDS 和 PS80 的情况下,过饱和度会下降。正如预期的那样,ASD 的 AK100 膜通量高于结晶粉末,并且随着 TPGS 浓度的增加而进一步提高。对于无定形和结晶形式的 AK100,根据 Caco-2 细胞研究中基于活性的计算得出的过饱和度比始终高于基于浓度的计算得出的过饱和度比。这项研究表明,在制剂开发过程中添加增溶辅料可以改善过饱和药物溶液的溶解和相行为。
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引用次数: 0
期刊
Journal of pharmaceutical sciences
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