Enhanced Solid-State Nuclear Magnetic Resonance Spectroscopy of Amorphous Solid Dispersions for Pharmaceutical Sciences

用于制药科学的非晶固体分散体的增强型固态核磁共振波谱分析

• 批准号: 2889117
• 金额: --
• 依托单位: University of Liverpool
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2889117
• 关键词: Enhanced; Solid; State; Nuclear; Magnetic

One of the greatest challenges faced in drug development is the low aqueous solubility of active pharmaceutical ingredients (APIs), inhibiting their biopharmaceutical performance.1 90% of molecules in drug discovery pipelines display poor water solubility which risks failure due to poor biological performance.2 Formation of amorphous solid dispersions (ASDs) can increase the bioavailability of poorly soluble drugs.3 ASDs consist of APIs in an amorphous state dispersed in an excipient matrix, showing high success in increasing the solubility of APIs.4 Polymers play a critical role in stabilising and inhibiting recrystallisation of the amorphous API in an ASD.5 Specific interactions between the API and polymer are known to aid miscibility in the dispersed systems. Polymer choice is imperative in ASD design to control the drug dissolution rate and stability, therefore an understanding of the interactions present within the dispersion are needed to inform their design.6 Hydroxypropylmethylcellulose acetyl succinate (HPMC-AS) is the most widely used polymer in commercially available ASDs due to its ability to increase the solubility and dissolution of poorly soluble drugs whilst impeding drug recrystallisation.7 The ability to provide structural information of amorphous solids,8 identify drug recrystallisation mechanisms,9 and measure intermolecular interactions between different components of ASDs is why Nuclear Magnetic Resonance (NMR) spectroscopy is an ideal tool to investigate ASDs for increased solubility of APIs.10 General aims of this project include a focus on understanding how HPMC-AS stabilises amorphous APIs on a molecular level. Measurements will be made on ASDs containing HPMC-AS to identify spatial proximities, intermolecular interactions and site-specific interactions between the polymer and different amorphous drugs.11 From this, an understanding on the role HPMC-AS plays in ASDs can be obtained to inform the formulation of successful ASDs, increasing the number of medicines that can be brought to market and the number of diseases that can currently be treated. (1) Schittny, A.; Huwyler, J.; Puchkov, M. Mechanisms of increased bioavailability through amorphous solid dispersions: a review. Drug Delivery 2020, 27 (1), 110-127.(2) Kalepu, S.; Nekkanti, V. Insoluble drug delivery strategies: review of recent advances and business prospects. Acta Pharmaceutica Sinica B 2015, 5 (5), 442-453.(3) Butar-Butar, M. E. T.; Wathoni, N.; Ratih, H.; Wardhana, Y. W. Solid Dispersion Technology for Improving the Solubility of Antiviral Drugs. Pharmaceutical Sciences and Research 2023, 10 (1), 3.(4) Iyer, R.; Petrovska Jovanovska, V.; Berginc, K.; Jaklic, M.; Fabiani, F.; Harlacher, C.; Huzjak, T.; Sanchez-Felix, M. V. Amorphous solid dispersions (asds): The influence of material properties, manufacturing processes and analytical technologies in drug product development. Pharmaceutics 2021, 13 (10), 1682.(5) Liu, H.; Taylor, L. S.; Edgar, K. J. The role of polymers in oral bioavailability enhancement; a review. Polymer 2015, 77, 399-415.(6) Hiew, T. N.; Zemlyanov, D. Y.; Taylor, L. S. Balancing solid-state stability and dissolution performance of lumefantrine amorphous solid dispersions: the role of polymer choice and drug-polymer interactions. Molecular pharmaceutics 2021, 19 (2), 392-413.(7) Butreddy, A. Hydroxypropyl methylcellulose acetate succinate as an exceptional polymer for amorphous solid dispersion formulations: A review from bench to clinic. European Journal of Pharmaceutics and Biopharmaceutics 2022.(8) Yuan, X.; Sperger, D.; Munson, E. J. Investigating miscibility and molecular mobility of nifedipine-PVP amorphous solid dispersions using solid-state NMR spectroscopy. Molecular pharmaceutics 2014, 11 (1), 329-337.(9) Aso, Y.; Yoshioka, S.; Kojima, S. Relationship between the crystallization rates of amorphous nifedipine, phenobarbital, and flopropione, and their molecular mobility as measured by th

药物开发中面临的最大挑战之一是活性药物成分（API）的水性溶解度低，抑制其生物药物性能。1药物发现管道中90％的分子表现出较差的水溶性表现出较差的水溶性，这会导致较差的生物学性能造成的危险。分散在赋形剂基质中的无定形状态中的API在增加API的溶解度方面表现出很高的成功。4聚合物在稳定和抑制ASD的无定形API的重结晶方面起着至关重要的作用。5ASD.5 API和聚合物之间的特异性相互作用在相分散系统中有助于混合性。在ASD设计中，必须选择聚合物的选择以控制药物的溶解速率和稳定性，因此，需要了解分散体内存在的相互作用以告知其设计。6羟基丙基甲基纤维素乙酰基琥珀酸酯（HPMC-AS）在其能力上增加了溶解性的药物，这是在其能力中增加了毒品，该药物是在溶解的能力中，该药物的溶解性不足，而溶解了溶解的毒品。 7提供无定形固体的结构信息，8个识别药物再结晶机制，9并测量ASDS不同组成部分之间的分子间相互作用是核磁共振（NMR）光谱镜检查是为什么对APIS的稳定性以及对APIS的稳定性进行研究的理想工具。分子水平。将对含有HPMC的ASD进行测量，以确定聚合物与不同无定形药物之间的空间邻近，分子间相互作用以及特定地点的相互作用。11从此，对HPMC-a在ASD中的作用的理解可以获得ASD中的HPMC-a扮演，可以获得可以为ASD的成功提供的，从而可以将其列出的数量和市场数量的数量来供应。 （1）Schittny，A。; Huwyler，J。； Puchkov，M。通过无定形固体分散体增加生物利用度的机制：综述。药物输送2020，27（1），110-127。（2）Kalepu，S。; Nekkanti，V。不溶性药物输送策略：审查最近的进步和业务前景。 Acta Pharmaceutica Sinica B 2015，5（5），442-453。（3）Butar-Butar，M。E. T。; Wathoni，n。; Ratih，H。; Wardhana，Y。W.可改善抗病毒药物溶解度的固体分散技术。药物科学与研究2023，10（1），3。（4）Iyer，R。; Petrovska Jovanovska，V。; Berginc，K。; Jaklic，M。； Fabiani，f。; Harlacher，C。； Huzjak，T。； Sanchez-Felix，M。V.无定形固体分散（ASD）：材料特性，制造过程和分析技术在药物开发中的影响。 Pharmaceutics 2021，13（10），1682。（5）Liu，H。;泰勒（L. S.） Edgar，K。J.聚合物在口服生物利用度增强中的作用；评论。 Polymer 2015，77，399-415。（6）Hiew，T。N。; D. Y。Zemlyanov； Taylor，L。S.平衡Lumefantrine无定形固体分散体的固态稳定性和溶出性能：聚合物选择和药物聚合物相互作用的作用。 Molecular Pharmaceutics 2021，19（2），392-413。（7）Butreddy，A。羟丙基甲基纤维素乙酸酯琥珀酸琥珀酸酯作为非晶态固体分散剂配方的特殊聚合物：从卧室到临床的综述。欧洲药物与生物制药杂志2022。（8）Yuan，X。; Sperger，d。;芒森（E. Molecular Pharmaceutics 2014，11（1），329-337。（9）ASO，Y。; Yoshioka，S。； Kojima，S。无定形硝苯地平的结晶速率，苯巴比妥和氟酮的关系与通过TH测量的分子迁移率之间的关系