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

药物开发中面临的最大挑战之一是活性药物成分（API）的低水溶性，抑制其生物制药性能。1药物发现管道中90%的分子显示出较差的水溶性，这可能会因较差的生物性能而导致失败。2无定形固体分散体（ASD）的形成可以增加难溶性药物的生物利用度。3 ASD由分散在赋形剂基质中的无定形状态的API组成，在增加API的溶解度方面取得了很大的成功。4聚合物在稳定和抑制无定形API的重结晶方面发挥着关键作用，ASD.5已知API和聚合物之间的特异性相互作用有助于分散体系中的分散性。聚合物的选择在ASD设计中是必要的，以控制药物溶出速率和稳定性，因此，需要了解分散体中存在的相互作用，以指导其设计。6乙酰琥珀酸羟丙基甲基纤维素（HPMC-AS）是市售ASD中最广泛使用的聚合物，因为其能够增加难溶性药物的溶解度和溶解度，同时阻止药物重结晶。能够提供无定形固体的结构信息，8确定药物重结晶机制，9并测量ASD不同组分之间的分子间相互作用，这就是为什么核磁共振（NMR）光谱是研究ASD以增加API溶解度的理想工具。10该项目的总体目标包括重点了解HPMC-AS如何在分子水平上稳定无定形API。将对含有HPMC-AS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性、分子间相互作用和位点特异性相互作用。11由此，可以了解HPMC-AS在ASD中的作用，从而为成功的ASD配方提供信息，增加可上市的药物数量和目前可治疗的疾病数量。(1)Schittny，A.; Huwyler，J.; Puchkov，M.无定形固体分散体提高生物利用度的机制综述。药物递送2020，27（1），110-127。(2)Kalepu，S.; Nekkanti，V.不溶性药物递送策略：最近进展和商业前景的回顾。药学学报B 2015，5（5），442-453. (3)Butar-Butar，M. E. T.; Wathoni，N.; Ratih，H.;瓦尔德纳岛W.提高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.无定形固体分散体（asds）：药物产品开发中材料特性、生产工艺和分析技术的影响。Pharmaceutics 2021，13（10），1682. (5)刘，H.;泰勒湖S.的;埃德加，K.聚合物在提高口服生物利用度中的作用;综述。Polymer 2015，77，399-415. (6)Hiew，T. N.的; Zemlyanov，D. Y的;泰勒湖S.平衡本芴醇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.醋酸羟丙基甲基纤维素琥珀酸酯作为无定形固体分散体制剂的特殊聚合物：从实验室到临床的综述。2022年欧洲制药和生物制药杂志。(8)元，X.; Sperger，D.; Munson，E. J.使用固态NMR光谱研究硝苯地平-PVP无定形固体分散体的溶解性和分子移动性。Molecular Pharmaceutics 2014，11（1），329-337. (9)阿索，Y.; Yoshioka，S.; Kojima，S.非晶硝苯地平、苯巴比妥和氟非他酮的结晶速率与其分子迁移率之间的关系

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