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)的低水溶解度，抑制了它们的生物制药性能。1药物发现管道中90%的分子表现出较差的水溶解性，这可能会因生物性能差而失败。2无定形固体分散体(ASD)的形成可以增加难溶药物的生物利用度。3 ASD由分散在赋形剂基质中的无定形API组成，在增加API的溶解度方面表现出很大的成功。4聚合物在ASD中稳定和抑制无定形API的重结晶方面发挥关键作用。5已知API和聚合物之间的特定相互作用有助于分散体系中的混溶。6羟丙基甲基纤维素乙酰丁二酸酯(HPMC-AS)是商业上可用的ASD中最广泛使用的聚合物，因为它能够增加难溶药物的溶解和溶解，同时阻碍药物重结晶。7提供无定形固体结构信息的能力，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光谱是研究ASD以增加原料药溶解度的理想工具。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原料药。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接近、分子间相互作用和特定部位的相互作用。11由此，可以了解HPMC-AS在ASD中的作用，从而为成功的ASD的配方提供信息，增加可以推向市场的药物数量和目前可以治疗的疾病数量。(1)Schittny，A.；Huwyler，J.；Puchkov，M.通过无定形固体分散体提高生物利用度的机制：综述。药物给药2020，27(1)，110-127。(2)Kalepu，S.；Nekkanti，V.不溶性药物给药策略：回顾最近的进展和商业前景。医药学报B 2015，5(5)，442-453。(3)Butar-Butar，M.E.T.；Wathoni，N.；Ratih，H.；Wardhana，Y.W.改善抗病毒药物溶解性的固体分散技术。《药学与研究》，2023，10(1)，3.(4)Iyer，R.；Petrovska Jovanovska，V.；Berginck，K.；Jaklic，M.；Fabiani，F.；Harlacher，C.；Huzjak，T.；Sanchez-Felix，M.V.无定形固体分散体(ASD)：材料特性、制造工艺和分析技术在药品开发中的影响。药剂学2021，13(10)，1682。(5)刘华；泰勒，L.S.；埃德加，KJ。聚合物在提高口服生物利用度中的作用；综述。聚合物2015，77,399-415。(6)Hew，T.N.；Zemlyanov，D.Y.；Taylor，L.S.平衡鲁米芬非晶固体分散体的固态稳定性和溶解性能：聚合物选择和药物-聚合物相互作用的作用。分子药剂学2021，19(2)，392-413。(7)Butreddy，A.羟丙基甲基纤维素醋酸酯作为无定形固体分散体配方的特殊聚合物：从工作台到临床的回顾。《欧洲制药学和生物制药杂志2022》。(8)袁，X.；Sperger，D.；Munson，E.J.使用固态核磁共振波谱研究硝苯地平-PVP非晶态固体分散体的相容性和分子迁移率。分子药剂学2014，11(1)，329-337。(9)Aso，Y.；Yoshioka，S.；Kojima，S.无定形硝苯地平、苯巴比妥和氟丙酮的结晶速率与其分子迁移率的关系

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