Solid-State Nuclear Magnetic Resonance of Pharmaceutical Amorphous Solid Dispersion

药物非晶态固体分散体的固态核磁共振

• 批准号: 1959812
• 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: 2017
• 资助国家: 英国
• 起止时间: 2017 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-1959812
• 关键词: Solid; State; Nuclear; Magnetic; Resonance

Most of the Active Pharmaceutic Ingredients (APIs), synthesized as crystalline forms, are subjected to dissolution problems although they exhibit thermodynamic stability. This poor solubility in water is related to the intrinsic physical-chemical characteristics of the crystalline state. From the point of view of pharmaceutical industries, these solubility issues represent a challenge to overcome. A general approach to improve the dissolution rate of a crystalline compound is to convert it into its corresponding amorphous form in a drug/polymer formulation matrix. These kinds of formulations are known as amorphous solid dispersions (ASDs); and is a promising strategy to increase the bioavailability of poorly soluble drugs and stabilize the thermodynamic instability of the amorphous species. The role of solid state NMR (ssNMR) is crucial to understanding the structure and the dynamics of ASD. Firstly, in my PhD course, I attended a safety induction at the University of Liverpool and at the Bristol-Myers Squibb. In addition, I received training on the NMR spectrometer equipped with different kind of ssNMR probe; during this training, I learnt the fundamental pulse sequences based on the cross polarization (CP) technique. Moreover, I have had a period to learn about ASD by studying some important reviews and papers. At the present, using NMR and calorimetric techniques, I have studied the chemical structure and physical properties of a range of suitable polymers to make an ASD, and I have started to study the polymorphism in two different APIs. The studied polymers are based on the hydroxypropyl methylcellulose acetate succinate unit with different ratio of acetate/succinate group and different particles granulometry. Polymers were purchased from ShinEtsu and used as received. They were: HMPC-AS-HG-spray dried and non-spray dried HMPC-AS-MF, HMPC-AS-LG, AQOAT-AS-MG, AQOAT-AS-HG and AQOAT-AS-LG. The studied APIs are Paracetamol and Naproxen. The commercial available most stable polymorph for both the drugs were purchased from Sigma-Aldrich. For each polymer and for both the drugs, by using the saturation recovery pulse sequence I have obtained the proton spin lattice relaxation time, T1(1H). This is a rapid and helpful NMR experiment to obtain crucial information to achieve good 13C CP experiments. By using the 13C CP experiments, with different contact time, it was possible to do an accurate assignment of the spectra peaks for each polymers and each drugs. As reported in the literature, the study of physical properties like carbon spin-lattice relaxation time, T1(13C), and carbon spin-lattice relaxation in the rotating frame, T1p, for each discrete component of an ASD are useful to estimate the final resulting formulation stability. For this reason, I obtained both T1(13C), and T1p, with different spin-lock radio frequency for each polymer and each drug. Finally, for each polymer and for both the commercial available crystalline drug forms, using the DSC facilities at Bristol-Myers Squibb, I achieved the glass transition temperature, Tg, and the melting temperature, Tm, values. This measure are useful to predict the finals formulation's Tg, at different drug/polymers loading. Starting from the most stable drugs crystalline forms, I have also attended to prepare all the know polymorphs by different re-crystallization methodologies. For all the resulting materials 13C CP has been run to determinate and discriminate different polymorphs. This work is on-going. To improve my scientific background in NMR spectroscopy I have attended scientific conferences and seminars.

大多数活性药物成分（API）以结晶形式合成，尽管它们表现出热力学稳定性，但仍存在溶出问题。这种在水中的不良溶解度与结晶状态的固有物理化学特性有关。从制药工业的角度来看，这些溶解度问题代表了需要克服的挑战。改善结晶化合物的溶出速率的一般方法是将其转化成药物/聚合物制剂基质中的其相应的无定形形式。这些种类的制剂被称为无定形固体分散体（ASD）;并且是增加难溶性药物的生物利用度和稳定无定形物质的热力学不稳定性的有前景的策略。固态NMR（ssNMR）的作用是至关重要的了解ASD的结构和动力学。首先，在我的博士课程中，我参加了利物浦大学和百时美施贵宝的安全入门课程。此外，我还接受了配备不同ssNMR探头的NMR光谱仪的培训;在培训期间，我学习了基于交叉极化（CP）技术的基本脉冲序列。此外，我有一段时间通过研究一些重要的评论和论文来了解ASD。目前，使用NMR和量热技术，我已经研究了一系列合适的聚合物的化学结构和物理性质，以制造ASD，我已经开始研究两种不同API的多晶型。所研究的聚合物是基于羟丙基甲基纤维素乙酸酯琥珀酸酯单元，具有不同的乙酸酯/琥珀酸酯基团比例和不同的颗粒粒度。聚合物购自ShinEtsu并按原样使用。它们是：HMPC-AS-HG-喷雾干燥和非喷雾干燥的HMPC-AS-MF、HMPC-AS-LG、AQOAT-AS-MG、AQOAT-AS-HG和AQOAT-AS-LG。研究的API为扑热息痛和萘普生。两种药物的市售最稳定的多晶型物购自Sigma-Aldrich。对于每种聚合物和两种药物，通过使用饱和恢复脉冲序列，我获得了质子自旋晶格弛豫时间T1（1H）。这是一个快速和有用的NMR实验，以获得关键信息，实现良好的13 C CP实验。通过使用13 C CP实验，在不同的接触时间下，可以对每种聚合物和每种药物的光谱峰进行准确的归属。如文献中所报道的，ASD的每个离散组分的物理性质如碳自旋-晶格弛豫时间T1（13 C）和旋转坐标系中的碳自旋-晶格弛豫T1 p的研究对于估计最终得到的制剂稳定性是有用的。出于这个原因，我获得了T1（13 C）和T1 p，每种聚合物和每种药物具有不同的自旋锁射频。最后，对于每种聚合物和两种市售结晶药物形式，使用Bristol-Myers Squibb的DSC设备，我获得了玻璃化转变温度Tg和熔融温度Tm值。该测量可用于预测不同药物/聚合物负载下的最终制剂的Tg。从最稳定的药物结晶形式开始，我还参与了通过不同的重结晶方法制备所有已知的多晶型物。对于所有所得材料，已运行13 C CP以确定和区分不同的多晶型物。这项工作正在进行中。为了提高我在NMR光谱学方面的科学背景，我参加了科学会议和研讨会。