Enhanced Solid-State NMR of Amorphous Solid Dispersion in Pharmaceutical Sciences

药物有两个关键成分：活性药物成分(API)和赋形剂。原料药是药物中产生预期反应或效果的部分，而赋形剂通常在化学上不起作用，但有助于将药物结合在一起，并使药物被归类为生物安全药物。为了获得所需的原料药标准，必须同时考虑药效学和药代动力学因素以及药物的治疗效果。药物的配方通常被认为是最稳定的治疗用形式，是结晶的，但这种状态会影响药物在体内的作用模式--它的生物利用度。特别令人感兴趣的是第二类药物中的原料药系列，因为它们的水溶性较弱，导致生物利用度较低，直接对应于药物吸收较低。在这种情况下，原料药的固体结晶形式被转化为固体无定形形式。这一过程是可取的，因为在不改变化学结构的情况下增加了溶解度。纯非晶态的API比晶态的API具有更高的能量，因此溶剂化所需的能量更少。尽管有这一优点，纯无定形原料药确实倾向于不稳定，因此经常返回到热力学上更稳定的结晶状态。为了防止这种情况的发生，人们研究了更稳定的非晶态API，包括非晶态固体分散体(ASD)。非晶态固体分散体通常是由聚合物载体(聚合物)作为赋形剂和API组成的二元体系。聚合物载体不仅是药物稳定性的关键，也是药物吸收和溶出速度的关键。由于从结晶到非晶态的过程在热力学上不是有利的，因此需要使用熔融挤出、珠粒涂层和喷雾干燥等加工技术来进行这种转换，从而获得稳定的ASD。在ASD的众多物理化学特性中，API与聚合物的混合是影响ASD稳定性的关键。固体核磁共振波谱是一种非常强大的技术，用于在原子尺度上确定固体的化学结构和动力学行为，并了解混合物中的空间近似性。本项目将主要集中于开发核磁共振波谱的能力，以加深对原料药在ASD中的稳定性的了解，以便将其用于制药科学，以提高原料药的生物利用度。这项工作将建立在先进的核磁共振方法和先前的知识基础上，从而进一步了解和探索ASD的稳定性，并改进药物在体内的溶解。

Pharmaceutical drugs have two key components: the Active Pharmaceutical Ingredients (API) and the excipient. The API is the part of the drug that produces the expected response or effect, whereas the excipient is usually chemically inactive but helps bind the drug together and allows the drug to be classed as biologically safe. To obtain the desired criteria for an API, both the pharmacodynamic and pharmacokinetic factors must be considered along with the therapeutic effect of the drug. The formulation of the drug is often thought of as the most stable form for therapeutic use and is crystalline but this state impacts the drugs mode of action in the body - its' bioavailability. Of particular interest are the family of APIs in Class II drugs due to their weak water solubility, which results in poor bioavailability and directly corresponds to lower drug absorption. In cases such as this, the solid crystalline form of the API is converted to the solid amorphous form. This process is desirable due to the increased solubility without alteration of the chemical structure. The pure amorphous form of an API has a much higher energy than that of a crystalline API and so less energy is required for solvation. Despite this advantage, the pure amorphous API does tend to be unstable and so often returns to the thermodynamically more stable crystalline state. To prevent this from happening, more stable forms of amorphous API including amorphous solid dispersion (ASD) have been investigated.ASDs are usually binary systems made from a polymeric carrier (polymer) as the excipient and the API. The polymeric carrier is key not only to the stability of the drug but also to the absorption and dissolution rates. As the process from crystalline to amorphous is not thermodynamically favourable, extra energy is required for this conversion using processing techniques such as melt extrusion, bead coating and spray drying resulting in a stable ASD. Amongst many physical and chemical characteristics, the key to the stability of ASD is the API-polymer mixing. Solid-state Nuclear Magnetic Resonance (NMR) spectroscopy is a very powerful technique used to determine chemical structure and dynamical behaviour of solids at the atomic scale, and understand spatial proximities in mixtures. This project will primarily focus on exploiting the capabilities of NMR spectroscopy to develop a deeper understanding of the stability of API in ASD for its use in pharmaceutical sciences to improve the bioavailability in APIs. The work will build on advanced NMR approaches and previous knowledge allowing for a further understanding and exploration of ASD stability to be carried out and resulting in improved dissolution of pharmaceutical drugs in vivo.