Malanovic Nermina, Birarda Giovanni, Eder Simone, Gruber-Woelfler Heidrun, Reiter Franz, Juraic Krunoslav, Hodzic Aden
Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria.
Field of Excellence BioHealth, University of Graz, 8010 Graz, Austria.
Pharmaceuticals (Basel). 2024 Mar 15;17(3):375. doi: 10.3390/ph17030375.
In this paper, we present the identification of polymorphisms at an early stage, identified by applying non-standard methods such as SAXS. We provide an analytical approach to polymorphism in the quality/purity of an active pharmaceutical ingredient (API), supplied to a generic company by two different suppliers (i.e., manufacturers). Changes in thermodynamic polymorphism firstly become visible in traces in the larger crystal lattices, which are visible on the SAXS spectrum only using the logarithmic scale, as shown in the result figures. Hence, we are here on the trail of the beginning of a new polymorph in nicomorphine, whose crystal waviness at the early stage is visible only in the additional symmetrical peaks identified and calculated using SAXS, while the chemical analyses excluded all kinds of chemical impurities. The chemical and structural properties were studied using the following techniques: SAXS, WAXS, DSC, dissolution, Raman spectroscopy, and FTIR. Only the SAXS technique could identify crucial differences and calculate the additional signals related to giant crystals, whilst a standard method such as WAXS showed none, and nor did the chemical analyses, such as Raman spectroscopy and FT-IR. This means that due to water in crystallization (known in nicomorphine) or thermodynamic waviness, the formation of the new polymorph starts first in traces, which become visible at larger distances from the crystal lattice, detectible only in the SAXS range. This is a very important premise and hypothesis for further research, and we believe that this work lays a new stone in understanding the origin of new unknown polymorphs and their mixtures. Therefore, the aim of this work is to show that the use of non-standard methods (i.e., SAXS) can be of great benefit to API analysis and the identification of polymorphic changes in the early phase, which can cause varied stability, solubility and bioavailability and thus different therapeutic effects or side effects.
在本文中，我们展示了通过应用诸如小角X射线散射（SAXS）等非标准方法在早期阶段对多晶型的鉴定。我们提供了一种分析方法，用于研究由两家不同供应商（即制造商）供应给仿制药公司的活性药物成分（API）在质量/纯度方面的多晶型情况。热力学多晶型的变化首先在较大晶格的痕迹中显现出来，如结果图所示，这些痕迹仅在使用对数刻度的SAXS光谱上可见。因此，我们正在追踪尼可吗啡中新多晶型的起始情况，其早期阶段的晶体波纹仅在使用SAXS鉴定和计算出的额外对称峰中可见，而化学分析排除了各种化学杂质。使用以下技术研究了化学和结构性质：SAXS、广角X射线散射（WAXS）、差示扫描量热法（DSC）、溶出度、拉曼光谱和傅里叶变换红外光谱（FTIR）。只有SAXS技术能够识别关键差异并计算与大晶体相关的额外信号，而诸如WAXS这样的标准方法以及拉曼光谱和傅里叶变换红外光谱等化学分析方法均未显示出差异。这意味着由于结晶过程中的水（在尼可吗啡中是已知的）或热力学波纹，新多晶型的形成首先在痕迹中开始，这些痕迹在距晶格较大距离处可见，仅在SAXS范围内可检测到。这是进一步研究的一个非常重要的前提和假设，我们相信这项工作为理解新的未知多晶型及其混合物的起源奠定了新的基础。因此，这项工作的目的是表明使用非标准方法（即SAXS）对API分析以及早期多晶型变化的鉴定可能非常有益，这些变化可能导致不同的稳定性、溶解度和生物利用度，从而产生不同的治疗效果或副作用。
