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In pharmaceutical product development, quality control of solid dosage forms is very important. Among them, the crystal form of the active ingredient is one of the key factors affecting the stability and efficacy of the drug. Today, we're going to talk about a common scenario in formulation development – the API is amorphous.
Among the drugs that have been marketed, there are many varieties of active ingredients in the pharmaceutical solid form that are amorphous, such as apalutamide, olaparib, enzalutamide, ceftolupidate, vemurafenib, itraconazole and so on. So, how to assess the risk of amorphous-crystalline transformation of APIs and formulations during production and storage when they start as amorphous or transition to amorphous during preparation?How to control the quality of the product?
Let's first take a closer look at this issue with a case study. Let's say we are developing a small molecule oral anti-cancer product with 5mg of active ingredient per tablet and an API ratio of 25%。During the development process, it was found that the crystalline state of the active ingredient would change to amorphous or other impurity crystal forms, and the amorphous content and other impurity crystal form content would have an impact on the efficacy. In order to ensure the quality of pharmaceutical products, we need to study the relationship between the crystal form transformation of APIs, evaluate the risk of crystal transformation of APIs during the production process and storage of APIs, and formulate corresponding quality control measures.
Figure: Transformation relationship between different crystal forms of compounds.
Source: Reference [1].
When evaluating the stability of amorphous drugs, we need to conduct in-depth research on different drug crystal forms, especially for amorphous drugs, it is necessary to ensure that the solid form of the drug remains unchanged during preparation and storage. When necessary, it is also necessary to carry out quality control of the impurity crystal form of the active ingredient in the API and the preparation, such as the development of impurity crystal form detection limit method, the development of impurity crystal form quantitative method, etc., to ensure the quality stability of subsequent batches.
When the API in the formulation is amorphous, a more appropriate method is needed to identify the solid form of the active ingredient in the formulation. The traditional powder X-ray diffraction technique (PXRD) is more accurate in the identification of crystalline states, but because the amorphous is a diffuse peak in the PXRD and there is no sharp diffraction peak, it is difficult for the PXRD to identify the amorphous state, and the solid form in the preparation cannot be intuitively determined. At this point, Raman spectroscopy can be considered.
Figure: The same amorphous pxrd spectrum and Raman spectrum.
Source: Xinyang Weikang can accurately locate the position of the active ingredient in the preparation and collect the signal of the active ingredient through multiple Raman single-point signal acquisition optimization. In addition, the amorphous signal in the Raman spectrum also has obvious characteristic peaks, which can clearly identify the differences between different solid-state forms, and at the same time can eliminate the interference of excipients. Therefore, for the formulations in the above cases, Raman spectroscopy is preferred for the identification of the solid form of the active ingredient. 
Figure: Imaging of the active ingredient in a Raman acquisition formulation.
Source: Xinyang Weikang In addition, usually the preparation contains a variety of excipients, such as lactose, microcrystalline cellulose, etc. When the proportion of excipients is high, when the pxrd method is used for identification, the pxrd signal of the excipients will mask the active ingredient signal, interfere with the identification of the polymorph of the active ingredient in the formulation, and the consistency of the active ingredient in the formulation cannot be identified, and Raman spectroscopy can also be used for identification. That's all there is to know about the consistency of the solid form when the active ingredient is amorphous in a solid dosage form. Hopefully, this information will help you better understand the study of the solid form of drugs. If you have other comments or ideas, please feel free to share your thoughts in the comment section. References:
1] wei n ,jia l ,shang z , et al.polymorphism of levofloxacin: structure, properties and phase transformation[j].Crystengcomm, 2019, welcomePay attention to Xinyang WellonHere we will provide you with more information about the latest developments and technical services in the pharmaceutical industry.