Nanogram-scale screening of amorphous solid dispersion and its stability with monitoring phase transition using low-frequency Raman spectroscopy

Abstract

In designing of amorphous solid dispersion (ASD) which improves the solubility and absorption of poorly soluble drugs, selecting an optimal polymer to stabilize the amorphous drug is essential for developing high-quality ASDs. However, the amount of drugs available in the early stages of development is limited to a small amount, so efficient polymer selection is essential. This work aims to investigate the utility of the nano-spot method combined with low-frequency (LF) Raman spectroscopy in polymer selection to design ASDs consisting of carbamazepine (CBZ). First, LF Raman could detect changes in the crystal forms of CBZ prepared by the nano-spot method in response to a temperature increase and humidification. Subsequently, ASDs consisting of CBZ and five different polymers prepared by natural drying or freeze drying of nano-sized droplets were evaluated using LF Raman and polarized microscopy to detect the crystallization and the changes in the crystal form of CBZ. Moreover, the relative physical stability of these ASDs was compared from its crystallization behavior. As a result, the order of relative physical stability of ASDs differed depending on the manufacturing method. From these results, we have successfully detected crystallized CBZ and their crystal form changes in ASDs prepared using minimal amounts with LF Raman measurement. In conclusion, monitoring crystal transitions in samples prepared by the nano-spot method with LF Raman spectroscopy can be a helpful tool for rapid assessment of potential polymorphic changes and drug stability in the early stages of drug development of ASDs.