Molecular miscibility of ASD blend components: an evaluation of (the added value of) solid state NMR spectroscopy and relaxometry.

Abstract

In order to evaluate the stability of an amorphous solid dispersion (ASD) it is crucial to be able to accurately determine whether the ASD components are homogeneously mixed or not. Several solid-state analysis techniques are at the disposal of the formulation scientist, such as for example modulated differential scanning calorimetry (mDSC) and solid-state nuclear magnetic resonance spectroscopy (ssNMR). ssNMR is a robust, versatile, and accurate analysis technique with a large number of application possibilities. Especially ssNMR relaxometry, which allows the measurement of the proton relaxation times T_1H and T_1ρH, is very useful for evaluating the miscibility of ASDs. In this paper, the miscibility of a model ASD, composed of indomethacin (IND) and poly(vinylpyrrolidone-co-vinyl acetate) (PVPVA), was assessed using mDSC and various ssNMR techniques, in order to compare the different techniques and to evaluate the advantages and disadvantages of each. It was found that measuring the relaxation times via the chemical shift selective carbon signals using ¹³C-cross-polarization magic angle spinning (¹³C-CPMAS) is still the golden standard to evaluate miscibility, even giving information about the miscibility at the nm scale. Although non-chemical shift selective ¹H-wideline measurements are significantly faster than ¹³C-CPMAS measurements to determine the relaxation times, the results are often hard to interpret, especially with regard to the T_1ρH relaxation times. 2D ¹H-¹³C dipolar heteronuclear correlation (dipolar HETCOR) NMR is an additional technique that can be used, and which provides information about the special proximity of ¹H and ¹³C nuclei with respect to each other and therefore about the miscibility of the components at the nm scale. Additionally, it often allows to acquire information regarding the intermolecular interactions and the functional groups involved. Nevertheless, optimalization of the experiments, data processing and interpretation of the results require some expertise. Compared to mDSC, the ssNMR techniques are more sensitive and robust and can often provide information about the miscibility at nm scale. However, mDSC is a very fast analysis technique that requires less optimalization. Therefore, it remains recommended to use mDSC always for a first screening and as a complementary analysis technique.