The comparison of seven different methods to quantify the amorphous content of spray dried lactose

The purpose of this work was to verify the usefulness, advantages and disadvantages of seven methods that are widely used to detect, and quantify the amorphous contents in pharmaceutical solids. Here, StepScan DSC, a type of modulated temperature calorimetry method, was applied for the first time to quantify amorphicity. The comparison of the analytical methods was undertaken with real (non-artificial) test samples, i.e. spray-dried lactose samples with various degrees of crystallinity. In these samples, it was essential that the amorphous and the crystalline portions are not present as separate particles, which is the case when physical (artificial) mixtures of totally amorphous and totally crystalline materials are used to produce the calibration curves. X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), StepScan DSC (SS-DSC), isothermal microcalorimetry (IMC), solution calorimetry (SC), Raman spectrometry and gravimetric moisture sorption (GMS) were utilized to quantify the amorphous contents. The results obtained with IMC, SC, Raman, SS-DSC and GMS were in good agreement with each other. Generally, XRPD is the only method that reveals the disordered/amorphous nature of the samples in the crystallographic sense and, in the present study, it also provided consistent results. The conventional DSC method resulted in great variations for the mean amorphicity values since the method is not suitable for lactose where the dehydration of the hydrate and recrystallization of the amorphate overlap during the measurement of the partially amorphous samples. The recrystallized products of totally and partially amorphous lactose samples were found to be different, the former also including crystalline anhydrate. This complicated the interpretation of the IMC and GMS results, where the recrystallization process was monitored and analyzed. Thus, caution is warranted when the amorphicity of real samples is quantified by means of the calibration curves obtained with the physical mixtures of amorphous and crystalline lactose. With SS-DSC, where the quantification was based on the measurement of the heat capacity change associated with glass transition, this problem was not encountered. Utilizing only one method may lead to erroneous conclusions and hence, on the basis the present results, it is advisable to employ a combination of spectroscopic (Raman) and calorimetric (IMC) or gravimetric (GMS) methods.