Influence of preparative techniques on the structure, stability and dissolution of amorphous drugs

Poorly soluble drugs are becoming increasingly common in the pharmaceutical setting. Such drugs often exhibit dissolution rate-limited absorption and therefore methods to increase the dissolution rate of such drugs are of considerable interest. One promising strategy to increase the dissolution rate is to prepare the drug in an amorphous form. However, since the amorphous form is thermodynamically unstable, it may crystallise at any stage of the "life cycle" of the pharmaceutical formulation, including during manufacturing, storage and administration, with the result being a loss of the increased dissolution rate. The stability of amorphous forms depends on a variety of factors such as thermal, structural, thermodynamic and kinetic properties of the compound in addition to preparation techniques, processing parameters and storage conditions. Amorphous drugs prepared by different preparative techniques and different processing parameters may exhibit different crystallisation behaviour or solid-state transformations during storage and dissolution. In this work, indomethacin is made amorphous using different preparative techniques such as melting, milling and spray-drying. Firstly, the amorphous drugs were prepared by the different methods and processing parameters and were characterised by x-ray powder diffraction, differential scanning calorimetry and spectroscopic methods. Secondly, the theoretical stability (based on thermodynamic equations) was correlated with the experimental stability. Furthermore, intrinsic dissolution studies of the prepared amorphous solids were performed. In addition in this study the interpretation of analytical data, and especially spectroscopic data was supported by the use of multivariate data analysis methods. In Chapter 2, the amorphous samples prepared by different preparative techniques were investigated and structural and thermal differences due to preparative techniques were revealed. The ranking of the samples with respect to stability was: quench cooled amorphous samples > cryo-milled (α-form) > spray dried > ball milled (α-form) > ball milled (γ-form) = cryo-milled (γ-form). While structural differences, identified using Raman spectroscopy (using multivariate analysis), did not appear to directly correlate with the physical stability ranking. The relaxation times, calculated by using the Adam Gibbs and Kohlrausch–Williams–Watts equations however were in accordance with the experimentally determined stability rank order. This study showed that correlation of physical stability with calculated relaxation time is possible for the amorphous forms of a single compound. In Chapter 3, pair-wise distribution function (PDF) analysis was performed on samples of indomethacin obtained by cryogenic ball milling (cryo-milling) for different periods of time to detect the extent of disorder induced. Using PDF analysis it was possible to determine the optimal cryo-milling time that facilitated the highest degree of disorder in the samples. In Chapter 4, the effect of cooling rate on the physicochemical properties of the resulting amorphous solids prepared from the melt was investigated. It was revealed that the minimum cooling rate required to obtain amorphous indomethacin was 1.2 K min-1, as assessed from the time-temperature-transformation diagram. The stability of the samples was found to increase as a function of cooling rate and was in agreement with descriptors for the glass forming ability and the kinetic exponent M from the autocatalytic Sestak-Berggren model. In Chapter 5, intrinsic dissolution studies were carried out for the amorphous solids prepared in Chapters 2 - 4. The samples cooled at different cooling rates showed no significant differences in their dissolution profiles and dissolution rates. In contrast, the dissolution rate of the cryo-milled samples depended on the milling time. The milling process appeared to continue to affect the degree of disorder in the solid material, enhancing its dissolution rate. It can be concluded that amorphous solids prepared by different preparative techniques and different processing parameters have different structural and thermal properties. These differences affect the physical stability and dissolution profiles of the amorphous solids. Some predictive relationships between the preparation and performance characteristics have been determined, which can support the development of optimised formulations containing amorphous drugs