Influence of PVP molecular weight on the microwave assisted in situ amorphization of indomethacin.

In situ amorphization is an approach that enables a phase transition of a crystalline drug to its amorphous form immediately prior to administration. In this study, three different polyvinylpyrrolidones (PVP K12, K17 and K25) were selected to investigate the influence of the molecular weight of the polymer on the degree of amorphization of the model drug indomethacin (IND) upon microwaving. Powder mixtures of crystalline IND and the respective PVP were compacted at 1:2 (w/w) IND:PVP ratios, stored at 54% RH and subsequently microwaved with a total energy input of 90 or 180kJ. After storage, all compacts had a similar moisture content (∼10% (w/w)). Upon microwaving with an energy input of 180kJ, 58±4% of IND in IND:PVP K12 compacts was amorphized, whereas 31±8% of IND was amorphized by an energy input of 90kJ. The drug stayed fully crystalline in all IND:PVP K17 and IND:PVP K25 compacts. After plasticization by moisture, PVP K12 reached a Tg below ambient temperature (16±2°C) indicating that the Tg of the plasticized polymer is a key factor for the success of in situ amorphization. DSC analysis showed that the amorphized drug was part of a ternary glass solution consisting of IND, PVP K12 and water. In dissolution tests, IND:PVP K12 compacts showed a delayed initial drug release due to a lack of compact disintegration, but reached a higher total drug release eventually. In summary, this study showed that the microwave assisted in situ amorphization was highly dependent on the Tg of the plasticized polymer.

Amorphization within the tablet: Using microwave irradiation to form a glass solution in situ.

In situ amorphization is a concept that allows to amorphize a given drug in its final dosage form right before administration. Hence, this approach can potentially be used to circumvent recrystallization issues that other amorphous formulation approaches are facing during storage. In this study, the feasibility of microwave irradiation to prepare amorphous solid dispersions (glass solutions) in situ was investigated. Indomethacin (IND) and polyvinylpyrrolidone K12 (PVP) were tableted at a 1:2 (w/w) ratio. In order to study the influence of moisture content and energy input on the degree of amorphization, tablet formulations were stored at different relative humidity (32, 43 and 54% RH) and subsequently microwaved using nine different power-time combinations up to a maximum energy input of 90kJ. XRPD results showed that up to 80% (w/w) of IND could be amorphized within the tablet. mDSC measurements revealed that with increasing microwaving power and time, the fractions of crystalline IND and amorphous PVP reduced, whereas the amount of in situ formed IND-PVP glass solution increased. Intrinsic dissolution showed that the dissolution rate of the microwaved solid dispersion was similar to that of a quench cooled, fully amorphous glass solution even though the microwaved samples contained residual crystalline IND.

Anhydrate to hydrate solid-state transformations of carbamazepine and nitrofurantoin in biorelevant media studied in situ using time-resolved synchrotron X-ray diffraction.

Transformation of the solid-state form of a drug compound in the lumen of the gastrointestinal tract may alter the drug bioavailability and in extreme cases result in patient fatalities. The solution-mediated anhydrate-to-hydrate phase transformation was examined using an in vitro model with different biorelevant media, simulated fasted and fed state intestinal fluids containing bile salt and dioleoylphosphatidylcholine (DOPC) micelles, DOPC/sodium dodecyl sulfate (SDS) mixture, bile salt solution and water. Two anhydrate compounds (carbamazepine, CBZ and nitrofurantoin, NF) with different overall transformation time into hydrate form were used as model compounds. The transformations were monitored using direct structural information from time-resolved synchrotron X-ray diffraction. The kinetics of these transformations were estimated using multivariate data analysis (principal component analysis, PCA) and compared to those for nitrofurantoin (NF). The study showed that the solution-mediated phase transformation of CBZ anhydrate was remarkably faster in the DOPC/SDS medium compared to transformation in all the other aqueous dispersion media. The conversion time for CBZ anhydrate in water was shorter than for DOPC/SDS but still faster than the conversion seen in fed and fasted state micellar media. The conversion of CBZ anhydrate to hydrate was the slowest in the solution containing bile salt alone. In contrast, the solution-mediated phase transformations of NF did only show limited kinetic dependence on the dispersion media used, indicating the complexity of the nucleation process. Furthermore, when the CBZ and NF material was compacted into tablets the transformation times were remarkably slower. Results suggest that variations in the composition of the contents of the stomach/gut may affect the recrystallization kinetics, especially when investigating compounds with relatively fast overall transformation time, such as CBZ.