Impact of amorphization and GI physiology on supersaturation and precipitation of poorly soluble weakly basic drugs using a small-scale in vitro transfer model.

Formulation of amorphous solid dispersions (ASD) is one possibility to improve poor aqueous drug solubility by creating supersaturation. In case of weakly basic drugs like ketoconazole (KTZ), supersaturation can also be generated during the gastrointestinal (GI) transfer from the stomach to the intestine due to pH-dependent solubility. In both cases, the supersaturation during dissolution can be stabilized by polymeric precipitation inhibitors. A small-scale GI transfer model was used to compare the dissolution performance of ASD versus crystalline KTZ with the polymeric precipitation inhibitor HPMCAS. Similar in vitro AUCs were found for the transfer from SGF pH2 into FaSSIF. Moreover, the impact of variability in gastric pH on drug dissolution was assessed. Here, the ASD performed significantly better at a simulated hypochlorhydric gastric pHof 4. Last, the importance of drug-polymer interactions for precipitation inhibition was evaluated. HPMCAS HF and LF grades with and without the basic polymer Eudragit EPO were used. However, EPO caused a faster precipitation probably due to competition for the interaction sites between KTZ and HPMCAS. Thus, the results are suited to assess the benefits of amorphous formulations vs. precipitation inhibitors under different gastrointestinal conditions to optimize the design of such drug delivery systems.

Miniaturized Measurement of Drug-Polymer Interactions via Viscosity Increase for Polymer Selection in Amorphous Solid Dispersions.

Drug-polymer interactions have a substantial impact on stability and performance of amorphous solid dispersions (ASD) but are difficult to analyze. Whereas there are many screening methods described for polymer selection based for example on glass forming ability, drug-polymer miscibility, supersaturation, or inhibition of recrystallization, the distinct detection of physico-chemical interactions mostly lacks miniaturized techniques. This work presents an interaction screening assessing the relative viscosity increase between highly concentrated polymer solutions with and without the model drug ketoconazole (KTZ). The fluorescent molecular rotor 9-(2-carboxy-2-cyanovinyl)julolidine was added to the solutions in a miniaturized setup in µL-scale. Due to its environment-sensitive emission behavior, the integrated fluorescence intensity can be used as a viscosity dye within this screening approach (FluViSc). Differences in relative viscosity increases through addition of KTZ were proposed to rank polymers regarding KTZ-polymer interactions. Absolute viscosities were measured with a cone-plate rheometer as a complimentary method and supported the results acquired by the FluViSc. Solid-state nuclear magnetic resonance (ss-NMR) relaxation time measurements and Raman spectroscopy were utilized to investigate drug-polymer interactions at a molecular level. Whereas Raman spectroscopy was not suited to reveal KTZ-polymer interactions, ss-NMR relaxation time measurements differentiated between the selected polymeric carriers hydroxypropylmethylcellulose acetate succinate (HPMCAS) and polyvinylpyrrolidone vinyl acetate 60:40 (PVP-VA64). Interactions were detected for HPMCAS/KTZ ASD while there was no hint for interactions between KTZ and PVP-VA64. These results were in correlation with the FluViSc. The findings were correlated with the dissolution performance of ASD and found to be predictive for supersaturation and inhibition of precipitation during dissolution.

How changes in molecular weight and PDI of a polymer in amorphous solid dispersions impact dissolution performance.

Polymers functionally contribute to supersaturation and precipitation inhibition of the active pharmaceutical ingredient (API) in amorphous solid dispersions (ASD). Therefore, it is necessary to monitor physicochemical changes of the polymeric carrier caused by the manufacturing process. This is especially important when the material is exposed to heat and shear stress as in case of hot-melt extrusion (HME). This study evaluated the impact of HME process conditions on physical characteristics of poly(vinylpyrrolidone-co-vinyl-acetate) 60:40 (PVP-VA64) which is a widely used polymer for HME. Focus was set on molecular weight (Mw) and polydispersity index (PDI), by means of absolute molar mass detection via multi-angle light scattering. The generation of a high Mw fraction together with a decrease of the average Mw was detected. In a next step, the influence of these changes on the dissolution behavior of ASD was evaluated. Different stress conditions were applied onto PVP-VA64 in placebo extrusions. The obtained stressed polymer samples were subsequently used to prepare verum ASD with ketoconazole by spray drying (SD). SD dispersions (SDD) of thermally stressed PVP-VA64 were compared to SDD prepared with bulk powder. Although there were only slight changes in Mw and PDI, they significantly impacted supersaturation and precipitation of the formulation.

Melt-based screening method with improved predictability regarding polymer selection for amorphous solid dispersions.

The predictability of preformulation screening tools for polymer selection in amorphous solid dispersions (ASD) regarding supersaturation and precipitation was systematically examined. The API-polymer combinations were scaled up by means of hot-melt extrusion and spray-drying to verify the predictions. As there were discrepancies between a solvent-based screening and performance of ASD, a new screening tool with improved predictability at minimal investments of time and material is presented. The method refinement resulted in a better correlation between the screening and ASD prototypes. So far, a purely solvent-based screening was used which consisted of film casting by rapid solvent evaporation. This approach was improved by applying a heating step after film casting. Four representative polymers were tested with two different model active pharmaceutical ingredients (API) under non-sink dissolution conditions. Polyvinylpyrrolidone (PVP) based polymers showed no benefit towards pure API in the solvent-based screening but good supersaturation as ASD formulations. The extrudates with the cellulose derivatives hydroxypropylmethylcellulose acetate succinate (HPMCAS) and cellulose acetate phthalate (CAP) showed lower supersaturation than predicted by the solvent-based screening but performed especially well as spray-dried dispersions (SDD). False negative results for PVP-co-vinyl acetate (PVP-VA64) could be avoided by using the new melt-based screening. Furthermore, comparing the results from the two different screening methods allowed predicting the performance of extrudates vs. SDD with cellulose derivatives as polymeric excipients.