High Bulk-Density Amorphous Dispersions to Enable Direct Compression of Reduced Tablet Size Amorphous Dosage Units.

Amorphous solid dispersions (ASDs) are an attractive option to improve the bioavailability of poorly water-soluble compounds. However, the material attributes of ASDs can present formulation and processability challenges, which are often mitigated by the addition of excipients albeit at the expense of tablet size. In this work, an ASD manufacturing train combining co-precipitation and thin film evaporation (TFE) was used to generate high bulk-density co-precipitated amorphous dispersion (cPAD). The cPAD/TFE material was directly compressed into tablets at amorphous solid dispersion loadings up to 89 wt%, representing a greater than 60% reduction in tablet size relative to formulated tablets containing spray dried intermediate (SDI). This high ASD loading was possible due to densification of the amorphous dispersion during drying by TFE. Pharmacokinetic performance of the TFE-isolated, co-precipitated dispersion was shown to be equivalent to an SDI formulation. These data highlight the downstream advantages of this novel ASD manufacturing pathway to facilitate reduced tablet size via high ASD loading in directly compressed tablets.

Characterization of Phase Transformations for Amorphous Solid Dispersions of a Weakly Basic Drug upon Dissolution in Biorelevant Media.

PURPOSE: The overall goal of this study was to investigate the dissolution performance and crystallization kinetics of amorphous solid dispersions (ASDs) of a weakly basic compound, posaconazole, dispersed in a pH-sensitive polymeric matrix consisting of hydroxypropyl methylcellulose acetate succinate (HPMC-AS), using fasted-state simulated media. METHODS: ASDs with three different drug loadings, 10, 25 and 50 wt.%, and the commercially available tablets were exposed to acidic media (pH 1.6), followed by transfer to, and dissolution in, intestinal media (pH 6.5). Parallel single stage dissolution experiments in only simulated intestinal media were also performed to better understand the impact of the gastric stage. Different analytical methods, including nanoparticle tracking analysis, powder x-ray diffraction, second harmonic generation and two-photon excitation ultraviolet fluorescence microscopy, were used to characterize the phase behavior of these systems at different stages of dissolution. RESULTS: Results revealed that all ASDs exhibited some degree of drug release upon suspension in acidic media, and were also vulnerable to matrix crystallization. Upon transfer to intestinal media conditions, supersaturation was observed. This was short-lived for some dispersions due to the release of the crystals formed in the acid immersion stage which acted as seeds for crystal growth. Lower drug loading ASDs also exhibited transient formation of amorphous nanodroplets prior to crystallization. CONCLUSIONS: This work emphasizes the significance of assessing the impact of pH change on dissolution and provides a fundamental basis of understanding the phase behavior kinetics of ASDs of weakly basic drugs when formulated with pH sensitive polymers.

Interplay of Supersaturation and Solubilization: Lack of Correlation between Concentration-Based Supersaturation Measurements and Membrane Transport Rates in Simulated and Aspirated Human Fluids.

Supersaturating formulations are increasingly being used to improve the absorption of orally administered poorly water-soluble drugs. To better predict outcomes in vivo, we must be able to accurately determine the degree of supersaturation in complex media designed to provide a surrogate for the gastrointestinal environment. Herein, we demonstrate that relying on measurements based on consideration of the total dissolved concentration leads to underestimation of supersaturation and consequently membrane transport rates. Crystalline and amorphous solubilities of two compounds, atazanavir and posaconazole, were evaluated in six different media. Concurrently, diffusive flux measurements were performed in a side-by-side diffusion cell to determine the activity-based supersaturation by evaluating membrane transport rates at the crystalline and amorphous solubilities. Solubility values were found to vary in each medium because of different solubilization capacities. Concentration-based supersaturation ratios were also found to vary for the different media. Activity-based measurements, however, were largely independent of the medium, leading to relatively constant values for the estimated supersaturation. These findings have important consequences for modeling and prediction of supersaturation impact on the absorption rate as well as for better defining the thermodynamic driving force for crystallization in complex media.

Variation in Supersaturation and Phase Behavior of Ezetimibe Amorphous Solid Dispersions upon Dissolution in Different Biorelevant Media.

The delivery of poorly water-soluble drugs using amorphous solid dispersions (ASDs) has been widely acknowledged as a promising strategy for enhancing oral bioavailability. Upon dissolution, ASDs have accelerated dissolution rates and yield supersaturated solutions leading to higher apparent solubilities. Understanding the complex phase behavior of ASDs during dissolution is crucial for developing an effective formulation. Since the absorption of a lipophilic, high permeability drug is determined primarily by the intraluminal dissolution process and the final concentration achieved, there is a need for evaluation in biorelevant dissolution media that simulate both fasting and fed gastrointestinal states. In this study, using ezetimibe as a model drug, three different ASDs were prepared using poly(acrylic acid) (PAA), polyvinylpyrrolidone (PVP), and hydroxypropyl methylcellulose acetyl succinate (HPMC-AS). Dissolution of ASDs was carried out in sodium phosphate buffer, fed-state simulated intestinal fluid (FeSSIF), and Ensure Plus to evaluate the impact of different dissolution media on release profile, supersaturation, and phase behavior. The supersaturation level and crystallization kinetics varied among the dispersions and were found to be highly dependent on the medium employed. The presence of solubilizing additives in biorelevant media greatly affected the generation and stabilization of supersaturated solutions. Second harmonic generation microscopy was found to enable the detection of crystals in all media including the highly turbid Ensure Plus system. In conclusion, it is important to evaluate the impact of complex biorelevant media on the dissolution performance of ASDs to better design supersaturating formulations for oral delivery.

π-π Stacking induced enhanced molecular solubilization, singlet oxygen production, and retention of a photosensitizer loaded in thermosensitive polymeric micelles.

Cancer photodynamic therapy (PDT) by photosensitizers (PS)-loaded polymeric micelles (PM) is hampered by the tendency of PS to aggregate in PM and/or by premature release of PS in the blood circulation. In the present study, aromatic thermosensitive PM, characterized by π-π stacking interaction, are used to encapsulate an axially solketal-substituted silicon phthalocyanine (Si(sol)2 Pc) with enhanced loading capacity, smaller size, and significantly improved retention of Si(sol)2 Pc compared with systems based on thermosensitive PM lacking aromatic groups. Interestingly, Si(sol)2 Pc is much less prone to aggregation in the aromatic PM, i.e., the amount of Si(sol)2 Pc that could be encapsulated without aggregation is 330 times higher in the aromatic PM than in the nonaromatic PM. Furthermore, Si(sol)2 Pc in the aromatic PM in a molecularly dissolved (non-aggregated) form displays three times more efficient singlet oxygen production than Si(sol)2 Pc aggregated in the non-aromatic PM. As a result, the photocytotoxicity of Si(sol)2 Pc-loaded aromatic PM to B16F10 cells is increased, compared with that of the non-aromatic PM, while no significant cytotoxicity is observed in the dark. Fluorescence-activated cell sorting (FACS) and confocal laser scanning microscopy (CLSM) analysis shows cell uptake of Si(sol)2 Pc loaded in the aromatic PM, and the Si(sol)2 Pc is taken up by the cells together with the micelles. The efficient singlet oxygen production of Si(sol)2 Pc dissolved in the aromatic PM makes it an interesting formulation for cancer PDT.