Drug-polymer miscibility, interactions, and precipitation inhibition studies for the development of amorphous solid dispersions for the poorly soluble anticancer drug flutamide.

The major goal of this research was to successfully formulate solid dispersion (SD) of the poorly soluble anticancer drug flutamide (FLT) using various hydrophilic polymers. Furthermore, to get more insight into SD, solid-state studies (miscibility and molecular interaction) were correlated with solution study (precipitation inhibition, dissolution). Hydrophilic polymers like PVP K90, HPMC, Eudragit EPO, and PEG 8000 were used at different drug-to-polymer w/w ratios. Solid-state miscibility studies were carried out using modulated differential scanning calorimetry (MDSC). SDs were prepared using solvent-evaporation technique and characterized by powder X-ray diffraction (PXRD) and MDSC. Infrared, Raman spectroscopy and molecular modeling were used to investigate drug-polymer interactions in the dispersions. Precipitation inhibition studies were carried out at various FLT-hydrophilic polymer ratios. Precipitation inhibition studies showed that PEG 8000 has the highest efficiency, followed by PVP K90, while HPMC and EPO showed no effect on precipitation inhibition. In the solid-state, MDSC of the physical mixture (PM) suggested that FLT is miscible to a greater extent with EPO and PEG 8000. Characterization of the amorphous dispersions using MDSC and PXRD concluded that FLT transformed from crystalline to amorphous form in the presence of PVP K90 and PEG 8000. Spectroscopic results confirmed stronger interaction of FLT with PVP K90 and PEG 8000, thereby confirming the in-solution precipitation and molecular modeling binding energy results. Amorphous dispersions formulated with PVP and PEG were stable and showed higher dissolution, an important property necessary to improve the physicochemical properties and drug delivery of poorly soluble anticancer drug FLT.

Role of Molecular Interactions for Synergistic Precipitation Inhibition of Poorly Soluble Drug in Supersaturated Drug-Polymer-Polymer Ternary Solution.

We are reporting a synergistic effect of combined Eudragit E100 and PVP K90 in precipitation inhibition of indomethacin (IND) in solutions at low polymer concentration, a phenomenon that has significant implications on the usefulness of developing novel ternary solid dispersion of poorly soluble drugs. The IND supersaturation was created by cosolvent technique, and the precipitation studies were performed in the absence and the presence of individual and combined PVP K90 and Eudragit E100. The studies were also done with PEG 8000 as a noninteracting control polymer. A continuous UV recording of the IND absorption was used to observe changes in the drug concentration over time. The polymorphic form and morphology of precipitated IND were characterized by Raman spectroscopy and scanning electron microscopy. The change in the chemical shift in solution (1)H NMR was used as novel approach to probe IND-polymer interactions. Molecular modeling was used for calculating binding energy between IND-polymer as another indication of IND-polymer interaction. Spontaneous IND precipitation was observed in the absence of polymers. Eudragit E100 showed significant inhibitory effect on nuclei formation due to stronger interaction as reflected in higher binding energy and greater change in chemical shift by NMR. PVP K90 led to significant crystal growth inhibition due to adsorption on growing IND crystals as confirmed by modified crystal habit of precipitate in the presence of PVP K90. Combination of polymers resulted in a synergistic precipitation inhibition and extended supersaturation. The NMR confirmed interaction between IND-Eudragit E100 and IND-PVP K90 in solution. The combination of polymers showed similar peak shift albeit using lower polymer concentration indicating stronger interactions. The results established the significant synergistic precipitation inhibition effect upon combining Eudragit E100 and PVP K90 due to drug-polymer interaction.

Comparison of biorelevant simulated media mimicking the intestinal environment to assess the solubility profiles of poorly soluble drugs.

During the discovery stage in lead identification/optimization, compounds are characterized for their solubilities in biorelevant media and these data are often used to model the in vivo behavior of the compounds and predict the fraction absorbed. These media are selected to closely approximate the composition of human intestinal fluid. Owing to the complexity and variability in human intestinal fluid composition, it is essential that the chosen simulated media mimic the in vivo condition as closely as possible. Several recipes have been developed and are routinely used in assessing the solubilities of compounds. It is necessary to revisit these recipes and modify them as the understanding of the human GI tract increases. In the present work, we have evaluated the solubilities of six model compounds in several media and have proposed slight modifications to the currently used recipes based on our own data and that reported in the literature.

Investigation and correlation of drug polymer miscibility and molecular interactions by various approaches for the preparation of amorphous solid dispersions.

Curcumin (CUR) was used as a poorly soluble drug whereas polyvinyl pyrrolidone K90 (PVP), Eudragit EPO (EPO), hydroxypropyl methylcellulose E5 (HPMC) and polyethylene glycol 8000 (PEG) were used as hydrophilic polymers. CUR polymer miscibility was evaluated by solubility parameter, melting point depression and glass transition temperature (Tg) measurements. Molecular interactions between CUR and polymers were determined by Fourier-transform infrared spectroscopy (FTIR) and Raman. Amorphous solid dispersions were prepared with CUR-polymer ratio of 70:30 (w/w) by solvent evaporation technique and were evaluated for dissolution enhancement using USP II method. Physical states of solid dispersions were characterized by X-ray diffraction (XRD) whereas thermal behaviors were investigated using modulated differential scanning calorimetry (MDSC). CUR-EPO system showed good miscibility through all the approaches, whereas immiscibility was found in other CUR-polymer systems. CUR-EPO and CUR-HPMC systems showed significant molecular interactions whereas CUR-PVP and CUR-PEG showed no molecular interactions. All solid dispersions showed significant dissolution enhancement with CUR-EPO showing highest dissolution rate during first 1h whereas CUR-HPMC was effective in maintaining high CUR concentrations for 6h. The study highlights the importance of investigating and correlating drug polymer miscibility and molecular interactions by various approaches for successful formulation of amorphous solid dispersions.

Amorphous stabilization and dissolution enhancement of amorphous ternary solid dispersions: combination of polymers showing drug-polymer interaction for synergistic effects.

The purpose of this study was to understand the combined effect of two polymers showing drug-polymer interactions on amorphous stabilization and dissolution enhancement of indomethacin (IND) in amorphous ternary solid dispersions. The mechanism responsible for the enhanced stability and dissolution of IND in amorphous ternary systems was studied by exploring the miscibility and intermolecular interactions between IND and polymers through thermal and spectroscopic analysis. Eudragit E100 and PVP K90 at low concentrations (2.5%-40%, w/w) were used to prepare amorphous binary and ternary solid dispersions by solvent evaporation. Stability results showed that amorphous ternary solid dispersions have better stability compared with amorphous binary solid dispersions. The dissolution of IND from the ternary dispersion was substantially higher than the binary dispersions as well as amorphous drug. Melting point depression of physical mixtures reveals that the drug was miscible in both the polymers; however, greater miscibility was observed in ternary physical mixtures. The IR analysis confirmed intermolecular interactions between IND and individual polymers. These interactions were found to be intact in ternary systems. These results suggest that the combination of two polymers showing drug-polymer interaction offers synergistic enhancement in amorphous stability and dissolution in ternary solid dispersions.

Studying the effect of lipid chain length on the precipitation of a poorly water soluble drug from self-emulsifying drug delivery system on dispersion into aqueous medium.

OBJECTIVE: The lipid excipients of the self-emulsifying drug delivery systems (SEDDS) could play a role in interfering with the drug precipitation to maintain its supersaturation, a step with possible major significance on the SEDDS. Thus, the effect of lipid chain length on indomethacin precipitation rate from SEDDS upon dilution was studied. METHOD: Indomethacin SEDDS were prepared using medium and long chain lipids at 5% and 13% (w/w) drug load. Two medium chain lipids Lauroglycol and Capryol, and two long chain lipids Labrafil and castor oil, were studied. The 13% w/w SEDDS were evaluated for drug release, and the physicochemical properties of the precipitated drug were characterized by PXRD, DSC, IR and Raman. KEY FINDINGS: The final optimized SEDDS consisted of Lauroglycol (lipid): Transcutol (co-solvent): Labrasol (surfactant). No precipitate was observed with long chain lipids SEDDS, whereas medium chain lipids SEDDS showed precipitation within 30 min of drug release from 13% w/w formulations. Precipitation studies showed that the medium chain lipids resulted in a modified indomethacin form possibly an ester. The ester formation signifies the interaction between indomethacin and medium chain length lipids. CONCLUSIONS: The study emphasizes the importance of lipids chain length of excipients in successful SEDDS formulations. The study provides insight into the underlying drug lipid interactions in SEDDS formulations.

Stability of vitamin B complex in multivitamin and multimineral supplement tablets after space flight.

The effect of storage in space on the stability of vitamin B complex in two commercial vitamin tablets was examined. Multiple vitamin samples returned after storage on the space shuttle and International Space Station (ISS) along with two ground control and three positive control groups were included in the study. Content of vitamin B(3) in the tablets and in vitro dissolution rate were determined using a modified high performance liquid chromatographic assay from USP/NF 2010. Results indicate that vitamin B(3) in one of the brands tested (#2) may be subject to marginal degradation after storage on ISS for 4 months as indicated by the chromatograms for all six tablets showing a split peak appearing as a notch at the peak tip. Chromatograms were not different for ground and flight samples for Brand #1 suggesting that this may be more suitable for use in space.