The Influence of the Strength of Drug-Polymer Interactions on the Dissolution of Amorphous Solid Dispersions.

In an earlier report, ionic interactions between ketoconazole (KTZ), a weakly basic drug, and poly(acrylic acid) (PAA), an anionic polymer, resulted in a dramatic decrease in molecular mobility as well as reduced crystallization propensity of amorphous solid dispersion (ASD) in the solid state. On the other hand, weaker dipole-dipole interactions between KTZ and polyvinylpyrrolidone (PVP) resulted in ASDs with higher crystallization propensity (Mistry Mol Pharm., 2015, 12 (9), 3339-3350). In this work, we investigated the behavior of the ketoconazole (KTZ) solid dispersions in aqueous media. In vitro dissolution tests showed that the PAA ASD maintained the level of supersaturation for a longer duration than the PVP ASD at low polymer contents (4-20% w/w polymer). Additionally, the PAA ASDs were more resistant to drug crystallization in aqueous medium when measured with synchrotron X-ray diffractometry. Two-dimensional 1H nuclear Overhauser effect spectroscopy (NOESY) NMR cross peaks between ketoconazole and PAA confirmed the existence of drug-polymer interactions in D2O. The interaction was accompanied by a reduced drug diffusivity as monitored by 2D diffusion ordered spectroscopy (DOSY) NMR and enthalpy-driven when characterized by isothermal titration calorimetry (ITC). On the other hand, drug-polymer interactions were not detected between ketoconazole and PVP in aqueous solution, with NOESY, DOSY, or ITC. The results suggest that interactions that stabilize ASDs in the solid state can also be relevant and important in sustaining supersaturation in solution.

Probing the Distribution of Water in a Multi-Component System by Solid-State NMR Spectroscopy.

PURPOSE: To characterize the distribution of water among various components in a powder blend using solid-state NMR spectroscopy. METHODS: Water sorption behavior of theophylline anhydrate and excipients was determined by dynamic vapor sorption (DVS) and Karl Fischer Titration (KFT) after storing them in humidity chambers for 1 week at room temperature (RT) and calibration curves were generated for water content vs. (1)H T 1 relaxation times. Powder blends (either with microcrystalline cellulose or lactose as diluent) were stored at different relative humidity (RH) conditions and analyzed periodically using solid-state NMR, powder X-ray diffraction, and KFT. RESULTS: Anhydrous theophylline converted to the hydrate at ≥ 84% RH. Based on the calibration curves of water content vs. relaxation times, the distribution of water in the powder blends was estimated. The total water content calculated using ssNMR was in good agreement with values measured using KFT. In blends stored at 90% RH, theophylline anhydrate-to-hydrate conversion did not occur in 1 week. CONCLUSIONS: The distribution of water in multi-component powder blends was successfully determined using correlation between (1)H T 1 relaxation times and total water content. Excipient water sorption inhibited hydrate formation in theophylline at 90% RH. Water distribution was affected by excipient type. The extent of water sorbed by excipients in blends was found to be different than their standalone equilibrium water content.

Role of the Strength of Drug-Polymer Interactions on the Molecular Mobility and Crystallization Inhibition in Ketoconazole Solid Dispersions.

The effects of specific drug-polymer interactions (ionic or hydrogen-bonding) on the molecular mobility of model amorphous solid dispersions (ASDs) were investigated. ASDs of ketoconazole (KTZ), a weakly basic drug, with each of poly(acrylic acid) (PAA), poly(2-hydroxyethyl methacrylate) (PHEMA), and polyvinylpyrrolidone (PVP) were prepared. Drug-polymer interactions in the ASDs were evaluated by infrared and solid-state NMR, the molecular mobility quantified by dielectric spectroscopy, and crystallization onset monitored by differential scanning calorimetry (DSC) and variable temperature X-ray diffractometry (VTXRD). KTZ likely exhibited ionic interactions with PAA, hydrogen-bonding with PHEMA, and weaker dipole-dipole interactions with PVP. On the basis of dielectric spectroscopy, the α-relaxation times of the ASDs followed the order: PAA > PHEMA > PVP. In addition, the presence of ionic interactions also translated to a dramatic and disproportionate decrease in mobility as a function of polymer concentration. On the basis of both DSC and VTXRD, an increase in strength of interaction translated to higher crystallization onset temperature and a decrease in extent of crystallization. Stronger drug-polymer interactions, by reducing the molecular mobility, can potentially delay the crystallization onset temperature as well as crystallization extent.

Modulating the dehydration conditions of adefovir dipivoxil dihydrate to obtain different physical forms of anhydrate.

The physical form of anhydrous adefovir dipivoxil (AD), obtained following the dehydration of AD dihydrate, was governed by the kinetics of water removal. The rate and extent of water removal following the dehydration of AD dihydrate was manipulated by altering the sample size, pan configuration, and heating rate in a differential scanning calorimeter. Interestingly, when there was moderate resistance to water removal, a new anhydrous polymorph (melting point 80°C) was obtained. High resistance to water removal resulted in amorphous AD. Variable temperature XRD of AD provided direct and unambiguous evidence of this new polymorph. We have prepared and characterized this new anhydrous polymorph as well as amorphous AD. Based on HPLC, AD dihydrate heated under different conditions in the DSC was observed to be chemically stable. When exposed to water vapor (RH ≥ 80%; 25°C), the new polymorph had a stronger propensity to convert to AD dihydrate than the amorphous anhydrate or AD form I.

Effect of high-pressure homogenization and stabilizers on the physicochemical properties of curcumin-loaded glycerol monooleate/chitosan nanostructures.

AIM: The objective of this study was to investigate the influence of the high-pressure homogenization (HPH) process and stabilizers on the physicochemical properties of glycerol monooleate (GMO)/chitosan nanostructures using curcumin as a model hydrophobic drug. MATERIALS & METHODS: The oil-in-water nanoemulsion of the GMO/chitosan system was prepared by sonication and HPH techniques using two different stabilizers (polyvinyl alcohol [PVA] and poloxamer 407). The particle size (PS), ζ-potential (ZP) and physical stability of the nanoemulsion were investigated. These nanoemulsions were lyophilized and characterized for PS, ZP, surface morphology, moisture content and physical form of the drug in the nanostructures. The in vitro release and the uptake of curcumin in Caco-2 cells were evaluated using an ultra-performance liquid chromatography method. RESULTS: Three cycles of HPH produced a 50-65% reduction in the PS of the nanoemulsion. A change in stabilizer, from PVA to poloxamer, did not affect the PS, physical stability, moisture content or the physical form of the drug in the formulation. However, there was a significant change in the ZP, surface morphology, in vitro release rate and cellular uptake from the two formulations. CONCLUSION: The process of HPH effectively reduces the PS of the GMO/chitosan nanoemulsions loaded with the hydrophobic drug. The type of stabilizer used affects several physicochemical properties of the GMO/chitosan nanostructures. Compared with PVA, poloxamer 407 is a more effective stabilizer for stabilizing the GMO/chitosan system containing a hydrophobic drug nanoemulsion at low concentrations.