Physical-Chemical Characterization and Formulation Considerations for Solid Lipid Nanoparticles.

Pure glyceryl mono-oleate (GMO) (lipid) and different batches of GMO commonly used for the preparation of GMO-chitosan nanoparticles were characterized by modulated differential scanning calorimetry (MDSC), cryo-microscopy, and cryo-X-ray powder diffraction techniques. GMO-chitosan nanoparticles containing poloxamer 407 as a stabilizer in the absence and presence of polymers as crystallization inhibitors were prepared by ultrasonication. The effect of polymers (polyvinyl pyrrolidone (PVP), Eudragits, hydroxyl propyl methyl cellulose (HPMC), polyethylene glycol (PEG)), surfactants (poloxamer), and oils (mineral oil and olive oil) on the crystallization of GMO was investigated. GMO showed an exothermic peak at around -10°C while cooling and another exothermic peak at around -12°C while heating. It was followed by two endothermic peaks between 15 and 30 C, indicative of GMO melting. The results are corroborated by cryo-microscopy and cryo-X-ray. Significant differences in exothermic and endothermic transition were observed between different grades of GMO and pure GMO. GMO-chitosan nanoparticles resulted in a significant increase in particle size after lyophilization. MDSC confirmed that nanoparticles showed similar exothermic crystallization behavior of lipid GMO. MDSC experiments showed that PVP inhibits GMO crystallization and addition of PVP showed no significant increase in particle size of solid lipid nanoparticle (SLN) during lyophilization. The research highlights the importance of extensive physical-chemical characterization for successful formulation of SLN.

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.

Compression-induced crystallization of amorphous indomethacin in tablets: characterization of spatial heterogeneity by two-dimensional X-ray diffractometry.

Tablets of amorphous indomethacin were compressed at 10, 25, 50, or 100 MPa using either an unlubricated or a lubricated die and stored individually at 35 °C in sealed Mylar pouches. At selected time points, tablets were analyzed by two-dimensional X-ray diffractometry (2D-XRD), which enabled us to profile the extent of drug crystallization in tablets, in both the radial and axial directions. To evaluate the role of lubricant, magnesium stearate was used as "internal" and/or "external" lubricant. Indomethacin crystallization propensity increased as a function of compression pressure, with 100 MPa pressure causing crystallization immediately after compression (detected using synchrotron radiation). However, the drug crystallization was not uniform throughout the tablets. In unlubricated systems, pronounced crystallization at the radial surface could be attributed to die wall friction. The tablet core remained substantially amorphous, irrespective of the compression pressure. Lubrication of the die wall with magnesium stearate, as external lubricant, dramatically decreased drug crystallization at the radial surface. The spatial heterogeneity in drug crystallization, as a function of formulation composition and compression pressure, was systematically investigated. When formulating amorphous systems as tablets, the potential for compression induced crystallization warrants careful consideration. Very low levels of crystallization on the tablet surface, while profoundly affecting product performance (decrease in dissolution rate), may not be readily detected by conventional analytical techniques. Early detection of crystallization could be pivotal in the successful design of a dosage form where, in order to obtain the desired bioavailability, the drug may be in a high energy state. Specialized X-ray diffractometric techniques (2D; use of high intensity synchrotron radiation) enabled detection of very low levels of drug crystallization and revealed the heterogeneity in crystallization within the tablet.

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.