Eman Atef

Formulation and in vitro and in vivo characterization of a phenytoin self-emulsifying drug delivery system (SEDDS)

The aim of this study is to develop and characterize a self-emulsifying drug delivery system (SEDDS) of phenytoin, and to compare its relative bioavailability to a commercially available suspension. Four phenytoin SEDDS were prepared and evaluated. Following emulsification, the optimized formula was selected to have the smallest mean particle size and the highest absolute zeta potential, which should yield the formation of a stable emulsion. Its dissolution characteristics were superior to the other SEDDS formulas. In vivo and in vitro tests were run to compare the optimized formula, SEDDS II, to a commercially available Dilantin suspension. The in vitro dissolution indicated a significant improvement in phenytoin release characteristics. The in vivo study using male rats showed a clear enhancement in phenytoin oral absorption from SEDDS compared to Dilantin suspension. The area under the curve AUC((-10min-->10h)) of phenytoin after SEDDS administration increased by 2.3 times compared to Dilantin (p<0.05), and the rate of absorption of phenytoin was significantly faster from the SEDDS. The concentration after 30min (C(30min)) of SEDDS administration was 4.9 times higher than C(30min) after Dilantin administration (p<0.05). A sustained effect of phenytoin in plasma was also observed. After 12 weeks storage, SEDDS II was found to be chemically and physically stable under stressed conditions.

Correlating the behavior of polymers in solution as precipitation inhibitor to its amorphous stabilization ability in solid dispersions

Our major goals were to understand the mechanism of dipyridamole (DPD) precipitation inhibition in the presence of polymers and to correlate the polymers-mediated precipitation inhibition in solution to the amorphous stabilization in the solid state. A continuous UV spectrophotometer was used to monitor the DPD concentration with time in the absence and presence of different polymers. Six polymers: PVP K90, hydroxypropylmethylcellulose (HPMC), Eudragit E100, Eudragit S100, Eudragit L100, and PEG 8000 were screened at different drug-to-monomer ratios. Solid dispersions were characterized by X-ray powder diffraction and modulated differential scanning calorimetry, whereas infrared (IR) and Raman were used to investigate the possible drug-polymer interactions. Eudragit E100 and HPMC were found to delay both DPD precipitation initiation time and precipitation rates. Eudragit S100 delayed only the precipitation initiation time and PVP K90 decreased only the precipitation rates. In solid state, Eudragit S100, PVP K90, HPMC, and Eudragit L100 were effective stabilizers of the DPD solid dispersion. Eudragit S100 was found to be most effective DPD-stabilizing polymer. The IR and Raman spectra of the solid dispersion of Eudragit S100 and HPMC showed peak shift, indicating drug-polymer molecular interactions. It is concluded that the drug-polymer interaction plays a significant role in precipitation inhibition and amorphous stabilization.

Correlation of Inhibitory Effects of Polymers on Indomethacin Precipitation in Solution and Amorphous Solid Crystallization Based on Molecular Interaction

PurposeTo correlate the polymer’s degree of precipitation inhibition of indomethacin in solution to the amorphous stabilization in solid state.MethodsPrecipitation of indomethacin (IMC) in presence of polymers was continuously monitored by a UV spectrophotometer. Precipitates were characterized by PXRD, IR and SEM. Solid dispersions with different polymer to drug ratios were prepared using solvent evaporation. Crystallization of the solid dispersion was monitored using PXRD. Modulated differential scanning calorimetry (MDSC), IR, Raman and solid state NMR were used to explore the possible interactions between IMC and polymers.ResultsPVP K90, HPMC and Eudragit E100 showed precipitation inhibitory effects in solution whereas Eudragit L100, Eudragit S100 and PEG 8000 showed no effect on IMC precipitation. The rank order of precipitation inhibitory effect on IMC was found to be PVP K90 > Eudragit E100 > HPMC. In the solid state, polymers showing precipitation inhibitory effect also exhibited amorphous stabilization of IMC with the same rank order of effectiveness. IR, Raman and solid state NMR studies showed that rank order of crystallization inhibition correlates with strength of molecular interaction between IMC and polymers.ConclusionsCorrelation is observed in the polymers ability to inhibit precipitation in solution and amorphous stabilization in the solid state for IMC and can be explained by the strength of drug polymer interactions.

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

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.

Quantifying Solid-State Mixtures of Crystalline Indomethacin by Raman Spectroscopy Comparison with Thermal Analysis

This paper investigates Raman spectroscopy as a quick and reliable method to quantify the alpha (α) and gamma (γ) polymorphic forms of indomethacin compared to differential scanning calorimetry (DSC). Binary mixtures with different ratios of α and γ indomethacin were prepared and analyzed by Raman and DSC. The Raman method was found to be more reliable and superior compared to DSC. The partial conversion of the alpha to gamma polymorphic form during the DSC measurement was the major limitation for the use of full DSC as a quantitative method and resulted in difference between the calculated and measured enthalpy of both polymorphic forms.

Using in situ Raman spectroscopy to study the drug precipitation inhibition and supersaturation mechanism of Vitamin E TPGS from self-emulsifying drug delivery systems (SEDDS)

We are reporting a new methodology of using Raman spectroscopy for studying the drug surfactant interactions in self-emulsifying drug delivery systems (SEDDS). The physicochemical properties of surfactants could affect the performance of drugs from lipid delivery systems. Thus the purpose of our research was to study the drug surfactant interactions on a molecular level to understand the mechanism of supersaturation and precipitation inhibition. Two surfactants, Labrasol® and Vitamin E TPGS, were used to formulate several SEDDS. The optimized SEDDS were further evaluated by a kinetic solubility study and in situ Raman spectroscopy for two model drugs. It was found that both drugs precipitated from Labrasol® SEDDS whereas TPGS was able to inhibit precipitation and achieve high drug supersaturation levels. In situ Raman spectroscopy indicated that hydrogen bonding with TPGS was the main factor responsible for inhibiting precipitation. This study was able to correlate the structure and physicochemical properties of the drugs and surfactants to their ability to prevent drug precipitation. Our study brings up a possible new systematic approach by using Raman spectroscopy in the development and optimization of lipid based delivery systems.

Using Raman Spectroscopy in Studying the Effect of Propylene Glycol, Oleic Acid, and Their Combination on the Rat Skin

The permeability enhancement effect of oleic acid (OA) and propylene glycol (PG) as well as their (1:1 v/v) combined mixture was studied using rat skin. The percutaneous drug administration is a challenge and an opportunity for drug delivery. To date, there is limited research that illustrates the mechanism of penetration enhancers and their combinations on the skin. This project aims to explore the skin diffusion and penetration enhancement of PG, OA, and a combination of PG-OA (1:1 v/v) on rat skin and to identify the potential synergistic effect of the two enhancers utilizing Raman spectroscopy. Dissected dorsal skin was treated with either PG or OA or their combination for predetermined time intervals after which the Raman spectra of the treated skin were collected with the enhancer. A spectrum of the wiped and the washed skin were also collected. The skin integrity was tested before and after exposure to PG. The skin histology proved that the skin integrity has been maintained during experiments and the results indicated that OA disrupted rat skin lipid as evident by changes in the lipid peak. The results also showed that PG and OA improved the diffusion of each other and created faster, yet reversible changes of the skin peaks. In conclusion, Raman spectroscopy is a potential tool for ex vivo skin diffusion studies. We also concluded that PG and OA have potential synergistic reversible effect on the skin.