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A congealable disperse phase encapsulation method was used to prepare sustained-release ibuprofen-wax microspheres. Microspheres prepared with paraffin wax, such as ceresine and microcrystalline waxes, using polyvinylpyrrolidone (PVP) as dispersant had a tendency to aggregate, but the addition of wax modifiers (stearyl alcohol and glyceryl monostearate) greatly reduced aggregation. Optimum modifier and dispersant concentrations were 20% (w/w) and 5% (w/v), respectively. The particle size distribution of the microspheres was log-normal. An increase in modifier, dispersant concentration, emulsification stirring speed, or temperature shifted the size distribution toward finer particles. Microcrystalline wax required a higher emulsification temperature and produced finer particles than ozokerite wax. The recovery of drug from the different microsphere formulations varied between 71 and 92%. Differential scanning calorimetry (DSC) of the single components and physical mixtures showed endothermic peaks at the respective melting-point ranges. The DSC of the ceresine and microcrystalline wax microspheres was similar to rescans of ternary mixtures of components of the microspheres with less prominent and lower melting temperatures than individual components or physical mixtures.
This investigation involved the evaluation of the emulsifier blend effect on the development of sustained release diclofenac microspheres intended for use in a suspension formulation. The microspheres were prepared using the hydrophobic congealable disperse phase method. The emulsifier blend consisted of glycerol, monostearate (GMS), a hydrophobic emulsifier with HLB = 3.8, and Tween 80, a hydrophilic emulsifier with a HLB value of 15. The effect of this blend on the encapsulation efficiency, size distribution and drug release from the microspheres was studied. A critical amount of GMS (> 0.2 g) was found to be necessary for good encapsulation efficiency. X-ray diffractograms revealed that the drug retains its crystalline state within the microspheres, indicating that the drug is present as a dispersion within the wax matrix. Increasing amounts of Tween 80 caused an increase in the drug release while increased amounts of GMS retarded the release. The hydrophilic emulsifier and the emulsifier blend influenced the size distribution of the formed microspheres. With an increase in the amount of hydrophilic emulsifier, there was an initial increase in the percent of desired size fraction (137.5 microns) of microspheres followed by a decrease. Microspheres with a larger size released the drug slowly compared to smaller size microspheres, while increase in drug load increased the rate of drug release. The release pattern fitted the Higuchi dissolution kinetics for spherical matrices. Different impeller blade designs formed microspheres that exhibited different release rates. The microspheres (mean size 137.5 microns), had a release profile that made them suitable to be formulated as a sustained release suspension.
A modified USP paddle method using minibaskets was used to study the effects of various formulations on in vitro dissolution of ibuprofen microspheres. Formulations containing waxes such as paraffin or ceresine wax without modifiers exhibited very slow dissolution profiles and incomplete release, which did not improve with increased drug loading or the preparation of smaller microspheres. The addition of modifiers such as stearyl alcohol and glyceryl monostearate greatly increased the dissolution rate, with 20% (w/w) near the optimum for predictable dissolution. Higher drug loading and decreased microsphere size increased the dissolution rate from microspheres containing modifier. Optimum formulations contained ceresine wax or microcrystalline wax and stearyl alcohol as a modifier, with a drug content of 17%. An increase in the encapsulation dispersant concentration had little effect on the dissolution profiles. The dissolution data from narrow size fractions of microspheres indicated spherical matrix drug release kinetics; the 50% dissolution time decreased with the square of the microsphere diameter. With appropriate modifiers, wax microsphere formulations of drugs with solubility characteristics similar to those of ibuprofen can offer a starting basis for predictable sustained release dosage forms.
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Ibuprofen microspheres were prepared from the racemate, (+)-S and (-)-R enantiomers using waxes such as ceresine and glyceryl stearate and stereospecifically characterized. The method of preparation of the microspheres was a hydrophobic congealable disperse phase encapsulation process and variables such as particle size, wax type, enantiomeric form were evaluated. Dissolution studies were carried out by a modified USP type II method and the samples were analysed by a stereospecific HPLC assay using S-(-)-1(1) naphthylethylamine as the derivatizing agent and fenoprofen as the internal standard. The mean particle sizes of (+)-S and (-)-R enantiomers determined by microscopy/image analysis were 64 and 99 microns respectively while that of the racemate was 48 microns. Differential Scanning Calorimetry (DSC) of ibuprofen and the enantiomers showed endothermic peaks at 72 and 55 degrees C respectively. Thermograms of the physical mixture and microspheres did not show the characteristic ibuprofen peak, indicating a change in crystallinity of the drug. Powder X-ray diffraction patterns of the enantiomers and racemic ibuprofen were found to be dissimilar indicating different crystal properties. The X-ray patterns for the microspheres did not show the characteristic peaks for the drug indicating that ibuprofen may be in solid solution with the waxes. Scanning electron micrographs of the microspheres showed a generally smooth and spongy appearance for the microspheres made of compritol and glyceryl stearate. Microspheres made from the paraffin waxes had rough and hard surface characteristics consistent with the higher melting point of the waxes. Ceresine microspheres made with the enantiomers had a rougher and more porous surface compared to the microspheres made with racemic ibuprofen. Stereospecific release of the recemate from the formulations was found to be sustained (T25 of 4 h), while release from the enantiomers was less sustained (T50 of 2 h). From the S:R ratios and statistical analysis of the data, the release of the enantiomers of ibuprofen from the formulations containing the racemate was found to be non-stereoselective.
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