Comminution of ibuprofen to produce nano-particles for rapid dissolution.
ABSTRACT A critical problem associated with poorly soluble drugs is low and variable bioavailability derived from slow dissolution and erratic absorption. The preparation of nano-formulations has been identified as an approach to enhance the rate and extent of drug absorption for compounds demonstrating limited aqueous solubility. A new technology for the production of nano-particles using high speed, high efficiency processes that can rapidly generate nano-particles with rapid dissolution rate has been developed. Size reduction of a low melting ductile model compound was achieved in periods less than 1h. Particle size reduction of ibuprofen using this methodology resulted in production of crystalline particles with average diameter of approximately 270nm. Physical stability studies showed that the nano-suspension remained homogeneous with slight increases in mean particle size, when stored at room temperature and under refrigerated storage conditions 2-8°C for up to 2 days. Powder containing crystalline drug was prepared by spray-drying ibuprofen nano-suspensions with mannitol dissolved in the aqueous phase. Dissolution studies showed similar release rates for the nano-suspension and powder which were markedly improved compared to a commercially available drug product. Ibuprofen nano-particles could be produced rapidly with smaller sizes achieved at higher suspension concentrations. Particles produced in water with stabilisers demonstrated greatest physical stability, whilst rapid dissolution was observed for the nano-particles isolated in powder form.
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ABSTRACT: The objective of this research was to investigate physicochemical properties of an active pharmaceutical ingredient (API) that influence cyclodextrin complexation through experimental and computational studies. Native β-cyclodextrin (B-CD) and two hydroxypropyl derivatives were first evaluated by conventional phase solubility experiments for their ability to complex four poorly water-soluble nonsteroidal anti-inflammatory drugs (NSAIDs). Differential scanning calorimetry was used to confirm complexation. Secondly, molecular modeling was used to estimate Log P and aqueous solubility (S o) of the NSAIDs. Molecular dynamics simulations (MDS) were used to investigate the thermodynamics and geometry of drug-CD cavity docking. NSAID solubility increased linearly with increasing CD concentration for the two CD derivatives (displaying an AL profile), whereas increases in drug solubility were low and plateaued in the B-CD solutions (type B profile). The calculated Log P and S o of the NSAIDs were in good concordance with experimental values reported in the literature. Side chain substitutions on the B-CD moiety did not significantly influence complexation. Explicitly, complexation and the associated solubility increase were mainly dependent on the chemical structure of the NSAID. MDS indicated that each NSAID-CD complex had a distinct geometry. Moreover, complexing energy had a large, stabilizing, and fairly constant hydrophobic component for a given CD across the NSAIDs, while electrostatic and solvation interaction complex energies were quite variable but smaller in magnitude.AAPS PharmSciTech 04/2014; · 1.58 Impact Factor
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ABSTRACT: Good flow and compaction properties are prerequisites for successful compaction process. Apart from initial profile, mechanical properties of pharmaceutical powders can get modified during unit processes like milling. Milled powders can exhibit a wide range of particle size distribution. Further downstream processing steps like compaction can be affected by this differential particle size distribution. This has greatest implications for formulations like high dose drugs wherein the active pharmaceutical ingredient (API) contributes the maximum bulk in the final formulation. The present study assesses the impact of dry coating with ultrafine particles of same material, on the flow and compaction properties of the core material. Ibuprofen was selected as model drug as it has been reported to have poor mechanical properties. Ultrafine ibuprofen (average size 1.75 μm) was generated by Dyno® milling and was dry coated onto the core ibuprofen particles (average size 180 μm). Compaction studies were performed using a fully instrumented rotary tablet press. Compaction data was analysed for compressibility, tabletability, compactibility profiles and Heckel plot. Dry coating of the ibuprofen exhibited greater compressibility and tabletability, at lower compaction pressure. However, at compaction pressure above 220 MPa, compressibility and tabletability of coated as well as uncoated materials were found to be similar. Heckel analysis also supported the above findings, as Py value of uncoated ibuprofen was found to be 229.49 MPa and for 2.0% ultrafine coated ibuprofen was found to be 158.53 MPa. Lower Py value of ultrafine coated ibuprofen indicated ease of plastic deformation. Superior compressibility and deformation behaviour of ultrafine coated ibuprofen attributed to increased interparticulate bonding area. This strategy can also be explored for improving tabletability of high dose poorly compressible drugs.International Journal of Pharmaceutics 10/2012; · 3.99 Impact Factor
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ABSTRACT: Ibuprofen was recrystallized in the presence of aqueous solution of cationic dextran derivative, Diethylaminoethyl Dextran (Ddex) using the melt-in situ granulation-crystallization technique in order to produce a stable amorphous ibuprofen-Ddex conjugates with improved morphological, micromeritic and thermo-analytical characteristics without the use of organic solvent. Ddex was used in this study because of its ability to form conjugates with various drug molecules and enhance their physicochemical characteristics and therapeutic activities. Cationic dextrans are also biocompatible and biodegradable. Mechanism of conjugation as well as the impact of conjugation on the ibuprofen crystal habit was investigated. Gaussian type normal particle size distribution was obtained and the size of the crystals in the crystanule conjugates decreased steadily, with increasing concentration of Ddex, to a minimum of 480nm (440 folds reduction, p<0.05, n=20) at Ddex molar concentration of 0.01mM. FT-IR spectra showed electrostatic interaction and hydrogen bonding between ibuprofen and Ddex which was confirmed with the 1H-NMR and 13C-NMR spectra. DSC curves exhibited single peaks from the binary ibuprofen-Ddex conjugate crystanules suggesting compatibility and formation of an eutectic product. The conjugate crystanules showed broad and diffuse endothermic peaks with a glass transition temperature (Tg) of 58.3 and 59.14 oC at Ddex molar concentrations of 1.56×10-4 and 3.125×10-4mM respectively confirming the existence of ibuprofen-Ddex crystanule conjugates in amorphous state. Higher concentrations of Ddex decreased Tg steadily. TGA curves showed first order degradation at low molar concentrations of Ddex up to 3.125×10-4mM which coincides with the critical granular concentration of the crystanules while higher concentrations exhibited second order degradation profile. This study provides the basis for the development of stable amorphous drug-polymer conjugates with potential practical application in controlled and extended drug release formulations.International Journal of Pharmaceutics 12/2013; · 3.99 Impact Factor