Ibuprofen Particles Research Articles

Pharmacokinetic Studies of Gel System Containing Ibuprofen Solid Nanoparticles.

In the therapy of rheumatoid arthritis, ibuprofen (IBU) is widely used; however, it has been limited the clinical use by its systemic side effect, such as gastrointestinal lesions. Therefore, we prepared topical gel ointment used IBU solid nanoparticles (IBUnano-gel formulation). In addition, we demonstrated their anti-inflammatory effect by using arthritis model rat (adjuvant-induced arthritis rat, AA rat). The gel formulations were prepared using additives (Carbopol 934, 2-hydroxypropyl-β-cyclodextrin and methylcellulose) and bead mill-method. The IBU particle size in the IBUnano-gel formulation was 208 nm. The increase in inflammation of the hind feet of AA rats was attenuated by the treatment with the IBUnano-gel formulation, and preventive effect was higher than that of a gel formulation containing IBUmicroparticles (IBUmicro-gel formulation, mean particle size 85.4 μm); the accumulation and permeability through the skin of IBU from the IBUnano-gel formulation were significantly larger in comparison with the IBUmicro-gel formulation. Further, no gastrointestinal lesions were observed in AA rats following the repetitive administration of the 5% IBUnano-gel formulation (0.30 g) for 42 days (once a day). These results suggest that the dermal application of IBU-nanoparticles provide effective and efficient therapy that spares patients from unwanted side effects.

Fluid bed film coating of fine ibuprofen particles

Fine pharmaceutical powders pose significant challenge in fluid bed (FB) film coating due to their high cohesion. Ibuprofen powders, considered as model Geldart group C powders with Sauter mean diameters of 41μm (coarse) and 22μm (micronized), could not be fluidized due to severe agglomeration, solid-bridging, and poor flowability. Dry coating, applied as a pre-processing method that coats nano-silica on the surface of ibuprofen, enabled sufficiently improved flow, hence fluidization via reduced cohesion. Resulting coarse and micronized ibuprofen powders were successfully polymer film coated in a top spray fluidized bed. As a major novelty, apart from pre-processing through 20nm silica surface coating that enabled fluidization, agglomeration during FB processing was minimized by introducing 180nm colloidal silica particles that were pH stabilized in polymer spraying suspension using NaOH. In contrast, lack of or poorly stabilized colloidal particles led to significant agglomeration. Spray rate and fluidization velocity were both investigated to understand their effect on agglomeration of the coarse ibuprofen powders. Increased spray rate led to increased agglomeration due to the overly wet conditions, while increased fluidization velocities unexpectedly led to increased agglomeration resulting from electrostatic charging. To simplify the experimental design, a simple scaling relationship was introduced to estimate the coating conditions for the micronized ibuprofen powders based on the processing conditions of the coarse ibuprofen powders. This relationship, based on the minimum fluidization velocity, led to comparable agglomeration levels for powders with Sauter mean diameters of 21 and 42μm. To the author's knowledge these are the first successful results where micronized pharmaceutical powders were polymer coated in a traditional top spray fluidized bed.

Impact of pore characteristics of silica materials on loading capacity and release behavior of ibuprofen

Impact of pore characteristics of porous silica supports on loading capacity and release behavior of ibuprofen was investigated. The porous silica materials and ibuprofen-loaded porous silica materials were thoroughly characterized by N2-sorption, thermal gravimetric and derivative weight analyses (TG-DTW), X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FT-IR), scanning electron microscope (SEM), transmission electron microscope (TEM) to determine the physical properties of materials, amount of ibuprofen adsorbed and position of ibuprofen. The detailed characterization reveals that the ibuprofen molecules adsorbed inside the mesopores. Increasing the mesopore size from 5nm to 10nm increased the ibuprofen loading from 0.74 to 0.85mmol/g, respectively. Incorporation of macropore into the structure of porous silica materials enhanced the ibuprofen loading capacity of 11.8–20.3%. The ibuprofen-loaded bimodal meso-macroporous silica materials exhibited the highest dissolution of 92wt.% within an hour. The ibuprofen particles deposited on the external surface of the porous silica materials showed a lower dissolution rate than the ibuprofen adsorbed inside the mesopores due to the formation of ibuprofen crystalline.

Dry Powder Coating using Planetary Centrifugal Mixer.

Extemporaneous compounding is an important part of pharmacy practice, and should be standardized and sophisticated to ensure the quality of the compounded preparations. Recently, we applied a planetary centrifugal mixer (PCM) to powder blending, which has attracted interest for its small scale and lack of contamination. In this study, we aimed to reveal the feasibility of dry powder coating through ordered mixing of fine particles using PCM. Cohesive lactose powders (Pharmatose450M) were dry coated with magnesium stearate (MgSt) using from 0.1 to 5%(w/w) content. The operational variables tested were operation time (1-30 min), operation speed (400-1000 rpm), vessel size (24-100 mL), and charging rate in the vessel (20-40%). The processed powders were evaluated for their surface morphology, flowability, and wettability. Furthermore, fine ibuprofen particles were coated with various lubricants, and then the dissolution profiles were examined. The crystallinity of ibuprofen was assessed using FT-IR and PXRD. Lactose powders were successfully coated with MgSt using PCM. When the level of MgSt was over 1%, the surface of the lactose powders was thoroughly covered. Angles of repose were 51° and 41° for unprocessed and processed powders with 1% MgSt, respectively. The contact angle of the water drop on the 1% MgSt sample leached to be 132°, changing to a hydrophobic surface. Investigations under various operational conditions revealed that higher improvement was observed upon higher speed and longer time, and a smaller charging rate in the vessel. Vessel size had no impact. Moreover, improved dissolution of ibuprofen coated with both hydrophilic and hydrophobic lubricants was observed owing to good dispersing behavior. Besides, no alteration of crystallinity was detected. PCM is an effective tool for dry powder coating with low impact stress. The presented method will contribute a great deal to making crushed tablets a functional powder.

Formulation and characterisation of nanosuspensions of BCS class II and IV drugs by combinative method

Drug nanocrystals are known to increase the solubility of Biopharmaceutics Classification System (BCS) class II and IV drugs. SmartCrystals are the second generation nanocrystals with particle size of less than 100 nm and increased the stability and solubility of drug and drug product. The combinative methods adopted for the preparation of SmartCrystals are reported to shorten the processing time to reduce the particle size of the drug. This study was carried out with the aim to prepare nanosuspensions of aprepitant and ibuprofen using two pretreatment methods, precipitation and ball milling in a combination of high-pressure homogenisation (HPH). Ball milling and precipitation resulted in nanosuspensions having a particle size less than 1 µ, which were subjected to high HPH. HPH further led to a reduction in the particle size. However, the precipitation method failed to reduce the size of ibuprofen particles to 1 µ.

Nanosizing of sodium ibuprofen by SAS method

The micro/nanosizing of drug particles has been identified as a potentially effective and broadly applicable approach. Sodium ibuprofen is a chiral nonsteroidal anti-inflammatory drug. This work aimed to recrystallize particles of sodium ibuprofen, reducing its particle size, using a Supercritical Anti-solvent (SAS) technique performed in a modified supercritical fluid extraction unit. For this purpose, the phase equilibrium of the system sodium ibuprofen+acetone+CO2 was also investigated at temperatures ranging from 35 to 55°C. Phase equilibrium data exhibited solid–vapor–liquid and vapor–liquid transitions. The average particle sizes of the SAS-precipitated ibuprofen were below 380±84nm for all the SAS conditions tested, reducing the original dimension of the samples from micrometric to nanometric order. The best SAS operational conditions, in order to produce the lowest estimated particle size and higher crystallinity were, respectively, using 0.5 and 1.0mgibuprofen/mL, and 1mLsolution/min, 1kgCO2/h, 110bar and 35°C. The DSC results indicated that, besides reducing the ibuprofen particle size, the SAS process appears to have changed the original sodium ibuprofen to the acid form. The PXRD and RAMAN results indicated that the SAS process at 1mgibuprofen/mL, 1mLsolution/min, 1kgCO2/h, 110bar and 35°C is the best condition to obtain ibuprofen particles with higher crystallinity.

Improvement of dissolution rate of poorly water-soluble drug by wet grinding with bio-compatible phospholipid polymer

An innovative technology to enhance drug dissolution rate was proposed in this study. Poorly water-soluble ibuprofen was ground in a bio-compatible and amphiphilic co-polymer solution made from 2-methacryloyloxyethyl phosphorylcholine (MPC) and butylmethacrylate (BMA) by using a novel multi-ring type wet grinding system. The dry particle of ibuprofen was produced by freeze drying of the slurry obtained by the wet grinding. It was found that the dissolution rate of ibuprofen was enhanced incredibly. Effect of the polymer content on the dissolution rate, size of ibuprofen particle in slurry and the crystallinity change was investigated. The effect of size decrease (increase in apparent interfacial contact area) and the crystallinity decrease contributed to enhance the dissolution rate. However, the most significant factor that dramatically enhanced the dissolution rate was the effect of bio-compatible and amphiphilic MPC polymer. Owing to the hydrophobic interaction, the hydrophobic surface of ibuprofen was covered by the hydrophobic polymer chain of the MPC polymer, facing its hydrophilic groups to water when the dry ibuprofen particle was dissolved in water. The “surfactant effect” contributed very much to enhance the initial dissolution rate of ibuprofen significantly.

Ibuprofen–polymer precipitation using supercritical CO2 at low temperature

A process for the SAS coprecipitation of ibuprofen with the polymers poly(l-lactic acid) and Eudragit L100 was successfully carried out. The particle size was reduced to micrometer and near nanometer ranges. The morphology of the raw material changed to spherical upon processing for both poly(l-lactic acid)/ibuprofen particles and eudragit/ibuprofen particles. The eudragit-based particles were significantly smaller than those obtained with poly(l-lactic acid). Ibuprofen release profiles were determined for simulated gastric and intestinal fluids in order to study the effect of the polymer and to identify the appropriate systems for different administration routes. The in vitro release profiles for both polymer/drug systems showed a slower and more controlled release in comparison to the unprocessed ibuprofen. Moreover, the effects of pressure, temperature, initial concentration of the solution and drug-to-polymer ratio on the particle size and morphology of these drug/polymer systems have been evaluated. According to the XRD, DSC and FTIR data, physicochemical interactions do not occur between ibuprofen and the polymers and a proportion of the ibuprofen molecules probably remained on the microparticle surface.

Squeezing out ultrafine hydrophobic and poor water-soluble drug particles with water vapour

This short communication describes a scalable new method to produce ultrafine hydrophobic or poorly soluble drug particles. Ultrafine Vitamin D3, Aspirin and Ibuprofen particles in the submicron range were produced. The method is an extension of the antisolvent vapour precipitation technique which exposes a droplet to an antisolvent vapour with reference to the dissolved materials within the droplet. In this work, the drug material was dissolved in ethanol droplets and then exposed to a convective stream of water vapour. Absorption of the water vapour into the droplet resulted in the precipitation of the particles. The precipitated submicron particles showed good dispersion behaviour in water droplets. This work will form the basis for using spray dryers as high-throughput scalable micro-precipitators.

Impact of active ingredients on the swelling properties of orally disintegrating tablets prepared by microwave treatment

The impact of different active pharmaceutical ingredients (APIs) loading on the properties of orally disintegrating tablets (ODTs) prepared according to our previously reported microwave (MW) treatment process was evaluated using famotidine (FAM), acetaminophen (AAP), and ibuprofen (IBU). None of the APIs interrupted the tablet swelling during the MW treatment and the tablet hardness were improved by more than 20 N. MW treatment, however, led to a significant increase in the disintegration time of the ODTs containing IBU, but it had no impact on that of the ODTs containing FAM or AAP. This increased disintegration time of the ODTs containing IBU was attributed to the relatively low melting point of IBU (Tm=76 °C), with the IBU particles melting during the MW treatment to form agglomerates, which interrupted the penetration of water into the tablets and delayed their disintegration. The effects of the MW treatment on the chemical stability and dissolution properties of ODTs were also evaluated. The results revealed that MW treatment did not promote the degradations of FAM and AAP or delay their release from the ODTs, while dissolution of the ODTs containing IBU delayed by MW treatment. Based on these results, the MW method would be applicable to the preparation of ODTs containing APIs with melting points higher than 110 °C.

Passivation of High-Surface-Energy Sites of Milled Ibuprofen Crystals via Dry Coating for Reduced Cohesion and Improved Flowability

Ibuprofen micronization with dry coating is investigated to examine its influence on passivation/stabilization of high-surface-energy sites and reduced cohesion. A fluid energy mill was used to micronize ibuprofen particles down to 5-28 μm with or without simultaneous nanosilica coating. Powder flow property and dispersibility were characterized using FT4 powder tester and Rodos/Helos laser diffraction particle sizer. Surface energy was characterized using a next generation inverse gas chromatography instrument. Uncoated micronized ibuprofen showed an increased Lifshitz-van der Waals (LW) dispersion component of surface energy with increasing milling intensity. In contrast, dry-coated milled powders showed a significant reduction in the LW component, whereas physical mixture of uncoated micronized ibuprofen and silica exhibited no reduction in surface energy, indicating that dry coating is necessary for the passivation of high-energy sites of ibuprofen created during micronization. Surface energy of pure micronized ibuprofen was highly heterogeneous, whereas dry-coated ibuprofen had greatly reduced heterogeneity. Micronization with dry coating also improved flowability and bulk density as compared with pure active pharmaceutical ingredient micronization without coating, or just blending with silica. Overall, dry coating leads to decreased cohesion and improved flowability because of reduced LW dispersive component of surface energy and creating nanoscale surface roughness.

Ibuprofen nanoparticles prepared by a PGSS™-based method

Abstract In this study, ibuprofen, a common non-steroidal anti-inflammatory drug with low water-solubility was used as a model drug for its nanosizing via a PGSS™ (particles from gas-saturated solutions)-based method. A modified PGSS™ process was employed to prepare PEG6000-ibuprofen composite particles after investigating the solid–liquid–gas phase equilibrium behavior of the PEG6000–ibuprofen–CO 2 system. The composite powder was then dispersed into water to remove PEG6000 and obtain ibuprofen nanoparticles. The effects of pressure, temperature, and mass fraction of ibuprofen in the composite on the ibuprofen particle size and particle morphology were investigated. Results showed that spherical ibuprofen nanoparticles with diameter of 20–500 nm were prepared at different conditions. Additionally, the dissolution rates of different ibuprofen particles were studied, indicating much faster dissolution of the obtained ibuprofen nanoparticles compared with the raw material and those from the direct physical mixing approach in the phosphate buffer solution (pH = 7.2 ± 0.02). This can be attributed to the reduced size and the reduced crystallinity of the ibuprofen particles from the modified PGSS™-based process.

Homogenization and Melt-Emulsification Techniques for Ibuprofen Particle Size Reduction: Effect of Tween 80 & Sonication

Ibuprofen suspensions were prepared by simple homogenization with melt-emulsification process. Tween 80 was used as stabilizer. The homogenized suspensions were evaluated and compared with melt emulsificated suspension. The pH value and rheology behavior were not difference. The viscosity was very low. Zeta potential was -10 to -25 mV. In this study, the suitable process to minimize particle size of ibuprofen suspension was melt emulsification follow by sonication. This process could be developed to obtain nanosuspension by adjust sonication process and improved formulation to obtain suitable nanosuspension.

Flow and compaction behaviour of ultrafine coated ibuprofen

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 analyzed 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 P(y) 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 P(y) 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.

Influence of particle size on the direct compression of ibuprofen and its binary mixtures

In this paper, ibuprofen from a commercial source and its fractioned samples with narrower size distribution were characterized to assess the effect of particle properties on compaction characteristics. The compaction behavior of binary mixtures of ibuprofen with spray-dried lactose was also studied. The tablet in-die densification rate and tablet out-of-die porosity and tensile strength were measured for all samples. It was found that the particle size of ibuprofen does not affect the yield stress as derived from a Heckel plot, however the yield stress increases with the increase of ibuprofen particle size in the binary mixtures. Particle size also affects the tablet out-of-die properties, with tablet porosity and tensile strength increasing with the decrease in particle size. The effect of adding a weak compacting powder such as lactose on the tablet tensile strength is very much dependent on the ibuprofen particle size and mass ratio of the binary mixtures. Mixing lactose with ibuprofen of similar size in equal mass has no effect on the tensile strength of the tablet whereas mixing it with ibuprofen of larger size reduces the strength compared to ibuprofen alone. Adding a smaller amount of lactose can lead to an increase in tablet strength, even though the particle size of ibuprofen and lactose is quite different. Theoretical analysis on the tablet strength based on particle–particle bond strength was also carried out to explain the experimental results.

Flowability of binary mixtures of commercial and reprocessed ibuprofen through high shear wet milling (HSWM) with lactose

This study investigates the flow properties of binary mixtures of both commercial ibuprofen and reprocessed ibuprofen through high shear milling with lactose powders. Ibuprofen is recrystallized in a 30% water–ethanol mixture before high shear wet milling (HSWM). In-situ Process Analytical Techniques (PAT) (Labmax®) is used to study the HSWM process dynamics, with particle size measured by a Lasentec Focused Beam Reflectance Measurement, FBRM®. The flow properties of the binary mixtures of the different ibuprofen particles and its binary mixtures with lactose were measured using a Schulze® RST-XS ring shear tester. Results show that the morphology of ibuprofen was changed from needle to hexagonal like crystals during recrystallization and crystal size was reduced dramatically by HSWM for 1h. The flowability of milled ibuprofen powders is reduced significantly due to its reduced size and change of surface morphology. Mixing the HSWM ibuprofen powders with lactose enhanced its flow properties. However, the increase of the mixture flowability for HSWM ibuprofen is less significant in comparison to the binary mixtures of lactose with commercial ibuprofen.

Influence of Solvent on the Morphology and Subsequent Comminution of Ibuprofen Crystals by Air Jet Milling

Crystal morphology plays an important role in drug processing and delivery, which may be controlled during crystallisation. In this study, ibuprofen particles with different size and morphology were produced by controlled crystallisation in order to evaluate their impact on particle size reduction. Results suggest that the micronisation behaviour of ibuprofen was markedly influenced by the morphology and size of starting materials. It was possible to reduce the size of ibuprofen particles to sizes less than 5 µm during dry milling, which is markedly below the reported brittle-ductile transition size. Results also indicate that the particle size reduction mechanism is influenced by the size and morphology of the starting ibuprofen crystals. Dissolution behaviour of ibuprofen was shown to be influenced by the solid surface chemistry of micronised drug particles. The molecular modelling study provided deeper understanding of the experimental findings observed in this study.

Preparation and Characterization of Ibuprofen Nanoparticles by using Solvent/ Antisolvent Precipitation

Ibuprofen as a non-steroidal anti-inflammatory drug (NSAID) show a low and variable oral bioavailability in water solution due to low aqueous solubility and slow dissolution rate. Reducing ibuprofen particles size is an effective and widely used approach to speed up dissolution by enlarging the effective surface area. The ibuprofen nanoparticles are prepared by solvent/antisolvent method. The prepared nanodrug show the accelerate dissolution rate in water solvent. In comparison with raw drug, the chemical structure of nanosized ibuprofen show not change but the crystallinity is reduced to 300- 400 nm. The decreasing of particles size ibuprofen is also due to an increase 2.33 times of dissolution in purified water in first 30 min.

Mechanistic Modelling and Mechanistic Monitoring: Simulation and Shadowgraph Imaging of Particulate Dissolution in the Flow-Through Apparatus

Accurate mechanistic modelling of a complex system requires insight into the process being simulated, in addition to a theoretical 'first-principles' approach. The current work uses a numerical mechanistic model to simulate dissolution of a particulate system in the flow-through dissolution apparatus. A shadowgraph imaging method is also used to monitor the dissolution process, providing real-time estimates of particle motion, number and total dissolution time. Experimental dissolution studies of ibuprofen particles are used to assess the accuracy of the model. The numerical model adequately predicts the ibuprofen particle dissolution rate at 16 mL min(-1) . Parameter sensitivity analysis identified dissolution test circumstances requiring more, or less, accuracy in the particle size and density calculations. The shadowgraph imaging method successfully determined the total dissolution time and decreasing particle numbers over time. The images confirmed the pulsing particle motion of the numerical model but revealed some more complex velocity patterns, assisting numerical model development. Further optimisation of the sampling window is required to capture all relevant particle motion and changing particle size distribution. A mechanistic model can successfully simulate particulate dissolution in the flow-through apparatus, and when used along with shadowgraph imaging, can give valuable insight into the dissolution process mechanisms and environment.

Design of Agglomerated Crystals of Ibuprofen During Crystallization: Influence of Surfactant

Objective(s) Ibuprofen is a problematic drug in tableting, and dissolution due to its poor solubility, hydrophobicity, and tendency to stick to surface. Because of the bad compaction behavior ibuprofen has to be granulated usually before tableting. However, it would be more satisfactory to obtain directly during the crystallization step crystalline particles that can be directly compressed and quickly dissolved. Materials and Methods Crystallization of ibuprofen was carried out using the quasi emulsion solvent diffusion method in presence of surfactant (sodium lauryl sulfate (SLS), Tween 80). The particles were characterized by differential scanning calorimetry (DSC), powder X-ray diffraction (XRPD) and were evaluated for particle size, flowability, drug release and tableting behavior. Results Ibuprofen particles obtained in the presence of surfactants consisted of numerous plate- shaped crystals which had agglomerated together as near spherical shape. The obtained agglomerates exhibited significantly improved micromeritic properties as well as tableting behavior than untreated drug crystals. The agglomerates size and size distribution was largely controlled by surfactant concentration, but there was no significant influence found on the tableting properties. The dissolution tests showed that the agglomerates obtained in presence of SLS exhibited enhanced dissolution rate while the agglomerates made in the presence of Tween 80 had no significant impact on dissolution rate of ibuprofen in comparison to untreated sample. The XRPD and DSC results showed that during the agglomeration process, ibuprofen did not undergo any polymorphic changes. Conclusion