Indomethacin Powder Research Articles

Solventless amorphization and pelletization using a high shear granulator. Part I; feasibility study using indomethacin

The aim of the current study was to investigate the feasibility of solventless amorphization and pelletization using a high shear granulator, to produce amorphous drug-layered pellets by simply mixing drug crystals and inactive spheres without using solvent and heating. Indomethacin crystals were mixed with microcrystalline cellulose spheres at a weight ratio of 1:10 using the granulator and the resulting particles were then characterized using solid-state and particle analytical techniques as well as pharmaceutically relevant tests. Amorphization of indomethacin crystals progressed with increasing processing time and decreasing jacket temperature. The amorphization rate increased as the spheres became larger and full amorphization was achieved using spheres of 414 and 649 μm in diameter. Indomethacin crystals were pulverized due to mechanical activation by the spheres and the resulting amorphous microparticles were then deposited on the spheres, yielding pellets with an amorphous layer. The pellets exhibited supersaturation characteristics and the dissolution rate was faster than that of quench-cooled indomethacin powder. However, the amorphous drug deposited on the pellets exhibited a lower physical stability than quench-cooled amorphous indomethacin, but recrystallization could be inhibited by co-processing with polyvinylpyrrolidone K-25 stabilizing the amorphous form. The findings suggest the feasibility of the solventless amorphization and pelletization technique.

Quantitative Evaluation of the Crystallinity of Indomethacin Using 1H T2 Relaxation Behaviors Measured by Time Domain NMR

We sought to demonstrate the usefulness of the T2 relaxation behaviors measured by time domain NMR (TD-NMR) for the quantitative evaluation of the crystallinity of an active pharmaceutical ingredient (API). This study used indomethacin as a model API. After blending amorphous and crystalline indomethacin powders at a designated ratio, T2 relaxation curves were measured by TD-NMR. Subsequently, we acquired a calibration curve to quantify crystallinity by curve fitting analysis. Validation demonstrated a good correlation between the theoretical and experimental percentage of crystallinity. Thus, this study succeeded in a precise estimation of crystallinity of indomethacin using TD-NMR. We also investigated whether the technique is practical by testing indomethacin powders with unknown proportion of crystallinity, and then compared their estimated crystallinity with that found using conventional evaluation techniques. The quantitative performance of the TD-NMR technique was comparable to that of Raman spectroscopy. Furthermore, indomethacin powder blended with excipients, which can be used to produce tablets, was tested. The TD-NMR technique was still able to quantify the crystallinity of indomethacin, even when excipients were incorporated into the sample. Therefore, the present study expands the horizon for evaluating the crystallinity of APIs in pharmaceutical sciences.

English

The non-steroidal anti-inflammatory drug (NSAID), indomethacin, is disadvantaged by its poor water solubility and gastrointestinal adverse effects. The aim of this work therefore was to formulate this drug into solid self emulsifying drug delivery system (SSEDDS) as an attempt to improve its aqueous solubility and anti-inflammatory property using shea butter or its blend with Bos indicus lipid. Proximate analysis was carried out on shea butter. Indomethacin-loaded SSEDDS containing lipid (shea butter, Vitellaria paradoxa), surfactant (Tween 65) and cosurfactant (Span 85) or lipid blends (shea butter/Bos indicus fat), surfactant blends (Tween 65/Tween 80) and cosurfactant (Span 85) were formulated. The drug-loaded SSEDDS were evaluated for visual isotropicity, emulsification time, aqueous dilution, refrigeration test, loading efficiency, in vitro drug release and anti-inflammatory properties. Results showed that Shea butter contained 92.8% fat, 1.52% moisture, 2.05% protein, 9.78% carbohydrate and trace amounts of fiber and ash. Pre/post formulation isotropicity tests showed that all batches of indomethacin SSEDDS were stable. SSEDDS containing shea butter as the lipid component recorded significantly (p < 0.05) longer emulsification times than those containing lipid blends. The T85 of most of the batches was within 30 min. Shea butter-based SSEDDS demonstrated significantly (p < 0.05) higher anti-inflammatory effect than unformulated indomethacin powder. In conclusion, Shea butter conferred stability to the formulations and contributed to acceptable in vitro and superior anti-inflammatory characteristics of indomethacin. Key words: Shea butter, Bos indicus fat, indomethacin, solid self emulsifying drug delivery system (SEDDS), anti-inflammatory.

Some in vitro and pharmacodynamic evaluation of indomethacin solid lipid microparticles

The purpose of this study was to investigate some in vitro and pharmacodynamic properties of indomethacin-loaded solid lipid microparticles (SLMs). A blend of homolipid from Caprahircus and Phospholipon® 90G comprised of the lipid matrix. The SLMs were prepared by the hot homogenisation technique. The effects of Carbosil® and sodium chloride on the release profile and particle size of the SLMs were investigated. The anti-inflammatory and gastro-protective characteristics of the SLMs were also studied. The particle size ranged from 5.0 to 20 µm. The encapsulation efficiency ranged from 46 to 72%; with sodium chloride-containing batches recording highest values. Maximum drug release was within 80 min. Significant (P < 0.05) anti-inflammatory effect was exerted by the SLM. Relative high ulcer index associated with unformulated indomethacin powder and the absence of gastric lesions in rats that received oral administration of SLM affirmed the gastro-protective potential of the SLM. In conclusion, improved anti-inflammatory and gastro-protective effects were achieved with indomethacin-loaded SMLs. Key words: Anti-inflammatory, gastro-protective, solid lipid microparticles (SLMs).

In-line monitoring and interpretation of an indomethacin anti-solvent crystallization process by near-infrared spectroscopy (NIRS)

PAT (process analytical technology) has been emphasized as one of key elements for the full implementation of QbD (quality-by-design) in the pharmaceutical area. NIRS (near-infrared spectroscopy) has been studied intensively as an in-line/on-line monitoring tool in chemical and biomedical industries. A precise and reliable monitoring of the particle characteristics during crystallization along with a suitable control strategy should be highly encouraged for the conformance to new quality system of pharmaceutical products. In this study, the anti-solvent crystallization process of indomethacin (IMC) was monitored using an in-line NIRS. IMC powders were produced via anti-solvent crystallization using two schemes; ‘S-to-A’ (solvent-to-antisolvent) and ‘A-to-S’ (antisolvent-to-solvent). In-line NIR spectra were analyzed by a PCA (principal component analysis) method. Although pure α-form IMC powder was resulted under A-to-S scheme, a mixture of the α-form and γ-form was produced for S-to-A case. By integrating the PCA results with off-line characterization (SEM, XRD, DSC) data, the crystallization process under each scheme was elucidated by three distinct consecutive steps. It was demonstrated that in-line NIRS, combined with PCA, can be very useful to monitor in real time and interpret the anti-solvent crystallization process with respect to the polymorphism and particle size.

Dissolution enhancement of indomethacin by inclusion into porous silica: 3-D ordered macroporous silica versus 2-D ordered mesoporous silica

The main aim of this study was to enhance the dissolution of a poorly water-soluble drug indomethacin (IMC) by inclusion into 3-D ordered macroporous (3DOM) silica and 2-D ordered mesoporous silica SBA-15, and to compare the drug loading and release properties of two kinds of porous silica. 3DOM silica with 3-D continuous and interconnected pores of 200 nm and SBA-15 silica with well-ordered 2-D cylindrical pores of 6.8 nm were successfully prepared, and loaded with IMC via a procedure involving a combination of adsorption equilibrium and solvent evaporation. Characterization of the original IMC powder, IMC-loaded 3DOM silica and IMC-loaded SBA-15 was carried out by scanning electron microscopy (SEM), differential scanning calorimetry (DSC), X-ray diffraction (XRD) and dissolution test. SEM images revealed the successful encapsulation of IMC into both porous silica. DSC and XRD studies evidenced that the crystallinity of IMC decreased markedly after confined into pores of porous silica: partial amorphous form in 3DOM silica and molecule state in SBA-15. Both 3DOM silica and SBA-15 formulations exhibited an enhanced dissolution of IMC as compared to its corresponding crystalline form. Remarkably, in comparison with SBA-15, 3DOM silica displayed a more rapid release profile, which may be ascribed to the 3-D interconnected pore networks and the highly accessible surface areas.

Structural evolution of indomethacin particles upon milling: Time‐resolved quantification and localization of disordered structure studied by IGC and DSC

The amorphization of indomethacin was induced by milling. The mass fraction of the amorphous phase in the drug milled for various time intervals was determined with differential scanning calorimetry (DSC). Because the surface fraction amorphized by milling can be much higher than the mass fraction, which can have a large impact on the powder properties, a method for quantification of surface fraction amorphized by milling using inverse gas chromatography (IGC) was developed. A calibration curve was constructed by mixing completely amorphous indomethacin (obtained after milling for 120 min) with various amounts of the initial crystalline sample. Linear part of the curve was then used to quantify the surface amorphous content of samples milled for different time intervals. Surface and mass amorphization kinetics were determined and fitted to a first‐order model. It was found that the surface amorphization rate is an order of magnitude higher than the mass amorphization rate. Results confirmed that IGC is a sensitive method for detection and quantification of the fraction of amorphous surface of milled indomethacin powder. If suitably combined with other techniques, this method represents a relatively general approach for the localization and quantification of the surface amorphous fraction in crystalline substances that transform into amorphous ones upon intensive milling. © 2009 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 99: 1968–1981, 2010

Using the low-frequency Raman spectroscopy to analyze the crystallization of amorphous indomethacin

This paper gives a detailed analysis of the low-frequency Raman spectrum (LFRS) in the 5–250 cm −1 region, corresponding to collective vibrations, in the crystalline forms and in the amorphous state of indomethacin (IMC). This study points out the high sensitivity of the LFRS to detect, identify and evaluate the first traces of crystallization in comparison with high-frequency regions where internal vibration bands are detected. This analysis reveals that amorphous IMC prepared by cryogrinding instantaneously partially crystallizes at room temperature in the stable γ phase, well below T g = 43 °C. A method based on the treatment of the LFRS to determine precise and very low volume of crystallized material within amorphous matrix is described and used to analyze the crystallization kinetics of ground amorphous IMC powder. This study demonstrates that Raman spectroscopy is also a well-adapted technique to point out small amount of amorphous state in crystalline matrix. Crystallization of ground IMC powder was also analyzed by isothermal microcalorimetry experiments, which is one of the most widely used methods to analyze isothermal crystallization and to evaluate crystallinity.

Drug agglomeration and dissolution – What is the influence of powder mixing?

This study determined the influence of mixing speed and time on the dissolution and deagglomeration of a micronised, poorly water-soluble drug, indomethacin, in lactose interactive mixtures. Mixing occurred in a Turbula mixer; dissolution studies were performed using the USP paddle method, and the extent of deagglomeration was determined using modelling strategies and laser diffraction particle sizing of the powder mixtures. During low energy mixing at low rates and short mixing times, dissolution profiles showed an unusual flat asymptote indicating incomplete extents of dissolution caused by agglomerates that did not readily disperse in the dissolution medium. The study showed that increasing both speed and time of mixing increased the extent of dissolution and deagglomeration of the indomethacin powder. Nonlinear least squares modelling of the dissolution data using a sigmoidal equation provided estimates of the extent and rate of dissolution. Mixing speed and time had a much greater influence on the extent of dissolution which was controlled by deagglomeration than on the initial dissolution rate which was related to dispersed indomethacin. While some deagglomeration did occur at higher mixing energies, the deagglomeration of the indomethacin was not complete with only about 58–80% of indomethacin particles overlapping with the primary indomethacin particle size distribution. The significant outcome of this study was that mixing conditions have a major influence on the mixing quality, especially in areas where agglomerate characteristics influence performance.

Corrosion Behavior of Copper in a Copper Bearing Intrauterine Device in the Presence of Indomethacin

As an improvement to the use of the copper bearing intrauterine device, indomethacin has been introduced to reduce the incidence of bleeding after insertion of the device. The effects of indomethacin on copper corrosion were studied in vitro in simulated uterine fluid. Electrochemical polarization resistance measurements indicated that indomethacin powder slightly increased the corrosion rate of copper if pH of the fluid was not under control and it did not change the corrosion rate if pH was adjusted daily to maintain some constancy. The experimental results for medication by indomethacin-releasing Silastic® were basically the same as those with powdered indomethacin. X-ray diffraction showed that only cuprous oxide was formed on the copper substrated surface and that indomethacin did not affect the corrosion products. As scanning electron microscopy demonstrated, however, in the presence of indomethacin the oxide particles formed were found to be more coarse and dense than in the absence of indomethacin.

Controlled-release preparation of indomethacin using calcium alginate gel.

Alginate gel beads containing indomethacin (IMC) were prepared using a gelation of alginate with calcium cation. Though IMC was not released from the beads at pH 1.2 because of its extremely low solubility in aqueous media, it was released according to the swelling of alginate gel at pH 6.8. The release of IMC from the beads decreased with the decreasing ratio of mannuronic acid (M) to guluronic acid (G) in alginate, and with the larger molecular weight of alginate. The maximum concentration and the area under the time curve of plasma concentration of IMC after oral administration of alginate gel beads to beagle dogs were lower than those of IMC powder. The absorption rate of IMC was lower and more prolonged after administration of beads containing IMC than IMC powder alone. The high plasma concentration of IMC was maintained because absorption continued for a longer period when the bead consisting of the alginate with 0.65 M-block/G-block ratio and 66000 molecular weight was administered. The availability of alginate gel beads of IMC was further demonstrated by oral administration to human volunteers. A serum concentration which was comparable to maximum serum concentration was maintained from 2 to 6 h after administration, while an effective serum concentration was maintained even 12 h after administration of the beads. These data suggest that alginate is useful for a controlled-release formulation of IMC.

Preparation of a controlled release drug delivery system of indomethacin: Effect of process equipment, particle size of indomethacin, and size of the nonpareil seeds

AbstractIndomethacin pellets (IS) were prepared by spraying a slurry of indomethacin, Eudragit® S-100, dibuty1 sebacate and alcohol onto an appropriate mesh fraction of nonpareil seeds using appropriate processing equipment. Factors affecting this layering process were studied and identified. The average particle diameter and the overall particle size distribution of the indomethacin powder were found to be critical factors influencing the physical properties of the IS pellets. Micronized indomethacin powder, having an average particle diameter of four microns and a particle size distribution ranging from one to thirteen microns, was found to be the optimum for this layering process. Altering the mesh fraction of the starting nonpareil seeds for the layering process was found to greatly affect the release characteristics of the drug from the beadlets. The Wurster column process was found to be better than a fluid-bed granulator process for the manufacture of IS beadlets.

Dissolution properties of indomethacin from coprecipitates with water-insoluble glucan.

The dissolution properties of indomethacin (IMC) from coprecipitates with water-insoluble glucan (WIG) were investigated with a view to application of WIG to pharmaceutical preparations. WIG was produced by an enzyme present in the culture fluid of Streptococcus mutans. Coprecipitates were prepared by evaporation of the solvent from IMC solution in which WIG was suspended. The X-ray diffraction patterns indicated that the size of crystals of IMC was decreased by the coprecipitation. The dissolution rate of IMC from the coprecipitates was significantly greater than that from the physical mixture or intact IMC powder. These results indicate that WIG can improve the dissolution properties of IMC.

Encapsulated hydrophilic polymer beads containing indomethacin as controlled release drug delivery systems.

Encapsulated hydrophilic polymer beads containing indomethacin were prepared by a combined technique of bead polymerization and phase separation. The drug delivery system consisted of the copolymer of 2-hydroxyethyl methacrylate and acrylamide as the core matrix and ethyl cellulose as the barrier membrane. The drug was incorporated into the polymer matrix during the formation of the beads. The system was found to be useful as a sustained release dosage form. Release of drug from the coated beads followed a zero-order rate up to 40% of the drug released. A linear relationship exists between the rate of release and the reciprocal amount of ethyl cellulose used for coating, indicating that the drug release was controlled by the coating thickness. Addition of polyvinyl pyrrolidone in the formulation significantly increased the amount of drug released. Blood level studies showed that drug absorption from the encapsulated beads was lower than that of indomethacin powder. It appeared that indomethacin was completely absorbed from the encapsulated beads.