Dissolution Rate Of Indomethacin Research Articles

Numerical simulation of five different screw configurations used during the preparation of hot-melt extruded Kollidon® and Soluplus® based amorphous solid dispersions containing indomethacin

This work developed immediate-release hot melt extruded pellets containing the poorly aqueous soluble drug Indomethacin with five different screw configurations for oral application. Moreover, numerical simulation concerning residence time was performed for each configuration to give valuable tools for better process understanding and ease of scale-up. The pellets were prepared using immediate-release matrix-forming polymers such as Kollidon® and Soluplus® by coupling hot melt extrusion (HME) with a die-surface cutting pelletizer. The HME extruded filaments were pelletized with a die-surface cutting pelletizer into 1.5 mm pellets. The extruded pellets were characterized by differential scanning calorimetry (DSC), Fourier-transform infrared (FTIR) spectroscopy, scanning electron microscopy (SEM), in vitro release testing, drug content, and stability studies. DSC data revealed the formation of the amorphous solid dispersions of Indomethacin in both polymeric blends. FTIR spectra did not reveal any incompatibilities between the drug and the polymers. SEM micrographs revealed a smooth surface without any cracks. In vitro release studies demonstrated that the Indomethacin dissolution rate was significantly improved from both polymeric matrices for all the tested screw configurations compared to the bulk drug. However, the numerical simulation studies showed no significant difference between predicted and experimental extrusion residence time for only four screw configurations. In conclusion, the current investigation revealed the potential use of the continuous hot-melt extrusion technology for large-scale production of Indomethacin pellets with good prediction tools for the experimental extrusion residence time with standard, conveying, distributive, one mixing screw configurations for both polymers.

Sasol ECOFT and Deutsche Aircraft join forces to accelerate power-to-liquid (PTL) aiming for carbon-neutral flight

T he dissolution rates of indomethacin (IMC) and nifedipine (NIF) as poorly water-soluble model drugs have been significantly improved by encapsulating their molecules in the porous structure of engineered-particles of lactose as a new biocompatible porous carrier. The formulation method used in this study utilized a template-based spray-drying technique for in-situ production of porous lactose followed by two solvent-based drug-loading methods: (i) adsorption from organic solution, and (ii) incipient wetness impregnation to incorporate the drugs inside the porous lactose. In both cases, the results of DSC and XRD have revealed the deposition of nano-sized crystals of drugs inside the nanopores due to the nanoconfinement phenomenon. Greater extents of drug loadings have been achieved during the indomethacin adsorption due to the hydrogen-bonding interaction with the surface of lactose, as determined by FTIR spectroscopy. The in vitro release studies in simulated gastric fluid (SGF) have shown faster release rates for the impregnated particles compared with drug-loaded particles via the adsorption method.

A Mathematical Model Based on an Adaptive Neuro-Fuzzy Inference System for Matrixes Including Indomethacin

This study is concerned about prediction of dissolution rate of Insoluble drugs from solid dispersion (SD) polymer matrixes by an Adaptive Neuro-Fuzzy Inference System (ANFIS). Polyethylene Glycols (PEGs) as the SD with different molecular weights were provided and dissolution rate of indomethacin (IND) was obtained experimentally. A USP dissolution method was used to monitor the dissolution profiles of matrixes. The numbers of rules were trained in a systematic procedure using the experimental data. Comparison of IND dissolution rate from different matrixes, Area under the Curve (AUC) of absorbance vs. time diagrams in the first 25 min for 72 different samples was determined. Results show a high correlation between observed and predicted data (r2=0.85). The calculated root mean square error for the results of the ANFIS model is equal to 1.02. The index of area AUC in the first 25 min is more repeatable. It seems that the model has practical value and different ratios of polymer for the desired dissolution rate can be predicted or having different polymer ratios in the matrix can predict the dissolution rate of IND. this method can be suggested for other pharmaceuticals formulations to save time and money to achieve the best formula.

Preparation of a crystalline salt of indomethacin and tromethamine by hot melt extrusion technology

Although salt formation is the most ubiquitous and effective method of increasing the solubility and dissolution rates of acidic and basic drugs, it consumes large quantities of organic solvents and is a batch process. Herein, we show that the dissolution rate of indomethacin (a poorly water-soluble drug) can be increased by using hot melt extrusion of a 1:1 (mol/mol) indomethacin:tromethamine mixture to form a highly crystalline salt, the physicochemical properties of which are investigated in detail. Specifically, pH–solubility studies demonstrated that this salt exhibited a maximal solubility of 19.34 mg/mL (>1000 times that of pure indomethacin) at pH 8.19. A solvent evaporation technique was also used for salt formation. Spectroscopic analyses (infrared, nuclear magnetic resonance) of both; demonstrated, in situ salt formation with proton transfer. Powder X-ray diffraction and differential scanning calorimetry confirmed the crystalline nature of salts formed by both methods. Even though a number of amorphous salts of acidic drugs have been reported, the formation of a crystalline salt of an acidic drug by hot melt extrusion is completely unprecedented, which makes this study an important benchmark for the pharmaceutical production industry.

Effect of Solid Dispersions with Polyethylene Glycol 1500 on the Solubility of Indomethacin

Solid dispersions (SDs) of indomethacin with polyethylene glycol 1500 (PEG-1500) were studied to determine their effect on indomethacin solubility. Production of SDs increased the solubility and dissolution rate of indomethacin in H2O. The solubility and dissolution rate of indomethacin from SDs increased by 1.8 – 2.2 and 3.1 – 4.4 times, respectively. Indomethacin became less crystalline and then amorphous during preparation of the SDs. Dissolution of the SDs solubilized indomethacin and formed colloidal solutions.

Improving the dissolution rate of hydrophobic drugs through encapsulation in porous lactose as a new biocompatible porous carrier

T he dissolution rates of indomethacin (IMC) and nifedipine (NIF) as poorly water-soluble model drugs have been significantly improved by encapsulating their molecules in the porous structure of engineered-particles of lactose as a new biocompatible porous carrier. The formulation method used in this study utilized a template-based spray-drying technique for in-situ production of porous lactose followed by two solvent-based drug-loading methods: (i) adsorption from organic solution, and (ii) incipient wetness impregnation to incorporate the drugs inside the porous lactose. In both cases, the results of DSC and XRD have revealed the deposition of nano-sized crystals of drugs inside the nanopores due to the nanoconfinement phenomenon. Greater extents of drug loadings have been achieved during the indomethacin adsorption due to the hydrogen-bonding interaction with the surface of lactose, as determined by FTIR spectroscopy. The in vitro release studies in simulated gastric fluid (SGF) have shown faster release rates for the impregnated particles compared with drug-loaded particles via the adsorption method.

Dissolution enhancement of indomethacin-chitosan hydrochloride composite particles produced using supercritical assisted atomization

This study investigated the formation of drug-carrier composite particles via a supercritical assisted atomization (SAA) process using 50% (v/v) aqueous ethanol as a solvent, and carbon dioxide as a spraying medium. Indomethacin (IMC), a poorly water-soluble drug, was used as a model drug and chitosan hydrochloride (CH), a water-soluble carrier, was used as a carrier for composite particles. The effects of size and different CH to IMC weight ratios in the composite particles on drug dissolution rate were investigated. XRD, DSC and FTIR analyses showed that the SAA-treated IMC transformed from γ-form (as-received IMC) to the meta-stable α-form. In vitro dissolution test showed that the IMC dissolution rate was enhanced because of the transformation in crystalline form, increased drug wettability due to water-soluble CH in composite particles, and high surface area due to the decreased size of composite particles. Furthermore, the composite particles demonstrated enhanced drug permeability in Caco-2 cell monolayer. Taken together, the enhanced permeability and dissolution rate could be beneficial for the bioavailability of active pharmaceutical ingredients (APIs).

Novel tablet formulation of amorphous indomethacin using wet granulation with a high-speed mixer granulator combined with porous calcium silicate

Solid dispersion techniques are useful for improving the dissolution of poorly water-soluble drugs. This study aimed to produce and evaluate solid dispersion tablets improving the solubility and oral bioavailability of a poorly water-soluble indomethacin (IND) by wet granulation method with a high-speed mixer granulator combined with porous calcium silicate (PCS). A low density of PCS is a major disadvantage which is a bulky volume and scattering. So, it is necessary to prepare a high density PCS granule. Our system is very simple. At first, IND ethanol solution was added to PCS in a high-speed mixer granulator. After mixing, the granulation started the addition of the binder water solution to the PCS/IND mixture. The solid dispersion granules were obtained after drying the mixture. The dissolution rates of IND from PCS tablets were markedly enhanced compared with the dissolution rate of the pure drug. IND did not recrystallize in granules prepared using water and this formulation provided superior bioavailability in rats. Our amorphous solid dispersions have been successfully employed to enhance both solubility and oral bioavailability of IND. Though the use of PCS, it may be possible to maximize the bioavailability benefit of amorphous solid dispersions administered as tablet dosage forms.

Design and Evaluation of Sustained Release Matrix Tablets of Indomethacin by Employing Gelucires and Badam Gum

Sustained release matrix tablets of indomethacin (IM) were developed by employing a relatively less used hydrophilic polymer badam gum and gelucires. The dissolution rate of IM is first improved by dispersing the drug in hydrophilic gelucire (50/13) and the dispersion is then embedded in the matrix of badam gum and hydrophobic gelucire (43/01). Different ratios of IM and gelucire (50/13) were employed, and the solid dispersions were prepared by melting and solvent methods. The dispersion prepared by employing solvent method resulted in much higher dissolving product than was possible with the melting method. The differential scanning calorimetry and infrared spectroscopy (IR) studies revealed that there are no interactions between IM and gelucire and the XRD studies indicated that the drug IM existed in amorphous state in gelucire dispersion. Matrix tablets were prepared by direct compression employing different proportions of badam gum and gelucire (43/01). The prepared tablets were found to be of optimum hardness, uniform weight and acceptable friability. The drug release was found to be dependent on the ratio drug: Gelucire in the solid dispersion and also on the proportion of the release retarding polymer employed – gelucire (43/01) or badam gum. The drug release data suggested that the release of the drug is the first order and is diffusion controlled

Enhancement of Solubility and Dissolution Rate of Indomethacin by Chitosan Based Solid Dispersion Technique.

Enhancement of Solubility and Dissolution Rate of Indomethacin by Chitosan Based Solid Dispersion Technique.

Preparation, Characterization and Stability Studies of Glassy Solid Dispersions of Indomethacin using PVP and Isomalt as carriers.

The purpose of the present study was to use the solid dispersion (SD) technique to improve the dissolution rates of indomethacin (IMC). IMC solid dispersions in PVP K30 and isomalt (GALEN IQ 990) were prepared using the solvent evaporation technique and a hot melt method in weight ratios of 2, 10 and 30% (IMC:PVP). Solid dispersions and physical mixtures were characterized by X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC) and dissolution test. Physical stability tests were also performed at different temperatures and humidity conditions. The dissolution rates of all solid dispersions were faster than those of their physical mixtures. In samples containing 2% or 10% of IMC, there were no significant differences between the dissolution rates of IMC in PVP and isomalt solid dispersions, but in samples containing 30% of IMC, the dissolution rates were higher in isomalt dispersions. The XRPD analysis showed no crystalline peaks in solid dispersions, indicating that IMC was amorphous within the carrier. The DSC results showed that an interaction occurred between the drug and the carrier in PVP and isomalt dispersions. Physical stability tests at severe storage conditions showed that the dissolution rate of IMC in PVP solid dispersions decreased, while the dissolution profile of IMC in isomalt solid dispersions did not change significantly. It was shown that the dissolution rates of IMC in PVP and isomalt solid dispersions were substantially increased compared with their physical mixtures and pure IMC.

Coamorphous Drug Systems: Enhanced Physical Stability and Dissolution Rate of Indomethacin and Naproxen

One of the challenges in drug development today is that many new drug candidates are poorly water-soluble, and one of the approaches to overcome this problem is to transfer a crystalline drug into its amorphous form, thus increasing dissolution rate and apparent solubility of the compound. In this study, a coamorphous drug/drug combination between the two nonsteroidal anti-inflammatory drugs, naproxen and γ-indomethacin, was prepared and investigated. At molar ratios of 2:1, 1:1 and 1:2, the drugs were quench cooled in order to obtain a coamorphous binary phase. Physical stability was examined at 277.15 and 298.15 K under dry conditions (phosphorus pentoxide) and analyzed with X-ray powder diffraction (XRPD). Intrinsic dissolution testing was carried out to identify dissolution advantages of the coamorphous form over its crystalline counterparts or amorphous indomethacin. Fourier transform infrared spectroscopy (FTIR) was used for analyses at the molecular level to detect potential molecular interactions. Differential scanning calorimetry (DSC) thermograms were employed to assess the glass transition temperatures (T(g)), and the results were compared with predicted T(g)s from the Gordon-Taylor equation. Results showed that naproxen could be made amorphous in combination with indomethacin while this was not possible with naproxen alone. Peak shifts in the FTIR spectra indicated molecular interactions between both drugs, and it is suggested that the two drugs formed a heterodimer. Therefore, samples at the 1:2 and 2:1 ratios showed recrystallization of the excess drug upon storage whereas the 1:1 ratio samples remained amorphous. Intrinsic dissolution testing showed increased dissolution rate of both drugs in the coamorphous form as well as a synchronized release for the 1:1 coamorphous blend. All T(g)s displayed negative deviations from the Gordon-Taylor equation with the 1:1 ratio showing the largest deviation. In a novel approach of predicting the glass transition temperature, the 1:1 drug ratio was inserted as an individual component in the Gordon-Taylor equation with the excess drug representing the second compound. This approach resulted in a good fit to the experimentally determined T(g)s.

Counter-intuitive enhancement in the dissolution of indomethacin with the incorporation of cohesive poorly water-soluble inorganic salt additives

The objective of this work was to investigate the influence of various micronized poorly water-soluble inorganic materials on the dissolution and de-agglomeration behaviour of a micronized, poorly water-soluble model drug, indomethacin, from lactose interactive mixtures. Dissolution of indomethacin was studied using the USP paddle method and the data were modelled with multi-exponential equations using a nonlinear least squares algorithm in order to obtain key parameter estimates. The dispersion of indomethacin mixtures was measured by laser diffraction. The addition of aluminium hydroxide and calcium phosphate to binary mixtures of indomethacin counter-intuitively improved the dissolution rate of indomethacin due to significant increases in both the estimated initial concentration and dissolution rate constant of dispersed particles of indomethacin. While some enhancement was due to pH changes in the dissolution medium, the presence of these poorly water-soluble inorganic salts caused de-agglomeration. Average particle size distributions indicated that the presence of aluminium hydroxide within the matrix of indomethacin had reduced the agglomerate concentration whilst increasing the dispersed particle concentration. These findings provide the first evidence of the ability of poorly water-soluble inorganic salts to enhance the de-agglomeration and dissolution of micronized powders, potentially translating to improved bioavailability of poorly water-soluble drugs.

Improvement of Absorption Rate of Indomethacin and Reduction of Stomach Irritation by Alginate Dispersions

The dissolution rates of indomethacin from low molecular weight (mol. wt) alginate dispersions were significantly enhanced in comparison with that of indomethacin alone. The dispersion with lower mol. wt alginate exhibited more rapid dissolution rate than that of dispersion with higher mol. wt alginate. These enhanced dissolution rates of indomethacin by alginate may be due to the improvement of wettability and the decrease of crystallinity and crystal size. The absorption rate from alginate dispersions was enhanced in comparison with that from indomethacin alone, and enhanced only the rate of bioavailability in beagle dogs and volunteers. In addition, indomethacin-induced gastric lesions were reduced by dispersing indomethacin in alginate.

Enhancement of dissolution rate of indomethacin: using liquisolid compacts.

The potential of liquisolid systems to improve the dissolution properties of a water-insoluble agent (indomethacin) was the purpose of this survey. In this study, different formulations of liquisolid tablets using different co-solvents (non-volatile solvents) were prepared and the effect of several amounts of them on the dissolution behaviour of indomethacin was investigated. It is worth mentioning that the ratio of microcrystalline cellulose (carrier) to silica (coating powder material) was 20 in all formulations. To evaluate any interaction between indomethacin and the other components in liquisolid formulations, the differential scanning calorimeter (DSC) was used. The results showed that the liquisolid formulations exhibited significantly higher drug dissolution rates in comparison with directly compressed tablet. The enhanced rate of indomethacin dissolution derived from liquisolid tablets was probably due to an increase in wetting properties and surface area of drug particles available for dissolution. Moreover, it was indicated that the fraction of molecularly dispersed drug (F M) in the liquid medication of liquisolid systems was directly proportional to their indomethacin dissolution rate (D R). An attempt was made to correlate the percentage drug dissolved in 10 min with the solubility of indomethacin in PEG 200 and glycerin. In conclusion, the liquisolid compacts technique can be a promising alternative for the formulation of water insoluble drugs, such as indomethacin into rapid release tablets.

Improvement of Dissolution Behavior for Poorly Water-Soluble Drug by Application of Cyclodextrin in Extrusion Process: Comparison between Melt Extrusion and Wet Extrusion

The purpose of this study was to improve dissolution behavior of poorly water-soluble drugs by application of cyclodextrin in extrusion processes, which were melt extrusion process and wet extrusion process. Indomethacin (IM) was employed as a model drug. Extrudates containing IM and 2-hydroxypropyl-beta-cyclodextrin (HP-beta-CyD) in 1:1 w/w ratio were manufactured by both melt extrusion process and wet extrusion process. In vitro drug release properties of IM from extrudates and physiochemical properties of extrudates were investigated. The dissolution rates of IM from extrudates manufactured by melt extrusion and wet extrusion with HP-beta-CyD were significantly higher than that of the physical mixture of IM and HP-beta-CyD. In extrudate manufactured by melt extrusion, gamma-form of IM changed to amorphous completely during melt extrusion due to heating above melting point of IM. On the other hand, in extrudate manufactured by wet extrusion, gamma-form of IM changed to amorphous partially due to interaction between IM and HP-beta-CyD and mechanical agitating force during process. Application of HP-beta-CyD in extrusion process is useful for the enhancement of dissolution rate for poorly water-soluble drugs.

Improvement of solubility and dissolution rate of indomethacin by solid dispersions in Gelucire 50/13 and PEG4000

The aim of this study was to prepare and characterize solid dispersions of water insoluble non-steroidal anti-inflammatory drug, indomethacin (IND), with polyethylene glycol 4000 (PEG4000) and Gelucire 50/13 (Gelu.) for enhancing the dissolution rate of the drug. The solid dispersions (SDs) were prepared by hot melting method at 1:1, 1:2 and 1:4 drug to polymer ratios. Scanning electron microscopy (SEM), X-ray powder diffractometry (XRD) and differential scanning calorimetry (DSC) were used to examine the physical state of the drug. Furthermore, the solubility and the dissolution rate of the drug in its different systems were explored. The data from the XRD showed that the drug was still detectable in its solid state in all SDs of IND–Gelu. and disappeared in case of higher ratio of IND–PEG4000. DSC thermograms showed the significant change in melting peak of the IND when prepared as SDs suggesting the change in crystallinity of IND. The highest ratio of the polymer (1:4) enhanced the drug solubility about 4-folds or 3.5-folds in case of SDs of IND–PEG or IND–Gelu., respectively. An increased dissolution rate of IND at pH 1.2 and 7.4 was observed when the drug was dispersed in these carriers in form of physical mixtures (PMs) or SDs. IND released faster from the SDs than from the pure crystalline drug or the PMs. The dissolution rate of IND from its PMs or SDs increased with an increasing amount of polymer.

Development and Characterization of New Indomethacin Self-Nanoemulsifying Formulations

In the present work a new indomethacin (IND) self-nanoemulsifying drug delivery formulation (SNEDDF) have been prepared to enhance its dissolution which in turn could provide a better chance for IND oral absorption. IND SNEDDF have been prepared using different concentrations of castor oil as a solvent for IND, Cremophor RH 40 (Cr-40) as surfactant and Capmul MCM-C8 (Ca-8) as co-surfactant. Droplets size and turbidity of IND SNEDDFs were measured. Dissolution profile of IND SNEDDFs filled in gelatin capsules was determined by using USP apparatus 2. Ternary phase diagram was constructed to identify the self-nanoemulsifying region after evaluation of IND SNEDDFs by the visual observation. The IND SNEDDFs were thermally characterized using differential scanning calorimetry (DSC) to ensure the compatibility among its ingredients. The present study revealed that the SNEDDFs increased IND dissolution rate and has the potential to enhance its bioavailability without interaction or incompatibility between the ingredients.

Improvement of the dissolution rate of indomethacin by a cogrinding technique using polyethylene glycols of various molecular weights

Indomethacin is an anti inflammatory drug which is used to relieve pain and inflammatory conditions. For poorly soluble drugs and highly permeable drugs such as indomethacin, the rate of oral absorption is often controlled by the dissolution rate in the gastrointestinal tract. Therefore together with the permeability, the solubility and dissolution behaviour of a drug are key determinants of its oral bioavailability. In this study, an attempt was made to enhance the dissolution rate of indomethacin using various molecular weights of polyethylene glycol (PEG2000, 6000 and 20000) by a cogrinding technique. The cogrinds containing different drug:PEG ratios (1:1, 1:2, 1:5, 1:10) were made and the dissolution rate of the drug from each of the formulations was studied at different pHs (1.2, 4.6 and 6.8). The results showed a significant increase in the dissolution rate of indomethacin at various pHs from cogrinds formulations, obtained by this cogrinding technique, in comparison to that of the pure drug powder, treated pure drug, or physical mixtures at all studied pHs. The dissolution results did not show significant differences between the dissolution rates of indomethacin from cogrinds containing PEG2000 with various drug:carrier ratios, whereas these differences were considerably significant for the cogrinds samples containing PEG20000. These results confirm that the dominant mechanism of low molecular weights of PEGs in increasing the indomethacin dissolution rate from cogrinds is the formation of a thin film of the PEG around the poorly soluble drug particles. In the case of high molecular weight PEGs, such as PEG20000, since the indomethacin:carrier ratios significantly affected the dissolution rate of indomethacin from the cogrinds, therefore, it seems that the increase in dissolution of indomethacin from these cogrinds was mainly caused by an improved solubility of the drug by the presence of these carriers. The particle size analysis showed small changes in the particle size diameter and powder surface area of indomethacin after grinding (16.3% reduction in median particle diameter and 18.8% increase in the total powder surface area). The XRD and FTIR spectra rejected any polymorphic changes or the production of amorphous indomethacin due to the cogrinding process. These spectra showed only slight changes in the crystal orientation after milling.

Dissolution mechanism of poorly water-soluble drug from extended release solid dispersion system with ethylcellulose and hydroxypropylmethylcellulose

The purpose of this study is to investigate the release mechanism of poorly water-soluble drug from the extended release solid dispersion systems with water-insoluble ethylcellulose (EC) and water-soluble hydroxypropylmethylcellulose (HPMC) (1:1). Indomethacin (IND) was used as a model of poorly water-soluble drug. Two kinds of solid dispersions were prepared by the solvent evaporation methods, which consist of the same formulation but exhibit different physical performance. It appeared that the dissolution behavior of IND depended on the structures of EC–HPMC matrices, which were governed by the preparation method. In addition, the dissolution behavior showed pH dependency that the dissolution rate of IND was slower in acidic medium than that in neutral medium. The experimental results revealed that the hydrophobic interaction between IND and EC occurred under lower pH and strongly delayed the dissolution rate of IND. The relationship between this hydrophobic interaction and the dissolution rate of IND was also proposed.