Dissolution Of Solid Dispersions Research Articles

DEVELOPMENT AND EVALUATION OF ITRACONAZOLE SOLID DISPERSION GEL CUTANEOUS DELIVERY

Objective: The objective of this research is to enhance the permeation of low bioavailable drugs with suitable dosage forms by utilizing various permeation enhancers. Methods: Solid dispersions (SDs) were prepared by kneading, whereas physical mixtures (PM) were prepared by simple mixing with polymers PEG 6000 and PEG 20000 and evaluated for various physicochemical parameters. Optimized SDs were converted to gels using a variety of polymers and were evaluated for in vitro and ex vivo permeation studies. Results: It was found that the percentage of drugs in SDs and PMs was within the limit. The dissolution of SDs and PMs was found to be the highest with PEG-6000 (99.78% within 240 min) compared to PEG 20000. The maximum drug release (92.9% within 8 h) was achieved with oleic acid in both in vitro and ex vivo permeation studies, as evidenced by the in vitro and ex vivo permeation studies. The developed formulations showed no incompatibility between drugs and excipients, as demonstrated by drug and excipient interaction studies. Conclusion: The results that were observed confirmed that the itraconazole PEG-6000 gel developed has promising effects on desirable skin permeation.

Formulation and Evaluation of Azithromycin Dihydrate Solid Dispersion with Esther of Polyethylene Glycol-6000 and Stearic Acid Using A Co-Grinding Technique

Azithromycin is a narrow-spectrum bacterial growth inhibitory antibiotic derived from macrolides with low dissolution in water. Several methods have been carried out to increase the dissolution of medicinal substances, one of which is solid dispersion. Solid dispersions are mixtures consisting of one or more active substances in an inert carrier. The purpose of this study was to determine the effect of formatting solid dispersions with PEG 6000 polymer and stearic acid on increasing the dissolution rate of azithromycin. The method of formatting solid dispersions uses the co-grinding method. Solid dispersion of azithromycin was prepared in four formulas with variations in the amount of PEG 6000. Tests carried out on solid dispersion samples of azithromycin were XRD, FTIR, SEM, solubility tests, and dissolution tests. Test results on azithromycin solid dispersions prepared by co-grinding showed that there was an effect of the amount of PEG 6000 on decreasing the intensity of azithromycin crystals, there was no chemical interaction between azithromycin and the carrier, differences in the morphology of pure azithromycin powder and solid dispersions, and an increase in the dissolution of solid dispersions in medium SIF.

Preparation and Characterization of pH-Independent Sustained-Release Tablets Containing Hot Melt Extruded Solid Dispersions of Clarithromycin : Tablets Containing Solid Dispersions of Clarithromycin.

The limited solubility of clarithromycin (CAM), coupled with low bioavailability and rapid elimination, are major shortcomings, needed to be addressed to achieve optimum therapeutic goals. Therefore, sustained-release (SR) tablets containing solid dispersion (SD) granules of CAM were prepared in this study. Initially, SD granules of CAM were prepared by hot melt extrusion (HME) technique using Kollidon VA64 as a hydrophilic carrier. The saturation solubility of SD showed almost 4.5-fold increase as compared to pure CAM in pH 6.8 medium. In vitro drug dissolution data indicated a substantial increase in the dissolution of SD as compared to that of pure CAM. The thermal stability of drug, carrier, and SD at elevated HME temperatures was evident from the results of thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC). Powder X-ray diffraction (PXRD) data and scanning electron microscope (SEM) images revealed a decrease in the crystallinity and the uniform dispersion of drug, respectively. Moreover, Fourier transformed infrared spectroscopy (FT-IR) data confirmed the formation of hydrogen bond between the carbonyl group of drug and the hydroxyl group of carrier. SD loaded sustained-release (SD-SR) matrix tablets were prepared with hydrophobic polymers (Eudragit RS100 and Eudragit RL100). The pH-independent swelling and permeability of both polymers were responsible for the sustained drug release from SD-SR tablets. Pharmacokinetic (PK) studies suggested a 3.4-fold increase in the relative bioavailability of SD-SR tablets as compared to that of pure CAM.

The effect of some acrylic polymers on dissolution of celecoxib solid dispersion formulations

Objective The purpose of the present study was firstly to identify the effectiveness of Eudragit® polymers (Eudragit® RL, RS, L100-55, L100, S100 and E100) in inhibition of celecoxib precipitation from buffer solutions (pH = 6.8). Furthermore, the influence of Eudragit® polymers on non-sink dissolution behavior of celecoxib from solid dispersions was investigated. Methods Solid dispersions were prepared by the rotary evaporation method. In vitro dissolution studies, FT-IR and differential scanning calorimetry were employed to characterize the formulations. Results The results revealed that Eudragit® E100, L100 and S100 inhibited precipitation of celecoxib efficiently. It is understood that crystallization during the dissolution of solid dispersions could happen through crystallization from solid matrix following contact with the dissolution medium or from the supersaturated solution produced following dissolution. The supersaturated drug concentrations attained from the dissolution of Eudragit®-celecoxib solid dispersions were almost similar, suggesting that crystallization from solid matrix did not occur readily. However, only solid dispersions containing efficient crystallization inhibitor polymers were able to maintain the supersaturated solution up to the end of the dissolution run. Conclusion Results revealed that the principal mechanism of attaining supersaturated solution of celecoxib from solid dispersions was related to crystallization inhibition from solution not from solid matrix.

Influence of Polymers on the Physicochemical Properties of Benzonal in Solid Dispersions

The influence of solid dispersions (SDs) on some physicochemical properties of benzonal is studied. Investigated: benzonal and its SD with polyvinylpyrrolidone-10 000 (PVP), polyethylene glycol-1500 (PEG), β-cyclodextrin (CD). The preparation of SD by the solvent removal method increases the solubility and dissolution rate of benzonal in water. The solubility increases by 3.5–5.5 times; and the speed of dissolving, by 4.0–10.0 times. The complex of physical and chemical research methods suggests that the preparation of an SD with the studied polymers is accompanied by loss of crystallinity and formation of a solid solution of benzonal in the polymer, as well as solubilization and formation of colloidal solutions of benzonal during subsequent dissolution of SD in water. The results obtained can be used in the development of fast-dissolving benzonal tablets with increased release and bioavailability.

Mechanistic elucidation of formation of drug-rich amorphous nanodroplets by dissolution of the solid dispersion formulation

Drug-rich amorphous nanodroplets have great potential to improve intestinal absorption of poorly water-soluble drugs. Spray-dried samples (SPDs) of glibenclamide (GLB) with hypromellose (HPMC) or hypromellose acetate succinate (HPMC-AS, grade AS-LF and AS-HF) were prepared to investigate how GLB-rich amorphous nanodroplets form during the dissolution of solid dispersions. The co-spray drying of AS-LF significantly enhanced GLB dissolution from the SPD, leading to the temporary formation of GLB-rich amorphous nanodroplets. However, the droplets gradually coarsened as AS-LF fails to inhibit coarsening. In contrast, the addition of HPMC to the SPD failed to aid GLB-rich amorphous nanodroplet formation during dissolution. The failure of formation of GLB-rich amorphous nanodroplet was caused by slow GLB dissolution, due to the poor controllability of the GLB dissolution by HPMC. The addition of AS-HF to the SPD produced amorphous GLB particles that contained a large amount of AS-HF during dissolution. Gel-like particles formed instead of GLB-rich amorphous nanodroplets. When the SPD containing AS-LF was dissolved in AS-HF solution, stably-dispersed GLB-rich amorphous nanodroplets were successfully formed owing to rapid GLB dissolution from the SPD containing AS-LF and strong coarsening inhibition by AS-HF. Formulation optimization considering both aqueous dissolution of the solid dispersion and the inhibition of nanodroplet coarsening achieved stably-dispersed drug-rich amorphous nanodroplets.

Tri-block polymer with interfacial layer formation ability and its use in maintaining supersaturated drug solution after dissolution of solid dispersions

BackgroundMaintaining a supersaturated drug solution after the dissolution of the solid dispersions of water insoluble drugs continues to be a great challenge and is important to the oral bioavailability enhancement of hardly soluble drugs.MethodsNimodipine solid dispersions were prepared by hot-melt extrusion and a special tri-block polymer was employed as a co-carrier. The solid dispersions were characterized by modulated differential scanning calorimetry, transmission electron microscopy, hydrogen-nuclear magnetic resonance and so on.ResultsThe tri-block polymer was able to inhibit the formation of drug crystals after dissolution of the solid dispersions. Due to the unique interfacial layer formation ability of the tri-block polymer, a special drug loading micelle which encapsulated the compound and the hydrophobic fragments of the copolymers appeared in the release media. The tri-block polymer was composed of a hydrophilic part forming the shell of micelles, a hydrophobic part shaping the core of micelles, and a special intermediate hydrophilicity part constructing the interfacial layer of micelles.ConclusionThe tri-block polymer was not only able to stabilize the supersaturated drug solution of solid dispersions to enhance the oral bioavailability of hardly soluble drugs, but is also a potential candidate to construct micelles for systemic administration, due to the good compatibility and organic solvents free micelle formation procedure.

Development and characterization of nifedipine-amino methacrylate copolymer solid dispersion powders with various adsorbents

Solid dispersions of nifedipine (NDP), a poorly water-soluble drug, and amino methacrylate copolymer (AMCP) with aid of adsorbent, that is, fumed silica, talcum, calcium carbonate, titanium dioxide, and mesoporous silica from rice husks (SRH), were prepared by solvent method. The physicochemical properties of solid dispersions, compared to their physical mixtures, were determined using powder X-ray diffractometry (PXRD) and differential scanning calorimetry (DSC). The surface morphology of the prepared solid dispersions was examined by scanning electron microscopy (SEM). The dissolution of NDP from solid dispersions was compared to NDP powders. The effect of adsorbent type on NDP dissolution was also examined. The dissolution of NDP increased with the ratio of NDP:AMCP:adsorbent of 1:4:1 when compared to the other formulations. As indicated from PXRD patterns, DSC thermograms and SEM images, NDP was molecularly dispersed within polymer carrier or in an amorphous form, which confirmed the better dissolution of solid dispersions. Solid dispersions containing SRH provided the highest NDP dissolution, due to a porous nature of SRH, allowing dissolved drug to fill in the pores and consequently dissolve in the medium. The results suggested that solid dispersions containing adsorbents (SRH in particular) demonstrated improved dissolution of poorly water-soluble drug when compared to NDP powder.

Characterization of Solid Dispersion of Itraconazole Prepared by Solubilization in Concentrated Aqueous Solutions of Weak Organic Acids and Drying.

The purpose of this study was to develop an amorphous solid dispersion (SD) of an extremely water-insoluble and very weakly basic drug, itraconazole (ITZ), by interaction with weak organic acids and then drying that would enhance dissolution rate of drug and physical stability of formulation. Aqueous solubility of ITZ in concentrated solutions of weak organic acids, such as glutaric, tartaric, malic and citric acid, was determined. Solutions with high drug solubility were dried using vacuum oven and the resulting SDs having 2 to 20% drug load were characterized by differential scanning calorimetry (DSC), powder X-ray diffractometry (PXRD) and attenuated total reflectance-Fourier transform infrared (ATR-FTIR) spectroscopy. The dissolution of SDs was initially studied in 250mL of 0.1N HCl (pH1.1), and any undissolved solids were collected and analyzed by PXRD. The pH of the dissolution medium was then changed from 1.1 to 5.5, particle size of precipitates were measured, and drug concentrations in solution were determined by filtration through membrane filters of varying pore sizes. The aqueous solubility of ITZ was greatly enhanced in presence of weak acids. While the solubility of ITZ in water was ~4ng/ mL, it increased to 25-40mg per g of solution at 25°C and 200mg per g of solution at 65°C at a high acid concentration leading to extremely high solubilization. PXRD of SDs indicated that ITZ was present in the amorphous form, wherein the acid formed a partially crystalline matrix. ATR-FTIR results showed possible weak interactions, such as hydrogen bonding, between drug and acid but there was no salt formation. SDs formed highly supersaturated solutions at pH1.1 and had superior dissolution rate as compared to amorphous drug and physical mixtures of drug and acids. Following the change in pH from 1.1 to 5.5, ITZ precipitated as mostly nanoparticles, providing high surface area for relatively rapid redissolution. A method of highly solubilizing an extremely water-insoluble drug, ITZ, in aqueous media and converting it into an amorphous form in a physically stable SD was successfully investigated. The dissolution rate and the extent of supersaturation of the drug in dissolution media improved greatly, and any precipitate formed at high pH had very small particle size.

A comparison of the effect of temperature and moisture on the solid dispersions: Aging and crystallization

The purpose of this work was to compare the effect of temperature and relative humidity (RH) on the physical stability and dissolution of solid dispersions. Cinnarizine-Soluplus® solid dispersions (SDs) at three different drug loadings (10, 20 and 35wt%) were prepared by hot melt extrusion and exposed to stress conditions: high temperatures (40 and 60°C), high relative humidities (75% and 94% RH) and accelerated conditions (40°C/75% RH) for 30 days, or stored at 25°C for up to 5 months. Changes in solid state and dissolution of SDs were investigated by differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD) and dissolution testing. For samples under stress conditions, the results showed a reduced dissolution and a recrystallization of the drug with an increased crystallinity in the order of 40°C/75% RH, >60°C/0% RH, >25°C/94% RH, >40°C/0% RH, >25°C/75% RH. For samples stored at 25°C, nonlinear physical aging was observed and the dissolution also decreased although the SDs were still amorphous. The results indicated that temperature and humidity seemed to have comparable effects on the crystallization of cinnarizine-Soluplus® SDs. It is not reasonable to regard recrystallization as a sign of reduced dissolution, and glass transition temperature (Tg) may be a good indicator of the changes in dissolution.

Study on solubilization effect of solid dispersion technology and inclusion technology on Pulsatillae total saponins

To study the effect of solid dispersion technology and inclusion technology on dissolution performance of Pulsatillae total saponins, and preliminarily investigate its mechanism. The solid dispersion of Pulsatillae total saponins-PEG 4000 was prepared by the melting method. The inclusion compound of Pulsatillae total saponins-hydroxypropyl-beta-cyclodextrin ( HP-beta-CD) was prepared by the freeze-drying method. The properties of solid dispersion and inclusion compound were identified by using IR, DSC and NMR. And the dissolution of solid dispersion and inclusion compound were also determined by the small glass method. IR, DSC and NMR results showed the formation of solid dispersion and inclusion compound. In terms of the dissolution, the inclusion compound ranked first, which was followed by solid dispersion and bulk pharmaceutical chemicals. The inclusion technology could significantly increase the dissolution of Pulsatillae total saponins, whereas the solid dispersion showed no notable solubilization effect.

Characterization during storage and dissolution of solid dispersions containing furosemide and hydroxypropyl methylcellulose

Solid dispersions containing furosemide and various amounts of hydroxypropyl methylcellulose (HPMC) were prepared by spray drying to investigate if the physical stability of amorphous furosemide during storage and dissolution could be improved by formulating the drug as a solid dispersion. All solid dispersions, containing 20, 50, or 80 w/w % HPMC, were stable for 730 days when stored at 22 °C and 33 % relative humidity (RH), whereas under accelerated storage conditions of 40 °C and 75 % RH the amorphous furosemide in the solid dispersions with 20 and 50 % HPMC converted to a crystalline form within 30 days of storage. In contrast, furosemide in solid dispersions containing 80 % HPMC stayed amorphous for 30 days. Dissolution experiments in conjunction with XRPD and in-line Raman spectroscopy showed that the addition of 80 % HPMC was necessary for complete avoidance of solid state conversion of amorphous furosemide to a crystalline form during dissolution.

Dissolution and Precipitation Behavior of Amorphous Solid Dispersions

Amorphous solid dispersions (ASDs) are widely utilized in the pharmaceutical industry for bioavailability enhancement of low solubility drugs. The important factors governing the dissolution behavior of these systems are still far from adequately understood. As a consequence, it is of interest to investigate the behavior of these systems during the dissolution process. The purpose of this research was twofold. First, the degree of supersaturation generated upon dissolution as a function of drug-polymer composition was investigated. Second, an investigation was conducted to correlate physical behavior upon dissolution with polymer loading. Felodipine and indomethacin were selected as model drugs and hydroxypropylmethylcellulose (HPMC) and polyvinylpyrrolidone (PVP) were used to form the dispersions. Diffusion and nuclear magnetic resonance spectroscopy experiments revealed that the extent of bulk supersaturation generated on dissolution of the ASD did not depend on the drug-polymer ratio. Interestingly, the maximum supersaturation generated was similar to the predicted amorphous solubility advantage. However, dynamic light scattering measurements revealed that particles on the submicron scale were generated during dissolution of the solid dispersions containing 90% polymer, whereas solid dispersions at a 50% polymer loading did not yield these nanoparticles. The nanoparticles were found to result in anomalous concentration measurements when using in situ ultraviolet spectroscopy. The supersaturation generated upon dissolution of the solid dispersions was maintained for biologically relevant timeframes for the HPMC dispersions, whereas PVP appeared to be a less effective crystallization inhibitor.

Nanoparticle Formation and Growth During In Vitro Dissolution of Ketoconazole Solid Dispersion

The aim of this study is to examine the physical mechanisms during the dissolution of a solid dispersion, so as to provide further understanding behind the enhanced dissolution properties. X-ray amorphous solid dispersions of ketoconazole (KC), a poorly aqueous soluble drug, were prepared by melt extrusion with polyvinlypyrrolidone 17 (PVP 17) and PVP-vinyl acetate (PVP-VA64) copolymer. Prior to dissolution, Raman mapping showed a fully homogeneous spatial distribution of KC in polymer and possible drug dispersion at molecular level, whereas Fourier transform infrared spectroscopy revealed no drug-polymer chemical interaction. During in vitro dissolution test, a burst release followed by a gradual decline in dissolution could be explained by the release of KC in molecular form followed by formation of drug nanoparticles and their subsequent growth to micron size range as shown by dynamic light scattering analysis. Observations using transmission electron microscopy and cryogenic scanning electron microscopy provided support to the suggested mechanisms. The results suggested that the release of KC from the solid dispersions was carrier controlled initially, and PVP 17 PF is more efficient in inhibiting particle growth as compared with PVP-VA64. The particle growth inhibition during dissolution may be an important consideration to achieve the full benefits of dissolution enhancement of solid dispersions.

Preparation of celecoxib solid dispersions for dermal application: in vitro characterization and skin irritation test

The purpose of this work was to improve the dissolution and skin permeability characterestics of celecoxib. Solid dispersions (SDs) of celecoxib were prepared using PEG 4000, PVP K30 and HPβCD by the kneading method. The dispersions were characterized by, (DSC), (XRD) and in vitro drug dissolution. The solubility and dissolution of SDs were markedly increased as compared to plain drug. The kneaded dispersions showing high dissolution were incorporated in an o/w cream and evaluated for in vitro drug permeation through rabbit skin. The permeation rate of celecoxib were significantly increased in the case of SDs when compared to plain drug. The anti-inflammatory effect of celecoxib-PVP K30 cream was more effective in inhibiting rat paw edema when compared to celecoxib cream. Skin irritancy and histopathological investigation of rat skin revealed its safety thus confirming the advantage of improved pharmacological activity and safety of celecoxib when administered topically as solid dispersion with PVPK30.

Effect of drug-carrier interaction on the dissolution behavior of solid dispersion tablets

The objective of this study was to compare the dissolution behavior of tablets prepared from solid dispersions with and without drug-carrier interactions. Diazepam and nifedipine were used as model drugs. Two types of carriers were used; polyvinylpyrrolidone (PVP K12, K30 and K60) and saccharides (inulin 1.8 kDa, 4 kDa and 6.5 kDa). Solid dispersions with various drug loads were prepared by lyophilization. It was found that the drug solubility in aqueous PVP solutions was significantly increased indicating the presence of drug-carrier interaction while the drug solubility was not affected by the saccharides indicating absence of drug-carrier interaction. X-ray powder diffraction and modulated differential scanning calorimetry revealed that all solid dispersions were fully amorphous. Dissolution behavior of solid dispersion tablets based on either the PVPs or saccharides was governed by both dissolution of the carrier and drug load. It was shown that a fast drug dissolution of solid dispersions with a high drug load could be obtained with carrier that showed interaction with the drug.

Improved dissolution of oleanolic acid with ternary solid dispersions.

The purpose of this study was to enhance the dissolution of oleanolic acid by solid dispersions consisting of the drug, a polymeric carrier, and a surfactant. Binary solid dispersions consisting of oleanolic acid and polyvinylpyrrolidone were prepared for comparison. Polysorbate 80, a nonionic surfactant, was incorporated into binary solid dispersions as the third component to prepare ternary solid dispersions. Solid dispersions were characterized by differential scanning calorimetry, Fourier transform infrared spectroscopy, and dissolution tests. The crystallinization of OA was prohibited in solid dispersions. Both the binary and ternary solid dispersions enhanced the dissolution of OA. Moreover, the dissolution of ternary solid dispersion was faster compared with that of binary solid dispersion. Polysorbate 80 played an important positive role in dissolution of the solid dispersion.

A calorimetric investigation into the interaction between paracetamol and polyethlene glycol 4000 in physical mixes and solid dispersions

The solubility, heat of solution and dissolution rate of paracetamol and polyethyelene glycol 4000 (PEG 4000) systems have been studied in order to clarify the nature of the interaction between the two components during dissolution of solid dispersions. The logarithmic solubility of paracetamol demonstrated a non-linear increase with concentration of PEG 4000, while linear relationships between heat of solution in water and concentration were seen for both individual components. However, the heat of solution of paracetamol was found to decrease with increasing concentrations of PEG 4000. Similarly, the heats of solution in water of physical mixes and solid dispersions prepared using two manufacturing protocols were found to be lower than the theoretical values calculated from those corresponding to the individual components. Drug release studies showed a marked increase in paracetamol dissolution rate when prepared as a solid dispersion, with behaviour consistent with carrier controlled dissolution observed at low drug contents which was ascribed to enhanced dissolution of the drug into the diffusion layer of the PEG 4000. The implications of the understanding of this mechanism for the choice of carrier and manufacturing protocol for solid dispersion products is discussed.