Preparation of Budesonide-Poly (Ethylene Oxide) Solid Dispersions Using Supercritical Fluid Technology

The purpose of this study was to investigate the possibility of preparing solid dispersions of the poorly soluble budesonide by supercritical fluid (SCF) technique, using poly (ethylene oxide) (PEO) as a hydrophilic carrier. The budesonide-PEO solid dispersions were prepared, using supercritical carbon dioxide (SC CO₂) as the processing medium, and characterized by scanning electron microscopy (SEM), powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), solubility test and dissolution test in order to understand the influence of the SCF process on the physical status of the drug. The endothermic peak of budesonide in the SCF-treated mixtures was significantly reduced, indicating that budesonide was in amorphous form inside the carrier system. This was further confirmed by SEM and PXRD studies. The enhanced dissolution rates of budesonide were observed from SCF-treated budesonide-PEO mixtures. The amorphous characteristic of the budesonide, the better mixing of drug and PEO powders in the presence of SC CO₂, together with the improved wettability of the drug in PEO, produced a remarkable enhancement of the in vitro drug dissolution rate. Thus, budesonide-PEO solid dispersions with enhanced dissolution rate can be prepared using organic solvent-free SCF process.     

Dissolution rate enhancement,in vitro evaluation and investigation of drug release kinetics of chloramphenicol and sulphamethoxazole solid dispersions

Formulation of solid dispersions is one of the effective methods to increase the rate of solubilization and dissolution of poorly soluble drugs. Solid dispersions of chloramphenicol (CP) and sulphamethoxazole (SX) as model drugs were prepared by melt fusion method using polyethylene glycol 8000 (PEG 8000) as an inert carrier. The dissolution rate of CP and SX were rapid from solid dispersions with low drug and high polymer content. Characterization was performed using fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC) and scanning electron microscopy (SEM). FTIR analysis for the solid dispersions of CP and SX showed that there was no interaction between PEG 8000 and the drugs. Hyper-DSC studies revealed that CP and SX were converted into an amorphous form when formulated as solid dispersion in PEG 8000. Mathematical analysis of the release kinetics demonstrated that drug release from the various formulations followed different mechanisms. Permeability studies demonstrated that both CP and SX when formulated as solid dispersions showed enhanced permeability across Caco-2 cells and CP can be classified as well-absorbed compound when formulated as solid dispersions.     

Characterization and Dissolution Study of Oxodipine from Solid Binary Systems

Thennomicroscopy and differential scanning calorimetry were employed to characterize solid binary systems prepared with oxodipine and PEG 6000, 2-hydroxypropyl-β-cyclodextrin or mannitol. DSC curves did not allow to diferentiate physical mixtures from solid dispersions. Thennomicroscopy revealed the interactions that can be produced between drug and each carrier, due to heat contribution, when the physical mixtures were observed; also this thermal technique permited us to ascertain the composition of particles that constitute the solid dispersions. Dissolution studies showed that the amelioration obtained in oxodipine dissolution from physical mixtures was due to the dessagregant action of the carriers, which obtained an increase of the drug surface in contact with the dissolution medium. The proportions and carrier nature influence the oxodipine dissolution, fundamentally from solid dispersions, where the interaction drug/carrier is stronger than in physical mixtures.     

Characteristics of bicalutamide solid dispersions and improvement of the dissolution

The purpose of our study was to formulate and evaluate bicalutamide (BL) solid dispersions (SD). The physicochemical properties were evaluated by differential scanning calorimetry (DSC), Fourier-Transform infrared (FT-IR) spectroscopy, Powder X-ray diffractometry (PXRD), dissolution studies, and stability studies. The dissolution studies demonstrated that the dissolution of BL from BL-SD increased with an increase in carrier content (PVP K30). X-ray assays and DSC results both confirmed the amorphous state of BL in BL-SD. Stability studies conducted after 6 months showed that BL exhibited excellent stability in the solid dispersion of PVP K30 (1:5).     

Characteristics of Bicalutamide Solid Dispersions and Improvement of the Dissolution

ABSTRACT

The purpose of our study was to formulate and evaluate bicalutamide (BL) solid dispersions (SD). The physicochemical properties were evaluated by differential scanning calorimetry (DSC), Fourier-Transform infrared (FT-IR) spectroscopy, Powder X-ray diffractometry (PXRD), dissolution studies, and stability studies. The dissolution studies demonstrated that the dissolution of BL from BL-SD increased with an increase in carrier content (PVP K30). X-ray assays and DSC results both confirmed the amorphous state of BL in BL-SD. Stability studies conducted after 6 months showed that BL exhibited excellent stability in the solid dispersion of PVP K30 (1:5).     

Investigating the effect of moisture protection on solid-state stability and dissolution of fenofibrate and ketoconazole solid dispersions using PXRD,HSDSC and Raman microscopy

Enhanced dissolution of poorly soluble active pharmaceutical ingredients (APIs) in amorphous solid dispersions often diminishes during storage due to moisture-induced re-crystallization. This study aims to investigate the influence of moisture protection on solid-state stability and dissolution profiles of melt-extruded fenofibrate (FF) and ketoconazole (KC) solid dispersions. Samples were kept in open, closed and Activ-vials^® to control the moisture uptake under accelerated conditions. During 13-week storage, changes in API crystallinity were quantified using powder X-ray diffraction (PXRD) (Rietveld analysis) and high sensitivity differential scanning calorimetry (HSDSC) and compared with any change in dissolution profiles. Trace crystallinity was observed by Raman microscopy, which otherwise was undetected by PXRD and HSDSC. Results showed that while moisture protection was ineffective in preventing the re-crystallization of amorphous FF, KC remained X-ray amorphous despite 5% moisture uptake. Regardless of the degree of crystallinity increase in FF, the enhanced dissolution properties were similarly diminished. Moisture uptake above 10% in KC samples also led to re-crystallization and significant decrease in dissolution rates. In conclusion, eliminating moisture sorption may not be sufficient in ensuring the stability of solid dispersions. Analytical quantification of API crystallinity is crucial in detecting subtle increase in crystallinity that can diminish the enhanced dissolution properties of solid dispersions.     

Itraconazole formation using supercritical carbon dioxide

A new method of preparing Itraconazole (C₃₅H₃₈Cl₂N₈O₄), a synthetic triazole antifungal agent, was developed using supercritical carbon dioxide (SC CO₂) while eliminating the use of toxic solvents. Dissolution amounts of the product were measured in gastric fluid and compared to those of conventional drug formulations. Different operating conditions (five levels of treatment temperature ranging between 110-140°C, four levels of treatment pressure ranging between 30-400 atm, and four different treatment times ranging from 10-60 minutes) were tested in order to produce a desired Itraconazole product, which does not degrade during the product formation and has the highest extent of dissolution in gastric fluid after one hour. Itraconazole dissolution of 100% at one-hour was achieved for the drug produced at the optimum treatment condition: 135°C, 300 atm, and 30 minutes. Extent of dissolution obtained from this solvent and detergent-free process is 10% higher than that of the conventional method involving toxic organic solvents. Itraconazole produced using SC CO₂ should provide minimal side effects in human body.     

Investigating the effect of moisture protection on solid-state stability and dissolution of fenofibrate and ketoconazole solid dispersions using PXRD, HSDSC and Raman microscopy

Enhanced dissolution of poorly soluble active pharmaceutical ingredients (APIs) in amorphous solid dispersions often diminishes during storage due to moisture-induced re-crystallization. This study aims to investigate the influence of moisture protection on solid-state stability and dissolution profiles of melt-extruded fenofibrate (FF) and ketoconazole (KC) solid dispersions. Samples were kept in open, closed and Activ-vials(?) to control the moisture uptake under accelerated conditions. During 13-week storage, changes in API crystallinity were quantified using powder X-ray diffraction (PXRD) (Rietveld analysis) and high sensitivity differential scanning calorimetry (HSDSC) and compared with any change in dissolution profiles. Trace crystallinity was observed by Raman microscopy, which otherwise was undetected by PXRD and HSDSC. Results showed that while moisture protection was ineffective in preventing the re-crystallization of amorphous FF, KC remained X-ray amorphous despite 5% moisture uptake. Regardless of the degree of crystallinity increase in FF, the enhanced dissolution properties were similarly diminished. Moisture uptake above 10% in KC samples also led to re-crystallization and significant decrease in dissolution rates. In conclusion, eliminating moisture sorption may not be sufficient in ensuring the stability of solid dispersions. Analytical quantification of API crystallinity is crucial in detecting subtle increase in crystallinity that can diminish the enhanced dissolution properties of solid dispersions.     

Dissolution Rate Study of Fresh and Aging Triamterene-Urea Solid Dispersions

Triamterene-urea solid dispersions of varying weight fractions were elaborated by the melting carrier method and their dissolution profiles compared with the pure drug and physical mixtures. The dissolution rates of triamterene from solid dispersions were faster than the pure drug and physical mixtures.

Solubility studies revealed a linear increase in the solubility of the triamterene with the increase of urea concentration.

The intrinsic dissolution rates, determined by the rotating disc method, showed linear dissolution profiles in spite of that the scanning electron microscopy examination revealed that the surfaces do not maintain constant during the dissolution process.

Aging of the different preparations for one year at room temperature does not induced significant changes in their dissolution profiles.     

Dissolution Rate Study of Fresh and Aging Triamterene-Urea Solid Dispersions

Triamterene-urea solid dispersions of varying weight fractions were elaborated by the melting carrier method and their dissolution profiles compared with the pure drug and physical mixtures. The dissolution rates of triamterene from solid dispersions were faster than the pure drug and physical mixtures.

Solubility studies revealed a linear increase in the solubility of the triamterene with the increase of urea concentration.

The intrinsic dissolution rates, determined by the rotating disc method, showed linear dissolution profiles in spite of that the scanning electron microscopy examination revealed that the surfaces do not maintain constant during the dissolution process.

Aging of the different preparations for one year at room temperature does not induced significant changes in their dissolution profiles.     

Preparation and physicochemical evaluation of a new tacrolimus tablet formulation for sublingual administration

The aim of this study was to develop a new fast-disintegrating tablet formulation containing 1?mg tacrolimus for sublingual application. First, solid dispersions containing tacrolimus (2.5%, 5% and 10% w/w) incorporated in Ac-Di-Sol(?) and carriers (inulin 1.8?kDa and 4?kDa, and polyvinylpyrrolidone (PVP) K30) were prepared by freeze drying. Subsequently, a tablet formulation composed of a mixture of the solid dispersions, Ac-Di-Sol(?), mannitol, Avicel(?) PH-101 and sodium stearyl fumarate was optimized concerning drug load in the solid dispersions and the type of carrier. Tablet weight was kept constant at 75?mg by adjusting the amount of Avicel(?) PH-101. Differential scanning calorimetry (DSC) and X-ray powder diffraction (XRPD) results indicated the absence of the drug in the crystalline state, which was confirmed by the scanning electron microscopy (SEM). These results suggest that tacrolimus incorporated in all of the solid dispersions was fully amorphous. Dissolution of the tablets containing solid dispersions with a low drug load highly depends on the type of carrier and increased in the order: PVP K30 < inulin 4?kDa < inulin 1.8?kDa. Solid dispersions with a drug load of 10% w/w incorporated in the carriers yielded optimal formulations. In addition, the physicochemical characteristics and the dissolution behavior of the tablet formulation containing inulin 1.8 kDa-based solid dispersions with a drug load of 10% w/w did not change after storage at 20°C/45%RH for 6 months indicating excellent storage stability.     

Preparation and characterization of spironolactone-loaded gelucire microparticles using spray-drying technique

The basic objectives of this study were to prepare and characterize solid dispersions of poorly soluble drug spironolactone (SP) using gelucire carriers by spray-drying technique. The properties of the microparticles produced were studied by differential scanning calorimetry (DSC), scanning electron microscopy, saturation solubility, encapsulation efficiency, and dissolution studies. The absence of SP peaks in DSC profiles of microparticles suggests the transformation of crystalline SP into an amorphous form. The in vitro dissolution test showed a significant increase in the dissolution rate of microparticles as compared with pure SP and physical mixtures (PMs) of drug with gelucire carriers. Therefore, the dissolution rate of poorly water-soluble drug SP can be significantly enhanced by the preparation of solid dispersion using spray-drying technique.     

Enhancement of the dissolution and permeation rates of meloxicam by formation of its freeze-dried solid dispersions in polyvinylpyrrolidone K-30

Freeze-drying (FD) and solvent evaporation (SE) were used to prepare solid dispersions (SDs) of meloxicam (MX) in polyvinylpyrrolidone K-30 (PVP). The SDs were prepared at different ratios, namely 1:1, 1:3, and 1:5 MX:PVP weight ratio. Differential scanning calorimetry (DSC), infrared absorption spectroscopy (IR), and x-ray powder diffractometry (XPD) were utilized to characterize the physicochemical properties of the SDs. Meloxicam (MX) in the solid dispersions appeared with less crystallinity form and was present in a complete amorphous form at higher PVP ratio. Dissolution rates of MX as a pure drug, physical mixtures (PMs), and SDs indicated a marked increase of the dissolution rate of MX in presence of PVP. The increase in the dissolution rate was dependent on the ratio of PVP and the method of preparation. In addition, the permeability of the drug through standard cellophane membrane and hairless mouse skin was also evaluated. The permeation rate of MX was significantly increased in the case of SDs and was dependent on the ratio of PVP. The results were primarily due to increase wettability, the solubilization of the drug by the carrier, and formation of MX amorphous form.     

In-vitro and in-vivo study of amorphous spironolactone prepared by adsorption method using supercritical CO2

Objective: The aim of this study was to improve the oral bioavailability of spironolactone (SP).

Method: SP was adsorbed on the fumed silica using supercritical CO₂ (scCO₂) technology and further compressed into tablets. The morphology was observed by scanning electron microscopy (SEM), and the crystalline form was investigated by differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD). The dissolution test was performed in water, 0.1?M HCl solution, pH 4.5 acetate buffers and pH 6.8 phosphate buffers using the paddle method. The pharmacokinetics was undertaken in six dogs in a crossover fashion.

Results: SP was successfully prepared into tablets and presented in amorphous state. SP-silica scCO₂ tablets displayed higher dissolution profiles than SP-silica physical mixtures tablets in different media. The AUC_0–t and C_max of SP-silica supercritical CO₂ was 1.61- and 1.52-fold greater than those of SP-silica physical mixtures (p?Conclusion: It is a promising method in improving dissolution and bioavailability by adsorbing SP, a poorly soluble drug, on the fumed silica using rapid expansion of supercritical solutions.     

Supercritical Antisolvent Versus Coevaporation— Preparation and Characterization of Solid Dispersions

The objective of this work was to improve the dissolution rate and aqueous solubility of oxeglitazar. Solid dispersions of oxeglitazar in PVP K17 (polyvinilpyrrolidone) and poloxamer 407 (polyoxyethylene-polyoxypropylene block copolymer) were prepared by supercritical antisolvent (SAS) and coevaporation (CoE) methods. Drug-carrier formulations were characterized by powder X-ray diffraction, Fourier transform infrared spectroscopy, scanning electron microscopy, gas chromatography, UV/VIS spectroscopy and in vitro dissolution tests. The highest dissolution rate (nearly 3-fold higher than raw drug) was achieved by preparation of drug/PVP K17 coevaporate. Oxeglitazar/PVP K17 solid dispersions were stabilized by hydrogen bonding but contained higher amount of residual dichloromethane (DCM) than poloxamer 407 formulations regardless of the method of preparation. SAS prepared oxeglitazar/poloxamer 407 dissolved more than two times faster than raw drug. However, unlike PVP K17, poloxamer 407 did not form a single phase amorphous solid solution with oxeglitazar which has been manifested in higher degrees of crystallinity, too. Among the two techniques, evaluated in this work, conventional coevaporation resulted in higher amorphous content but SAS reduced residual solvent content more efficiently.     

Enhancement of the Dissolution and Permeation Rates of Meloxicam by Formation of Its Freeze-dried Solid Dispersions in Polyvinylpyrrolidone K-30

ABSTRACT

Freeze-drying (FD) and solvent evaporation (SE) were used to prepare solid dispersions (SDs) of meloxicam (MX) in polyvinylpyrrolidone K-30 (PVP). The SDs were prepared at different ratios, namely 1:1, 1:3, and 1:5 MX:PVP weight ratio. Differential scanning calorimetry (DSC), infrared absorption spectroscopy (IR), and x-ray powder diffractometry (XPD) were utilized to characterize the physicochemical properties of the SDs. Meloxicam (MX) in the solid dispersions appeared with less crystallinity form and was present in a complete amorphous form at higher PVP ratio. Dissolution rates of MX as a pure drug, physical mixtures (PMs), and SDs indicated a marked increase of the dissolution rate of MX in presence of PVP. The increase in the dissolution rate was dependent on the ratio of PVP and the method of preparation. In addition, the permeability of the drug through standard cellophane membrane and hairless mouse skin was also evaluated. The permeation rate of MX was significantly increased in the case of SDs and was dependent on the ratio of PVP. The results were primarily due to increase wettability, the solubilization of the drug by the carrier, and formation of MX amorphous form.     

Supercritical antisolvent versus coevaporation: preparation and characterization of solid dispersions

The objective of this work was to improve the dissolution rate and aqueous solubility of oxeglitazar. Solid dispersions of oxeglitazar in PVP K17 (polyvinilpyrrolidone) and poloxamer 407 (polyoxyethylene-polyoxypropylene block copolymer) were prepared by supercritical antisolvent (SAS) and coevaporation (CoE) methods. Drug-carrier formulations were characterized by powder X-ray diffraction, Fourier transform infrared spectroscopy, scanning electron microscopy, gas chromatography, UV/VIS spectroscopy and in vitro dissolution tests. The highest dissolution rate (nearly 3-fold higher than raw drug) was achieved by preparation of drug/PVP K17 coevaporate. Oxeglitazar/PVP K17 solid dispersions were stabilized by hydrogen bonding but contained higher amount of residual dichloromethane (DCM) than poloxamer 407 formulations regardless of the method of preparation. SAS prepared oxeglitazar/poloxamer 407 dissolved more than two times faster than raw drug. However, unlike PVP K17, poloxamer 407 did not form a single phase amorphous solid solution with oxeglitazar which has been manifested in higher degrees of crystallinity, too. Among the two techniques, evaluated in this work, conventional coevaporation resulted in higher amorphous content but SAS reduced residual solvent content more efficiently.     

Drug–polymer miscibility,interactions, and precipitation inhibition studies for the development of amorphous solid dispersions for the poorly soluble anticancer drug flutamide

The major goal of this research was to successfully formulate solid dispersion (SD) of the poorly soluble anticancer drug flutamide (FLT) using various hydrophilic polymers. Furthermore, to get more insight into SD, solid-state studies (miscibility and molecular interaction) were correlated with solution study (precipitation inhibition, dissolution). Hydrophilic polymers like PVP K90, HPMC, Eudragit EPO, and PEG 8000 were used at different drug-to-polymer w/w ratios. Solid-state miscibility studies were carried out using modulated differential scanning calorimetry (MDSC). SDs were prepared using solvent-evaporation technique and characterized by powder X-ray diffraction (PXRD) and MDSC. Infrared, Raman spectroscopy and molecular modeling were used to investigate drug-polymer interactions in the dispersions. Precipitation inhibition studies were carried out at various FLT-hydrophilic polymer ratios. Precipitation inhibition studies showed that PEG 8000 has the highest efficiency, followed by PVP K90, while HPMC and EPO showed no effect on precipitation inhibition. In the solid-state, MDSC of the physical mixture (PM) suggested that FLT is miscible to a greater extent with EPO and PEG 8000. Characterization of the amorphous dispersions using MDSC and PXRD concluded that FLT transformed from crystalline to amorphous form in the presence of PVP K90 and PEG 8000. Spectroscopic results confirmed stronger interaction of FLT with PVP K90 and PEG 8000, thereby confirming the in-solution precipitation and molecular modeling binding energy results. Amorphous dispersions formulated with PVP and PEG were stable and showed higher dissolution, an important property necessary to improve the physicochemical properties and drug delivery of poorly soluble anticancer drug FLT.     

Characterization of poly(ethylene oxide) as a drug carrier in hot-melt extrusion

Poly(ethylene oxide) (PEO) as a drug carrier in hot-melt extrusion was studied by using a model drug, nifedipine, in a twin-screw extruder. Binary mixtures of PEO and nifedipine have been shown to be amenable to hot-melting at a temperature as low as 70°C, well below nifedipine's melting point (172°C). Hot-stage microscopy provided visual evidence that nifedipine can form a miscible dispersion with PEO at 120°C. Complete loss of nifedipine crystallinity when extrudated at and above 120°C with a drug loading of 20% (w/w) was further confirmed by differential scanning calorimetry (DSC) and X-ray diffraction. Cross-sectional imaging of the extrudates using scanning electron microscopy indicated homogeneous drug distribution inside PEO when the processing temperature was above 120°C. Raman spectroscopy confirmed drug-PEO interactions at a molecular level. Cryo-milled extrudates showed significant improvement in dissolution rate compared to either pure nifedipine or the physical mixture of PEO and nifedipine. A state of supersaturation was achieved after 10-minute release in pH 6.8 phosphate buffer. Finally, stability study demonstrated that the solid dispersion system is chemically stable for at least 3 months under the conditions of both 25°C/60% RH and 40°C/75% RH. Overall, PEO appears to be a promising aid/carrier to solublize poorly soluble drugs through the formation of solid dispersion via hot-melt extrusion, thereby improving dissolution and absorption.     

Characterization of Poly(Ethylene Oxide) as a Drug Carrier in Hot-Melt Extrusion

ABSTRACT

Poly(ethylene oxide) (PEO) as a drug carrier in hot-melt extrusion was studied by using a model drug, nifedipine, in a twin-screw extruder. Binary mixtures of PEO and nifedipine have been shown to be amenable to hot-melting at a temperature as low as 70°C, well below nifedipine's melting point (172°C). Hot-stage microscopy provided visual evidence that nifedipine can form a miscible dispersion with PEO at 120°C. Complete loss of nifedipine crystallinity when extrudated at and above 120°C with a drug loading of 20% (w/w) was further confirmed by differential scanning calorimetry (DSC) and X-ray diffraction. Cross-sectional imaging of the extrudates using scanning electron microscopy indicated homogeneous drug distribution inside PEO when the processing temperature was above 120°C. Raman spectroscopy confirmed drug-PEO interactions at a molecular level. Cryo-milled extrudates showed significant improvement in dissolution rate compared to either pure nifedipine or the physical mixture of PEO and nifedipine. A state of supersaturation was achieved after 10-minute release in pH 6.8 phosphate buffer. Finally, stability study demonstrated that the solid dispersion system is chemically stable for at least 3 months under the conditions of both 25°C/60% RH and 40°C/75% RH. Overall, PEO appears to be a promising aid/carrier to solublize poorly soluble drugs through the formation of solid dispersion via hot-melt extrusion, thereby improving dissolution and absorption.