Enhancement of dissolution rate of valdecoxib by solid dispersions technique with PVP K 30 & PEG 4000: preparation and in vitro evaluation

Solid dispersions of valdecoxib were prepared with the objective of dissolution enhancement by melt granulation technique using polyvinyl pyrollidone (PVP K 30) and polyethylene glycol (PEG 4000) alone (1:1) and in combination (1:0.5:0.5). Phase solubility studies showed a linear increase in valdecoxib solubility with increase in polymer concentration in both the cases. The FTIR spectroscopic studies showed the stability of valdecoxib and absence of well defined valdecoxib—PVP K 30–PEG 4000 interaction. Powder X-ray diffraction (XRD) and differential scanning calorimeter (DSC) were used to characterize the solid state of the dispersion, indicated a complete transformation of drug from crystalline to amorphous form. In vitro dissolution studies performed in 0.1 N HCl showed a significant enhance in dissolution rate when PEG 4000 and PVP K 30 were used in combination. Improved drug dissolution by both the carriers may be attributed to the improved wettability, reduction in drug crystallinity and solubilizing effects from solid dispersions of valdecoxib. Accelerated stability studies of solid dispersion with PVP K 30 and PEG 4000 does not show any significant change in the drug content and dissolution profile in 6 months study period. This study concluded that the dissolution rate of valdecoxib can be modulated by appropriate levels of hydrophilic carriers.     

Thermal analysis study of flavonoid solid dispersions having enhanced solubility

Purposes of this paper were to prepare and study new drug delivery systems for both flavanone glycosides and their aglycones based on solid-dispersion systems. These compounds are poor water soluble drugs, so an enhancement of their dissolution is a high priority. Solid-dispersion systems were prepared using PVP, PEG and mannitol as drug carrier matrices. Characterizations of these dispersions were done by differential scanning calorimeter (DSC) and X-ray diffraction (XRD). The glass transition (T_g) temperature of PVP was only recorded in the DSC thermograms of PVP solid-dispersions of both flavanone glycosides and their aglycones, while in case of PEG and mannitol solid-dispersions endotherms of both glycosides and aglycones were noticed with low peak intensity, indicating that high percent of drug is in amorphous state. The XRD patterns of all PVP solid-dispersions of aglycones show typical amorphous materials, but XRD patterns of their glycosides reveal the presence of crystalline material. However, in all solid dispersions shifts in T_g of PVP as well as T_m of PEG were observed, indicating the existence of some interactions between drugs and matrices. SEM and TEM microscopy revealed that PVP/aglycone flavanone compounds are nanodispersed systems while all the other solid dispersions are microcrystalline dispersions. The solubility of both flavanone glycosides and their aglycones was directly affected by the new physical state of solid dispersions. Due to the amorphous drug state or nano-dispersions in PVP matrices, the solubility was enhanced and found to be 100% at pH 6.8 in the nano-dispersion containing 20 mass% of aglycones. Also solubility enhancement was occurred in solid dispersions of PEG and mannitol, but it was lower than that of PVP nano-dispersions due to the presence of the drug compounds in crystalline state in both matrices.     

Physicochemical characterization of finasteride:PEG 6000 and finasteride:Kollidon K25 solid dispersions, and finasteride: ��-cyclodextrin inclusion complexes

Finasteride is a practically insoluble in water drug that belongs to the Class II of the BCS (poor solubility and high permeability). Solid dispersions are solid products consisting of at least two different components, generally a hydrophilic matrix and a hydrophobic drug. Solid dispersions are a successful strategy to improve drug release of poorly water-soluble drugs such as finasteride. Natural cyclodextrins are doughnut-shaped molecules with an internal hydrophobic cavity and a hydrophilic external surface. The lipophilic cavity enables cyclodextrins to form non-covalent inclusion complexes with a wide variety of poorly water-soluble drugs such as finasteride. The aim of this study was to investigate the formation of finasteride:PEG 6000 and finasteride:Kollidon K25 solid dispersions and finasteride:??-cyclodextrin inclusion complexes by solvent evaporation method using a mixture of water:ethanol (1:1). The formation of finasteride:PEG 6000 and finasteride:Kollidon K25 solid dispersions and finasteride:??-cyclodextrin inclusion complexes was investigated and characterized by differential scanning calorimetry (DSC), infrared (IR) spectroscopy, and dissolution studies from capsules containing a quantity equivalent to 5 mg of finasteride. The DSC thermograms revealed the transformation of finasteride into the amorphous state in solid dispersions with PEG 6000 and Kollidon K25, and in inclusion complexes with ??-cyclodextrin. The IR spectra demonstrated molecular interaction in solid dispersions of finasteride with PEG 6000, and in inclusion complexes with ??-cyclodextrin. Dissolution rate of solid dispersions and inclusion complexes was significantly greater than that of corresponding physical mixtures and pure drug, indicating that the formation of solid dispersions and inclusion complexes increased the solubility of the poorly soluble drug, finasteride.     

Solubility, dissolution rate and bioavailability enhancement of irbesartan by solid dispersion technique

The objective of present work was to enhance the solubility and bioavailability of poorly aqueous soluble drug Irbesartan (IBS). The solid dispersions were prepared by spray drying method using low viscosity grade HPMC E5LV. Prepared solid dispersions were characterized by dissolution study, fourier transform infrared spectroscopy (FT-IR), scanning electron microscopy (SEM), differential scanning calorimetry (DSC) and X-ray diffraction studies (XRD). Results of the SEM, DSC and XRD study showed the conversion of crystalline form of IBS to amorphous form. The dissolution rate was remarkably increased in case of solid dispersion compared to pure IBS. Solubility and stability of solid dispersion was increased due to surfactant and wetting property, slowing devitrification and having anti-plasticization effect of HPMC E5LV. In vivo studies were performed in healthy rabbits (New Zealand grey) and compared with plain IBS. Solid dispersions showed increase in relative bioavailability than the plain IBS suspension. In conclusion, the prepared solid dispersions showed remarkable increase in solubility, dissolution rate and hence bioavailability of poorly water soluble drug Irbesartan.     

Nimesulide/cyclodextrin/PEG 6000 ternary complexes: physico-chemical characterization, dissolution studies and bioavailability in rats

Purpose Ternary solid dispersions were prepared in order to estimate the effect of a double hydrophilization by cyclodextrins and PEG 6000 on nimesulide apparent characteristics. Ternary solid dispersions of nimesulide, cyclodextrins and PEG 6000 were characterized using DSC, FT-IR, dissolution studies and evaluating the bioavailability in rats. Methods Ternary solid dispersions were prepared either using native powders or using a preformed inclusion complex of nimesulide and cyclodextrin. Inclusion complexes and pure drug were used as references. Circulating nimesulide was measured out in rat plasma after orally administration of our different products (ternary solid dispersions, inclusion complexes and pure drug). Results An improvement of the nimesulide dissolution rate was obtained with inclusion complexes and ternary solid dispersion. In rat plasma, inclusion complexes and ternary solid dispersion improved T _max. Conclusions A second hydrophilization of inclusion complexes by PEG 6000 does not allow to achieve better results concerning nimesulide concentration in rat plasma or in dissolution studies than with inclusion complexes alone.     

Enhancement of solubility, dissolution and bioavailability of ibuprofen in solid dispersion systems

To improve its solubility, dissolution, and bioavailability; Ibuprofen-polyethylene glycol 8000 (PEG 8000) solid dispersions (SDs) with different drug loadings were prepared, characterized by scanning electron microscopy (SEM) and differential scanning calorimetry (DSC), and evaluated for solubility, in-vitro release, and oral bioavailability of ibuprofen in rats. Loss of individual surface properties during melting and solidification as revealed by SEM micrographs indicated the formation of effective SDs. Absence or shifting towards the lower melting temperature of the drug peak in SDs and physical mixtures in DSC study indicated the possibilities of drug-polymer interactions. Quicker release of ibuprofen from SDs in rat intestine resulted in a significant increase in AUC and C(max), and a significant decrease in T(max) over pure ibuprofen. Preliminary results of this study suggested that the preparation of ibuprofen SDs using PEG 8000 as a meltable hydrophilic polymer carrier could be a promising approach to improve solubility, dissolution and bioavailability of ibuprofen.     

Formulation of a Poorly Water-Soluble Drug Sirolimus in Solid Dispersions to Improve Dissolution

An attempt has been made to enhance solubility and dissolution of sirolimus by solid dispersion and complexation technique using various hydrophilic excipients. Sirolimus an immunosuppressant agent has low bioavailability due to its low aqueous solubility. Solid dispersion of sirolimus in PEG-6000, Poloxamer-188, and Mannitol were prepared by fusion and solvent evaporation method. Beta-CD complexation of sirolimus was prepared by kneading method. In vitro dissolution studies were carried out in 0.4% SLS in water, which showed that the solid dispersion containing PEG 6000 (1:1), which was prepared by solvent evaporation method, showed faster dissolution rate than the other formulations and β-cyclodextrin complex. Solid dispersions containing PEG 6000 was further investigated by x-ray powder diffraction, differential scanning calorimetry (DSC), and FTIR. X-ray powder diffraction and DSC patterns suggested that the drug state changed from crystalline to amorphous form in the formulation.     

Preparation of solid dispersion for ethenzamide-carbopol and theophylline-carbopol systems using a twin screw extruder

In the present study, we prepared solid dispersions of water-insoluble and soluble drugs (ethenzamide (ETZ) and theophylline (THEO)) by the twin screw extruder method, which made it possible to control both kneading and heating at the same time under the fusion point of each drug, using three types of the controlled-release high-molecular-weight substance Carbopol (CAR) as the carrier. The solid dispersions obtained were evaluated and compared with those prepared by the organic solvent method. These products showed significantly increased solubility of ETZ, but the solubility of THEO was reduced indicating that CAR slows the release of THEO. It is important not only to simply knead under high pressure but to select the optimal operation temperature to bring these drugs into a semi-fusion state. Solid dispersions obtained by this method showed X-ray diffraction and differential scanning calorimetry (DSC) patterns similar to those obtained by the organic solvent method indicating that the former can be used as a simple and effective method for preparation of solid dispersions.     

Improvement of the dissolution rate of silymarin by means of solid dispersions

Solid dispersions of silymarin were prepared by the fusion method with the intention of improving the dissolution properties of silymarin. Polyethylene glycol 6000 (PEG 6000) was used as the inert hydrophilic matrix. The dissolution studies of the solid dispersions were performed in vitro. And the results obtained showed that the dissolution rate of silymarin was considerably improved when formulated in solid dispersions with PEG 6000 as compared to original drug, and the increased dissolution rate might be favorable for further oral absorption.     

Preparation, characterization and in vivo evaluation of antihyperglycemic activity of microwave generated repaglinide solid dispersion

The influence of microwave technology on the in vitro dissolution rate and in vivo antihyperglycemic activity of a poorly water soluble drug, repaglinide (RG) was studied. Solid dispersions were prepared by conventional fusion method and microwave method using poloxamer 188. The dispersions were characterized by solubility study, dissolution study, Fourier transform infrared spectroscopy (FT-IR), differential scanning calorimetry (DSC), X-ray powder diffraction (XRD) and scanning electron microscopy (SEM). Microwave generated solid dispersions exhibited remarkable improvement in solubility and dissolution rate compared to that of pure RG. Results of DSC, XRD and SEM study showed conversion of crystalline form of RG to amorphous form. In vivo studies revealed that the microwave generated solid dispersion showed significant improvements in antihyperglycemic activity as compared to RG alone, thus confirming the advantage of improved pharmacological activity of RG by microwave method. In conclusion, microwave method could be considered as simple, efficient and solvent free promising alternative method to prepare solid dispersion of poorly water soluble drug RG with significant enhancement in solubility, dissolution rate and antihyperglycemic activity.     

Thermal,spectroscopic, and dissolution studies of ketoconazole–Pluronic F127 system

One strategy for improving the dissolution of poorly water soluble drugs is to prepare solid dispersions such as binary mixtures with hydrophilic carriers. These mixtures are generally characterized by better solubility than those of the individual components from which they are formed. In the present study, solid dispersions of ketoconazole (KET) with Pluronic F127 (PLU) were prepared by the grinding method. Solid–liquid equilibria in the system being studied were investigated by differential scanning calorimetry. A phase diagram for the whole range of compositions was constructed. The investigation revealed that ketoconazole and Pluronic F127 form a simple eutectic system containing 4.4 % w/w of ketoconazole at the eutectic point. The results of Fourier transform infrared spectroscopy and X-ray powder diffractometry studies of obtained mixtures suggest that there is no drug-carrier interaction and both components are crystalline in the solid dispersion with the whole range of composition. The prepared mixtures show an appreciable improvement of the dissolution rate of KET in 0.5 % w/v sodium lauryl sulfate. The improvement of the dissolution rate of drug is additionally increased by effective solubilization.     

Effects of compositions on the stability of polyols-in-oil-in-water (P/O/W) multiple emulsions

Polyols-in-oil-in-water (P/O/W) multiple emulsions were successfully prepared by using polyols as inner aqueous phase to avoid instabilities caused by water. The influence of polyols, oils and emulsifiers on the morphology and stability of P/O/W multiple emulsions were studied and the stability mechanisms of this new kind of multiple emulsions were also explored. Glycerol that has the worst solubility in oil phase contributed to the formation of stable inner droplets which agree with the Ostwald Ripening theory. Mineral oil worked well with the system proving that oils possessing similar solubility parameters with the hydrophobic group of emulsifiers benefited for system stability. Several typical surfactants had been investigated in this article, and it turned out that emulsifiers Cetyl PEG/PPG-10/1 Dimethicone and the block copolymer Poloxamer 407 were suitable for the P/O/W system. The stability of the system affected by different compositions was evaluated based on microscopic observation and rheological measurements. The novel multiple emulsions will provide enlightening recommendations for future investigations and applications in cosmetic, food and pharmaceuticals, including drug delivery and the encapsulation of hydrophilic actives and actives that are soluble in polyols.     

Quercetin-PVP K25 solid dispersions

Quercetin is a flavonoid very well studied and has already entered clinical trials emerging as prospective anticancer drug candidate. In addition, quercetin has being reported to its free-radical scavenging activity and suggests potential uses for the prevention and treatment of pathologies as atherosclerosis, chronic inflammation, and others. However, quercetin is sparingly soluble in water, which may be responsible for its limited absorption upon oral administration. The solid dispersion of quercetin with polyvinylpyrrolidone Kollidon^® 25 (PVP K25) suggests an interesting way to increase quercetin solubility, antioxidant activity, and consequently bioavailability. Then, the purpose of this study was to prepare solid dispersions of quercetin with PVP K25 and evaluate their thermal characterization, antioxidant activity and quercetin improvement solubility. For this purpose, quercetin-PVP K25 solutions were dried and quercetin-PVP K25 solids were obtained. The formation of quercetin-PVP K25 solid dispersion was evaluated by solubility studies, powder X-ray diffraction (XRD), fourier transform infrared spectroscopy (FT-IR), differential scanning calorimetry (DSC), thermogravimetry (TG), and antioxidant activity. It was observed that PVP K25 was able to provide quercetin clear aqueous solutions and that quercetin solubility was increased in a PVP K25 concentration dependent manner, improving solubility even 436-fold the pure quercetin. The results obtained with XRD, FT-IR, DSC, and TG demonstrated possible quercetin-PVP K25 solid dispersion formation. Besides, the antioxidant activity of the quercetin-PVP K25 solid dispersions dissolved in aqueous solution and pure quercetin dissolved in methanol showed IC₅₀ value of 0.61 ± 0.03 and 1.00 ± 0.02 μg/mL, respectively, demonstrating that the solid dispersions presented a significant increase in antioxidant activity (P < 0.05). Putting results together, it was possible to conclude there was the formation of quercetin-PVP K25 solid dispersion.     

Pharmaceutical performance of solid dispersions containing poly(ethylene) glycol 6000 and diazepam or temazepamInfluence of grinding

The effect of grinding on the physical properties and pharmaceutical performance of solid dispersions made of poly(ethylene) glycol 6000 (PEG6000) and temazepam or diazepam was studied using differential scanning calorimetry (DSC), X-ray powder diffraction and dissolution experiments. DSC-analysis of flash-cooled dispersions revealed that amorphous PEG present immediately after grinding crystallised upon aging mainly into the twice folded modification and to a small extent into the extended form. DSC-analysis of dispersions kept in the slab form for 1 month and subsequently ground, revealed that in the abscence of the grinding impulse crystallisation of PEG6000 takes place in the same way as in dispersions ground immediately after preparation and then aged for 1 month. Grinding solid dispersions immediately after preparation resulted in superior dissolution properties compared with solid dispersions kept in the monolith-slab form and subsequently ground. This difference in dissolution properties was found to be attributed to the drug and not to the polymer, more precisely, it was suggested that the drug particle size in ground dispersions was smaller than in dispersions kept in the slab form and subsequently ground. These findings suggest that grinding of solid dispersions immediately after preparation is the preparation method of choice instead of liquid filling of hard gelatin capsules resulting in monoliths. This revised version was published online in July 2006 with corrections to the Cover Date.     

Thermal analysis of the system triamterene-d-mannitol

Thermal analysis (DSC and HSM), and equilibrium solubility determinations were carried out to elucidate the mechanism of interaction at the solid state in the binary system triamterene-D-mannitol. Physical mixtures (5–90% w/w triamterene) and solid dispersions (5 up to 40% w/w triamterene) were prepared and studied. From DSC and HSM results, the thermal changes were associated with the variations in composition of the binary mixture, being more pronounced in the range 20–50% w/w. The binary phase diagram was proposed, although the exact position of the eutectic was uncertain. This is in accordance with a partial dissolution process detected by HSM. A linear increase in the solubility of triamterene with increasing aqueous mannitol concentration was obtained. The thermodynamic parameters of the solution properties were calculated, with an activation energy value of 96.081 kJ/mole. The solubilization increase was associated with complexation processes and hydrogen bonding formation. Dedicated to Professor Lisa Heller-Kallai on the occasion of her 65^th birthday     

Physicochemical properties of the binary system glibenclamide and polyethylene glycol 4000

Solid dispersions of the antidiabetic drug glibenclamide and polyethylene glycol 4000 (macrogol 4000) were prepared by the melting method in order to increase the solubility of this poorly water-soluble compound. The temperature/composition phase diagram of the components was analyzed by hot-stage microscopy and differential scanning calorimetry, showing a monotectic. Polarized light hot stage microscopy and X-ray-powder diffraction confirmed, that glibenclamide is mainly present in a non-crystalline state after melting and solidifying of a 10% (w/w) mixture, which results in an enhanced solubility compared to physical mixtures. The solubility and dissolution rate of the drug increases clearly with decreasing drug/polymer ratio. Moreover, it was observed for the first time that a drug could crystallize as whiskers at the surface of aged solid dispersion particles. Besides relaxation phenomena, this crystallization mechanism may be responsible for a deterioration of liberation properties and bioavailability of solid dispersion based drug products with increasing storage time. This revised version was published online in July 2006 with corrections to the Cover Date.     

Melting behavior of pure polyethylene glycol 6000 and polyethylene glycol 6000 in solid dispersions containing diazepam or temazepam: a DSC study

The purpose of the present study was to investigate the melting behavior of polyethylene glycol 6000 (PEG 6000) as such as well as in solid dispersions containing diazepam or temazepam, prepared by solvent and fusion methods, using differential scanning calorimetry (DSC). It was shown that the melting behavior of pure PEG 6000 is influenced by the crystallization procedure applied. Fusion at 80°C followed by cooling always yielded three different crystal modifications. The rate of cooling (under controlled conditions) was found to have a significant influence on the relative distribution of the three modifications: the lower the cooling rate, the higher the relative amount of the extended modification. Crystallization from organic solution yielded mainly the once folded form. The presence of diazepam and temazepam influenced the relative amount of the different PEG 6000 modifications. Both drugs decreased the formation of the more stable modification, while the formation of the twice folded form was induced. However, in the case of temazepam the contribution of the extended form at higher drug levels increased in dispersions obtained from organic solutions.     

Stability and solution concentration enhancement of resveratrol by solid dispersion in cellulose derivative matrices

Resveratrol is a highly biologically active phytoalexin, found in many plant materials that are common elements of the human diet, such as grapes, nuts, and red wine. The therapeutic or disease preventative potential of this natural polyphenolic antioxidant has been limited in part due to its poor aqueous solubility and low oral bioavailability. We hypothesized that solid dispersion of resveratrol (Res) in cellulose derivative matrices might afford amorphous dispersions, from which supersaturated Res solutions would be produced in the human gastrointestinal (GI) tract, resulting in higher Res bioavailability. We carried out structure–property studies employing cellulose esters with a range of physical characteristics but possessing features suitable for use in amorphous solid dispersions: carboxymethylcellulose acetate butyrate (CMCAB), hydroxypropylmethylcellulose acetate succinate (HPMCAS) and cellulose acetate adipate propionate (CAAdP). The cellulose derivative results were compared with those of a negative control, pure crystalline Res, and a positive control, Res/poly(vinylpyrrolidinone) (PVP). Solid dispersions were characterized by powder X-ray diffraction (XRPD), modulated differential scanning calorimetry (MDSC), nuclear magnetic resonance (NMR) and Fourier transform infrared spectroscopy (FT-IR) of solid dispersions. HPMCAS and PVP solid dispersions afforded faster and more complete Res release at pH 6.8; however Res is also released from PVP matrices at pH 1.2. The carboxyl-containing cellulose derivatives release Res to only a small extent at pH 1.2. This combination of solution and solid phase stabilization against crystallization, and pH-triggered drug release makes these cellulose esters attractive candidates for Res bioavailability enhancement.     

Formulation of betacyclodextrin based nanosponges of itraconazole

Nanosponges are betacyclodextrins crosslinked with carbonate bonds. The polymer formed is nanoparticulate in nature. Itraconazole is a BCS Class II drug that has a dissolution rate limited poor bioavailability. Rationale of the work was to enhance the solubility of Itraconazole so that the bioavailability problems are solved. Solid dispersion technique has been used for drug incorporation. The effect of a ternary component copolyvidonum on solubility of itraconazole has been studied. Phase solubility studies has been carried out with a rationale of comparing the solubilization efficiency of nanosponges, copolyvidonum and combination. The dispersions were characterized by differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD) and photon correlation spectroscopy (PCS). It was found that the solubility of itraconazole was enhanced more than 50-folds with a ternary solid dispersion system. Using copolyvidonum in conjunction with nanosponges helps to increase the solubilization efficiency of nanosponges as evident from the phase solubility studies.     

Dissolution-enhancing mechanism of alkalizers in poloxamer-based solid dispersions and physical mixtures containing poorly water-soluble valsartan

The purpose of this study was to investigate the effects of alkalizers in dissolution rate and crystal structure of valsartan (VAL) in Poloxamer 407 (POX)-based solid dispersions (SD). VAL, a poorly-water soluble drug was selected as a model drug because of its low solubility at low pH. The POX-based SDs containing alkalizers (Na?CO?, MgO, meglumine and arginine) were prepared by melting method. The dissolution tests were performed using the United States Pharmacopeia (USP) paddle II method in enzyme-free simulated gastric fluid (pH 1.2) for 2 h. Microenvironmental pH (pH(M)) was examined potentiometrically by using a surface pH electrode. Dissolution rate of SD incorporating Na?CO? was drastically increased. The differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD) data indicated that crystalline structure of VAL in SD was transformed to amorphous form by the addition of alkalizers but could not explain the differences in the dissolution rates. The molecular interaction between VAL and Na?CO? was observed in the Fourier transform infrared spectroscopy (FT-IR) spectra by the shift of C=O band from 1732 to 1719 cm?1 and the disappearance of carbonyl group at 1598 cm?1. Furthermore, Na?CO? efficiently modulated pH(M) by providing a favorable microenvironment for drug dissolution. A combination of SD method and use of alkalizer is a promising approach to modulate release rate of poorly water-soluble and ionizable drug with an aid of changes of drug crystallinity, molecular interaction and pH(M).