Tamoxifen-Loaded Eudragit Nanoparticles: Quality by Design Approach for Optimization of Nanoparticles as Delivery System.

Nanoparticles have numerous applications as drug carriers in drug delivery. The aim of the study was to produce tamoxifen nanoparticles with a defined size and higher encapsulation for efficient tissue uptake with controlled drug release. The quality by design approach was utilized to produce tamoxifen-loaded Eudragit nanoparticles by identifying the significant process variables using the nanoprecipitation method. The process variables (amount of drug, polymer, and surfactant) were altered to analyze the influence on particle size (PS), % encapsulation efficiency (EE). The results showed that the drug and polymer individually as well as collectively have an impact on PS, while the surfactant has no impact on the PS. The %EE was influenced by the surfactant individually and in interaction with the drug. The linear regression model was endorsed to fit the data showing high R2 values (PS, 0.9146, %EE, 0.9070) and low p values (PS, 0.0004, EE, 0.0005). The PS and EE were confirmed to be 178 nm and 90%, respectively. The nanoparticles were of spherical shape, as confirmed by SEM and TEM. The FTIR confirmed the absence of any incompatibility among the ingredients. The TGA confirmed that the NPs were thermally stable. The in vitro release predicted that the drug release followed Higuchi model.

Development and Application of a Modified Method to Determine the Encapsulation Efficiency of Proteins in Polymer Matrices.

A modified method to determine protein encapsulation efficiency in polymer matrices has been developed and applied to two proteins and two polymers to demonstrate its wide range of applicability. This study was pursued due to the wide variation in reported protein encapsulation efficiency of polymer-based microcapsules, even when the protein, the polymer, and the microcapsule manufacturing method were consistent. Hemoglobin (Hb) and bovine serum albumin (BSA) were chosen as model proteins and ethylcellulose and poly(lactic-co-glycolic acid) (PLGA) as model polymers. The polymer of the microcapsule was dissolved in dichloromethane/ethanol or dichloromethane/ethyl acetate for ethylcellulose or PLGA microcapsules, respectively. Liberated proteins were simultaneously precipitated, pelleted by centrifugation, isolated by decanting the polymer solution, redissolved in 10% w/v sodium dodecyl sulfate in 0.8 N sodium hydroxide, and quantified using a modified Lowry assay. Blank microcapsules and exogenously added proteins demonstrated ≥ 93.8% recovery of proteins. The mean encapsulation efficiency of ethylcellulose or PLGA microcapsules was 52.4 or 76.9% for Hb and 86.4 or 74.7% for BSA, respectively. This demonstrates the effective use of centrifugation and the importance of an appropriate cosolvent system in the measure of encapsulation efficiency where one solvent dissolves the polymer while the other solvent quantitatively precipitates the liberated protein. It is evident that an alkaline solution of sodium dodecyl sulfate is efficient at quantitatively dissolving precipitated proteins. Remediation of problems observed with current methods and high reproducibility suggest that this modified method is generally applicable to the measure of protein encapsulation efficiency of polymer microcapsules.

Use of extrusion aids for successful production of Kollidon® CL-SF pellets by extrusion-spheronization.

OBJECTIVE: Fine particle ethylcellulose (FPEC) or poly(ethylene oxide) (PEO) addition to a Kollidon CL-SF was investigated to address low yield and poor sphericity in extruded-spheronized pellets. SIGNIFICANCE: The success of crospovidone as a diluent in extrusion-spheronization was dependent on a small particle size of the polymer. FPEC aided production of rugged and spherical pellets using a large particle size grade, Polyplasdone® XL. PEO acted as an extrusion-spheronization aid when ethylcellulose was the diluent. These extrusion-spheronization aids could serve in this role when Kollidon® CL-SF (K CL-SF) is the diluent. METHODS: The influence of formulation and process variables on pellet properties was investigated using design of experiments. A planetary mixer was used to prepare powder blends and the wetted mass after addition of water. An EXD 60 extruder produced extrudate that was spheronized in a Q230 marumerizer. Wet pellets were dried in a forced-air oven. RESULTS: FPEC improved rounding up but reduced pellet yield. Poly(ethylene oxide) imparted desired characteristics to the wetted mass, the extrudate, and the spheronized pellets. Pellet average diameter, yield, sphericity, aspect ratio, friability, and dissolution profile were assessed. Equations for pellet characteristics facilitated discussion of the influences of factors and their interactions. Optimization was performed on pellets that included PEO. CONCLUSIONS: PEO proved to be an exceptional extrusion-spheronization aid in the preparation of pellets using K CL-SF. It facilitated wetted mass extrusion with minimal mass loss to the extruder, and markedly improved the sphericity of the pellets produced by marumerization. Immediate release pellets were obtained.

Development and Characterization of Chitosan Cross-Linked With Tripolyphosphate as a Sustained Release Agent in Tablets, Part I: Design of Experiments and Optimization.

Certain issues with the use of particles of chitosan (Ch) cross-linked with tripolyphosphate (TPP) in sustained release formulations include inefficient drug loading, burst drug release, and incomplete drug release. Acetaminophen was added to Ch:TPP particles to test for advantages of drug addition extragranularly over drug addition made during cross-linking. The influences of Ch concentration, Ch:TPP ratio, temperature, ionic strength, and pH were assessed. Design of experiments allowed identification of factors and 2-factor interactions that have significant effects on average particle size and size distribution, yield, zeta potential, and true density of the particles, as well as drug release from the directly compressed tablets. Statistical model equations directed production of a control batch that minimized span, maximized yield, and targeted a t50 of 90 min (sample A); sample B that differed by targeting a t50 of 240-300 min to provide sustained release; and sample C that differed from sample B by maximizing span. Sample B maximized yield and provided its targeted t50 and the smallest average particle size, with the higher zeta potential and the lower span of samples B and C. Extragranular addition of a drug to Ch:TPP particles achieved 100% drug loading, eliminated a burst drug release, and can accomplish complete drug release.

Investigation of the in vitro performance difference of drug-Soluplus® and drug-PEG 6000 dispersions when prepared using spray drying or lyophilization.

PURPOSE: To evaluate the physicochemical and in vitro characteristics of solid dispersions using BCS II model drugs with Soluplus® and one of its component homopolymers, PEG 6000. METHODS: Nifedipine (NIF) and sulfamethoxazole (SMX) of 99.3% and 99.5% purity, respectively, were selected as BCS II model drugs, such that an improved dissolution rate and concentration in the gastrointestinal tract should increase oral bioavailability. Soluplus® is an amorphous, tri-block, graft co-polymer with polyvinyl caprolactam, polyvinyl acetate, and polyethylene glycol (PCL:PVAc:PEG6000) in the ratio 57:30:13. PEG 6000 (BASF) is a waxy material with melting point of about 60 °C. Solid dispersions were prepared using lyophilization or spray drying techniques. Dissolution study, crystallinity content, and analysis for new chemical bond formation have been used to evaluate the dispersed materials. RESULTS: Although each polymer improved the drug dissolution rate, dissolution from Soluplus® was slower. Enhanced dissolution rates were observed with NIF solid dispersions, but the dissolution profiles were quite different due to the selected technique, polymer, and dissolution medium. For SMX, there was similarity across the dissolution profiles despite the medium, polymer, or applied technique. Each polymer was able to maintain an elevated drug concentration over the three hour duration of the dissolution profile, i.e., supersaturation was supported by the polymer. DSC thermograms revealed no melting endotherm, suggesting that the drug is amorphous or molecularly dispersed. CONCLUSION: NIF and SMX solid dispersions were successfully prepared by spray drying and lyophilization using Soluplus® or PEG 6000. Each polymer enhanced the drug dissolution rate; NIF dissolution rate was improved to a greater extent. Dispersions with PEG 6000 had a faster dissolution rate due to its hydrophilic nature. DSC analysis showed that no crystalline material exists in the dispersions.

Use of к-carrageenan, chitosan and Carbopol 974P in extruded and spheronized pellets that are devoid of MCC.

The search for excipients to replace microcrystalline cellulose (MCC) in the production of pellets by extrusion-spheronization in cases of drug incompatibility or the lack of pellet matrix disintegration forms the basis of this study. A combination of к-carrageenan as a spheronization aid, chitosan as a diluent and Carbopol(®) 974P as a binder in the production of pellets containing no MCC has been investigated using acetaminophen as a model drug. Design of experiments allowed assessment of formulation and processing effects on pellet responses that included size, shape, fines, yield and friability. Statistical analysis revealed that the main factors and some of the two-factor interactions had a significant effect on pellet characteristics. Formulations containing high levels of к-carrageenan required more water to produce a wetted mass with good extrudability and extrudate capable of being spheronized. Although only a low level of Carbopol was used in the formulation, it imparted cohesiveness to the wetted mass as well as the extrudate. Furthermore, it was discovered that Carbopol could act as an extrusion aid, enabling the wetted mass to flow easily through the extruder screen holes without building up heat. Spherical and rugged pellets were produced that met the immediate release criterion.

Use of the Flory-Huggins theory to predict the solubility of nifedipine and sulfamethoxazole in the triblock, graft copolymer Soluplus.

CONTEXT: Drug dispersed in a polymer can improve bioavailability; dispersed amorphous drug undergoes recrystallization. Solid solutions eliminate amorphous regions, but require a measure of the solubility. OBJECTIVE: Use the Flory-Huggins Theory to predict crystalline drugs solubility in the triblock, graft copolymer Soluplus® to provide a solid solution. MATERIALS AND METHODS: Physical mixtures of the two drugs with similar melting points but different glass forming ability, sulfamethoxazole and nifedipine, were prepared with Soluplus® using a quick technique. Drug melting point depression (MPD) was measured using differential scanning calorimetry. The Flory-Huggins Theory allowed: (1) interaction parameter, χ, calculation using MPD data to provide a measure of drug-polymer interaction strength and (2) estimation of the free energy of mixing. A phase diagram was constructed with the MPD data and glass transition temperature (Tg) curves. RESULTS: The interaction parameters with Soluplus® and the free energy of mixing were estimated. Drug solubility was calculated by the intersection of solubility equations and that of MPD and Tg curves in the phase diagram. DISCUSSION: Negative interaction parameters indicated strong drug-polymer interactions. The phase diagram and solubility equations provided comparable solubility estimates for each drug in Soluplus®. Results using the onset of melting rather than the end of melting support the use of the onset of melting. CONCLUSION: The Flory-Huggins Theory indicates that Soluplus® interacts effectively with each drug, making solid solution formation feasible. The predicted solubility of the drugs in Soluplus® compared favorably across the methods and supports the use of the onset of melting.

Use of the Flory-Huggins theory to predict the solubility of nifedipine and sulfamethoxazole in the triblock, graft copolymer Soluplus.

CONTEXT: Drug dispersed in a polymer can improve bioavailability; dispersed amorphous drug undergoes recrystallization. Solid solutions eliminate amorphous regions, but require a measure of the solubility. OBJECTIVE: Use the Flory-Huggins Theory to predict crystalline drugs solubility in the triblock, graft copolymer Soluplus® to provide a solid solution. MATERIALS AND METHODS: Physical mixtures of the two drugs with similar melting points but different glass forming ability, sulfamethoxazole and nifedipine, were prepared with Soluplus® using a quick technique. Drug melting point depression (MPD) was measured using differential scanning calorimetry. The Flory-Huggins Theory allowed: (1) interaction parameter, χ, calculation using MPD data to provide a measure of drug-polymer interaction strength and (2) estimation of the free energy of mixing. A phase diagram was constructed with the MPD data and glass transition temperature (Tg) curves. RESULTS: The interaction parameters with Soluplus® and the free energy of mixing were estimated. Drug solubility was calculated by the intersection of solubility equations and that of MPD and Tg curves in the phase diagram. DISCUSSION: Negative interaction parameters indicated strong drug-polymer interactions. The phase diagram and solubility equations provided comparable solubility estimates for each drug in Soluplus®. Results using the onset of melting rather than the end of melting support the use of the onset of melting. CONCLUSION: The Flory-Huggins Theory indicates that Soluplus® interacts effectively with each drug, making solid solution formation feasible. The predicted solubility of the drugs in Soluplus® compared favorably across the methods and supports the use of the onset of melting.

A Quality by Experimental Design Approach to Assess the Effect of Formulation and Process Variables on the Extrusion and Spheronization of Drug-Loaded Pellets Containing Polyplasdone® XL-10.

Successful pellet production has been reported in literature with cross-linked poly(vinylpyrrolidone), Polyplasdone® XL-10 and INF-10. In the present study, a quality by experimental design approach was used to assess several formulation and process parameter effects on the characteristics of Polyplasdone® XL-10 pellets, including pellet size, shape, yield, usable yield, friability, and number of fines. The hypothesis is that design of experiments and appropriate data analysis allow optimization of the Polyplasdone product. High drug loading was achieved using caffeine, a moderately soluble drug to allow in vitro release studies. A five-factor, two-level, half-fractional factorial design (Resolution V) with center point batches allowed mathematical modeling of the influence of the factors and their two-factor interactions on five of the responses. The five factors were Polyplasdone® level in the powder blend, volume of water in the wet massing step, wet mixing time, spheronizer speed, and spheronization time. Each factor and/or its two-factor interaction with another factor influenced pellet characteristics. The behavior of these materials under various processing conditions and component levels during extrusion-spheronization have been assessed, discussed, and explained based on the results. Numerical optimization with a desirability of 0.974 was possible because curvature and lack of fit were not significant with any of the model equations. The values predicted by the optimization described well the observed responses. The hypothesis was thus supported.

Use of fine particle ethylcellulose as the diluent in the production of pellets by extrusion-spheronization.

The effect of small ethylcellulose particle size on the manufacture and properties of pellets produced by extrusion-spheronization was investigated. A factorial design revealed the effects of microcrystalline cellulose (MCC), polyethylene oxide (PEO), water, and spheronization speed and time on pellet properties. Response surface modeling allowed optimization of the responses with expansion to a central composite design. Pellet yield, size, shape, friability and drug release profile were studied, along with surface and interior morphology. Pellets were spherical irrespective of the formulation and process variables and exhibited physical and mechanical characteristics appropriate for further processing. Yield in the 12/20 mesh cut was lower with FPEC than observed with coarse particle ethylcellulose (CPEC), but FPEC-containing pellets were more rugged and the PEO to obtain optimal pellets was lower for FPEC compared to CPEC. Immediate release products were obtained and ethylcellulose particle size was of no consequence to drug release. Observed responses for the optimized product agreed with predicted values, demonstrating the success of the optimization procedure. These results suggest that FPEC is a good diluent for extrusion-spheronization.

Crospovidone interactions with water. II. Dynamic vapor sorption analysis of the effect of Polyplasdone particle size on its uptake and distribution of water.

Polyplasdone of different particle size was used to study the sorption, desorption, and distribution of water, and to seek evidence that larger particles can internalize water. The three samples were Polyplasdone® XL, XL-10, and INF-10. Moisture sorption and desorption isotherms at 25 °C at 5% intervals from 0 to 95% relative humidity (RH) were generated by dynamic vapor sorption analysis. The three products provided similar data, judged to be Type III with a small hysteresis that appears when RH is below 65%. An absent rounded knee in the sorption curve suggests that multilayers form before the monolayer is completed. The hysteresis indicates that internally absorbed moisture is trapped as the water is desorbed and the polymer sample shrinks, thus requiring a lower level of RH to continue desorption. The fit of the Guggenheim-Anderson-de Boer (GAB) and the Young and Nelson equations was accomplished in the data analysis. The W(m), C(G), and K values from GAB analysis are similar across the three samples, revealing 0.962 water molecules per repeating unit in the monolayer. A small amount of absorbed water is identified, but this is consistent across the three particle sizes.

Crospovidone interactions with water. I. Calorimetric study of the effect of Polyplasdone particle size on its uptake and distribution of water.

The ability of crospovidone to take up and distribute water in the polymer samples was studied using differential scanning calorimetry (DSC). Polyplasdone(®) is an example of crospovidone that, although insoluble in water, serves as a superdisintegrant. Three samples of Polyplasdone(®) with different mean particle size were studied to see the effect of particle size on the water uptake and distribution characteristics. Water was shown to plasticize Polyplasdone(®) samples by a reduction in the glass transition temperature as the water content was increased. Although the particle sizes covered a wide range, there was essentially no difference in the ability to take up or distribute water. Three types of water were observed, namely water closely associated with the polymer, water built up as multilayers, and bulk water. Although the water closely associated with the polymer could not be detected by DSC, it could be calculated by mass balance and by extrapolation of the data to the x-axis in a plot of freezable water content as a function of the actual water content. A split in the melting endotherm of water that freezes supported the premise of two forms of freezable water. The number of water molecules per repeating unit could be calculated.

Chitosan as a pore former in coated beads for colon specific drug delivery of 5-ASA.

A multiparticulate product for colon-specific delivery of a small molecule drug has been developed and characterized. Microcrystalline cellulose core beads containing 5-aminosalicylic acid produced by extrusion-spheronization were coated with chitosan and Aquacoat(®) ECD mixtures according to a factorial design. Coated beads were characterized in terms of drug release, shape, and friability. The optimum formulation was enteric coated and exposed to media simulating conditions in the stomach, small intestine, and colon. Release studies in simulated intestinal fluid revealed that the drug release rate from the coated beads, which were spherical and rugged, depended on the level of chitosan in the coat and the coat thickness. Enlarged pores observed on the surface of the coated beads exposed to the medium containing rat cecal and colonic enzymes are believed to have caused a significant enhancement of the drug release rate compared to the control exposed only to simulated gastric and intestinal fluids. The release mechanisms involved polymer relaxation and dissolved drug diffusion for simulated intestinal fluid and simulated colonic fluid, respectively. From the facilitated drug release in a colonic environment and the inhibition of drug release under gastric and intestinal conditions, it can be concluded that this multiparticulate system demonstrates the potential for colon-specific drug delivery.

Coated hydralazine hydrochloride beads for sustained release after oral administration.

Hydralazine hydrochloride is an antihypertensive used alone or in combination with isosorbide nitrate for the treatment of congestive heart failure. Since control of blood pressure should be continuous, sustained release delivery of this drug is considered therapeutically beneficial. Core beads for oral administration of this drug were prepared by extrusion-spheronization. Using experimental design to define the coat that was applied, the core beads were coated using a fluid bed coater to different coat thickness with combinations of two commercially available products dissolved in a hydroalcoholic solvent. The coat is a film with a combination of ethylcellulose and hydroxypropylcellulose that can provide desirable release profiles. Visually spherical and rugged bead products were obtained. Two products were identified that exhibited essentially a zero order release profile following a 2-h lag time with release of greater than 70% of the drug over the next 10 h in simulated intestinal fluid.

The use of spray-drying to enhance celecoxib solubility.

The present research investigates the enhancement of the dissolution rate of celecoxib by using spray-drying to prepare a solid dispersion with various polymers, namely Kollicoat IR® (Kollicoat), polyvinyl alcohol (PVA) 22000, or polyethylene glycol 6000 (PEG). The investigated drug-to-polymer mass ratios were 1:1, 1:2, and 1:4 by weight. Hydroalcoholic or methylene chloride solvent systems were used. The obtained yields ranged from 65% to 78%, whereas the entrapment efficiencies were between 68% and 82%. The results revealed an increase in the dissolution rate of the prepared particles up to 200% within 20 min. The prepared particles were investigated using differential scanning calorimetry, scanning electron microscopy, X-ray diffraction, and Fourier transform infrared spectroscopy. The increased dissolution rate was attributed to hydrogen bond formation between celecoxib and each polymer together with the reduced size of the formed particles offering a greater overall surface area. It was concluded that spray-drying may be considered a successful one-step technique to improve the dissolution rate of celecoxib when using Kollicoat, PVA, or PEG as the carrier polymer.

Biochemically altered human erythrocytes as a carrier for targeted delivery of primaquine: an in vitro study.

The aim of this study was to investigate human erythrocytes as a carrier for targeted drug delivery of primaquine (PQ). The process of PQ loading in human erythrocytes, as well as the effect of PQ loading on the oxidative status of erythrocytes, was also studied. At PQ concentrations of 2, 4, 6, and 8 mg/mL and an incubation time of 2 h, the ratios of the concentrations of PQ entrapped in erythrocytes to that in the incubation medium were 0.515, 0.688, 0.697 and 0.788, respectively. The maximal decline of erythrocyte reduced glutathione content was observed at 8 mg/mL of PQ compared with native erythrocytes p < 0.001. In contrast, malondialdehyde and protein carbonyl were significantly increased in cells loaded with PQ (p < 0.001). Furthermore, osmotic fragility of PQ carrier erythrocytes was increased in comparison with unloaded cells. Electron microscopy revealed spherocyte formation with PQ carrier erythrocytes. PQ-loaded cells showed sustained drug release over a 48 h period. Erythrocytes were loaded with PQ successfully, but there were some biochemical as well as physiological changes that resulted from the effect of PQ on the oxidative status of drug-loaded erythrocytes. These changes may result in favorable targeting of PQ-loaded cells to reticulo-endothelial organs. The relative impact of these changes remains to be explored in ongoing animal studies.

Rheological and mucoadhesive characterization of poly(vinylpyrrolidone) hydrogels designed for nasal mucosal drug delivery.

Poly(vinylpyrrolidone) (PVP) hydrogels were crosslinked by gamma irradiation to add structure and rigidity, and then rheological and mucoadhesive properties were evaluated. The effects of PVP concentration, radiation dose, and additives, such as poly(ethylene glycol) (PEG) and glycerol, on rheological properties were investigated. In an oscillatory analysis, an increase in polymer concentrations increased the storage modulus (G') and the loss modulus (G″) but decreased the loss tangent (tan δ < 1). The relationships between G'or G″ and the frequency levelled off at higher frequencies, which is indicative of polymer chain entanglement and network formation. Each of the 6% PVP hydrogels exhibited plastic flow with rheopectic behavior. PVP concentration, radiation dose, and the presence of PEG or glycerol influenced the rheological and mucoadhesive properties of the hydrogels. However, adding acyclovir to the formulation did not have a profound effect on the rheological behavior of the hydrogels. The results suggest that a 3% PVP hydrogel with 1% PEG crosslinked with 20 kGy is the most appropriate hydrogel. The results demonstrated the successful complementary application of oscillatory and flow rheometry to characterize and develop a hydrogel for mucosal drug administration.

Colon-specific drug delivery using ethylcellulose and chitosan in the coat of compression-coated tablets.

BACKGROUND: This study investigates a new means to achieve colon-specific drug delivery. OBJECTIVE: This study assesses the use of chitosan and ethylcellulose in the coat of a compression-coated tablet to achieve colon-specific drug delivery. The effects of chitosan type and its level as well as the coat thickness were evaluated. MATERIALS AND METHODS: Caffeine-containing core tablets were prepared by direct compression. Three chitosan samples with different molecular weight and degree of deacetylation were used. Direct compression produced the finished coated tablet. The product was tested for its potential in colon-specific drug delivery by conducting release studies in simulated gastric and intestinal fluids. Enzymes harvested from rat cecal and colonic contents contributed to a medium to study drug release under colonic conditions. RESULTS: Essentially no drug was released until action on the tablet by either the acidic pH or the presence of enzymes in the release medium. Chitosan type had no effect on drug release as long as the coating level was the same. Lowering the chitosan level in the coat or increasing the coat thickness increased the lag time. DISCUSSION: The type of chitosan can be changed and yet the product is still susceptible to enzyme or pH effects. This indicates that chitosan present in the coat is still available for such action by the release medium. One can control the chitosan level or the thickness of the coat to achieve a desired delivery profile. CONCLUSION: As colonic media can dramatically promote drug release, the potential for colon-specific drug delivery is confirmed.

Technology evaluation: Kollicoat IR.

INTRODUCTION: Developments in industrial pharmacy are often linked to the discovery of pharmaceutical excipients. Although recently introduced as a material for immediate release coatings, Kollicoat IR already has other applications. AREAS COVERED: In this review, the different properties and pharmaceutical applications of Kollicoat IR as an excipient are discussed. In the first part, the chemical structure and the physicochemical characteristics are examined. The second part is a presentation of the available Kollicoat IR products followed by a brief overview of the preclinical studies completed for its use as an instant release coating material. EXPERT OPINION: Although the polymer was intended as an immediate release coating material for tablets, grafting PEG with polyvinyl alcohol to form this polymer provides physicochemical properties that lead to ever-broadening applications. Understanding its properties can lead to the development of a new use for Kollicoat IR. The addition of Kollicoat IR to an ethylcellulose or polyvinyl acetate tablet coat was successful at modifying the drug release rate. Designing a successful controlled release coat simply requires acknowledgment of the drug release mechanism from the mixture of polymers that includes Kollicoat IR. Moreover, the interaction between Kollicoat IR and poorly soluble drugs produces fast-dissolving solid dispersions prepared using hot stage extrusion, spray drying, or freeze drying.

Comparative study of itraconazole-cyclodextrin inclusion complex and its commercial product.

Itraconazole (ITZ) solid complex using hydroxypropyl-beta-cyclodextrin (ITZ-HP-beta-CD) with 20% polyvinylpyrrolidone was prepared by a co-evaporation method. The complex improved antifungal activity against C. parapasilosis and C. albicans. The complex demonstrated good flow and compressibility characteristics. The complex was formulated as a capsule dosage form and drug release was evaluated. Capsules containing ITZ-HP-beta-CD at a molar ratio of 1:3 with 20% polyvinylpyrrolidone have a faster dissolution rate than commercial capsules (Sporanox). About 88% of ITZ was released in less than 30 min and the initial dissolution rate exhibited a 3.5-fold increase compared to the commercial product. UV spectrophotometeric, HPLC, and antimicrobial methods were used to determine ITZ concentration in the release medium and the results obtained by these methods are reported. It was found that HPLC analysis is a suitable and reliable method for determination of the drug concentration with a coefficient of variation less than 10%. The intraday precision showed a coefficient of variation less than 3.96%, and that for interday was less than 4.99%. The HPLC method was more accurate and precise than the antimicrobial and UV-spectrophotometric methods for determination of ITZ concentration present in the release medium.