Influence of chitosan and its glutamate and hydrochloride salts on naproxen dissolution rate and permeation across Caco-2 cells

Chitosan and its glutamate and hydrochloride salts were evaluated for their efficacy in improving the dissolution behaviour of naproxen (a poorly water-soluble antiinflammatory drug) and its transport in vitro across Caco-2 cell monolayers. Drug-polymer physical mixtures and coground products, prepared at two different w/w ratios (30/70 and 10/90), were characterized by differential scanning calorimetry, X-ray powder diffractometry, scanning electron microscopy, and tested for dissolution properties. Coground systems were more effective than physical mixtures in improving drug dissolution and chitosan base, in spite of its lower water solubility, showed higher solubilizing power than its salts. According to the solid state analyses results, this effect was directly related to its stronger amorphizing power. Transport studies showed that only coground mixtures with chitosan glutamate salt allowed a significant drug apparent permeability improvement; however, they did not exhibit appreciable effects on the Caco-2 tight junctions (measured by the trans-epithelial electrical resistance variations), thus indicating that their enhancer effect was mainly due to an improved naproxen transport by transcellular passive diffusion rather than through the paracellular route. The direct compression properties and antiulcerogenic activity together with the demonstrated dissolution and permeation enhancer abilities toward naproxen make chitosan glutamate an optimal carrier for developing fast-action oral solid dosage forms of this drug.     

Comparison of the effect of chitosan and polyvinylpyrrolidone on dissolution properties and analgesic effect of naproxen.

The solubilizing and absorption enhancer properties towards naproxen of chitosan and polyvinylpyrrolidone (PVP) have been investigated. Solid binary systems prepared at various drug-polymer ratios by mixing, cogrinding or kneading, were characterized by differential scanning calorimetry, X-ray diffractometry, Fourier transform infrared spectroscopy, and scanning electron microscopy, and tested for dissolution behavior. Both carriers improved drug dissolution and their performance depended on the drug-polymer ratio and the system preparation method. Chitosan was more effective than PVP, despite the greater amorphizing power of PVP as revealed by solid state analyses. The 3/7 (w/w) drug-carrier coground systems with chitosan and PVP were the best products enabling, respectively, an improvement of 4.8 and 3.6 times of drug dissolution efficiency. In vivo experiments in mice demonstrated that administration of 45 mg/kg of drug coground with PVP or chitosan resulted, respectively, in a 25 and 60% reduction of acetic acid-induced writhings in comparison to pure drug, which, instead, was statistically ineffective as compared to the control group. Moreover, the 3/7 (w/w) drug-chitosan coground product demonstrated an antiwrithing potency 2.4 times higher than the coground with PVP. Thus, the direct-compression properties and antiulcerogenic activity, combined with the demonstrated solubilizing power and analgesic effect enhancer ability towards the drug, make chitosan particularly suitable for developing a reduced-dose fast-release solid oral dosage form of naproxen.     

Characterization of physicochemical properties of naproxen systems with amorphous beta-cyclodextrin-epichlorohydrin polymers

Ground mixtures of naproxen with amorphous β-cyclodextrin-epichlorohydrin soluble (βCd-EPS) or insoluble cross-linked (βCd-EPI) polymers were investigated for both solid phase characterization (Differential Scanning Calorimetry, powder X-ray Diffractometry) and dissolution properties (dispersed amount method). The effect of different grinding conditions and of drug-to-carrier ratio was also evaluated. Co-grinding induced a decrease in drug crystallinity to an extent which depended on the grinding time, and was most pronounced for the cross-linked insoluble polymer, particularly in combinations at the lowest drug content. Both cyclodextrin polymers were more effective in improving the naproxen dissolution properties, not only than the parent βCd but also than hydroxyalkyl-derivatives, and their performance was almost comparable to that of methyl-derivatives, previously found as the best carriers for naproxen. Dissolution efficiencies of naproxen from physical mixtures with βCd-EPS, thanks to the high water solubility of this Cd-derivative, were up to three times higher than those from the corresponding products with βCd-EPI. However this difference in their performance became much less evident in co-ground products and tended to progressively diminish with increasing the polymer content in the mixture, according to the better amorphizing power shown by βCd-EPI during the co-grinding process. The 10/90 (w/w) drug–carrier co-ground products exhibited the best dissolution properties, giving dissolution efficiencies about 30 times higher than that of naproxen alone.     

Dissolution and Permeation Properties of Naproxen From Solid-State Systems With Chitosan

The purpose of this study was to investigate the influence of different types of chitosan and of the preparation technique of the drug–polymer combination in improving the dissolution and permeation abilities of naproxen, a very poorly water-soluble anti-inflammatory drug. Drug–chitosan systems were prepared by simple physical mixing, kneading, cogrinding, or coevaporation using five types of chitosan (base and glutamate or hydrochloride salts, both at two different molecular weights). The products were tested for drug-dissolution behavior and for permeation properties through both Caco-2 cell monolayers and artificial lipophilic membranes. All combinations with chitosan base were significantly (p < .01) more effective in enhancing drug-dissolution rate than those with both its salts, probably in virtue of its higher amorphizing effect toward the drug, as observed in solid-state studies. A different rank order was found in permeation experiments in which chitosan glutamate was the most powerful partner in improving the drug-apparent permeability (p < .01), followed by the hydrochloride salt (p < .05), whereas no significant effect was obtained with chitosan base. Cogrinding was the most powerful technique in promoting both dissolution and permeation properties of the drug, thus pointing out the importance of the preparation method in obtaining efficacious drug-carrier systems. Finally, the good correspondence between permeation experiments with Caco-2 cells and those with the artificial lipophilic membrane indicated the suitability of this latter in preformulation studies for a rapid screening of the best carrier and the most efficient drug-carrier preparation method for improving the biopharmaceutical properties of drugs.     

Comparative study of ibuproxam complexation with amorphous beta-cyclodextrin derivatives in solution and in the solid state.

The complexing, solubilizing and amorphizing abilities toward ibuproxam (a poorly water-soluble anti-inflammatory agent) of some randomly substituted amorphous beta-cyclodextrin derivatives (i.e. methyl- (MebetaCd), hydroxyethyl- (HEbetaCd), and hydroxypropyl- (HPbetaCd) beta-cyclodextrins) were investigated and compared with those of the parent beta-cyclodextrin. Equimolar drug-cyclodextrin solid systems were prepared by blending, cogrinding, coevaporation, and colyophilization. Drug-carrier interactions were studied in both the liquid and solid state by phase solubility analysis, supported by molecular modelling, differential scanning calorimetry, X-ray powder diffractometry, Fourier transform infrared spectroscopy and scanning electron microscopy. All the betaCd derivatives showed greater solubilizing efficacies toward ibuproxam than the parent one, due to their higher water solubility. On the contrary, a clear reduction of complexing ability was observed, indicative of some steric interferences to drug inclusion due to the presence of substituents, as confirmed by molecular modelling studies. However, this negative effect was not reflected in the dissolution behaviour (evaluated according to the dispersed amount method) of their solid binary systems, probably thanks to the greater amorphizing properties shown (DSC and X-ray analyses) by betaCd derivatives. In fact their dissolution efficiencies were not significantly different (MebetaCd) or only slightly lower (HEbetaCd and HPbetaCd) than those of the corresponding products with beta-cyclodextrin. Colyophilized products were in all cases the most effective, followed by coground and coevaporated systems, whose dissolution efficiencies were over four times higher than the corresponding physical mixtures and about 15 times higher than the pure drug.     

Dissolution and permeation properties of naproxen from solid-state systems with chitosan

The purpose of this study was to investigate the influence of different types of chitosan and of the preparation technique of the drug-polymer combination in improving the dissolution and permeation abilities of naproxen, a very poorly water-soluble anti-inflammatory drug. Drug-chitosan systems were prepared by simple physical mixing, kneading, cogrinding, or coevaporation using five types of chitosan (base and glutamate or hydrochloride salts, both at two different molecular weights). The products were tested for drug-dissolution behavior and for permeation properties through both Caco-2 cell monolayers and artificial lipophilic membranes. All combinations with chitosan base were significantly (p < .01) more effective in enhancing drug-dissolution rate than those with both its salts, probably in virtue of its higher amorphizing effect toward the drug, as observed in solid-state studies. A different rank order was found in permeation experiments in which chitosan glutamate was the most powerful partner in improving the drug-apparent permeability (p < .01), followed by the hydrochloride salt (p < .05), whereas no significant effect was obtained with chitosan base. Cogrinding was the most powerful technique in promoting both dissolution and permeation properties of the drug, thus pointing out the importance of the preparation method in obtaining efficacious drug-carrier systems. Finally, the good correspondence between permeation experiments with Caco-2 cells and those with the artificial lipophilic membrane indicated the suitability of this latter in preformulation studies for a rapid screening of the best carrier and the most efficient drug-carrier preparation method for improving the biopharmaceutical properties of drugs.     

Preparation of microparticles of naproxen with Eudragit RS and Talc by spherical crystallization technique

Microparticles of naproxen with Eudragit RS and talc were prepared by the spherical crystallization technique, i.e. quasi-emulsion solvent diffusion method. The obtained microparticles were evaluated by micromeritic properties, yield, encapsulation efficiency, drug physical state and dissolution rate of drug. The influence of formulation factors and preparation condition (drug: polymer ratio, talc: polymer ratio, SLS concentration, stirring speed) on the properties of the microparticles were also examined. The resultant microparticles were finely spherical and uniform with high incorporation efficiency and yield. Greater encapsulation efficiency was obtained by increasing the drug: polymer ratio and talc: polymer ratio and by reducing the SLS %. The dissolution rate of naproxen from microparticles was enhanced significantly with increasing the ratio of drug: polymer and stirring rate, and sustained by increasing SLS % in crystallization medium. The results of X-ray diffraction and differential scanning calorimeter analysis indicated that naproxen was highly dispersed in microparticles, so as amorphous state. Studies carried out to characterize the micromeritic properties of formulations, such as flowability and packability showed that microparticles were suitable for further pharmaceutical manipulation (e.g. capsule filling). Hence, the spherical crystallization technique can be successfully used for obtaining spherical microparticles, generating a heterogeneous matrix system and providing sustained drug release.     

Characterisation of the thermal,spectroscopic and drug dissolution properties of mefenamic acid and polyoxyethylene–polyoxypropylene solid dispersions

The aim of this study was to investigate the solubility of mefenamic acid (MA), a highly cohesive, poorly water-soluble drug in a copolymer of polyoxyethylene–polyoxypropylene (Lutrol F68®), and to understand the effect drug polymer solubility has on in vitro dissolution of MA. Solid dispersions (SD) of MA were prepared by a hot melt method, using Lutrol F68® as a thermoplastic polymeric platform. High-speed differential scanning calorimetry (Hyper-DSC), Raman spectroscopy, powder X-ray diffractometry (PXRD) and hot-stage/fluorescence microscopy were used to assess the solubility of the drug in molten and solid polymer. Drug dissolution studies were subsequently conducted on single-phase solid solutions and biphasic SD using phosphate buffer pH 6.8 as dissolution media. Solubility investigations using Hyper-DSC, Raman spectroscopy and hot-stage microscopy suggested MA was soluble in molten Lutrol F68® up to a concentration of 35% (w/w). Conversely, the solubility in the solid-state matrix was limited to <15% (w/w); determined by Raman spectroscopy, PXRD and fluorescence microscopy. As expected the dissolution properties of MA were significantly influenced by the solubility of the drug in the polymer matrix. At a concentration of 10% (w/w) MA (a single phase solid solution) dissolution of MA in phosphate buffer 6.8 was rapid, whereas at a concentration of 50% (w/w) MA (biphasic SD) dissolution was significantly slower. This study has clearly demonstrated the complexity of drug–polymer binary blends and in particular defining the solubility of a drug within a polymeric platform. Moreover, this investigation has demonstrated the significant effect drug solubility within a polymeric matrix has upon the in vitro dissolution properties of solid polymer/drug binary blends. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:4545–4556, 2009     

Interaction of naproxen with ionic cyclodextrins in aqueous solution and in the solid state

The possible role of the cyclodextrin charge in the interaction with an acidic drug such as naproxen (pK_a 4.8) has been evaluated. Sulfobutylether-ß-cyclodextrin (SBE-ßCyd) and trimethylammonium-ß-cyclodextrin (TMA-ßCyd) were selected as, respectively, anionically and cationically charged carriers and their performance was compared with that of the parent ß-cyclodextrin (ßCyd) and of its methyl-derivative (MeßCyd) previously found as the best partner for the drug. Interactions in solution were investigated by phase-solubility, fluorescence and circular dichroism analyses. Equimolar drug–carrier products prepared by different techniques (blending, cogrinding, sealed-heating, colyophilization) were characterized by differential scanning calorimetry and X-ray powder diffractometry and tested for drug dissolution properties. Anionic charges of SBE-ßCyd did not negatively influence interactions in unbuffered aqueous solutions (pH ≈5) with the acidic drug. In fact, it was a very effective carrier, exhibiting solubilizing and complexing properties considerably better than the parent ßCyd and comparable to those of MeßCyd. On the contrary, the positive charges of TMA-ßCyd did not favour interactions with the counter-ionic drug (despite the presence of about 60% ionised drug) and it was less efficacious also than native ßCyd. Therefore, the role of the Cyd charge on the complexing and solubilizing properties towards naproxen was not important whereas other factors, such as steric hindrance effects and favourable hydrophobic interactions were significant in determining the drug affinity for the Cyd inclusion. Solid state studies evidenced similar amorphizing properties of both charged Cyds towards naproxen. On the other hand, dissolution tests, in agreement with solution studies, showed that all products with SBE-ßCyd exhibited significantly better dissolution properties than the corresponding ones with TMA-ßCyd. A clear influence of the preparation method of drug–Cyd solid systems on the performance of the end product was also observed. Colyophilization was the most effective technique, followed by the cogrinding one. Colyophilized product with SBE-ßCyd allowed a 10-times increase in drug dissolution efficiency (D.E.) (with respect to the five-times increase obtained with the corresponding coground product) and a reduction of t_50% from about 60 min (for the coground product) to less than 2 min.     

Comparison of surface modification and solid dispersion techniques for drug dissolution

Surface modification and solid dispersion formulations using hydrophilic excipients can significantly alter the dissolution behaviour of hydrophobic drug materials. The effect of these techniques used individually and in combination on the dissolution properties of the hydrophobic drug, phenylbutazone (PB), are compared. PB was treated with a poloxamer, Synperonic((R)) F127 by an adsorption method. Solid dispersions (10 and 20% w/w) were prepared with untreated PB or PB previously modified with Synperonic((R)) F127 (PBT) in molten F127. Dissolution tests of capsule formulations of PB, PBT and solid dispersion formulations, in pH 6.4 buffer at 37+/-0.5 degrees C demonstrated that after 140 min, release of PB was 16.7%, but 71.4% from the solid dispersion, whereas from the PBT formulation 85.6% was released. The Synperonic((R)) F127 content of PBT was only 0.05% of that in the solid dispersion formulation which suggests that it is the nature of the drug polymer contact rather than the amount of polymer which is more critical in influencing dissolution behaviour. Comparison of PBT and the 10% w/w solid dispersion of PBT in F127 showed similar amounts of drug in solution after 140 min. However there was a significantly higher release rate for PBT. Both formulation techniques offer significant improvements in drug release over untreated PB, and a combination of techniques changes the rate but not the extent of release in comparison with the surface modification technique alone.     

Physicochemical characterization of solid dispersions of three antiepileptic drugs prepared by solvent evaporation method

We have investigated the solid dispersion and dissolution profiles of three antiepileptic drugs (carbamazepine (CBZ), oxcarbazepine (OXC) and rufinamide (RFN)) with different aqueous solubilities, prepared by the solvent evaporation method. Solid dispersions of the three drugs in hydroxy-propylmethylcellulose (HPMC), with drug:polymer ratios of 1:4, were prepared and characterized by differential scanning calorimetry (DSC), Fourier transformation infrared (FTIR) spectroscopy, X-ray diffraction (XRD) and scanning electron microscopy. The release mechanism was also investigated and the kinetic order of the solid dispersions was evaluated. It appeared that the dissolution behaviour depended on the physicochemical properties of the drug and drug-polymer interactions. DSC thermographs showed amorphous forms for all drugs confirmed by XRD patterns. The FTIR spectra of CBZ and OXC demonstrated drug interactions with HPMC through hydrogen polymer bonds. Thus, solid dispersions of these drugs had an improved dissolution profile. In contrast, solid dispersions of RUF showed modest enhancement of dissolution, suggesting negligible drug-polymer interactions. The different dissolution behaviour is attributed to the extent of interactions between the polymer hydroxyl group and the drug amide groups.     

Hydrogels based on interpenetrating network of chitosan and polyvinyl pyrrolidone for pH-sensitive delivery of repaglinide

The aim of this study was to develop a pH-sensitive chitosan/polyvinyl pyrrolidone (PVP) based controlled drug release system for repaglinide. The hydrogels were synthesised by crosslinking chitosan and PVP blend with glutaraldehyde to form a semi-interpenetrating polymer network (semi-IPN). These semi-IPNs were studied for their content uniformity, swelling index (SI), mucoadhesion, wettability, in vitro release and their release kinetics. The hydrogels showed more than 95% loading of repaglinide. These hydrogels showed high swelling and mucoadhesion under acidic conditions. The swelling was found due to the protonation of a primary amino group on chitosan. In acidic condition chitosan was ionized, and adhesion occurred between the positively charged chitosan and the negatively charged mucus. In the physiological condition less swelling was noticed. In vitro release study revealed that formulation containing chitosan (2% w/v) and PVP (4% w/v) in the ratio of 14:6 w/w showed complete drug release after 12h. Release profile showed that all the formulations followed non-fickian diffusion mechanism (diffusion coupled with swelling). Fourier transform infrared (FTIR) spectroscopic analysis revealed proper crosslinking of polymer and formation of semi-IPN as well as presence of drug in the formulation. Differential scanning calorimetry (DSC) and powder x-ray diffraction (p-XRD) study revealed the presence of repaglinide in crystalline form in the formulations. The surface morphology of semi-IPN was studied before and after dissolution in simulated gastric fluid (SGF, pH 1.2) which indicated generation of open channel-like structure in hydrogel after dissolution. The results of study suggest that semi-IPNs of chitosan/PVP are potent candidates for delivery of repaglinide in acidic environment.     

Development and in vitro evaluation of novel floating chitosan microcapsules for oral use: comparison with non-floating chitosan microspheres

Floating (F) microcapsules containing melatonin (MT) were prepared by the ionic interaction of chitosan and a negatively charged surfactant, sodium dioctyl sulfosuccinate (DOS). The DOS/chitosan complex formation was confirmed employing infrared spectroscopy, differential scanning calorimetry (DSC), solubility and X-ray diffraction analysis. The characteristics of the F microcapsules generated compared with the conventional non-floating (NF) microspheres manufactured from chitosan and sodium tripolyphosphate (TPP) were also investigated. The effect of various factors (crosslinking time, DOS and chitosan concentrations, as well as drug/polymer ratio) on microcapsule properties were evaluated. The use of DOS solution in coagulation of chitosan produced well-formed microcapsules with round hollow core and 31.2-59.74% incorporation efficiencies. Chitosan concentration and drug/polymer ratio had a remarkable effect on drug entrapment in DOS/chitosan microcapsules. The dissolution profiles of most of microcapsules showed near zero order kinetics in simulated gastric fluid (S.G.F: pH 1.2). Moreover, release of the drug from these microcapsules was greatly retarded with release lasting for several hours (t(50%) (S.G.F.): 1.75-6.7 h, depending on processing factors), compared with NF microspheres where drug release was almost instant. Most of the hollow microcapsules developed tended to float over simulated biofluids for more than 12 h. Swelling studies conducted on various drug-free formulations, clearly indicated that DOS/chitosan microcapsules showed less swelling and no dissolution in S.G.F. for more than 3 days, whereas, TPP/chitosan microspheres were markedly swollen and lost their integrity in S.G.F. within 5 h. Therefore, data obtained suggest that the F hollow microcapsules produced would be an interesting gastroretentive controlled-release delivery system for drugs.     

New binary solid dispersion of indomethacin with surfactant polymer: From physical characterization to in vitro dissolution enhancement

This article investigated preparation of solid dispersions containing a poor water-soluble drug, indomethacin (IND), and a new surfactant polymer, polyoxyethylene 32 distearate (POED). Solid dispersions were prepared by the melting method and characterized by DSC, hot-stage microscopy (HSM), X-ray diffraction (XRD) and scanning electron microscopy (SEM). DSC and HSM analyses performed on IND/POED physical mixtures indicated that IND could dissolve in liquid POED. The materials showed complete miscibility at liquid state. Combination of DSC, XRD, and SEM revealed that these materials had limited miscibility at the solid state. Up to 20% w/w IND in POED, we did not detect significant modification of physical properties of the polymer. It supports the formation of a solid solution of IND in solid POED. Above 20% w/w, the solid dispersions presented particular behavior upon heating (recrystallization of IND) and at the solid state (presence of some IND crystallites). Under 3-month storage at 25°C/53% RH, the solid dispersions demonstrated a good stability of the samples. Finally, in vitro dissolution studies showed that IND release was greatly improved (5.5–12 times as fast) by formation of solid dispersion. This enhancement was principally attributed to the high dispersion of IND in POED and to the polymer surfactant properties. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99: 1399–1413, 2010     

Formation and characterization of solid dispersions of piroxicam and polyvinylpyrrolidone using spray drying and precipitation with compressed antisolvent

Solid dispersions of a poorly water-soluble drug piroxicam in polyvinylpyrrolidone (PVP) were prepared by precipitation with compressed antisolvent (PCA) and spray drying techniques. Physicochemical properties of the products and drug-polymer interactions were characterized by powder X-ray diffraction, Fourier transform infrared spectroscopy, and differential scanning calorimetry, etc. Piroxicam was found amorphously dispersed in both solid dispersion systems with the drug to polymer weight ratio of 1:4. Spectra data indicated the formation of hydrogen bonding between the drug and the polymer. Both techniques evaluated in this work resulted in improved dissolution of piroxicam. By comparison, PCA-processed solid dispersions showed distinctly superior performance in that piroxicam dissolved completely within the first 5 min and the dissolution rate was at least 20 times faster than raw drug did within the first 15 min. PCA processing could provide an effective pharmaceutical formulation technology to improve the bioavailability of poorly water-soluble drug.     

Enhanced solubility and dissolution rate of itraconazole by a solid dispersion technique.

The aim of the present study was to improve the solubility and dissolution rate of a poorly water-soluble drug, itraconazole, by a solid dispersion technique. Solid dispersion particles of itraconazole were prepared with various pH-independent and -dependent hydrophilic polymers and were characterized by differential scanning calorimetry, powder X-ray diffraction and scanning electron microscopy. Of the polymers tested, pH-dependent hydrophilic polymers, AEA and Eudragit E 100, resulted in highest increases in drug solubility (range, 141.4-146.9-fold increases). The shape of the solid dispersion particles was spherical, with their internal diameter ranging from 1-10 microm. The dissolution rate of itraconazole from the tablets prepared by spray drying (SD-T) was fast, with > 90% released within 5 min.SD-T prepared with AEA or Eudragit E 100 at a 1:1 drug hydrophilic polymer ratio (w/w) showed approximately 70-fold increases in the dissolution rate over a marketed product.     

Physicochemical characterization of tacrolimus-loaded solid dispersion with sodium carboxylmethyl cellulose and sodium lauryl sulfate

To develop a novel tacrolimus-loaded solid dispersion with improved solubility, various solid dispersions were prepared with various ratios of water, sodium lauryl sulfate, citric acid and carboxylmethylcellulose-Na using spray drying technique. The physicochemical properties of solid dispersions were investigated using scanning electron microscopy, differential scanning calorimetery and powder X-ray diffraction. Furthermore, their solubility and dissolution were evaluated compared to drug powder. The solid dispersion at the tacrolimus/CMC-Na/sodium lauryl sulfate/citric acid ratio of 3/24/3/0.2 significantly improved the drug solubility and dissolution compared to powder. The scanning electron microscopy result suggested that carriers might be attached to the surface of drug in this solid dispersion. Unlike traditional solid dispersion systems, the crystal form of drug in this solid dispersion could not be converted to amorphous form, which was confirmed by the analysis of DSC and powder X-ray diffraction. Thus, the solid dispersion system with water, sodium lauryl sulfate, citric acid and CMC-Na should be a potential candidate for delivering a poorly water-soluble tacrolimus with enhanced solubility and no convertible crystalline.     

Solid dispersions of itraconazole and enteric polymers made by ultra-rapid freezing

The primary objective of the study is to investigate the influence of composition parameters including drug:polymer ratio and polymer type, and particle structure of enteric solid dispersions on the release of ITZ under sink and supersaturated dissolution conditions. Modulated differential scanning calorimetry (MDSC) was utilized to define the level of ITZ miscibility with each polymer. The compositions were completely miscible at 60% ITZ for both polymers and as high as 70% in HP-55. High potency composition glass transition temperatures (T(g)) correlated with predicted T(g)'s from the Gordon-Taylor equation, however, recrystallization exotherms revealed pure amorphous regions indicating that phase separation occurred during particle formation. Furthermore, in vitro studies including X-ray powder diffraction (XRD), scanning electron microscopy (SEM), surface area analysis (BET), and dissolution were performed to determine differences between low potency (completely miscible) and high potency (partially miscible) compositions. Dissolution studies on low potency ITZ compositions revealed that miscibility plays an active role in ITZ release under sink conditions, and square root diffusion through the enteric polymer is observed. Supersaturated dissolution profiles revealed high potency compositions had maximum saturation levels (C/Ceq(max)) between 10.6- and 8-times equilibrium solubility, but had higher cumulative extents of supersaturation, compared to low potency compositions which had C/Ceq(max) values of 15-19.6. However, these low potency compositions rapidly precipitated leading to significantly lower AUCs (p<0.05). The change in the miscibility of the solid dispersion had a pronounced effect of drug release (sink) while differences in potency influenced supersaturated dissolution profiles.     

Characterization of solid dispersions of itraconazole and hydroxypropylmethylcellulose prepared by melt extrusion--Part I

Solid dispersions containing different ratios of itraconazole and hydroxypropylmethylcellulose (HPMC) were prepared by solvent casting. Based on dose, differential scanning calorimetry and dissolution results, a drug/polymer ratio of 40/60 w/w was selected in order to prepare dispersions by melt extrusion. The melt extrusion process was characterized using a design of experiments (DOE) approach. All parameter settings resulted in the formation of an amorphous solid dispersion whereby HPMC 2910 5 mPas prevents re-crystallization of the drug during cooling. Dissolution measurements demonstrated that a significantly increased dissolution rate was obtained with the amorphous solid dispersion compared to the physical mixture. The outcome of DOE further indicated that melt extrusion is very robust with regard to the itraconazole/HPMC melt extrudate characteristics. Stability studies demonstrated that the itraconazole/HPMC 40/60 w/w milled melt extrudate formulation is chemically and physically stable for periods in excess of 6 months as indicated by the absence of degradation products or re-crystallization of the drug.     

Physicochemical characterization of solid dispersions of the antiviral agent UC-781 with polyethylene glycol 6000 and Gelucire 44/14

The purpose of this study was to prepare and characterize solid dispersions of the antiviral thiocarboxanilide UC-781 with PEG 6000 and Gelucire 44/14 with the intention of improving its dissolution properties. The solid dispersions were prepared by the fusion method. Evaluation of the properties of the dispersions was performed using dissolution studies, differential scanning calorimetry, Fourier-transform infrared spectroscopy and X-ray powder diffraction. To investigate the possible formation of solid solutions of the drug in the carriers, the lattice spacings [d] of PEG 6000 and Gelucire 44/14 were determined in different concentrations of UC-781. The results obtained showed that the rate of dissolution of UC-781 was considerably improved when formulated in solid dispersions with PEG 6000 and Gelucire 44/14 as compared to pure UC-781. From the phase diagrams of PEG 6000 and Gelucire 44/14 it could be noted that up to approximately 25% w/w of the drug was dissolved in the liquid phase in the case of PEG 6000 and Gelucire 44/14. The data from the X-ray diffraction showed that the drug was still detectable in the solid state below a concentration of 5% w/w in the presence of PEG 6000 and Gelucire 44/14, while no significant changes in the lattice spacings of PEG 6000 or Gelucire 44/14 were observed. Therefore, the possibility of UC-781 to form solid solutions with the carriers under investigation was ruled out. The results from infrared spectroscopy together with those from X-ray diffraction and differential scanning calorimetry showed the absence of well-defined drug–polymer interactions.