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The oral administration of therapeutic proteins copes with important challenges (mainly degradation and poor absorption) making their potential therapeutic application extremely difficult. The aim of this study was to design and evaluate the potential of the combination between mucus-permeating nanoparticles and permeation enhancers as a carrier for the oral delivery of the monoclonal antibody bevacizumab, used as a model of therapeutic protein. For this purpose, bevacizumab was encapsulated in PEG-coated albumin nanoparticles as a hydrophobic ion-pairing complex with either sodium deoxycholate (DS) or sodium docusate (DOCU). In both cases, complex formation efficiencies close to 90% were found. The incorporation of either DS or DOCU in PEG-coated nanoparticles significantly increased their mean size, particularly when DOCU was used. Moreover, the diffusion in mucus of DOCU-loaded nanoparticles was significantly reduced, compared with DS ones. In a C. elegans model, DS or DOCU (free or nanoencapsulated) disrupted the intestinal epithelial integrity, but the overall survival of the worms was not affected. In rats, the relative oral bioavailability of bevacizumab incorporated in PEG-coated nanoparticles as a complex with DS (B-DS-NP-P) was 3.7%, a 1000-fold increase compared to free bevacizumab encapsulated in nanoparticles (B-NP-P). This important effect of DS may be explained not only by its capability to transiently disrupt tight junctions but also to their ability to increase the fluidity of membranes and to inhibit cytosolic and brush border enzymes. In summary, the current strategy may be useful to allow the therapeutic use of orally administered proteins, including monoclonal antibodies., (© 2023. The Author(s).)

This study aims to provide a thorough characterization of Brij O2-stabilized gliadin nanoparticles to be used for the potential oral administration of various compounds. Different techniques were used in order to evaluate their physico-chemical features and then in vivo studies in rats were performed for the investigation of their biodistribution and gastrointestinal transit profiles. The results showed that the gliadin nanoparticles accumulated in the mucus layer of the bowel mucosa and evidenced their ability to move along the digestive systems of the animals. The incubation of the nanosystems with Caenorhabditis elegans, used as an additional in vivo model, confirmed the intake of the particles and evidenced their presence along the entire gastrointestinal tract of these nematodes. The gliadin nanoparticles influenced neither the egg-laying activity of the worms nor their metabolism of lipids up to 10 μg/mL of nanoformulation. The systems decreased the content of the age-related lipofuscin pigment in the nematodes in a dose-dependent manner, demonstrating a certain antioxidant activity. Lastly, dihydroethidium staining showed the absence of oxidative stress upon incubation of the worms together with the formulations, confirming their safe profile. This data paves the way for the future application of the proposed nanosystems regarding the oral delivery of various bioactives., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Gemfibrozil (GEM) is a hypolipidemic agent, which is effective in reducing serum cholesterol and triglyceride levels. Complexation of GEM with native β-cyclodextrin (β-CD) and with the derivatives hydroxypropyl-β- and randomly methylated β-CD (HPβ-CD and Meβ-CD) was studied in aqueous solution of pH 2.8 and 7.0. The stability constants were determined by spectrofluorimetry, 1 H-NMR spectroscopy and solubility assays. Considering the well-known difficulties to obtain similar stability constants by different techniques, the agreement of the values obtained supports the reliability of the results presented. The advantages and drawbacks of each analytical technique for the study of inclusion complexation were discussed as well. In addition, the thermodynamic parameters of complexation, enthalpy (ΔH) and entropy (ΔS), were determined and related to the type of molecular interactions that take place between GEM and the different cyclodextrins. Finally, solid dispersions were prepared by co-evaporation, kneading, vacuum desiccation, and coprecipitation, and complexation was evaluated by X-ray diffraction.

The unexpected dissolution behaviour of amorphous diflunisal-chitosan solid dispersions (kneading method) with respect to the crystalline co-evaporated systems is the starting point of this research. This work is an in-depth study of the diflunisal release behaviour from either chitosan or carboxymethylchitosan dispersions. The microstructure is not usually considered when designing this type of products; however, it is essential to understand the process of solvent penetration and subsequent drug release through a polymeric system, as has been evidenced in this study. In accordance with the kinetic data analysed, it is possible to conclude that the porous structure, conditioned by the sample preparation method, can be considered the main factor involved in diflunisal release. The low mean pore size (1-2 μm), low porosity, and high tortuosity of the amorphous kneaded products are responsible for the slow drug release in comparison with the crystalline coevaporated systems, which exhibit larger pore size (8-10 μm) and lower tortuosity. Nevertheless, all diflunisal-carboxymethylchitosan products show similar porous microstructure and overlapping dissolution profiles. The drug release mechanisms obtained can also be related to the porous structure. Fickian diffusion was the main mechanism involved in drug release from chitosan, whereas an important contribution of erosion was detected for carboxymethylchitosan systems, probably due to its high solubility.

Inclusion complexation of rifampicin (RIF) with several types of cyclodextrins (βCD, hydroxypropyl-βCD, γCD, hydroxypropyl-γCD) in aqueous solutions at different pH values was investigated to assess the interactions between RIF and cyclodextrins (CDs). Molecular modeling was performed to determine the possible interactions between RIF and CDs at several pH values. The inclusion complexes were characterized by differential scanning calorimetry, Fourier transform infrared spectroscopy, powder X-ray diffractometry, and scanning electron microscopy. Moreover, this study evaluated the dissolution profile and antibacterial activity of the formed complexes. Phase solubility analysis suggested the formation of RIF-CD affirmed 1:1 stoichiometry at all pH values (except RIF-βCD at pH 4.0 and both βCD and γCD at pH 9.0). The inclusion complexation of RIF with CD successfully increased the percentage of RIF released in in vitro studies. The inclusion complexes of RIF exhibited more than 60% of RIF released in 2 h which was significantly higher ( p < 0.05) than release of pure RIF, which was only less than 10%. Antibacterial activity of RIF-CD complexes (measured by the minimum inhibitory concentration of RIF against Staphylococcus aureus and methicillin-resistant Staphylococcus aureus ) was lower for both RIF-βCD and RIF-HPγCD at pH 7.0 to pure RIF suspension. In conclusion, this work reports that both βCD and γCD can be used to enhance the solubility of RIF and thus, improve the effectivity of RIF by decreasing the required daily dose of RIF for the treatment of bacterial infections.

The aim of this work was to prepare and evaluate cyclodextrins-modified poly(anhydride) nanoparticles to enhance the oral administration of glibenclamide. A conjugate polymer was synthesized by incorporating hydroxypropyl-β-cyclodextrin to the backbone of poly(methylvinyl ether-co-maleic anhydride) via Steglich reaction. The degree of substitution of anhydride rings by cyclodextrins molecules was calculated to be 4.9% using H-NMR spectroscopy. A central composite design of experiments was used to optimize the preparative process. Under the optimal conditions, nanoparticles displayed a size of about 170 nm, a surface charge of -47 mV and a drug loading of 69 µg GB/mg. X-ray diffraction studies confirmed the loss of the crystalline structure of GB due to its dispersion into the nanoparticles, either included into cyclodextrin cavities or entrapped in the polymer chains. Glibenclamide was mainly release by Fickian-diffusion in simulated intestinal fluid. GB-loaded nanoparticles produced a hypolipidemic effect over C. elegans N2 wild-type and daf-2 mutant. The action mechanism included daf-2 and daf-28 genes, both implicated in the insulin signaling pathway of C. elegans. In summary, the covalent linkage of cyclodextrin to the poly(anhydride) backbone could be an interesting strategy to prepare nanoparticles for the oral administration of glibenclamide., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Nimodipine may be of interest to treat behavioral alterations and memory deficits. However, its oral administration is hampered by a low bioavailability. The aim of this work was to develop pegylated nanoparticles as oral carriers of nimodipine and test their capability to both reverse the anxiety and protect against cognitive impairment of in stressed mice. Pegylated nanoparticles (NMD-NP/PEG), with a size of 190 nm and a payload of 68 µg/mg, significantly improve the oral bioavailability of nimodipine; about 7-times higher than for the control drug solution (62% vs 9%). The effect of oral nimodipine on the anxiety and cognitive capabilities in a model of stressed mice was also evaluated. NMD-NP/PEG displayed a poor effect on the anxiety-like behavior of animals. Nevertheless, only the treatment with NMD-NP/PEG exerted a protective effect against the memory impairments induced by chronic corticosterone administration, improving the cognitive capabilities of animals when compared with controls. These pegylated nanocarriers may represent a useful strategy to develop new oral treatments for preventing from cognitive impairments., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Bevacizumab-loaded nanoparticles (B-NP) were prepared by a desolvation process followed by freeze-drying, without any chemical, physical or enzymatic cross-linkage. Compared with typical HSA nanoparticles cross-linked with glutaraldehyde (B-NP-GLU), B-NP displayed a significantly higher mean size (310 nm vs. 180 nm) and a lower negative zeta potential (-15 mV vs. -36 mV). On the contrary, B-NP displayed a high payload of approximately 13% when measured by a specific ELISA, whereas B-NP-GLU presented a very low bevacizumab loading (0.1 μg/mg). These results could be related to the inactivation of bevacizumab after reacting with glutaraldehyde. From B-NP, bevacizumab was released following an initial burst effect, proceeded by a continuous release of bevacizumab at a rate of 6 μg/h. Cytotoxicity studies in ARPE cells were carried out at a single dose up to 72 h and with repeated doses over a 5-day period. Neither bevacizumab nor B-NP altered cell viability even when repeated doses were used. Finally, B-NP were labeled with 99m Tc and administered as eye drops in rats. 99m Tc-B-NP remained in the eye for at least 4 h while 99m Tc-HSA was rapidly drained from the administration point. In summary, HSA nanoparticles may be an appropriate candidate for ocular delivery of bevacizumab., (Copyright © 2018 Elsevier B.V. All rights reserved.)

This work describes the feasibility of poly(anhydride) nanoparticles as carriers for the oral administration of glibenclamide (GB) as well as the in vivo evaluation of their hypolipidemic effect in a C. elegans model. For this purpose, and in order to increase the GB payload, the drug was encapsulated in nanoparticles in presence of cyclodextrins (either βCD or HPβCD). The optimized nanoparticles displayed a size of about 220 nm and a negative zeta potential (-40 mV), with a drug loading up to 52 μg/mg. Small-angle neutron scattering studies suggested an internal fractal-like structure, based on the repetition of spherical blocks of polymeric units (about 5 nm) grouped to form the nanoparticle. X-ray diffraction study confirmed the absence of crystalline GB molecules due to its dispersion into the nanoparticles, either entrapped in the polymer chains and/or included into cyclodextrin cavities. GB-loaded nanoparticles induced a significant reduction in the fat content of C. elegans. This hypolipidemic effect was slightly higher for the nanoparticles prepared with coencapsulated HPβCD (8.2%) than for those prepared with βCD (7.9%) or in the absence of cyclodextrins (7.0%). In summary, the coencapsulation of cyclodextrins into poly(anhydride) nanoparticles could be an interesting strategy to develop new oral formulations of glibenclamide., (Copyright © 2017 Elsevier B.V. All rights reserved.)

The aim of this work was to evaluate the capability of zein nanoparticles as oral carriers for glibenclamide (GB). Nanoparticles were prepared by a desolvation procedure in the presence of lysine as stabilizer. A central composite design was used to optimize this preparative process. Under the selected conditions, nanoparticles displayed a size of about 190 nm, a surface charge of -37mV and a payload of 45µg GB/mg. Small-angle neutron scattering and X-ray diffraction techniques suggested an internal fractal-like structure, based on the repetition of spherical blocks of zein units (about 20nm) grouped to form the nanoparticles. This structure, stabilized by lysine molecules located at the surface, would determine the release of GB (molecularly trapped into the nanoparticles) by a pure diffusion mechanism. Moreover, GB-loaded nanoparticles induced a significant hypolipidemic effect with a reduction of about 15% in the fat content of C. elegans worms. In addition, did not induce any significant modification in the lifespan of worms. In summary, the employment of zein nanoparticles as delivery systems of glibenclamide may be an interesting approach to develop new oral formulations of this antidiabetic drug., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Glibenclamide is an antidiabetic drug showing low bioavailability as consequence of its low solubility. To solve this drawback, the interaction with cyclodextrins has been proposed. The formation of GB-βCDs inclusion complexes was carried out using different methods, βCD derivatives and drug-to-cyclodextrin ratios. The structures of the corresponding complexes have been studied by molecular modelling, X-ray diffraction and differential thermal analysis. The dissolution behavior of inclusion complexes has been compared to that of pure GB. Dimeric inclusion complexes were obtained with different CD disposals, head-to-head for βCD and head-to-tail for HPβCD and RMβCD. Amorphous inclusion complexes were obtained by employing methods of freeze-drying or coevaporation in ammonia-water. However, crystalline structures were formed by kneading and coevaporation in ethanol/water in the case of GB-βCD complexes. The arrangement of these structures depended on the GB:βCD ratio, yielding cage type structures for 1:3 and 1:5 ratios and channel-type structures for higher GB contents. The amount of GB released and its dissolution rate was considerably increased by the use of amorphous inclusion complexes; whereas, slower GB release rates were found from crystalline inclusion complexes formed by kneading or coevaporation in ethanol/water. In addition, it was found that the porous structure strongly conditioned the GB dissolution rate from crystalline products., (Copyright © 2017 Elsevier B.V. All rights reserved.)

The sorption and release of tyrosol and caffeic acid, two biophenolic antioxidants with known health benefits, in different insoluble cyclodextrin polymers have been studied. Cyclodextrin polymers were synthesized by cross-linking β-cyclodextrin or 50:50 w/w nominal mixtures of α- and β-cyclodextrins using either epichlorohydrin (EP) or toluene-2,4-diisocyanate (TDI) as cross-linking agents. An analogous sucrose polymer was prepared using EP as cross-linking reagent. Freundlich isotherms and isosteric heats of sorption for tyrosol and caffeic acid in the insoluble β-cyclodextrin polymer cross-linked with epichlorohydrin at 50 °C were obtained and discussed. Finally, the release of tyrosol and caffeic acid has been studied from loaded polymer disks, the microstructures of which were characterized by mercury intrusion porosimetry. Caffeic acid shows greater affinity than tyrosol for the polymeric matrices as it presents a higher sorption and a lower and slower release. However, tyrosol has a higher isosteric heat of sorption for low coverages.

Glibenclamide is a sulfonylurea used for the oral treatment of type II diabetes mellitus. This drug shows low bioavailability as consequence of its low solubility. In order to solve this problem, the interaction with cyclodextrin has been proposed. This study tries to provide an explanation about the processes involved in the formation of GB-βCDs complexes, which have been interpreted in different ways by several authors. Among native cyclodextrins, βCD presents the most appropriate cavity to host glibenclamide molecules showing A L solubility diagrams (K 1:1 ≈1700M -1 ). However, [Formula: see text] solubility profiles were found for βCD derivatives, highlighting the coexistence of several phenomena involved in the drug solubility enhancement. At low CD concentration, the formation of inclusion complexes can be studied and the stability constants can be calculated (K 1:1 ≈1400M -1 ). Whereas at high CD concentration, the enhancement of GB solubility would be mainly attributed to the formation of nanoaggregates of CD and GB-CD complexes (sizes between 100 and 300nm). The inclusion mode into βCD occurs through the cyclohexyl ring of GB, adopting a semi-folded conformation which maximizes the hydrogen bond network. As consequence of all these phenomena, a 150-fold enhancement of drug solubility has been achieved using β-cyclodextrin derivatives. Thus, its use has proven to be an interesting tool to improve the oral administration of glibenclamide in accordance with dosage bulk and dose/solubility ratio requirements., (Copyright © 2017 Elsevier B.V. All rights reserved.)

The interactions of diflunisal (DF) with chitosans (CS) of different molecular weights and carboxymethylchitosan (CMCS), a water-soluble derivative, have been investigated. The interactions in solution have been studied by solubility assays in which the highest solubilisation (13-fold) was obtained with CMCS. Solid dispersions were prepared by coevaporation and kneading methods. Solid state characterisation was performed by X-ray diffraction analysis, scanning electron microscopy, thermomicroscopy, differential thermal analysis and infrared spectroscopy. Drug-polymer electrostatic interactions and hydrogen bonds are the main binding forces in these systems. The kneading method gave rise to amorphous systems regardless of the polymer employed. However, coevaporation resulted in the formation of different polymorphs of diflunisal (form II or III) depending on the type of polymer used. Therefore, it seems that drug-polymer interactions determine the crystallization pattern of the drug. Finally, diflunisal release from these systems improved markedly with CMCS and significantly in the presence of low molecular weight CS., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Tyrosol and caffeic acid are biophenols that contribute to the beneficial properties of virgin olive oil. The influence of hydroxypropyl-β-cyclodextrin (HPβ-CD) on their respective antioxidant capacities was analyzed. The ORAC antioxidant activity of tyrosol (expressed as μM Trolox equivalents/μM Tyrosol) was 0.83 ± 0.03 and it increased up to 1.20 ± 0.11 in the presence of 0.8 mM HPβ-CD. However, the ORAC antioxidant activity of caffeic acid experienced no change. The different effect of HPβ-CD on each compound was discussed. In addition, the effect of increasing concentrations of different cyclodextrins in the development of ORAC-fluorescence (ORAC-FL) assays was studied. The ORAC signal was higher for HPβ-CD, followed by Mβ-CD, β-CD, γ-CD and finally α-CD. These results could be explained by the formation of inclusion complexes with fluorescein.

Background: The influence of beta-cyclodextrin (beta-CD) polymers on drug release from hydroxypropyl methylcellulose (HPMC) matrices has not been reported in the literature., Aim: The influence of monomeric beta-CD and both soluble and insoluble beta-CD polymers on drug release from tablets containing either 30% or 50% hydroxypropyl methylcellulose has been studied using diflunisal (DF) as model drug., Method: The DF-beta-CD inclusion complex (1:1 M) was prepared by coevaporation and characterised using X-ray diffraction, differential thermal analysis, and IR spectroscopy. The dissolution assays were performed according to the USP paddle method., Results: The incorporation of beta-CD in the complexed form increases drug release from hydroxypropyl methylcellulose tablets in comparison with the physical mixture because of the better solubilization of the drug. The soluble polymer promotes drug release to a higher extent than the physical mixture with monomeric beta-CD, but the insoluble polymer, which is itself a hydrogel, gives rise to the most retarded release profile, probably by retention of the drug in its structure. The formulations containing physical mixtures with either beta-CD or the soluble polymer present an optimum adjustment to zero-order release kinetics, and the inclusion complex followed non-Fickian diffusion according to the Korsmeyer-Peppas model., Conclusion: The release profile of DF from a HPMC matrix can be modulated in different ways by the use of either monomeric or polymeric beta-CD.

The interactions of gemfibrozil with gamma- and HP-gamma-cyclodextrin (CD) have been studied in aqueous solution by fluorescence and NMR spectroscopy and by solubility measurements and in the solid state by X-ray diffraction, thermal analysis and FTIR spectroscopy. The influence of the technique employed in the analysis of complexation is discussed. The fluorescence of gemfibrozil increased in the presence of gamma- and hydroxypropyl-gamma-cyclodextrin (HP-gamma-CD), especially with the later, because the inclusion of the aromatic ring in the cavity, evidenced by 1H NMR, has a protective effect on the excited state of the drug. The fluorescence enhancement allowed the determination of the binding constants at pH 2.8. Complexation was a both entropy and enthalpy driven process. The solubility diagrams obtained with gamma-CD and HP-gamma-CD were B(s) and A(L) type, respectively. The apparent stability constants calculated from the solubility data at 25 degrees C were compared with those obtained from the fluorescence assays. It was found that drug solubilization with gamma-CD involves other contributions together with the inclusion phenomena. Solid complexes of gemfibrozil with gamma-CD (and not with HP-gamma-CD) have been obtained by kneading, coevaporation and coprecipitation methods. The solid complexes crystallised in the channel structure, in a process involving the carboxyl and aryl-ether groups.

Naftifine (NF) is an antifungal drug poorly soluble in basic aqueous solutions. Complexation with cyclodextrins (CDs) improves the physicochemical characteristics of many drugs. The aim of this work is to characterize the interactions between NF and alpha-CD, beta-CD, hydroxypropylbeta-CD, methylbeta-CD, and gamma-CD. The studies have been developed in pH 12 aqueous solutions at 25 degrees C and in the solid state. The apparent stability constants of the complexes have been determined from phase-solubility diagrams. In the solid state, crystalline and amorphous complexes have been characterized using X-ray diffraction patterns, thermal analysis, and Fourier transform infrared spectroscopy. The solubility of NF improves with all the CDs studied, with the exception of alpha-CD. Different types of diagrams have been found depending on the CD used. The interaction between NF and hydroxypropylbeta-CD is stronger than that with beta-CD due to the specific properties of the substituents. The coevaporation method can be said the best method in preparing the solid complexes, except for NF-alpha-CD; again, there is no evidence of complexation. Furthermore, the presence of different types of CD structures upon complexation (i.e., cage or channel) has been discussed. Dissolution rate studies have been performed, and a positive influence of complexation in the solid state has been observed.

Coprecipitates of diflunisal and polyvinylpyrrolidone (PVP K15, K30, and K90) and physical mixtures were studied using x-ray diffraction analysis, infrared (IR) spectroscopy, differential scanning calorimetry (DSC), and hot-stage microscopy. X-ray diffraction results revealed an almost amorphous state, even in coprecipitates with a high content of drug, next to 70%, which was independent of the polymer molecular weight. The IR spectra of 70:30 drug-PVP solid dispersions suggest the formation of diflunisal-PVP hydrogen bonds. For 70:30 drug-polymer ratio, the physical mixture showed linear dissolution kinetics of free crystals, but the corresponding coprecipitates exhibit two different dissolution processes. When the 25:75 drug-polymer dispersion is analyzed by hot-stage microscopy, only solid plates of PVP are observed; the absence of drug particles may be due to a molecular dispersion of the drug into the polymer. Moreover, polymorphic changes of diflunisal were detected in the solid dispersions in comparison with the corresponding physical mixtures, which are always formed by polymorph II. At high concentrations of drug (75:25 and 80:20), x-ray diffraction patterns of solid dispersions showed the partial recrystallization of the drug, displaying the main diffraction peaks of polymorph I when ethanol was used as coprecipitation solvent, whereas diflunisal form IV was obtained in chloroform.

Fluorescence, (1)H-NMR and molecular mechanics have been used to study the inclusion complexes of nabumetone (4,6-methoxy-2-naphthyl-butan-2-one; NAB) with beta-cyclodextrin (beta-CD), randomly methylated-beta (M beta-CD) and hydroxypropyl-beta-cyclodextrins (HP beta-CD). The emission spectrum of NAB shows a maximum whose fluorescence intensity increases with the different beta-CDs growing concentrations. This phenomenon allows calculation of the stability constants at 15, 25, 37 and 45 degrees C. The thermodynamic parameters Delta H degrees and Delta S degrees for the inclusion process were obtained from the temperature dependence of the stability constants. Molecular mechanics calculations, together with proton NMR measurements, for the complex with beta-CD prove that the complex can be formed by penetration through any of the rims, with the naphthalene nucleus included and the substituents outside the cavity. The influence of NaClO(4) in the aforementioned complexes has been analysed by spectrofluorimetric measurements. It has been found that the stability constants for the complexes decrease with the salt concentration; the causes are discussed., (Copyright-Copyright 2001 John Wiley & Sons, Ltd.)

The polymorphism of glisentide has been investigated. Three polymorphs (I, II, III) have been prepared by recrystallization from different solvents and other polymorphic form (IV) was obtained by heating polymorph III at 100 degrees C. In addition, two 1:1 stoichiometric solvates containing carbon tetrachloride and dioxane have been crystallized and finally, an amorphous solid has been obtained. It has been observed that the polarity of the recrystallisation solvent and its ability to form hydrogen bonds have a great influence on the polymorphism of glisentide. The different solid forms of glisentide have been characterized using X-ray diffraction analysis, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), IR spectroscopy and optical microscopy. The recrystallization of polymorph I in melted form II and also the transition of form III-IV have been detected by DSC and X-ray diffraction analysis.

The present study was carried out to investigate the physico-chemical characteristics of diflunisal-PEG 4000 solid dispersions prepared by melting, solvent and melting-solvent methods. The solvents chosen were chloroform, methanol and ethanol-water due to the fact that the drug presents different polymorphic forms in these solvents. The characterization of solid dispersions was performed by X-ray powder diffraction because this technique has the advantage over other identification methods that it can detect both drug and ligand simultaneously. The X-ray diffraction patterns of the diflunisal-PEG systems suggested that the drug/polymer ratio and the solvent nature play an important role in the crystallization of the drug. In this regard, diflunisal crystallizes in form I at high concentrations of the drug (drug/polymer 2:1) in the solidified melt dispersions, however, polymorph III is mainly obtained as the polymer content increases (1:1 and 2:3). Likewise, in solid systems obtained by the solvent and melting solvent methods the drug solidifies in form III in ethanol/water and methanol while polymorph IV crystallizes in chloroform. Finally, DSC thermograms and hot-stage microscopy data of solid dispersions prepared by the melting method have allowed to draw the diflunisal-PEG 4000 solid-liquid phase diagram.

Naproxen is a nonsteroidal anti-inflammatory drug characterized by its low wettability and poor water solubility. Solid dispersions naproxen:PEG 4000 have been prepared in order to improve the solubility and dissolution rate of the drug, since these factors can be the limiting steps for absorption and bioavailability of poorly soluble drugs. X-ray diffraction analysis, infrared spectroscopy and differential scanning calorimetry detected no physico-chemical interaction between the drug and the inert carrier PEG 4000. The phase diagram of the naproxen-PEG 4000 system produced by DSC and hot stage microscopy is reported. The intrinsic dissolution rate of naproxen is calculated. The dissolution kinetics of solid dispersions prepared by the solvent and melt methods are compared with those of free drug and physical mixture. The studies were carried out at 37 degrees C and pH 1.2 according to the dispersed amount method. The dissolution profiles obtained indicate that a significant dissolution enhancement occurs with solid dispersions in comparison with the physical mixture. In addition, the physical mixture showed a dissolution rate higher than the free drug. Dissolution rate constants were determined by fitting the experimental data to the cube root function, to get straight line plots.

Diflunisal is a nonsteroidal anti-inflammatory drug that is poorly soluble in water. The present study describes the formulation of solid dispersions of the drug designed to increase its solubility. X-ray diffraction and DSC were used to examine the physico-chemical characteristics of solid dispersions of diflunisal and polyvinylpyrrolidone (PVP) prepared by the solvent method, using percentage proportional compositions ranging from 20:80 to 50:50. X-ray diffraction analysis detected that diflunisal is present in solid dispersions in crystalline or amorphous state depending on the PVP content. The thermal behavior of diflunisal observed in the DSC curves of solid dispersion systems, was attributed to a solid-state interaction. The increased release of the PVP-drug dispersion as compared to the PVP-drug physical mixture was attributed to the formation of a complex resulting from the interaction of the drug and the polymer.

A sulindac-beta-cyclodextrin complex was obtained by the coprecipitation method. Kneaded solids and physical mixtures were also prepared. The complex was shown by x-ray powder diffraction to be noncrystalline whereas pure drug and any of the other sulindac-beta-CD system were crystalline. the endothermic peak of sulindac due to the fusion of drug disappeared in DSC thermograms for the coprecipitate product, which confirmed the interaction between sulindac and beta-CD in the solid state. After a 1-year storage drug crystals could not be observed by x-ray diffractometry, which indicated that the complex formed was stable. The complex showed the fastest dissolution rate which might be attributed to the high-energy noncrystalline state and the inclusion complex formation in solution. UV spectra were modified and the apparent solubility of the drug increased with the addition of beta-CD, which confirmed the interaction between sulindac and the ligand in solution. The apparent stability constant, K1:1, for the complex at pH 2 and 25, 30, and 37 degrees C was 340, 220, and 160 M-1, respectively, which confirmed the influence of temperature on the complex stability. The value of K1:1 at pH 6 and 25 degrees C was 139 M-1, which indicated that the complex is formed easier with the non-ionized sulindac. The enthalpy change, delta H degree, showed that the binding process is exothermic.

In this report the interactions of sulindac with polyvinylpyrrolidone K30 (PVP K30), both in the solid state and in aqueous solution, have been investigated. Solid dispersions of sulindac with PVP K30 were prepared by the solvent method in ethanol from various drug-to-polymer weight ratios. X-ray powder diffraction and differential scanning calorimetry have shown that PVP inhibits the crystallization of sulindac. The stabilization of the noncrystalline state of sulindac was shown by x-ray diffractometry after a 1-year storage. There was a considerable increase in the release rate of the drug when the polymer content was increased and the intrinsic dissolution rate values of these systems were calculated. From the UV spectra a bathochromic shift and a well-defined isosbestic point were observed at pH 2 and 6, which confirmed an interaction between the drug and the polymer in solution. Moreover, the apparent solubility of sulindac has been modified as a function of the polymer concentrations. The binding process between the drug and PVP was exothermic from the stability constant values at 25, 30, and 37 degrees C at pH 2.

The polymorphism of sulindac was investigated. Two polymorphs (I and II) and a new crystalline form (form III) of sulindac were prepared by recrystallization in different solvents. In addition, three new pseudopolymorphs (solvates) from acetone, chloroform, and benzene were obtained, with each containing 1 mol of solvent to 2 mol of sulindac. Different sulindac polymorphs and pseudopolymorphs were characterized by X-ray diffractometry, infrared spectroscopy, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), and hot-stage microscopy. The transition behavior of the crystalline forms of sulindac, their melting points, and their enthalpies were investigated by DSC. The melting of form II was observed at 184 degrees C, and form I subsequently recrystallized from this melt. Similarly, form III melts at 145 degrees C and then recrystallizes to form I. We also investigated the influence of the crystallization solvent on sulindac crystal shape.

Three polymorphs (I, II, and III forms) and a new crystal form (form IV) of diflunisal were prepared and characterized by powder X-ray diffractometry, differential scanning calorimetry (DSC), hot-stage microscopy, IR spectroscopy, and dissolution studies. According to the different X-ray diffraction profiles, an identification system for the polymorphs can be developed based on the different peak positions of the diffraction patterns. The mutual transition behavior of the polymorphs was investigated and the melting points and melting enthalpies were determined from DSC and thermomicroscopy data. All forms first recrystallize to the more stable form (form I) and then melt at 210 degrees C; only one weak transition peak was detected corresponding to transformation of form III to form I. Differences observed in IR spectra indicate that intramolecular hydrogen bonding occurs between hydroxyl and carbonyl groups and/or between fluorine atoms. The intrinsic dissolution rates were determined from compressed disks in an aqueous medium. Unexpectedly the dissolution rate of form IV was lower than that of the most stable modification form I.