Conformational analysis and spectroscopic properties of antichagasic nifurtimox.

Considering the health relevance of Chagas' disease, recent research efforts have focused on developing more efficient drug delivery systems containing nifurtimox (NFX). This paper comprehensively investigates NFX through conformational analysis and spectroscopic characterization. Using a conformer-rotamer ensemble sampling tool (CREST-xtb), five distinct conformers of NFX were sampled within a 3.0 kcal mol-1 relative energy window. Subsequently, such structures were used as inputs for geometry optimization by density functional theory (DFT) at B3LYP-def2-TZVP level of theory. Notably, harmonic vibrational frequencies were calculated to establish an in-depth comparison with experimental results and existing literature for the NFX or similar molecules and functional groups, thereby achieving a widely reasoned assignment of the mid-infrared band absorptions for the first time. Moreover, UV-VIS spectra of NFX were obtained in several solvents, enabling the determination of the molar absorptivity coefficient for the two electronic transitions observed for NFX. Among the aprotic solvents, a bathochromic effect was observed in the function of the dielectric constants. Furthermore, a hypochromic effect was observed when the drug was dissolved in protic solvents. These findings offer crucial support for new drug delivery systems containing NFX while demonstrating the potential of spectrophotometric studies in establishing quality control assays for NFX drug products.

Melt crystallization and thermal degradation profile of the antichagasic drug nifurtimox.

Despite nifurtimox (NFX) being a traditional drug for treating Chagas disease, some of its physicochemical properties are still unknown, especially its thermal behavior, which brings important outcomes regarding stability and compatibility. In this work, a comprehensive study of NFX's thermal properties was conducted to assist incremental innovations that can improve the efficacy of this drug in novel pharmaceutical products. For this purpose, thermal analyses associated with spectroscopy and spectrometry techniques were used. DSC analyses revealed that the melt crystallization of the NFX led to its amorphous form with the possible formation of a minor fraction of a different crystalline phase. Coats-Redfern method using TGA results indicated the activation energy of NFX non-isothermal degradation as 348.8 ± 8.2 kJ mol-1, which coincides with the C-NO2 bond dissociation energy of the 2-nitrofuran. Investigation of the isothermal degradation kinetics using FTIR 2D COS showed the possible detachment of radical NO2 and ethylene from the NFX structure, which could affect its mechanism of action. A preliminary mechanism for the thermal degradation of this drug was also proposed. The results enhanced the understanding of NFX's thermal properties, providing valuable insights, especially for developing NFX-based pharmaceutical products that involve thermal processing.

Preformulation and Long-Term Stability Studies of an Optimized Palatable Praziquantel Ethanol-Free Solution for Pediatric Delivery.

To date, the treatment for cysticercosis and neurocysticercosis consists of a single oral intake of praziquantel (5-10 mg/kg), which since it is only available as tablets, hinders its administration to pediatric patients. Praziquantel is a poorly water-soluble drug which represents a challenge for its formulation in solution, particularly for the pediatric population. Thus, this study aimed to develop a palatable solution for praziquantel using pharmaceutical-accepted co-solvent systems. A design of experiments approach was applied to identify the optimal conditions for achieving a suitable amount of praziquantel in solution using co-solvent mixtures. Thus, praziquantel solubility increased from 0.38 up to 43.50 mg/mL in the optimized system. A taste masking assay in healthy human volunteers confirmed a successful reduction of drug bitterness after the addition of selected flavors and a sweetener. Stability studies were also conducted at different temperatures (4, 25, and 40 °C) for 12 months Even though the presence of the three known impurities of praziquantel was observed, their amounts never exceeded the acceptance criteria of the USP. Thus, this novel approach should be considered a valuable alternative for further preclinical studies considering the high prevalence of this infection worldwide.

Formulation of benznidazole-lipid nanocapsules: Drug release, permeability, biocompatibility, and stability studies.

Benznidazole, a poorly soluble in water drug, is the first-line medication for the treatment of Chagas disease, but long treatment periods at high dosages cause several adverse effects with insufficient activity in the chronic phase. According to these facts, there is a serious need for novel benznidazole formulations for improving the chemotherapy of Chagas disease. Thus, this work aimed to incorporate benznidazole into lipid nanocapsules for improving its solubility, dissolution rate in different media, and permeability. Lipid nanocapsules were prepared by the phase inversion technique and were fully characterized. Three formulations were obtained with a diameter of 30, 50, and 100 nm and monomodal size distribution with a low polydispersity index and almost neutral zeta potential. Drug encapsulation efficiency was between 83 and 92 % and the drug loading was between 0.66 and 1.04 %. Loaded formulations were stable under storage for one year at 4 °C. Lipid nanocapsules were found to protect benznidazole in simulated gastric fluid and provide a sustained release platform for the drug in a simulated intestinal fluid containing pancreatic enzymes. The small size and the almost neutral surface charge of these lipid nanocarriers improved their penetration through mucus and such formulations showed a reduced chemical interaction with gastric mucin glycoproteins. LNCs. The incorporation of benznidazole in lipid nanocapsules improved the drug permeability across intestinal epithelium by 10-fold compared with the non-encapsulated drug while the exposure of the cell monolayers to these nanoformulations did not affect the integrity of the epithelium.

Solving the delivery of Lactococcus lactis: Improved survival and storage stability through the bioencapsulation with different carriers.

Probiotics are live microorganisms that confer beneficial effects on the health of the host if administered in adequate amounts (106  CFU viable microorganisms/g of food). As the most frequent route of administration of these microorganisms is oral, the number of them that remains viable through the gastrointestinal tract decreases substantially. Thus, in this research work, we developed a series of alginate-based microparticles using different adjuvants such as methylcellulose, carboxymethylcellulose, chitosan, carbopol, ß-cyclodextrin, starch, carrageenan, and Eudragit® RS 100 as carriers for improving the survival of Lactococcus lactis. The alginate-based formulations exhibited very good drug encapsulation efficiency, up to 90%. Release studies from selected microparticles revealed that almost 100% of bacteria were in solution at 30 min. By scanning electron microscopy, irregular nonporous particles with a size between 200 and 500 µm were seen. In particular, microparticles formulated with alginate-carboxymethylcellulose and alginate-methylcellulose exhibited the best protection for the bacterial cells against both simulated gastric juice and simulated intestinal juice. In addition, those microparticulate systems were able to maintain the viability of the encapsulated bacteria in large numbers for at least 24 weeks. Thus, the present study confirmed that these alginate-based microparticles are a valuable approach for keeping the viability and storage stability of L. lactis.

Improving the oral delivery of benznidazole nanoparticles by optimizing the formulation parameters through a design of experiment and optimization strategy.

Chagas disease is a neglected tropical disease affecting the American continent and also some regions of Europe. Benznidazole, approved by FDA, is a drug of choice but its poor aqueous solubility may lead to a low bioavailability and efficacy. Therefore, the aim of this study was to formulate nanoparticles of benznidazole for improving its solubility, dissolution and permeability. A Plackett-Burman design was applied to identify the effect of 5 factors over 4 responses. Then, a Central Composite design was applied to estimate the values of the most important factors leading to the best compromise between highest nanoprecipitation efficiency, drug solubility and lower particle size. The optimized nanoparticles were evaluated for in vitro drug release in biorelevant media, stability studies and transmission electron microscopy. Biocompatibility and permeability of nanoparticles were evaluated on the Caco-2 cell line. The findings of the optimization process indicated that concentration of drug and stabilizer influenced significantly the particle size while concentration of stabilizer and organic/water phase volume ratio mainly influenced the drug solubility. Stability studies suggested that benznidazole nanoparticles were stable after 12 months at different temperatures. Minimal interactions of those nanoparticles and mucin glycoproteins suggested favorable properties to address the intestinal mucus barrier. Cell viability studies confirmed the safety profile of the optimized formulation and showed an increased permeation through the Caco-2 cells. Thus, this study confirmed the suitability of the design of experiment and optimization approach to elucidate critical parameters influencing the quality of benznidazole nanoparticles, which could lead to a more efficient management of Chagas disease by oral route.

The Effect of Different Formulations of Praziquantel in Reducing Worms in the Prepatent Period of Schistosomiasis in Murine Models.

Schistosomiasis is a widely distributed parasitic disease and one of the most important neglected tropical diseases globally, for which Praziquantel® (PZQ) is the only available treatment. In this context, tests with new PZQ formulations become relevant for disease control. This study evaluated the effects of PZQ treatment in the prepatent phase of schistosomiasis using two formulations: nanoencapsulated (PZQ-NANO) and active pharmaceutical ingredient (PZQ-API). Five experimental groups were established, for which the following serological parameters were evaluated: ALT, AST, ALP, and TP. Animals treated with PZQ-API at 15 and 30 days post-infection showed decreased eggs per gram of feces (EPG) compared to untreated infected animals. The same animals showed reductions of 63.6 and 65.1%, respectively, at 60 days post-infection. Animals treated with PZQ-NANO experienced no significant changes in EPG at any time of observation. Animals treated with either PZQ-API or PZQ-NANO had higher ALT and AST levels in the patent period (60 and 90 days post-infection). Treatment with PZQ, either API or NANO, at 15 days post-infection reduced AST, ALT, and TP levels. It is concluded that prepatent treatment with PZQ-API can reduce the parasite load of infected animals and that treatment at 15 days post-infection can prevent increased serum levels of ALT, AST, and TP.

Design and optimization of pH-sensitive Eudragit nanoparticles for improved oral delivery of triclabendazole.

Design of Experiments (DoE) techniques were used to identify and optimize the parameters involved in the formulation of triclabendazole pH-sensitive Eudragit® nanoparticles (NPs). Using a Placket Burmann design, Eudragit® E, Eudragit® RS, and two stabilizers (PVP and PVA) were evaluated for NPs formulation by nanoprecipitation. Based on the screening results, Eudragit E 100® and PVP were selected as excipients, and their levels were studied and optimized using a central composite design, obtaining an optimum nanoparticulated system with a Size of 240 nm, a PDI of 0.420, and a ZP of 46.3 mV. Finally, a full characterization of the optimum system was carried out by XRD, DSC, equilibrium solubility, and dissolution rate in biorelevant mediums. As observed in XRD and DSC, the nanoencapsulation process produced a remarkable reduction in drug crystallinity that improved drug solubility and dissolution rate. Although more than 90% of TCBZ was dissolved in acidic mediums at 10 min, no increase in solubility or dissolution rate was observed in simulated saliva. Consequently, the development of pH-sensitive Eudragit® NPs would be a promising strategy in developing an immediate gastric release TCBZ formulation for oral delivery.

Surfactant-Free Glibenclamide Nanoparticles: Formulation, Characterization and Evaluation of Interactions with Biological Barriers.

PURPOSE: The aim of this work was to formulate and characterize surfactant-free glibenclamide nanoparticles using Eudragit RLPO and polyethylene glycol as sole stabilizer. METHODS: Glibenclamide nanoparticles were obtained by nanoprecipitation and evaluated in terms of drug content, encapsulation efficiency, apparent saturation solubility, drug release profile, solid state and storage stability. The influence of different stirring speed on the particle size, size distribution and zeta potential of the nanoparticles was investigated. The nanoparticle biocompatibility and permeability were analyzed in vitro on Caco-2 cell line (clone HTB-37) and its interaction with mucin was also investigated. RESULTS: It was found that increasing the molecular weight of polyethylene glycol from 400 to 6000 decreased drug encapsulation, whereas the aqueous solubility and dissolution rate of the drug increased. Particle size of the nanoformulations, with and without polyethylene glycol, were between 140 and 460 nm. Stability studies confirmed that glibenclamide nanoparticles were stable, in terms of particle size, after 120 days at 4°C. In vitro studies indicated minimal interactions of glibenclamide nanoparticles and mucin glycoproteins suggesting favorable properties to address the intestinal mucus barrier. Cell viability studies confirmed the safety profile of these nanoparticles and showed an increased permeation through epithelial cells. CONCLUSION: Taking into consideration these findings, polyethylene glycol is a useful polymer for stabilizing these surfactant-free glibenclamide nanoparticles and represent a promising alternative to improve the treatment of non-insulin dependent diabetes.

Elucidating the Splitting Behavior of Tablets to Optimize the Pharmacotherapy in Veterinary Medicine.

It is well known that the splitting of tablets can bring serious risks to the health of the treated animals, e.g., the possible adverse reactions caused by overdoses of fenbendazole or aspirin. In this regard, this work aimed to evaluate, for the first time, the splitting behavior of commercial veterinary tablets and identifying the technological aspects that interfere in this process. Tablets were cut in halves using a tablet splitter and were analyzed regarding mass variation, mass loss, friability, and hardness. Microstructural and morphological evaluations were also performed. For most of the tablets, organic flavor additives provided more uniformity and cohesive matrix, which preserved its hardness after the cut and led to subdivision results within acceptable limits for mass measurements and friability. Apart from the microstructure, the most critical technological aspect for a correct splitting performance in such tablets was the presence of a score. Thus, the results presented here allow us to guide the manufacturing of veterinary drug products in order to produce tablets more adapted to the splitting process.

In vitro studies and preclinical evaluation of benznidazole microparticles in the acute Trypanosoma cruzi murine model.

Chagas disease is a serious parasitic infection caused by Trypanosoma cruzi. Unfortunately, the current chemotherapeutic tools are not enough to combat the infection. The aim of this study was to evaluate the trypanocidal activity of benznidazole-loaded microparticles during the acute phase of Chagas infection in an experimental murine model. Microparticles were prepared by spray-drying using copolymers derived from esters of acrylic and methacrylic acids as carriers. Dissolution efficiency of the formulations was up to 3.80-fold greater than that of raw benznidazole. Stability assay showed no significant difference (P > 0.05) in the loading capacity of microparticles for 3 years. Cell cultures showed no visible morphological changes or destabilization of the cell membrane nor haemolysis was observed in defibrinated human blood after microparticles treatment. Mice with acute lethal infection survived 100% after 30 days of treatment with benznidazole microparticles (50 mg kg-1 day-1). Furthermore, no detectable parasite load measured by quantitative polymerase chain reaction and lower levels of T. cruzi-specific antibodies by enzyme-linked immunosorbent assay were found in those mice. A significant decrease in the inflammation of heart tissue after treatment with these microparticles was observed, in comparison with the inflammatory damage observed in both infected mice treated with raw benznidazole and untreated infected mice. Therefore, these polymeric formulations are an attractive approach to treat Chagas disease.

Nanodelivery of nitazoxanide: impact on the metabolism of Taenia crassiceps cysticerci intracranially inoculated in mice.

Aim: To formulate nanocapsules and nanoemulsions of nitazoxanide (NTZ) and evaluate the metabolic effect on Taenia crassiceps cysticerci inoculated intracranially into mice. Materials & methods: NTZ nanosystems were formulated through solvent diffusion methodology. These nanoformulations were administered perorally and their impact on glycolysis, the tricarboxylic acid cycle and fatty acid metabolism in T. crassiceps cysticerci was investigated. Results: Gluconeogenesis and protein catabolism were significantly increased by the nanoformulations when compared with the control group and the NTZ-treated group. All the other metabolic pathways were inhibited by the nanoformulation treatments. Conclusion: The remarkable metabolic modifications that occur in this in vivo model through the application of these developed nanosystems confirm their capability to deliver NTZ into targeted tissues.

A Novel Prototype Device for Microencapsulation of Benznidazole: In Vitro/In Vivo Studies.

This study was aimed to design a simple and novel prototype device for the production of polymeric microparticles. To prove the effectiveness of this device, benznidazole microparticles using chitosan as carrier and NaOH, KOH, or SLS as counter ions were used. For comparison, benznidazole microparticles were prepared by the conventional dripping technique (syringe and gauge) using the same excipients. Microparticles were characterized in terms of encapsulation efficiency, particle shape, size and surface topography, crystallinity characteristics, thermal behavior, and dissolution rate. Then, the pharmacokinetic parameters were evaluated after the oral administration of the microparticles to healthy Wistar rats. The prepared formulations, by means of this device, showed good drug encapsulation efficiency (> 70%). Release studies revealed an increased dissolution of benznidazole from chitosan microparticles prepared using the novel device. It achieved more than 90% in 60 min, while those of the conventional microparticles and raw drug achieved 65% and 68%, respectively, during the same period. Almost spherical benznidazole microparticles with a smooth surface and size around 10-30 µm were observed using scanning electron microscopy. Thermal analysis and X-ray diffraction studies suggested a partial reduction of drug crystallinity. Moreover, the relative oral bioavailability of the novel benznidazole microparticles showed that the area under the curve for the microencapsulated drug was 10.3 times higher than the raw drug. Thus, these findings indicate that the designed glass prototype device is a useful alternative to formulate benznidazole polymeric microparticles with improved biopharmaceutical properties and could be useful for other therapeutic microparticulate systems.

Improving the Dissolution of Triclabendazole from Stable Crystalline Solid Dispersions Formulated for Oral Delivery.

Triclabendazole belongs to the class II/IV of the Biopharmaceuticals Classification System, and its low aqueous solubility represents a major drawback during the development of effective dosage forms. Therefore, the goal of this study was to elucidate whether polymeric solid dispersions would represent a suitable approach to overcome such disadvantage. Due to the lack of information on triclabendazole release, four different dissolution media were evaluated to analyze drug dissolution rate. The polymeric solid dispersions were characterized by X-ray diffraction and Fourier transform infrared spectroscopy. The selected final formulations were further stored for 24 months, and their physical stability was evaluated by means of X-ray diffraction and drug dissolution assays. Drug solubility studies indicated that poloxamer 407 (P407) solubilized a higher amount of drug than polyethylene glycol 6000. Drug-to-carrier ratio, nature of the selected carriers, and the type of dissolution media were important factors for increasing dissolution. By infrared spectroscopy, there were no specific interactions between the drug and polymers. The physicochemical characterization of the systems showed a detectable evidence of drug amorphization by increasing the carrier ratio. Micromeritic studies indicated that raw triclabendazole, physical mixtures, and reference formulation showed poor flow properties, in contrast to the triclabendazole:P407 solid dispersion sample. Both the crystalline properties and dissolution rate of selected samples were very similar after 24 months at room temperature. Thus, considering physical stability and dissolution studies, the development of the solid dispersion is a very suitable methodology to improve triclabendazole dissolution and, potentially, its biopharmaceutical performance.

Nanocarriers for effective delivery of benznidazole and nifurtimox in the treatment of chagas disease: A review.

Neglected tropical diseases (NTDs) constitute a group of infectious diseases prevalent in countries with tropical and subtropical climate that affect the poorest individuals and produce high chronic disability associated with serious problems for the health system and socioeconomic development. Chagas disease or American trypanosomiasis is included on the NTDs list. However, even though this disease affects more than 10 million people, mostly in Latin America, causing the death of over 10,000 people every year, only two drugs are approved for its treatment, benznidazole and nifurtimox. These antiparasitic agents were developed almost half a century ago and present several biopharmaceutical disadvantages such as low aqueous solubility and permeability limiting their bioavailability. In addition, both therapeutic agents are available only as tablets and a liquid pediatric formulation is still lacking. Therefore, novel pharmaceutical strategies to optimize the pharmacotherapy of Chagas disease are urgently required. In this regard, nanotechnological approaches may be a crucial alternative for the delivery of both drugs ensuring an effective pharmacotherapy although the successful bench-to-bedside translation remains a major challenge. The present work reviews in detail the formulation and in-vitro/in-vivo analysis of different nanoformulations of nifurtimox and benznidazole in order to enhance their solubility, dissolution, bioavailability and trypanocidal activity.

Development and characterization of benznidazole nano- and microparticles: A new tool for pediatric treatment of Chagas disease?

Benznidazole (BNZ) is the drug of choice for the treatment of Chagas disease in many countries. However, its low water solubility produces low and/or variable oral bioavailability. Thus, the aim of this work was to formulate micro- and nanoparticles based on Eudragit® RS PO and Eudragit® RL PO as a convenient approach to increase the dissolution rate of BNZ. The microparticles were obtained by means of spray-drying process while the nanoparticles were prepared through the nanoprecipitation technique and further freeze-drying. The results indicated that nanoparticles were obtained in 86% yield while microparticles were obtained in 68% yield. In both cases, the encapsulation efficiency of particles was greater than 78% while drug loading capacity was nearly 24% w/w and 18% w/w, after spray-drying and freeze-drying procedures, respectively. Images of scanning electron microscopy showed that the particles obtained by spray-drying and freeze-drying were in the micrometer and nanometer scale, respectively. FT-IR spectra of BNZ-loaded particles obtained by both methods showed characteristic bands of BNZ confirming that part of drug remained on their surface. Thermal analysis revealed that the drug crystallinity after both methods decreased. Physical stability evaluation of the nanoparticles confirmed that Pluronic® F68 was suitable to keep the particles size in a range of 300 nm after 70 days storage at 4 ± 2 °C. In-vitro release studies showed increased dissolution rate of drug from the particles obtained by both methods respect to untreated BNZ. The kinetics of drug release in acid media followed the Higuchi kinetics indicating drug diffusion mechanism from particles.

Chitosan-based nanodelivery systems applied to the development of novel triclabendazole formulations.

Triclabendazole is a poorly-water soluble (0.24 µg/mL) compound classified into the Class II/IV of the Biopharmaceutical Classification System. It is the drug of choice to treat fascioliasis, a neglected parasitic disease worldwide disseminated. Triclabendazole is registered as veterinary medicine and it is only available for human treatment as 250 mg tablets. Thus, the aim of this work was to develop novel drug delivery systems based on nanotechnology approaches. The chitosan-based nanocapsules and nanoemulsions of triclabendazole were fully characterized regarding their particle size distribution, polydispersity index and zeta potential, in-vitro release and stability in biological media. Cytotoxicity evaluation and cellular uptake studies using CaCo-2 cell line were also investigated. The results indicated an average hydrodynamic size around ~160 nm were found for unloaded nanoemulsions which were slightly increased up to ~190 nm for loaded one. In contrast, the average hydrodynamic size of the nanocapsules increased from ~160 nm up to ~400 nm when loaded with triclabendazole. The stability studies upon 30 days storage at 4, 25 and 37°C showed that average size of nanoemulsions was not modified with varying amounts of loaded TCBZ while an opposite result was seen in case of loaded nanocapsules. In addition, a slight reduction of zeta potential values over time was observed in both triclabendazole nanosystems. Release of TCBZ from nanoformulations over 6 h in simulated gastric fluid was 9 to 16-fold higher than with untreated TCBZ dispersion. In phosphate buffer saline solution there was no drug release for neither nanocapsules nor nanoemulsions. Cell viabilities studies indicated that at certain concentrations, drug encapsulation can lower its cytotoxic effects when compared to untreated drug. Confocal laser scanning microscopy study has shown that nanocapsules strongly interacted with Caco-2 cells in vitro which could increase the passage time of triclabendazole after oral administration. The results of this study constitute the first step towards the development of nanoformulations intended for the oral delivery of anti-parasitic drugs of enhanced bioavailability.

In vivo treatment of experimental neurocysticercosis with praziquantel nanosuspensions-a metabolic approach.

Neurocysticercosis is the most common parasitic infection of the nervous system and currently represents a serious public health issue in many regions of Latin America, Asia, and Africa. To date, praziquantel is one of the chosen drugs for the treatment of neurocysticercosis. Its mechanism of action is based on the inhibition of different biochemical pathways within the parasite which contribute to its death. Thus, the aim of this work was to analyze, for the first time, whether the nanoformulations of praziquantel would modify the energetic pathway of Taenia crassiceps cysticerci, after an intracranial inoculation in BALB/c mice. Praziquantel nanosuspensions were formulated with polyvinyl alcohol, poloxamer 188, and poloxamer 407, as stabilizers. These formulations exhibited particle size in a range of 74-285 nm and zeta potential values in a range of - 8.1/- 13.2 depending on the type of stabilizer. Physical stability study at both 4 ± 2 and 25 ± 2 °C indicated that praziquantel (PZQ) nanoparticles were stable in terms of solubility and particle size after 120-day storage. In vivo studies demonstrated that those nanosystems were able to produce significant modifications on the concentrations of oxaloacetate, citrate, pyruvate, alpha-ketoglutarate, malate, succinate, lactate, beta-hydroxybutyrate, fumarate, and propionate involved in the metabolism of Taenia crassiceps cysticerci. Therefore, these nanoformulations may be considered as a promising tool to deliver praziquantel to the brain for the effective management of neurocysticercosis.

Solving the Delivery Problems of Triclabendazole Using Cyclodextrins.

Triclabendazole is the first-line drug of choice to treat and control fasciolasis, a neglected parasitic human disease. It is a class II/IV compound according to the Biopharmaceutics Classification System. Thus, the aim of this study was to improve aqueous solubility and dissolution rate of triclabendazole complexed with 2-hydroxylpropyl-ß-cyclodextrin (HP-ß-CD) and methyl-ß-cyclodextrin (Me-ß-CD) at 1:1 and 1:2 M ratio. The impact of storage on the solubility, dissolution profile, and solid-state properties of such complexes was also investigated. Drug-carrier interactions were characterized by infrared spectroscopy, differential scanning calorimetry, X-ray diffractometry, and scanning electron microscopy. The solubility of triclabendazole improved up to 256- and 341-fold using HP-ß-CD and Me-ß-CD, respectively. In particular, the drug complexed with Me-ß-CD showed a positive deviation from linearity, suggesting that its solubility increases with an increasing concentration of Me-ß-CD concentration in a nonlinear manner. The drug dissolution was found to be improved through complex formation with HP-ß-CD and Me-ß-CD. In particular, the 1:2 M ratio complexes exhibited higher dissolution than the corresponding 1:1 M ratio complexes. The physicochemical characterization of the systems showed strong evidence of amorphous phases and/or of the formation of an inclusion complex. Stored at 25 °C, 60% RH for 24 months, drug complexed with ß-cyclodextrins (CDs) at 1:2 M ratio remained amorphous. Based on these findings, it is postulated that the formation of triclabendazole-CD inclusion complexes produced significant enhancement in both the dissolution and solid-state properties of the drug, which may lead to the development of triclabendazole novel formulations with improved biopharmaceutical characteristics.

Structural Elucidation of Poloxamer 237 and Poloxamer 237/Praziquantel Solid Dispersions: Impact of Poly(Vinylpyrrolidone) over Drug Recrystallization and Dissolution.

Praziquantel (PZQ) is the recommended, effective, and safe treatment against all forms of schistosomiasis. Solid dispersions (SDs) in water-soluble polymers have been reported to increase solubility and bioavailability of poorly water-soluble drugs like PZQ, generally due to the amorphous form stabilization. In this work, poloxamer (PLX) 237 and poly(vinylpyrrolidone) (PVP) K30 were evaluated as potential carriers to revert PZQ crystallization. Binary and ternary SDs were prepared by the solvent evaporation method. PZQ solubility increased similarly with PLX either as binary physical mixtures or SDs. Such unpredicted data correlated well with crystalline PZQ and PLX as detected by solid-state NMR (ssNMR) and differential scanning calorimetry in those samples. Ternary PVP/PLX/PZQ SDs showed both ssNMR broad and narrow superimposed signals, thus revealing the presence of amorphous and crystalline PZQ, respectively, and exhibited the highest PZQ dissolution efficiency (up to 82% at 180 min). SDs with PVP provided a promising way to enhance solubility and dissolution rate of PZQ since PLX alone did not prevent recrystallization of amorphous PZQ. Based on ssNMR data, novel evidences on PLX structure and molecular dynamics were also obtained. As shown for the first time using ssNMR, propylene glycol and ethylene glycol constitute the PLX amorphous and crystalline components, respectively.