Drug Nanocrystals in Oral Absorption: Factors That Influence Pharmacokinetics.

Despite the safety and convenience of oral administration, poorly water-soluble drugs compromise absorption and bioavailability. These drugs can exhibit low dissolution rates, variability between fed and fasted states, difficulty permeating the mucus layer, and P-glycoprotein efflux. Drug nanocrystals offer a promising strategy to address these challenges. This review focuses on the opportunities to develop orally administered nanocrystals based on pharmacokinetic outcomes. The impacts of the drug particle size, morphology, dissolution rate, crystalline state on oral bioavailability are discussed. The potential of the improved dissolution rate to eliminate food effects during absorption is also addressed. This review also explores whether permeation or dissolution drives nanocrystal absorption. Additionally, it addresses the functional roles of stabilizers. Drug nanocrystals may result in prolonged concentrations in the bloodstream in some cases. Therefore, nanocrystals represent a promising strategy to overcome the challenges of poorly water-soluble drugs, thus encouraging further investigation into unclear mechanisms during oral administration.

Organic solvent-free benznidazole nanosuspension as an approach to a novel pediatric formulation for Chagas disease.

Aim: Benznidazole (BNZ), a class-II drug, is the primary treatment for Chagas disease, but its low aqueous solubility presents challenges in formulation and efficacy. Nanosuspensions (NS) could potentially address these issues.Methods: BNZ-NS were prepared using a simple, organic solvents-free nano-milling approach. Physicochemical characterizations were conducted on both NS and lyophilized solid-state BNZ-nanocrystals (NC).Results: BNZ-NS exhibited particle size <500 nm, an acceptable polydispersity index (0.23), high Z-potential, and physical stability for at least 90 days. BNZ-NC showed tenfold higher solubility than pure BNZ. Dissolution assays revealed rapid BNZ-NS dissolution. BNZ-NC demonstrated biocompatibility on an eukaryotic cell and enhanced BNZ efficacy against trypomastigotes of Trypanosoma cruzi.Conclusion: BNZ-NS offers a promising alternative, overcoming limitations associated with BNZ for optimized pharmacotherapy.

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A New Ciprofibrate Calcium Salt with Improved Solubility and Intrinsic Dissolution Rate.

Ciprofibrate (CIP) is an active pharmaceutical ingredient (API) classified as class II on the basis of biopharmaceutical classification system (BCS), what indicates that it has low solubility in aqueous solvents. The use of API salts has attracted attention due to their improvements in solubility, tolerability, higher rate and extent of absorption, and faster onset of the therapeutic effect. In this work, a new crystalline CIP monohydrated calcium salt (Ca(CIP)2.H2O) was successfully obtained and its crystal structure determined by single crystal X-ray diffraction analysis (SCXRD). Additionally, Ca(CIP)2.H2O was widely characterized by powder X-ray diffraction (PXRD), Fourier-transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA) and submitted to solubility, intrinsic dissolution and accelerated stability studies. Ca(CIP)2.H2O exhibited higher solubility and dissolution rate than CIP-free form and was stable up to 6 months at 40 °C (75 %RH). Therefore, Ca(CIP)2.H2O may be a viable alternative for use in solid dosage forms.

Significant progress in improving Atorvastatin dissolution rate: Physicochemical characterization and stability assessment of self-dispersible Atorvastatin/Tween 80® nanocrystals formulated through wet milling and freeze-drying.

Atorvastatin (ATV) is a first-line drug for the treatment of hyperlipidemia. This drug presents biopharmaceutical problems, partly due to its low solubility and dissolution rate. In this work, nanocrystals of ATV stabilized with Tween 80® were designed by wet milling. A full factorial design was applied to optimize the process. Additionally, a cryoprotectant agent (maltodextrin, MTX) was identified, which allowed maintaining the properties of the nanocrystals after lyophilization. The storage stability of the nanocrystals was demonstrated for six months in different conditions. The obtained nanocrystal powder was characterized using SEM, EDXS, TEM, DSC, TGA, FT-IR, and XRD, showing the presence of irregular crystals with semi-amorphous characteristics, likely due to the particle collision process. Based on the reduction in particle size and the decrease in drug crystallinity, a significant increase in water and phosphate buffer (pH 6.8) solubility by 4 and 6 times, respectively, was observed. On the other hand, a noticeable increase in the dissolution rate was observed, with 90 % of the drug dissolved within 60 min of study, compared to 30 % of the drug dissolved within 12 h in the case of the untreated drug or the physical mixture of components. Based on these results, it can be concluded that the nano-milling of Atorvastatin stabilized with Tween 80® is a promising strategy for developing new formulations with improved biopharmaceutical properties of this widely used drug.

Nanonization techniques to overcome poor water-solubility with drugs.

INTRODUCTION: Most drugs used in therapy have low water-solubility, a factor that could reduce their dissolution rate and oral bioavailability, representing a challenge in pharmaceutical development. Nanonization of drugs is the reduction of particles to nanoscale, increasing the surface area and consequently the saturation solubility and dissolution rate and resulting in higher bioavailability. AREAS COVERED: This review provides an overview of the consequences of the poor water-solubility and the main strategies applied to increase the solubility of poorly water-soluble drugs. The relationship between the biopharmaceutical classification system and the solubilization process of the drug is also considered. Finally, it includes how drug nanoparticles and nanocarriers, especially lipid-based nanosystems, can overcome these challenges and which of these approaches are already available on the market. EXPERT OPINION: Due to the growing importance of nanomedicines, especially for applications in poorly water-soluble drugs, it is important to clearly establish the specifications and quality criteria for nanonized drugs to ensure the quality and safety of nanoparticles.

Synthesis and characterization of mesoporous SBA-15 and SBA-16 as carriers to improve albendazole dissolution rate.

Albendazole (ABZ, anti-parasitic active pharmaceutical ingredient) is a crystalline low water-soluble drug, thus the dissolution rate in gastrointestinal fluids is limited. Consequently, the improvement of the water solubility and dissolution rate of ABZ implies a great challenge for a more efficient treatment of hydatidosis. In this context, SBA-15 and SBA-16 ordered mesoporous silica materials were synthetized and loaded with ABZ. X-ray diffraction, FT-IR spectroscopy, nitrogen physisorption manometry, particle size distribution and scanning electronic microscopy were used to characterize unloaded and loaded materials (ABZ/SBA-15 and ABZ/SBA-16). The loaded ABZ amount in the carriers was estimated by elemental analysis. For the loaded materials, the drug solubility and release profile were evaluated. In addition, mathematical models were compared to explain the dissolution kinetics of ABZ from mesoporous solids. ABZ was successfully loaded into the mesopores. The amorphous state of the adsorbed ABZ was confirmed by differential scanning calorimetry that resulted in a notable increment in the dissolution rate compared to crystalline ABZ. Drug release behaviors were well simulated by the Weibull model for ABZ/SBA-15 and by the Gompertz function for pure ABZ and ABZ/SBA-16. The SBA-15 carrier exhibited the highest drug loading and dissolution rate becoming a promising material to improve ABZ bioavailability.

The Influence of Matrix Technology on the Subdivision of Sustained Release Matrix Tablets.

The subdivision of sustained release tablets is a controversial issue, especially concerning its impact on dissolution profiles. The purpose of this study was to elucidate the behavior upon subdivision of this class of tablets. For this, three common sustained release matrices containing different technologies were selected, e.g., a tablet comprised of a multiple-unit particulate system (MUPS), a lipid matrix tablet, and a polymeric inert matrix tablet. These tablets were studied concerning their physicochemical performance, dissolution rate, and kinetic profile before and after their subdivision. When subdivision occurred in the scoreline, mass variation and mass loss were below the mean values described in the literature. The dissolution of tablets with inert matrices and some lipid tablets that had their matrices preserved along the dissolution was influenced directly by tablet surface area, which increased after the subdivision. Such a result implies possible clinical consequences, especially in the case of drugs with a narrow therapeutic window, such as clomipramine. Conversely, the subdivision of MUPS tablets did not interfere in the dissolution profile since the drug was released from the granules that resulted from tablet disintegration. Hence, MUPS technology is the most recommended to produce sustained release matrix tablets intended for dose adjustment upon subdivision.

Liquisolid pellets: A pharmaceutical technology strategy to improve the dissolution rate of ritonavir.

Liquisolid pellets (LPs) prepared by extrusion-spheronization are promising delivery systems to improve the dissolution rate of poorly water-soluble drugs. However, developing LPs for high dose drugs (e.g. antiretroviral ritonavir, RTV) is a major challenge due to technical and quality constraints. In this study, formulations LP1 and LP2 were obtained (RTV 100 mg/unit dose) using microcrystalline cellulose (carrier), Kollidon® CL-SF (coating and disintegrating material) and high load (30%, w/w) of Kolliphor® EL or PEG 400 (non-volatile solvent). LP1 and LP2 had narrow size distribution, good morphological properties, and excellent flowability. The partial conversion of RTV polymorph I to the less soluble form II occurred during the preparation of the liquid medications. LP1 (containing Kolliphor® EL) achieved 82.64 ±â€¯2.17% of drug dissolved in 30 min (Q30min), compared with 53.14 ±â€¯0.6% and 42.42 ±â€¯2.09% for LP2 (containing PEG 400) and Norvir® tablets, respectively. Also, LP1 promoted 1.9-fold/1.7-fold and 8.19-fold/8.29-fold increases in Q30min/DE60min (dissolution efficiency) as compared to neat RTV polymorphs I and II, respectively.

Irbesartan desmotropes: Solid-state characterization, thermodynamic study and dissolution properties.

Irbesartan (IBS) is a tetrazole derivative and antihypertensive drug that has two interconvertible structures, 1H- and 2H-tautomers. The difference between them lies in the protonation of the tetrazole ring. In the solid-state, both tautomers can be isolated as crystal forms A (1H-tautomer) and B (2H-tautomer). Studies have reported that IBS is a polymorphic system and its forms A and B are related monotropically. These reports indicate form B as the most stable and less soluble form. Therefore, the goal of this contribution is to demonstrate through a complete solid-state characterization, thermodynamic study and dissolution properties that the IBS forms are desmotropes that are not related monotropically. However, the intention is also to call attention to the importance of conducting strict chemical and in solid-state quality controls on the IBS raw materials. Hence, powder X-ray diffraction (PXRD) and Raman spectroscopy (RS) at ambient and non-ambient conditions, differential scanning calorimetry (DSC), hot stage microscopy (HSM), Fourier transform infrared (FT-IR) and scanning electron microscopy (SEM) techniques were applied. Furthermore, intrinsic dissolution rate (IDR) and structural stability studies at 98% relative humidity (RH), 25 °C and 40 °C were conducted as well. The results show that in fact, form A is approximately four-fold more soluble than form B. In addition, both IBS forms are stable at ambient conditions. Nevertheless, structural and/or chemical instability was observed in form B at 40 °C and 98% RH. IBS has been confirmed as a desmotropic system rather than a polymorphic one. Consequently, forms A and B are not related monotropically.

Development and in vitro evaluation of solid dispersions as strategy to improve albendazole biopharmaceutical behavior.

AIM: Solid dispersions using Poloxamer 407 as carrier were developed to improve albendazole (ABZ) solubility and dissolution profiles. METHODS: ABZ/poloxamer solid dispersions were prepared, and dissolution profiles were mathematically modeled and compared with physical mixtures, pharmaceutical ABZ and a commercial formulation. RESULTS: Poloxamer 407 increased exponentially ABZ solubility, in about 400% when 95% w/w of polymer compared with its absence. Solid dispersions initial dissolution rate was three to 20-fold higher than physical mixtures, the drug and the commercial formulation. All the solid dispersions required less than 2.2 min to reach an 80% of ABZ dissolution, while the commercial formulation needed around 40 min. CONCLUSION: Solid dispersions improved ABZ solubility and dissolution rate, which could result in a faster absorption and an increased bioavailability.

Dissolution Enhancement in Cocoa Extract, Combining Hydrophilic Polymers through Hot-Melt Extrusion.

The aim of this study was to improve the physicochemical properties of cocoa extract (CE) using hot-melt extrusion (HME) for pharmaceutical proposes. A mixture design was applied using three distinct hydrophilic polymeric matrices (Soluplus, Plasdone S630, and Eudragit E). Systems obtained by HME were evaluated using morphologic, chromatographic, thermic, spectroscopic, and diffractometric assays. The flow, wettability, and dissolution rate of HME powders were also assessed. Both CE and its marker theobromine proved to be stable under heating according to thermal analysis and Arrhenius plot under isothermal conditions. Physicochemical analysis confirmed the stability of CE HME preparations and provided evidence of drug⁻polymer interactions. Improvements in the functional characteristics of CE were observed after the extrusion process, particularly in dissolution and flow properties. In addition, the use of a mixture design allowed the identification of synergic effects by excipient combination. The optimized combination of polymers obtained considering four different aspects showed that a mixture of the Soluplus, Plasdone S630, and Eudragit E in equal proportions produced the best results (flowability index 88%; contact angle 47°; dispersibility 7.5%; and dissolution efficiency 87%), therefore making the pharmaceutical use of CE more feasible.

Preparation and Characterization of Poloxamer 407 Solid Dispersions as an Alternative Strategy to Improve Benznidazole Bioperformance.

Benznidazole (BZL), the first line drug for Chagas disease treatment, presents a low solubility, limiting the possibilities for its formulation. In this work, solid dispersions' (SDs) technology was exploited to increase BZL kinetic solubility and dissolution rate, seeking for an improvement in its bioperformance. A physical mixture (PM) and an SD using Poloxamer 407 as carrier were prepared and characterized. Dissolution tests were performed, and data were analyzed with the lumped model, which allowed to calculate different parameters of pharmaceutical relevance. A bioactivity assay was also carried out to probe the SD anti-trypanocidal activity. Among the most relevant results, the initial dissolution rate of the BZL SD was near 3, 4 and about 400-fold faster than the PM, a commercial formulation (CF) and an extracted BZL, respectivley. The times needed for an 80% of drug dissolution were 3.6 (SD), 46.4 (PM), and 238.7 min (CF); while the dissolution efficiency values at 30 min were 85.2 (SD), 71.2 (PM), and 65.0% (CF). Survival curves suggested that using Poloxamer 407 as carrier did not alter the anti-trypanocidal activity of BZL. These results allow to conclude that SDs can be an effective platform for immediate release of BZL in an oral administration.

Enhanced delivery of fixed-dose combination of synergistic antichagasic agents posaconazole-benznidazole based on amorphous solid dispersions.

Posaconazole (PCZ) and benznidazole (BNZ) are known to show synergetic effect in treating the acute and chronic phases of Chagas disease, a neglected parasitic disease. However, as both compounds are poorly water soluble, the development of amorphous solid dispersions (ASDs) of a PCZ/BNZ fixed-dose combination in a water-soluble polymer becomes an attractive option to increase their apparent solubility and dissolution rate, potentially improving their oral bioavailability. The initial approach was to explore solvent evaporated solid dispertion (SD) systems for a PCZ/BNZ 50:50 (wt%) combination at several total drug loading levels (from SD with 10% to 50% drug loading) in water-soluble carriers, including polyvinylpyrrolidone (PVP K-30) and vinylpyrrolidone-vinyl acetate copolymer (PVPVA 64). Based on comparison of non-sink in vitro dissolution performance, ASD systems based on PVPVA was identified as the most effective carrier for a 50:50 (w/w %) fixed-dose combination of PCZ/BNZ to increase their apparent solubility and dissolution rate, mainly at 10% drug loading, which shows more expressive values of area under the curve (AUC) (7336.04 ±â€¯3.77 min.µL/mL for PCZ and 15,795.02 ±â€¯7.29 min.µL/mL for BNZ). Further characterization with polarized microscopy, powder X-ray diffraction, and thermal analysis reveals that there exists a threshold drug loading level at about 30% PCZ/BNZ, below which ASDs are obtained and above which a certain degree of crystallinity tends to result. Moreover, infrared spectroscopic analysis reveals the lack of hydrogen bonding interactions between the drugs (PCZ and BNZ) and the polymer (PVPVA) in the ASD, this is also confirmed through molecular dynamics simulations. The molecular modeling results further show that even in the absence of meaningful hydrogen bonding interactions, there is a greater tendency for PVPVA to interact preferentially with PCZ and BNZ through electrostatic interactions thereby contributing to the stability of the system. Thus, the present SD system has the advantage of presenting a fixed-dese combination of two synergistic antichagasic agents PCZ and BNZ together in amorphous form stabilized in the PVPVA matrix with enhanced dissolution, potentially improving their bioavailability and therapeutic activity in treating Chagas disease.

Crystalline Ethylene Oxide and Propylene Oxide Triblock Copolymer Solid Dispersion Enhance Solubility, Stability and Promoting Time- Controllable Release of Curcumin.

AIMS AND BACKGROUND: The design and development of an effective medicine are, however, often faced with a number of challenges. One of them is the close relationship of drug's bioavailability with solubility, dissolution rate and permeability. The use of curcumin's (CUR) therapeutic potential is limited by its poor water solubility and low chemical stability. The purpose was to evaluate the effect of polymer and solid dispersion (SD) preparation techniques to enhance the aqueous solubility, dissolution rate and stability of the CUR. The recent patents on curcumin SD were reported as (i) curcumin with polyvinylpyrrolidone (CN20071 32500 20071214, WO2006022012 and CN20151414227 20150715), (ii) curcumin-zinc/polyvinylpyrrolidone (CN20151414227 20150715), (iii) curcumin-poloxamer 188 (CN2008171177 20080605), (iv) curcumin SD prepared by melting method (CN20161626746-20160801). MATERIALS AND METHODS: SD obtained by co-preciptation or microwave fusion and the physical mixture of CUR with Poloxamer-407 (P-407), Hydroxypropylmetylcellulose-K4M (HPMC K4M) and Polyvinylpyrrolidone-K30 (PVP-K30) were prepared at the ratios of 1:2; 1:1 and 2:1. The samples were evaluated by solubility, stability, dissolution rate and characterized by SEM, PXRD, DSC and FTIR. RESULTS: The solubility, stability (pH 7.0) and dissolution rate were significantly greater for SD (CUR:P-407 1:2). The PXRD,SEM and DSC indicated a change in the crystalline state of CUR. The enhancement of solubility was dependent on a combination of factors including the weight ratio, preparation techniques and carrier properties. The drug release data fitted well with the Weibull equation, indicating that the drug release was controlled by diffusion, polymer relaxation and erosion occurring simultaneously. CONCLUSION: Thus, these SDs, specifically CUR:P-407 1:2 w/w, can overcome the barriers of poor bioavailability to reap many beneficial properties.

Development of solid dispersions of ß-lapachone in PEG and PVP by solvent evaporation method.

ß-lapachone (ßlap) has shown potential use in various medical applications. However, its poor solubility has limited its systemic administration and clinical applications. The aim of this work is to develop solid dispersions of ßlap using poly (ethylene glycol) (PEG 6000) and polyvinylpyrrolidone (PVP K30) as hydrophilic polymers and evaluate the dissolution rate in aqueous medium. Solid dispersions were prepared by solvent evaporation method using different weight ratios of ßlap and hydrophilic polymer (1:1, 1:2, and 1:3). Characterization performed by differential scanning calorimetry, Fourier transform infrared spectroscopy, X-ray diffraction, and scanning electron microscopy showed that ßlap was molecularly dispersed within the polymer matrix. The in vitro dissolution tests showed an enhancement in the dissolution profile of ßlap as solid dispersions prepared in both PVP and PEG, although the former showed better results. The drug:polymer ratio influenced ßlap dissolution rate, as higher amounts of hydrophilic polymer led to enhanced drug dissolution. Thus, this study demonstrated that solid dispersions of ßlap in PVP offers an effective way to overcome the poor dissolution of ßlap.

Hot Melt Extrudates Formulated Using Design Space: One Simple Process for Both Palatability and Dissolution Rate Improvement.

This work aimed at obtaining an optimized itraconazole (ITZ) solid oral formulation in terms of palatability and dissolution rate by combining different polymers using hot melt extrusion (HME), according to a simplex centroid mixture design. For this, the polymers Plasdone® (poly(1-vinylpyrrolidone-co-vinyl acetate) [PVP/VA]), Klucel® ELF (2-hydroxypropyl ether cellulose [HPC]), and Soluplus® (SOL, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol) were processed using a laboratory HME equipment operating without recirculation at constant temperature. Samples were characterized by physicochemical assays, as well as dissolution rate and palatability using an e-tongue. All materials became homogeneous and dense after HME processing. Thermal and structural analyses demonstrated drug amorphization, whereas IR spectroscopy evidenced drug stability and drug-excipient interactions in HME systems. Extrudates presented a significant increase in dissolution rate compared to ITZ raw material, mainly with formulations containing PVP/VA and HPC. A pronounced improvement in taste masking was also identified for HME systems, especially in those containing higher amounts of SOL and HPC. Data showed polymers act synergistically favoring formulation functional properties. Predicted best formulation should contain ITZ 25.0%, SOL 33.2%, HPC 28.9%, and PVP/VA 12.9% (w/w). Optimized response considering dissolution rate and palatability reinforces the benefit of polymer combinations.

Fluidized Bed Hot-Melt Granulation as a Tool to Improve Curcuminoid Solubility.

Curcumin is the main bioactive component of Curcuma longa L. and has recently aroused growing interest from the scientific community. Unfortunately, the medicinal properties attributed to curcuminoids are impaired by their low oral bioavailability or low solubility in aqueous solutions. Many strategies have been studied to improve curcumin solubility; however, the preparation of granules using hydrophilic materials has never been attempted. The aim of this work was to develop curcumin granules by fluidized bed hot-melt granulation using the hydrophilic carrier Gelucire® 50:13. A two-level factorial design was used to verify the influence of Gelucire® 50:13 and lactose contents found in the granules on their size, morphology, bulk and tapped densities, flow, moisture content, and water activity. The granules obtained were also evaluated by differential scanning calorimetry, thermogravimetric analysis, X-ray powder diffraction, and infrared spectrometry. The curcumin solubility and dissolution rates in water were determined by liquid chromatography. The best formulation provides an increase of curcumin solubility of 4642-fold and 3.8-fold compared to the physical mixture. The dissolution tests showed a maximum drug release from granules after 45 min of 70% at pH 1.2 and 80% at pH 5.8 and 7.4, while for non-granulated curcumin, the release was below 20% in all pH. The solid-state characterization and solubility measurement showed good stability of granules over 9 months. The results attest that the fluidized bed hot-melt granulation with hydrophilic binders is an attractive and promising alternative to obtain solid forms of curcumin with enhanced bioavailability.

Very fast dissolving acid carboxymethylcellulose-rifampicin matrix: Development and solid-state characterization.

One of the main obstacles to the successful treatment of tuberculosis is the poor and variable oral bioavailability of rifampicin (RIF), which is mainly due to its low hydrophilicity and dissolution rate. The aim of this work was to obtain a hydrophilic new material that allows a very fast dissolution rate of RIF and therefore is potentially useful in the development of oral solid dosage forms. The acid form of carboxymethylcellulose (CMC) was co-processed with RIF by solvent impregnation to obtain CMC-RIF powder, which was characterized by polarized optical microscopy, powder x-ray diffraction, DSC-TGA, hot stage microscopy, 13C and 15N solid-state NMR and FT-IR spectroscopy. In addition, the CMC-RIF matrices were subjected to water uptake and dissolution studies to assess hydrophilicity and release kinetics. CMC-RIF is a crystalline solid dispersion. Solid-state characterization indicated that no ionic interaction occurred between the components, but RIF crystallized as a zwitterion over the surface of CMC, which drastically increased the hydrophilicity of the solid. The CMC-RIF matrices significantly improved the water uptake of RIF and disintegrated in a very short period immediately releasing RIF. As CMC improves the hydrophilicity and delivery properties of RIF, CMC-RIF is very useful in the design of oral solid dosage forms with very fast dissolution of RIF, either alone or in combination with other antitubercular drugs.

Design and in vitro characterization of ivermectin nanocrystals liquid formulation based on a top-down approach.

The aim of this study was to develop ivermectin (IVM) nanosuspensions (NSs) to improve the dissolution rate of this poorly water-soluble drug. Different NSs combining different stabilizers, i.e. poloxamer 188 (P188), polysorbate 80 (T80), polyvinylpyrrolidone (PVP), and sodium lauryl sulfate (SLS), were prepared by high-pressure homogenization. The stabilizers were selected based on the saturation solubility and IVM stability within 72 h. The screening of formulations was performed by considering the drug content within the nanosize range. The best formulation (IVM:T80:PVP 1:0.5:0.5 wt%) was characterized in terms of the particle size distribution, morphology, crystallinity, drug content, and in vitro dissolution profile. This NS was also evaluated from a stability point of view, by conditioning samples at a constant temperature and relative humidity for six months. The fresh and conditioned best NSs Z-sizes were 174.6 and 215.7 nm, respectively; while both NSs showed low polydispersity indexes. The faster dissolution rate for the IVM NS was attributed to the presence of nanoparticles and changes to the crystal structure (i.e. amorphization) that further improved solubility. The best NS had a 4-fold faster initial dissolution rate than raw IVM, and is thus a promising formulation for the treatment of human and animal parasitic diseases.

Fluidized Bed Hot Melt Granulation with Hydrophilic Materials Improves Enalapril Maleate Stability.

This work aimed at developing enalapril maleate granules in order to improve its stability in solid dosage form. Granules were prepared by hot melt granulation using a fluidized bed apparatus. Gelucire 50/13®, polyethylene glycol 6000 e Poloxamer 407® were studied and compared as binders in 2 × 2 factorial designs where the proportions of enalapril maleate, binders and spray dried lactose were varied. The granulation process resulted in high yields and granule sizes that indicated the prevalence of particles coating. Furthermore, the granules obtained showed adequate flowability and a fast dissolution rate of enalapril maleate with almost 100% of the drug released in 10 min. The stability of enalapril maleate in hard gelatin capsules showed that the drug stability was greatly increased in granules, since for raw drug, the remaining content of enalapril maleate after 91 days was 68.4% and, for granules, the content was always above 93%. This result was confirmed by the quantification of the degradation products, enalaprilat and diketopiperazine, which were found in very low content in granules samples. The results demonstrate that fluidized bed hot melt granulation with hydrophilic binders is a suitable alternative for improving the chemical stability of enalapril maleate.