Multivariate Analysis of Solubility Parameters for Drug-Polymer Miscibility Assessment in Preparing Raloxifene Hydrochloride Amorphous Solid Dispersions.

The success of obtaining solid dispersions for solubility improvement invariably depends on the miscibility of the drug and polymeric carriers. This study aimed to categorize and select polymeric carriers via the classical group contribution method using the multivariate analysis of the calculated solubility parameter of RX-HCl. The total, partial, and derivate parameters for RX-HCl were calculated. The data were compared with the results of excipients (N = 36), and a hierarchical clustering analysis was further performed. Solid dispersions of selected polymers in different drug loads were produced using solvent casting and characterized via X-ray diffraction, infrared spectroscopy and scanning electron microscopy. RX-HCl presented a Hansen solubility parameter (HSP) of 23.52 MPa1/2. The exploratory analysis of HSP and relative energy difference (RED) elicited a classification for miscible (n = 11), partially miscible (n = 15), and immiscible (n = 10) combinations. The experimental validation followed by a principal component regression exhibited a significant correlation between the crystallinity reduction and calculated parameters, whereas the spectroscopic evaluation highlighted the hydrogen-bonding contribution towards amorphization. The systematic approach presented a high discrimination ability, contributing to optimal excipient selection for the obtention of solid solutions of RX-HCl.

Efficacy of focal applications of a mycoinsecticide to control Aedes aegypti in Central Brazil.

Entomopathogenic fungi can achieve important innovative outcomes for integrated mosquito control especially of Aedes aegypti, the key vector of arboviruses to humans in the tropics and subtropics. This study sought to design and to develop a simple dissemination device to attract and to infect gravid A. aegypti adults with a granular formulation of the ascomycete Metarhizium humberi IP 46, and to validate this device in the laboratory as well as in semi-field and field conditions. Hydrogel (polyacrylamide potassium polyacrylate) was confirmed to be a suitable substitute for water used in the device that attracted gravid females under field conditions. Females laid eggs on black polyethylene terephthalate carpet fixed in the device that also proved to be a suitable substrate for a granular formulation of fungal microsclerotia and/or conidia. The plastic device (29.5 cm high) was divided into a lower closed compartment with a water reservoir and an upper, laterally open but covered compartment with continuously hydrated gel and the fungal formulation attached to the carpet. The uppermost compartment permitted free circulation of mosquito adults. The device attracted both male and female A. aegypti. The fungal formulations of IP 46 propagules tested in the device were effective against adults in laboratory, semi-field, and field settings. Findings in the laboratory, semi-field, and especially in field conditions strengthen the value and utility of this innovative device for focal applications of a mycoinsecticide against this important mosquito vector.Key points• Low-cost and simple disseminating device for focal control of Aedes aegypti.• Granulized Metarhizium humberi IP 46 and hydrogel yield extended control.• Findings in field tests strengthen benefit of the device for focal application.

Optimization of granular formulations of Metarhizium humberi microsclerotia with humectants.

Granular microsclerotial formulations of entomopathogenic fungi deserve attention because of their post-application, in situ production of new conidia that enhance and prolong mycoinsecticidal efficacy against a target pest insect. Because high ambient moisture is a crucial condition to induce fungal development and conidiogenesis on granules, we tested the impacts of the additions of three humectants-glycerin, propylene glycol, and polyethylene glycol 400-on water absorption by pellets incorporating microsclerotia of Metarhizium humberi IP 46 with microcrystalline cellulose or vermiculite carriers, and on the production of infective conidia of IP 46 microsclerotia in ambient humidities suboptimal for routine conidiogenesis. Glycerin facilitated greater and faster absorption of water than the other humectants. Microcrystalline cellulose absorbed low quantities of water without any added humectant whereas vermiculite did not. IP 46 did not grow or sporulate on pellets prepared with or without glycerin at 86% relative humidity (RH) or on control pellets without glycerin at 91% RH; conidial production on pellets prepared with vermiculite or microcrystalline cellulose and 10% glycerin reached 1.1 × 105 conidia/mg and 1 × 105 conidia/mg, respectively, after 20 days of exposure at 91% RH. Hence, these results strongly support glycerin as a suitable humectant for granular microsclerotial formulations of this fungus.

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.

Preparation of benznidazole pellets for immediate drug delivery using the extrusion spheronization technique.

Recent advances in the treatment of Chagas disease have followed combinations of drugs that act synergistically against infection, predominantly including benznidazole (BNZ) and azoles derivatives. Possible incompatibilities between these drugs, slow dissolution of BNZ and dose adjustment difficulties are technological obstacles to the development of multidrug formulations. Thus, in the present study, BNZ pellets were developed using extrusion spheronization for immediate drug delivery. Preformulation studies were then performed using thermal analysis and infrared spectroscopy and compatibility between the drug and selected excipients (polyethylene glycol 6000, sodium starch glycolate, microcrystalline cellulose and sodium croscarmellose) was investigated. No chemical decomposition of BNZ was observed, even in samples submitted to wet granulation and thermal stress. Subsequently, formulations were elaborated according to a simplex lattice experimental design using polyethylene glycol, sodium starch glycolate and sodium croscarmellose as disintegrating agents. In these experiments, BNZ pellets showed appropriate physicochemical characteristics, including high drug load capacity and excellent flow properties. The mixture experimental design allowed identification of adequate compositions of disintegrating agents and achieved rapid disintegration and dissolution of pellets. Optimum performance was achieved using polyethylene glycol and sodium croscarmellose at 5.0% w/w each. The present BNZ pellets are versatile alternatives to treat Chagas disease and provide insights into the preparation of multidrug systems.

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.

Effect of ultraviolet-A radiation on the production of Leptolegnia chapmanii (Saprolegniales: Saprolegniaceae) zoospores on dead Aedes aegypti (Diptera: Culicidae) larvae and their larvicidal activity.

Impact of UV-radiation in entomopathogens in aquatic environments remains little investigated. The present study reports on the effect of UV-A on the larvicidal activity of Leptolegnia chapmanii zoospores in Aedes aegypti; on the production of zoospores in larvae killed by the pathogen and then exposed to UV-A; and on the activity of these zoospores against healthy larvae. Whereas the virulence of free zoospores in A. aegypti larvae was affected by a UV-A exposure time longer than 10min, production of zoospores in larvae and their virulence were not hampered at a maximal 8h exposure of dead larvae to UV-A. Findings suggest that dead larvae and zoosporangia provide a certain protection to zoospores against UV-A and emphasize the susceptibility of free encysted zoospores to such radiation.

Customizable Three-Dimensional Printed Earring Tap for Treating Affections Caused by Aesthetic Perforations.

This work aimed to develop a three-dimensional (3D) wearable drug-loaded earring tap to treat affections caused by aesthetic perforations. The initial phase involved a combination of polymers to prepare filaments for fused deposition modeling (FDM) 3D printing using a centroid mixture design. Optimized filament compositions were used in the second phase to produce 3D printed earring taps containing the anti-inflammatory naringenin. Next, samples were assessed via physicochemical assays followed by in vitro skin permeation studies with porcine ear skin. Two filament compositions were selected for the study's second phase: one to accelerate drug release and another with slow drug dissolution. Both filaments demonstrated chemical compatibility and amorphous behavior. The use of the polymer blend to enhance printability has been confirmed by rheological analysis. The 3D devices facilitated naringenin skin penetration, improving drug recovery from the skin's most superficial layer (3D device A) or inner layers (3D device B). Furthermore, the devices significantly decreased transdermal drug delivery compared to the control containing the free drug. Thus, the resulting systems are promising for producing 3D printed earring taps with topical drug delivery and reinforcing the feasibility of patient-centered drug administration through wearable devices.

Impact of cross-linking and drying method on drug delivery performance of casein-pectin microparticles.

Pectin is a heteropolysaccharide which has been investigated for the development of colon-specific drug delivery systems. Polymers have been associated with pectin to reduce its aqueous solubility and improve the performance of drug delivery systems. Pectin-casein interaction is widely known in food research, but it has not been fully considered by pharmaceutical scientists. Thus, this study investigated the potential of casein-pectin microparticles as a drug delivery system and clarified the impact of cross-linking and drying methods on the in vitro release of indomethacin (IND) or acetaminophen (PCT) from microparticles. Microparticles were prepared by coacervation and dried by spray or spouted bed methods. Drug recovery, in vitro drug release, size, morphology, and the thermal and diffractometric properties of dried microparticles were determined. Spray-dried non-cross-linked microparticles were able to prolong IND release, and pectin was still degraded by pectinolytic enzymes. On the other hand, glutaraldehyde cross-linking prevented the enzymatic breakdown of pectin without improving IND release. Spouted bed drying reduced IND recovery from all microparticles when compared with spray drying, thus the successful spouted bed drying of microparticles depends on the chemical characteristics of both the drug and the polymer. Release data from PCT microparticles suggested that the microparticle formulation should be improved to bring about a more efficient delivery of water-soluble drugs. In conclusion, casein-pectin microparticles show great potential as a drug delivery system because casein reduces the water solubility of pectin. The drying method and cross-linking process had significant effects on the in vitro performance of these microparticles.

Effect of stearic acid on enalapril stability and dissolution from multiparticulate solid dosage forms.

Enalapril maleate (EM) is a widely used anti-hypertensive drug which is unstable when mixed with excipients. Enalaprilate and diketopiperazine (DPK) are the main degradation products of enalapril. The in situ preparation of enalapril sodium salt (NaE) has been used to improve drug stability in dosage forms; however, gas release and product rejection ensue when the chemical reaction for obtaining the sodium salt is not completely finished before packaging. This study evaluated the effect of stearic acid (SA) on enalapril stability in microcrystalline cellulose (MCC) pellets containing EM or NaE. MCC pellets containing SA were prepared by the extrusion-spheronization technique and characterized. Enalapril stability and dissolution were then evaluated. DPK and enalaprilate formation were reduced by the addition of SA in pellets containing EM. The overall enalapril degradation in these formulations was lower when compared with pellets containing EM or even NaE prepared without SA. The immediate-release characteristic was maintained by the addition of 5% crospovidone to all the formulations tested. The incorporation of SA into NaE pellets resulted in unexpected enalapril degradation, caused by the interaction of these compounds, as suggested by a thermal analysis of the SA-NaE binary mixture. The findings presented here showed that formulations containing SA could substitute the formation of NaE, since they provide better enalapril stability in solid dosage forms. In addition, it is suggested that the stabilization effects would be observed for other N-carboxyalkyl dipeptide analogs with angiotensin converting enzyme inhibition activity, since these new entities share the same degradation pathway of enalapril.

Preformulation and characterization of raloxifene-loaded lipid nanoparticles for transdermal administration.

Transdermal administration of raloxifene hydrochloride (RLX)-loaded nanostructured lipid carriers (NLCs) has been proposed to circumvent its low oral bioavailability (2%). Preformulation studies were carried out to evaluate drug-excipient compatibility of various adjuvants commonly used for NLC preparation (waxes, cholesterol, compritol, gelucire, span 60, span 80, span 85, tween 80, poloxamer 188, oleic acid, caprylic/capric triglyceride, and castor oil). It was used differential scanning calorimetry (DSC), isothermal stress testing (IST), and solubility studies. The most promising excipients were chosen for NLC obtention, and full characterization was done, including in vitro skin permeation. DSC curves suggested drug-excipient interaction among some compounds, and the IST study showed incompatibility of RLX with waxes, compritol, cholesterol, span 60, and poloxamer 188. Solubility studies helped select gelucire, caprylic/capric triglyceride, span 80, and tween 80 for NLC production. Twelve NLCs were obtained (NLC1 to NLC12), but NLC7 and NLC8 were the most promising ones. In vitro release studies demonstrated that NLC7 and NLC8 were able to control RLX release (14.74 and 9.07% at 24 h, respectively) compared with the unloaded drug (> 90% at 24 h). Unloaded RLX did not permeate the diffusion cells' receptor medium and showed higher drug skin retention (11-fold) than RLX-loaded NLC. NLC reduced RLX skin retention, favoring drug permeation to deeper skin layers. NLC7 increased drug flux is 2.4-fold. NLC7 is a promising formulation for RLX transdermal drug delivery.

Curcuma longa L. Effects on Akt/mTOR Pathway and NF-κB Expression During Skin Wound Healing: An Immunohistochemical Study.

Skin ulcers, wounds, or burns represent a burden for health care worldwide. Our aim was to explore the effects of mucoadhesive formulation with Curcuma longa L. extract mucoadhesive formulation containing curcumin (MFC) on skin healing in Wistar rats. Fifty-four rats were randomly allocated into 3 groups: control, vehicle, and MFC. A full-thickness circular wound was induced on the back of each animal. Two daily applications of the products were performed according to the experimental group. On days 3, 10, and 21, 6 animals in each group were euthanized. Clinical analysis was based on wound area. Histologic analysis was performed in hematoxylin and eosin-stained sections, with re-epithelization and inflammation being assessed by means of semiquantitative scores. To analyze the Akt/mTOR pathway, immunohistochemistry for phospho Akt (pAkt) and phospho ribosomal protein S6 were investigated. In addition, nuclear factor kappa-light-chain-enhancer of activated B cells immunolabeling was performed. Clinical analysis revealed wounds with a smaller area on days 3 and 10 in curcumin-treated animals. Histologically, MFC had a significant impact on inflammatory events on days 3 and 10 and promoted faster re-epithelization, which was evidenced on day 10. MFC-treated wounds exhibited pAkt upregulation on day 10 and both pAkt and phospho ribosomal protein S6 downregulation on day 21. Nuclear factor kappa-light-chain-enhancer of activated B cells expression varied through the evaluation periods; however, no significant difference was observed between groups. Collectively, our results indicate that MFC is efficient in accelerating cutaneous wound repair through modulation of the inflammatory process and stimulus of re-epithelization by an Akt/mTOR-dependent mechanism.

Enhanced nail delivery of voriconazole-loaded nanomicelles by thioglycolic acid pretreatment: A study of protein dynamics and disulfide bond rupture.

This work aimed to select an effective penetration enhancer (PE) for nail pretreatment, develop voriconazole (VOR)-loaded nanomicelles, and evaluate their ability to deliver VOR to the nail. A complete analysis of nail protein dynamics, bond rupture, and microstructure was performed. Alternative methods as electron paramagnetic resonance (EPR) and the Ellman's reagent (DTNB) assay were also evaluated. Nanomicelles were produced and characterized. The PE hydrated the hooves, following the order: urea ≈ cysteine ≈ glycolic acid < thioglycolic acid (TGA) < NaOH. SEM images and methylene blue assay showed enlarged pores and roughness of porcine hooves after incubation with NaOH and TGA. EPR was demonstrated to be the most sensitive technique. DTNB assay quantified higher thiol groups for samples treated with TGA (p < 0.05). A stratigraphic analysis with Raman spectroscopy demonstrated that hooves treated with TGA presented a higher SH/SS ratio at the edges, affecting protein secondary structure. In vitro permeation studies demonstrated significant VOR permeation (29.44 ± 6.13 µg/cm2), 10-fold higher than previous studies with lipid nanoparticles. After TGA pretreatment, VOR permeation was further enhanced (3-fold). TGA pretreatment followed by VOR-loaded nanomicelles demonstrates a promising approach for onychomycosis treatment. The novel methods for protein analysis were straightforward and helpful.

Prevalence of tablet splitting in a Brazilian tertiary care hospital.

BACKGROUND: Although a highly common practice in hospital care, tablet splitting can cause dose variation and reduce drug stability, both of which impair drug therapy. OBJECTIVE: To determine the overall prevalence of tablet splitting in hospital care as evidence supporting the rational prescription of split tablets in hospitals. METHODS: Data collected from inpatients' prescriptions were analyzed using descriptive statistics and used to calculate the overall prevalence of tablet splitting and the percentage of split tablets that had at least one lower-strength tablet available on the market. The associations between the overall prevalence and gender, age, and hospital unit of patients were also assessed. The results of laboratory tests, performed with a commercial splitter, allowed the calculation of the mass loss, mass variation, and friability of the split tablets. RESULTS: The overall prevalence of tablet splitting was 4.5%, and 78.5% of tablets prescribed to be split had at least one lower-strength tablet on the market. The prevalence of tablet splitting was significantly associated with the patient's age and hospital unit. Laboratory tests revealed mean values of mass loss and variation of 8.7% (SD 1.8) and 11.7% (SD 2.3), respectively, both of which were significantly affected by the presence of coating and scoreline. Data from laboratory tests indicated that the quality of 12 of the 14 tablets deviated in at least one parameter examined. CONCLUSIONS: The high percentage of unnecessary tablet splitting suggests that more regular, rational updates of the hospital's list of standard medicines are needed. Also, inappropriate splitting behavior suggests the need to develop tablets with functional scores.

Hot melt-extrusion improves the properties of cyclodextrin-based poly(pseudo)rotaxanes for transdermal formulation.

This study aimed to investigate whether hot-melt extrusion (HME) processing can modify the interactions between drugs, cyclodextrins and polymers, and in turn alter the microstructure and properties of supramolecular gels. Mixtures composed of amphiphilic polymer (Soluplus), cyclodextrin (HPßCD or αCD), plasticizer (PEG400 or PEG6000) and colloidal silicon dioxide were processed by HME. Carvedilol (CAR) was added to the formulation aiming its transdermal delivery. Extrudates were characterized by HPLC, XRPD, FTIR, DSC, and solid-state NMR. Gels prepared from extrudates (HME gels) or the corresponding physical mixtures (PM gels) in PBS were analyzed regarding components ordering (NMR, SEM), rheology, and CAR diffusion rate. HME led to the loss of the crystalline lattice of CAR and αCD, without causing any drug degradation. Solid NMR indicated that HME promoted the interaction of α-CD and HPßCD with the other components. HME gels had no coarsely disperse particles in their structure and behaved as weak gels (G' ~ G″). In contrast, PM gels contained drug crystals and showed elastic behavior (G' > G″). In general, HME gels were less viscous than PM ones and led to higher drug flux, especially those prepared using HPßCD. Moreover, the association of HPßCD and PEG6000 provided faster drug flux from supramolecular gels regardless the higher gel viscosity. The results evidenced that HME processing can decisively modify the arrangement of the components in the supramolecuar gels and, consequently, their properties, notably increasing drug release rate.

Hydroxypropyl-ß-cyclodextrin-complexed naringenin by solvent change precipitation for improving anti-inflammatory effect in vivo.

The flavonoid naringenin (NAR) exhibits an outstanding anti-inflammatory potential; however, stability problems and reduced solubility hinder its commercial insertion. This work aimed to obtain solid-state hydroxypropyl-ß-cyclodextrin (CD) inclusion complexes with NAR using, for the first time, the solvent change precipitation method. For this, molecular modeling and physicochemical characterizations were conducted, followed by in vitro and in vivo assays. The complexation method showed thermal and spectroscopic evidence of NAR inclusion complexes formation, suggesting an improvement of its stability. Additionally, 30 min-dissolution efficiency of the complex was 57.2 %, whereas NAR, as supplied, showed only 14.3 %, a four-fold enhancement. In vitro and in vivo performance attested the potent anti-inflammatory and antinociceptive profile of NAR with significant suppression of TNF-α production. Moreover, NAR complexation with CD improved its therapeutic effect, which showed similar activity to that achieved with NAR as supplied but employing only 1/5 of its dose.

The subdivision behavior of polymeric tablets.

The subdivision behavior of polymeric tablets produced with the well-known polymers Soluplus® (SOL), polyvinyl pyrrolidone co-vinyl acetate (PVPVA) and hydroxypropyl methylcellulose (HPMC) was evaluated in this study. The polymeric tablets were submitted to different post-treatments (aging, thermal and exposure to compressed gaseous carbon dioxide) and its mechanical, spectroscopic and microstructure properties were assessed. SOL tablets showed the best results for tablet subdivision, particularly, the mean mass variation (3.9%) was significantly lower than the other two polymeric tablets (7.2% and 9.1% for PVPVA and HPMC, respectively), and showed better results than common tablets produced from powder matrices (7-14%). SOL tablets were also more sensitive to the different post-treatments applied, which reduced the mass loss and friability from 1.5% and 0.8%, respectively, to values close to zero and without altering their porosity. The thermal treatment of PVPVA tablets, in turn, also led to similar subdivision results, with mass loss of 0.3% and friability of 0.02%. In contrast, the granules of HPMC presented compaction difficulties making its tablets unsuitable for the subdivision process, even after additional post-treatment. Polymeric matrices with uniform internal structure and appropriate mechanical strength are the key to a better adaptation for the tablet subdivision.

Anti-hyperalgesic and anti-inflammatory effects of citral with ß-cyclodextrin and hydroxypropyl-ß-cyclodextrin inclusion complexes in animal models.

Citral (CIT) is a monoterpene formed by the geranial and neral stereoisomers. CIT is the major compound of Cymbopogon citratus essential oil, commonly known as "lemongrass", and has demonstrated potential antihyperalgesic, anti-nociceptive and anti-inflammatory effects. However, CIT shows high volatility, low solubility in water and consequent low bioavailability, which limits its use. Therefore, the aim of this study was to evaluate cell viability, anti-hyperalgesic and anti-inflammatory effects of inclusion complexes of CIT on ß-cyclodextrin (ß-CD) and hydroxypropyl-ß-cyclodextrin (HP-ß-CD). Initially, physical mixture (PM) and freeze-dried inclusion (FD) complexes of CIT/ß-CD and CIT/HP-ß-CD were obtained in the molar ratio (1:1). The samples were characterized by DSC, TG/DTG, FT-IR, XRD, SEM and the complexation efficiency were performed by HPLC. Cell viability assay was performed by rezasurin reduction technique in J774 macrophages cell line. The motor activity through rota rod apparatus, mechanical hyperalgesia and pleurisy induced by carrageenan were evaluated in mice. The complexation of CIT was evidenced with ß-CD and HP-ß-CD by the characterization techniques analyzed. The complexation efficiency of CIT/ß-CD and CIT/HP-ß-CD were 78.6% and 71.7%, respectively. The CIT, CIT/ß-CD and CIT/HP-ß-CD showed cell viability in macrophages and did not interfere in the motor activity of mice. Besides that, the samples demonstrated antihyperalgesic and anti-inflammatory activity due to the reduction in total leukocytes and TNF-α levels. However, CIT/ß-CD has better pharmacological effects among the three samples evaluated. Therefore, CIT/ß-CD has potential for the development of products to treat inflammatory and pain reactions.

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.

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.