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Made available in DSpace on 2021-06-25T11:15:38Z (GMT). No. of bitstreams: 0 Previous issue date: 2021-07-31 Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) The high incidence and costs of chronic wounds in the elderly have motivated the search for innovations to improve product performance and the healing process while reducing costs. In this study, bioadhesive nanostructured lipid carriers (NLC) were developed for the co-encapsulation of compounds with antioxidant (α-tocopherol and quercetin) and antimicrobial (tea tree oil) activity for management of wounds. The NLC was produced with shea butter and argan oil, and modified with sodium alginate or chitosan to confer bioadhesive properties. Spherical nanoparticles of ~307–330 nm and zeta potential varying from −21.2 to +11.8 mV were obtained. Thermal analysis demonstrated that the lipid matrix reduced tea tree oil thermal loss (~1.8-fold). Regardless of the type of polysaccharide employed, the NLCs promoted cutaneous localization of antioxidants in damaged (subjected to incision) skin, with a ~74 to 180-fold higher delivery into the skin compared to percutaneous delivery. This result is consistent with the similar bioadhesive properties of chitosan or sodium alginate-modified NLC. Nanoencapsulation of tea tree oil did not preclude its antimicrobial effects against susceptible and resistant strains of S. aureus and P. aeruginosa, while co-encapsulation of antioxidants increased the NLC-induced fibroblasts migration, supporting their potential usefulness for management of wounds. Instituto de Ciências Biomédicas Universidade de São Paulo School of Pharmaceutical Sciences São Paulo State University (UNESP) Faculdade de Ciências Farmacêuticas Universidade de São Paulo School of Pharmaceutical Sciences São Paulo State University (UNESP) CAPES: 001 FAPESP: 2013/16617-7 FAPESP: 2015/07993-0 FAPESP: 2017/19059-6 FAPESP: 2017/19374-9 FAPESP: 2018/13877-1 FAPESP: 2019/26048-6 CNPq: 306866/2020-0

Recently, the U.S. Food and Drug Administration (FDA) approved the first oral antiviral drug to treat mild to moderate cases of coronavirus disease. The combination of nirmatrelvir with an already used protease inhibitor class drug, ritonavir, has led to Paxlovid®. Several studies considered drug repositioning as the first trial for new drugs. The precise identification and quantification of polymorphs in raw materials and finished products are important to researchers involved in pharmaceutical development and quality control processes. In this work, we study the solid-state behavior of the antiretroviral drugs ritonavir and lopinavir in raw materials and in milled compositions. The results indicate that mixtures of ritonavir Forms I and II are found in different batches of raw materials from the same manufacturer; besides three equal crystalline samples, an amorphous batch was found in lopinavir. Furthermore, the milling process of the already amorphous lopinavir seems to facilitate the amorphization of ritonavir as well as the production of some unexpected crystalline forms of ritonavir. A phase transition of ritonavir Form I to Form II is only observed when co-milling with amorphous lopinavir. These findings reveal significant variations in phase purity of raw materials that affect the processing and solid-state properties, representing risks for the product quality.

Dissolution testing is important in assessing the in vitro drug release performance for oral administration dosage forms. However, currently, a simple and efficient in vitro test to investigate critical factors that may impact the drug release and bioavailability at the development stage of a drug-loaded nanoemulsion (NE) is lacking. Thus, in this study, we developed a new combined biphasic and modified cylinder (BP + MC) method to evaluate the dissolution profile of NEs. Flubendazole (FLZ), a Biopharmaceutical Classification System (BCS) Class II drug, offers a new prospective for drug repositioning for treating lung cancer and cryptococcal meningitis. We compared the drug release profiles of three different FLZ formulations (micronized as a suspension, loaded in NE, and solubilized in oil) by using three different methods (dialysis bag, modified cylinder method, and a new BP + MC method). The results showed potential higher drug release of FLZ from the suspension compared to FLZ-loaded NE at pH 1.2, and higher drug release from FLZ-loaded NE compared to other forms in octanol phase. These results correlate well with the in vivo test performed in mice carried out in our previous works. Furthermore, the partition mechanism of the drug released from the NE is discussed in-depth in this article, as well as the advantage of drug-loaded NEs over other preparations in creating supersaturable conditions. Based on the results, we provide new insights into how dissolution methods for a poorly water-solubility drug can be designed. Therefore, we present this new combined BP + MC method as a potential new discriminative dissolution test for future studies when developing drug-loaded NE and comparing with other dosage forms.

Ciprofibrate (CIP) is a highly lipophilic and poorly water-soluble drug, typically used for dyslipidemia treatment. Although it is already commercialized in capsules, no previous studies report its solid-state structure, thus, information about the correlation with its physicochemical properties lacking. In parallel, recent studies have led to the improvement of drug administration, including encapsulation in polymeric nanoparticles (NPs). Here, we present CIP’s crystal structure determined by PDRX data. We also propose an encapsulation method for CIP in micelles produced from Pluronic P123/F127 and PEO-b-PCL, aiming to improve its solubility, hydrophilicity, and delivery. We determined the NPs’ physicochemical properties by DLS, SLS, ELS, and SAXS and the loaded drug amount by UV-Vis spectroscopy. Micelles showed sizes around 10–20 nm for Pluronic and 35–45 nm for the PEO-b-PCL NPs with slightly negative surface charge and successful CIP loading, especially for the latter, a substantial reduction in ζ-potential may be evidenced. For Pluronic nanoparticles, we scanned different conditions for the CIP loading, and its encapsulation efficiency was reduced while the drug content increased in the nanoprecipitation protocol. We also performed in vitro release experiments, results demonstrate that probe release is driven by Fickian diffusion for the Pluronic NPs and a zero-order model for PEO-b-PCL NPs.

Objectives: This study aimed to describe the preparation and in vitro evaluation of a surface-modified nanostructured lipid carrier (NLC) using chitosan and dextran for co-delivery of buparvaquone (BPQ) and polymyxin B (PB) against leishmaniasis. Methods: The NLC was prepared using high-pressure homogenisation. Polymyxin B binding and surface modification with biopolymers were achieved by electrostatic interaction. In vitro cytotoxicity was assessed in mouse peritoneal macrophages, and leishmanicidal activity in amastigotes of Leishmania infantum. Results: The performance attributes of BPQ-NLC, BPQ-NLC-PB[A −] (anionic) and BPQ-NLC-PB[C +] (cationic) were respectively: Z-average 173.9 ± 1.6, 183.8 ± 4.5 and 208.8 ± 2.6 nm; zeta potential −19.6 ± 1.5, −20.1 ± 1.1 and 31.1 ± 0.8 mV; CC 50 583.4 ± 0.10, 203.1 ± 0.04 and 5.7 ± 0.06 μM; IC 50 229.0 ± 0.04, 145.7 ± 0.04 and 150.5 ± 0.02 nM. The NLC in vitro leishmanicidal activity showed up to 3.1-fold increase when compared with free BPQ (P < 0.05, α = 0.05). Conclusions: The developed NLC proved to be a promising formulation with which to overcome the drawbacks of current leishmaniasis treatment by the co-delivery of two alternative drugs and a macrophage targeting modified surface.

The levitation of samples in an acoustic field has been of interest in the preparation and study of amorphous solid dispersions (ASD). Here, niclosamide-polymer solutions were levitated in a multi-emitter single-axis acoustic levitator and analyzed for 10 min at a High-resolution synchrotron X-ray powder diffraction beamline. This assembly enabled high-quality and fast time-resolved measurements with microliter sample size and measurement of solvent evaporation and recrystallization of niclosamide (NCL). Polymers HPMCP-55S, HPMCP-50, HPMCP-55, Klucel®, and poloxamers were not able to form amorphous dispersions with NCL. Plasdone® and Soluplus® demonstrated excellent properties to form NCL amorphous dispersions, with the last showing superior solubility enhancement. Furthermore, this fast levitation polymer screening showed good agreement with results obtained by conventional solvent evaporation screening evaluated for five days in a stability study, carried out at 40 °C/75% RH. The study showed that acoustic levitation and high-resolution synchrotron combination opens up a new horizon with great potential for accelerating ASD formulation screening and analysis.

We use X-ray pair distribution function (PDF) analysis applied to high-energy synchrotron X-ray powder diffraction data to evaluate the amorphous solid dispersions interactions and their aging stability. The obtained systems are based on hydroxypropyl methylcellulose (hypromellose) derivatives and flubendazole (FBZ) drug dispersions prepared using a spray-dryer technique. We carry out stability studies under aging parameters (40 °C/75% relative humidity) to tune the systems’ recrystallization. The results reveal that ion-base interactions between the drug-polymer matrix are responsible for reducing clustering processes yielding slower recrystallization and different ordering in the hypromellose phthalate (HPMCP/FBZ) and hypromellose acetate succinate (HPMC-AS/FBZ) systems and complete drug clustering in hypromellose (HPMC-E3/FBZ). The structural ordering was accessed using differential X-ray PDFs that revealed the region between 3.5 A and 5.0 A could be related to FBZ intermolecular interactions and is more ordered for the least stable system (HPMC-E3/FBZ) and less ordered for the most stable system (HPMCP/FBZ). These results show that the ion-base interactions between drug and matrix occur at these intermolecular distances.

This work describes an exploratory experimental and in silico study of the influence of polymorphism, particle size, and physiology on the pharmacokinetics of lercanidipine hydrochloride (LHC). Equilibrium and kinetic solubility studies were performed on LHC forms I and II, as a function of pH and buffer composition. GastroPlus® was used to evaluate the potential effect of solubility differences due to polymorphism, particle size, and physiological conditions, on the drug pharmacokinetics. The results indicated that solubilities of LHC polymorphs are strongly dependent on the composition and pH of the buffer media. The concentration ratio (CI/CII) is particularly large for chloride buffer (CI/CII = 3.3-3.9) and exhibits a slightly decreasing tendency with the pH increase for all other buffers. Based on solubility alone, a higher bioavailability of form I might be expected. However, exploratory PBPK simulations suggested that (i) under usual fasted (pH 1.3) and fed (pH 4.9) gastric conditions, the two polymorphs have similar bioavailability, regardless of the particle size; (ii) at high gastric pH in the fasted state (e.g., pH 3.0), the bioavailability of form II can be considerably lower than that of form I, unless the particle size is < 20 μm. This study demonstrates the importance of investigating the effect of the buffer nature when evaluating the solubility of ionizable polymorphic substances. It also showcases the benefits of using PBPK simulations, to assess the risk and pharmacokinetic relevance of different solubility and particle size between crystal forms, for diverse physiological conditions.

Olive oil has been extensively applied in the pharmaceutical and cosmetic industries due to its biological properties. These are attributed to monounsaturated fatty acids like oleic acid and other minor components, such as phenolics and triterpenic acids. Oil-in-water nanoemulsion may enhance the solubility of poorly water-soluble drugs, which comprise about 40% of the currently marketed ones. However, the development of vegetable oil nanoemulsions is challenging due to their complex composition. In this study, olive oil nanoemulsions were prepared using high-pressure homogenization (HPH) and d -phase emulsification (DPE), as high- and low-energy processes, respectively. DPE has the potential to overcome the drawbacks of conventional Phase Inversion Methods. Aiming to achieve a deeper understanding of HPH and DPE processes, a design of experiment approach was successfully applied. This approach allowed identifying and understanding the relationship between input factors and their associated output response, at the stage of the nanoemulsion development. Moreover, in a specific range of critical process parameters and compositions, within the design space, nanoemulsions with similar mean particle sizes of 275 nm were achieved with equal composition, regardless of the use of the HPH or DPE process.

The development of nanoscale emulsions containing high concentration of vegetable oil and low concentration of surfactant is considered challenging in conventional low-energy processes such as the Phase Inversion Temperature (PIT) and Phase Inversion Composition (PIC) methods. For the first time, a stable 20–30 nm oil-in-water nanoemulsion, containing 40.0% (w/w) olive oil was obtained with 2.0% (w/w) single hydrophilic surfactant, applying D-Phase Emulsification (DPE) process in combination with the Box-Behnken statistical design. The preparation of control samples using the PIT and PIC methods resulted in the absence of emulsion formation under the same composition and conditions followed by the DPE process. As a variable influencing the mean particle size of the nanoemulsion in this specific process, the polyol was confirmed to be crucial as the fourth component. An isotropic phase was revealed in place of a liquid crystalline structure or conventional microemulsion phase, enabling easy dispersion of the high oil content in the oil-in-surfactant intermediate phase, during this process. The presence of an initial isotropic phase indicated that there is no need for a strict adjustment of the hydrophilic-lipophilic balance (HLB), nor of the initial water-in-oil phase as in conventional low-energy methods. The results obtained in the present study confirmed the unique feature of the DPE process, overcoming the limitation of conventional low energy methods, for the development of nanoemulsions with high vegetable oil content as a drug delivery system.

An orally disintegrating tablet is a novel formulation that dissolves in the saliva within a few seconds and without requiring of drinking additional water. This dosage form is a powerful way to deliver active drugs ingredients because it has many advantages. Many studies have compared this form of tablet with the ordinary forms in vitro and in vivo and found that orally disintegrating tablets have superior patient compliance and drug solubility. However, there are some criteria for the active pharmaceutical ingredients to prepare tablets as fast dissolve forms. There are several ways to prepare this dosage form and each method has its pros and cons. Technologies of preparation and various examples of orally disintegrating tablet available in the market using different preparing procedures are presented in this review. Taste masking is required form some active pharmaceutical ingredients to be formed as orally disintegrating tablets. In vitro evaluation and quality control measures of orally disintegrating tablet is also discussed in this review.

Leishmaniasis, a neglected tropical disease, is prevalent in 98 countries with the occurrence of 1.3 million new cases annually. The conventional therapy for visceral leishmaniasis requires hospitalization due to the severe adverse effects of the drugs, which are administered parenterally. Buparvaquone (BPQ) showed in vitro activity against leishmania parasites; nevertheless, it has failed in vivo tests due to its low aqueous solubility. Though, lipid nanoparticles can overcome this holdback. In this study we tested the hypothesis whether BPQ-NLC shows in vivo activity against L. infantum. Two optimized formulations were prepared (V1: 173.9 ± 1.6 nm, 0.5 mg of BPQ/mL; V2: 232.4 ± 1.6 nm, 1.3 mg of BPQ/mL), both showed increased solubility up to 73.00-fold, and dissolution up to 83.29%, while for the free drug it was only 2.89%. Cytotoxicity test showed their biocompatibility (CC50554.4 µM). Besides, the V1 dose of 0.3 mg/kg/day for 10 days reduced the parasite burden in 83.4% ±18.2% (p0.05) in the liver. BPQ-NLC showed similar leishmanicidal activity compared to miltefosine. Therefore, BPQ-NLC is a promising addition to the limited therapeutic arsenal suitable for leishmaniasis oral administration treatment.

Cryptococcal meningitis is caused by Cryptococcus spp. and predominantly affects patients with acquired immunodeficiency syndrome. However, an increase in the number of nonHIV patients diagnosed with cryptococcosis raises concerns worldwide. The current antifungal therapy has some limitations such as being unavailable in some countries, high cost, toxicity, and the need for trained professionals for intravenous administration, which compromises patient compliance, resulting in treatment withdrawal and increased fungal resistance. In this regard, new alternative drugs, especially those administered orally and at affordable cost are desired. However, these drugs face challenges due to the gastrointestinal (GI) and blood-brain barriers (BBB). In this present work, we developed a new oil-in-water nanoemulsion containing flubendazole (FLZ) for oral administration using a unique low-energy process for treating cryptococcosis. The combination of D -phase emulsification (DPE) process and design of experiment (DoE) resulted in a stable FLZ-loaded nanoemulsion with 35-nm mean particle size, 60.0% oil phase with 3.0% surfactant phase (both % w/w), at 25 °C process temperature without using specific equipment. The careful selection of components for developing this nanoemulsion as a drug carrier is thoroughly discussed herein, including the interaction of lipid components with brain transporters, the type of surfactant as a permeability enhancer through BBB, as well as the choice of the drug. The use of statistical design combined with the DPE process, and selection of components, resulted in reducing approximately 30% of fungal burden in mice brain, and safety testing in an invertebrate model showed nontoxicity by this nanoemulsion. This work reports a step-by-step alternative process for designing a nanoemulsion with improved efficacy and safety, even containing a drug at a significantly reduced concentration compared to previously published works. This nanoemulsion provides multiple benefits - overcoming GI and BBB barriers, and affordable production cost - delivering a new antifungal alternative for treating cryptococcosis.

Made available in DSpace on 2020-12-10T19:59:33Z (GMT). No. of bitstreams: 0 Previous issue date: 2020-02-01 Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) Castor oil is an environmentally friendly alternative to hydrocarbon-based feedstocks for the synthesis of polyurethanes due to its major constituent, ricinoleic acid. This work aimed to obtain and characterize castor oil-based polyurethane (coPU) systems containing domperidone and verapamil hydrochloride, separately, as model drugs. The drug-loaded coPU systems were obtained by solvent evaporation method and were characterized by differential scanning calorimetry, thermogravimetry, Fourier transform infrared spectroscopy and X-ray powder diffraction. Additionally, dissolution studies and scanning electron microscopy were performed. Verapamil hydrochloride was successfully incorporated in coPU, once it interacted through hydrogen bonds, and this system showed as a potential candidate for sustained drug release. Domperidone precipitated during solvent evaporation, resulting in a drug suspension into the polymer matrix. However, around 20% of domperidone interacted chemically with the polymer by the reaction of the active hydrogen of domperidone imidazole groups with the terminal isocyanate of the prepolymer. Finally, the drug release profile is guided by the drug-polymer physicochemical interaction, which will depend on the drug and polymer functional groups that are stereochemically available. Univ Sao Paulo, Fac Pharmaceut Sci, Dept Pharm, BR-05508000 Sao Paulo, Brazil Fed Univ ABC UFABC, Ctr Nat & Human Sci CCNH, BR-09210580 Santo Andre, SP, Brazil Sao Paulo State Univ, Chem Inst, Dept Phys Chem, BR-14800060 Araraquara, SP, Brazil Sao Paulo State Univ, Chem Inst, Dept Phys Chem, BR-14800060 Araraquara, SP, Brazil FAPESP: 2013/14744-1

Cancer related to lymphangiogenesis has gained a great deal of attention in recent decades ever since specific markers of this intriguing system were discovered. Unlike the blood system, the lymphatic system has unique features that can advance cancer in future metastasis, or, conversely, can provide an opportunity to prevent or treat this disease that affects people worldwide. The aim of this review is to show the recent research of cancer treatment associated with the lymphatic system, considered one of the main gateways for disseminating metastatic cells to distant organs. Nanostructured systems based on theranostics and immunotherapies can offer several options for this complex disease. Precision targeting and accumulation of nanomaterials into the tumor sites and their elimination, or targeting the specific immune defense cells to promote optimal regression of cancer cells are highlighted in this paper. Moreover, therapies based on nanostructured systems through lymphatic systems may reduce the side effects and toxicity, avoid first pass hepatic metabolism, and improve patient recovery. We emphasize the general understanding of the association between the immune and lymphatic systems, their interaction with tumor cells, the mechanisms involved and the recent developments in several nanotechnology treatments related to this disease.

Background Acid straightener products are widely used, and it can cause changes in the hair shaft properties. The pH value of these products established by ANVISA (Brazil's National Health Surveillance Agency) as secure is above 2.0. However, the industries are interested in working at lower pH values in order to increase the straightening effect. Unfortunately, there are a lot of products in the market with pH value under the permitted. Objective Analyze two different pH values (1.0 and 2.0) of acid straightener formulation and the influence of this difference in the hair shaft properties. In order to provide information to professionals as cosmetologists, dermatologists, and hairdressers. Methods Combing and colorimetric analyses, tensile strength, differential scanning calorimetry (DSC), environmental scanning electron microscope (ESEM), and tryptophan content. Results The tresses treated at pH 1.0 had a better result in the straightening capacity, improving the combing test in 59.4%, while those at pH 2.0, only in 33.0% compared with virgin hair. However, the tensile strength, at pH 1.0 decreased by 16.0% and 9.0% to the pH 2.0. In addition, the tryptophan content was lower in the tresses treated with formulation at pH 1.0. The DSC analysis showed impairment in the straightened tresses. The images by ESEM, indicated a possible formation of a film around the fiber. Conclusions It was possible to conclude that the pH value interferes in the hair shaft properties. Tresses treated with pH 1.0 had more modifications than tresses treated with pH 2.0.

This chapter reviews the use of nanostructured systems for treating hair disorders. Hair is an intriguing organ, which involves complex and dynamic interactions, such as cell lifecycles and their impact from external and internal damage. Hair appearance reflects the social lifestyles and wellness of individuals, which causes concerns once this visual aspect is negatively affected. Understanding the primary sources of each disorder is essential for the best treatment, although several causes are still being studied. In the first section, we describe the structure of different parts of hair. The second section provides in-depth coverage of several types of nanostructured systems. Lastly, the third section reports on the main hair disorders and recent research based on nanostructured systems addressing these specific needs and treatments.

Considering the increased incidence of sporotrichosis and other fungal infections in rural and urban areas, and the limitations and adverse effects of oral itraconazole therapy, we studied nanostructured lipid carriers (NLC) as topical delivery systems to increase itraconazole localization in skin lesions and associate efficacy with reduced systemic exposure. Unloaded and itraconazole-loaded NLC showed nanometric size (~216–340 nm), negative zeta potential (~ -17 mV), and high entrapment efficiency (~97%). NLC treatment decreased transepidermal water loss, an index of cutaneous barrier function, in intact skin and in tissues damaged with a linear incision (to mimic lesions) by 23–36%, and reduced drug transdermal delivery by ~2-fold, demonstrating its ability to localize itraconazole within the skin. The unloaded and itraconazole-loaded NLC were considered safe, as indicated by scores of 0.5 and 0.6 in HET-CAM models, respectively, and lack of toxicity (measured by survival and health index) on the Galleria mellonella larvae. The values obtained for minimum inhibitory concentration and minimum fungicidal concentration on Sporothrix brasiliensis yeasts were 0.25 and 32 μg/mL, respectively. The drug in solution displayed similar values, indicating that encapsulation does not hinder itraconazole antifungal effect. NLC treatment improved the survival rate and health index of G. mellonella larvae infected with S. brasiliensis yeasts and C. albicans, demonstrating antifungal efficacy. Taken together, itraconazole encapsulation in NLC represents a viable strategy to optimize cutaneous localization without compromising its efficacy against fungal infections.

Drug repositioning may be defined as a process when new biological effects for known drugs are identified, leading to recommendations for new therapeutic applications. Niclosamide, present in the Model List of Essential Medicines, from the World Health Organization, has been used since the 1960s for tapeworm infection. Several preclinical studies have been shown its impressive anticancer effects, which led to clinical trials for colon and prostate cancer. Despite high expectations, proof of efficacy and safety are still required, which are associated with diverse biopharmaceutical challenges, such as the physicochemical properties of the drug and its oral absorption, and their relationship with clinical outcomes. Nanostructured systems are innovative drug delivery strategies, which may provide interesting pharmaceutical advantages for this candidate. The aim of this review is to discuss challenges involving niclosamide repositioning for cancer diseases, and the opportunities of therapeutic benefits from nanosctrutured system formulations containing this compound.

The water/aceto­nitrile solvent of afatinib exhibits pseudo-inversion symmetry. Exact inversion symmetry is broken by swapping of oxygen and CH2 moieties of its tetra­hydro­furanyl substituents, which can be traced back to C—H⋯N and C—H⋯O inter­actions of the aceto­nitrile solvent mol­ecules with the tetra­hydro­furanyl units., Afatinib (systematic name: N-{4-(3-chloro-4-fluoro­anilino)-7-[(tetra­hydro­furan-3-yl)­oxy]quinazolin-6-yl}-4-(di­methyl­amino)­but-2-enamide), is a specific in­hibitor of the ErbB family of tyrosine kinases. The free base form crystallizes from aceto­nitrile as a mixed water–aceto­nitrile solvent, C24H25ClFN5O3·0.25C2H3N·2H2O. It crystallizes with two independent mol­ecules (A and B) in the asymmetric unit of the chiral space group P4212, but exhibits close to perfect pseudo-inversion symmetry, emulating P4/ncc that relates the two mol­ecules to each other. Exact inversion symmetry is however broken by swapping of oxygen and CH2 moieties of the outer tetra­hydro­furanyl substituents of the two independent mol­ecules. This can, in turn, be traced back to C—H⋯N and C—H⋯O inter­actions of the aceto­nitrile solvent mol­ecules with the tetra­hydro­furan oxygen and CH2 units. In the crystal, neighboring mol­ecules are connected via N—H⋯O hydrogen bonds between the secondary amine and the amide keto O atom. Additional hydrogen bonds are formed through the water solvent mol­ecules, which are engaged in O—H⋯O and O—H⋯N hydrogen bonds connecting to the di­methyl­amino N atom, the amide keto O atom, and one of the quinazoline N atoms of a neighboring mol­ecule, leading to an intricate three-dimensional hydrogen-bonded superstructure. There are two types of channels stretching along the direction of the c axis; one along the fourfold rotational axis, occupied by aceto­nitrile solvent mol­ecules situated on that axis, and parallel channels which are not occupied by any solvent.

Made available in DSpace on 2019-10-06T05:45:57Z (GMT). No. of bitstreams: 0 Previous issue date: 2019-08-15 Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) As a new strategy for treatment of ductal carcinoma in situ, biocompatible and bioadhesive nanoemulsions for intraductal administration of the cytotoxic agent piplartine (piperlongumine) were optimized in this study. To confer bioadhesive properties, the nanoemulsion was modified with chitosan or hyaluronic acid. Tricaprylin was selected as the nanoemulsion non-polar phase due to its ability to dissolve larger drug amounts compared to isopropyl myristate and monocaprylin. Use of phosphatidylcholine as sole surfactant did not result in a homogeneous nanoemulsion, while its association with polysorbate 80 and glycerol (in a surfactant blend) led to the formation of nanoemulsions with droplet size of 76.5 +/- 1.2 nm. Heating the aqueous phase to 50 degrees C enabled sonication time reduction from 20 to 10 min. Inclusion of either chitosan or hyaluronic acid resulted in nanoemulsions with similar in vitro bioadhesive potential, and comparable ability to prolong mammary tissue retention (to 120 h) in vivo without causing undesirable histological alterations. Piplartine was stable in both nanoemulsions for 60 days; however, the size of loaded NE-HA was maintained at a similar range for longer periods of time, suggesting that this nanoemulsion may be a stronger candidate for intraductal delivery. Univ Sao Paulo, Inst Biomed Sci, Dept Pharmacol, Av Prof Lineu Presses 1524, Sao Paulo, SP, Brazil Sao Paulo State Univ, Sch Pharmaceut Sci Araraquara, Araraquara, SP, Brazil Univ Sao Paulo, Inst Biomed Sci, Dept Immunol, Sao Paulo, SP, Brazil Univ Sao Paulo, Sch Pharmaceut Sci, Sao Paulo, SP, Brazil Univ Fed Ceara, Dept Inorgan & Organ Chem, Fortaleza, Ceara, Brazil Sao Paulo State Univ, Sch Pharmaceut Sci Araraquara, Araraquara, SP, Brazil FAPESP: 2013/16617-7 FAPESP: 2018/03418-0 FAPESP: 2018/13877-1 CNPq: 443549/2014-1 CAPES: 001 FAPESP: 2017/04174-4 FAPESP: 2017/23213-0 FAPESP: 2017/19059-6 FAPESP: 2018/18813-1

Orotic acid (OA), a heterocyclic compound also known as vitamin B13, has shown potent antimalarial and cardiac protection activities; however, its limited water solubility has posed a barrier to its use in therapeutic approaches. Aiming to overcome this drawback, OA freeze-dried nanocrystal formulations (FA, FB, and FC) were developed by using the high-energy milling method. Polysorbate 80 (FA) and povacoat® (FC) were used alone and combined (FB) as stabilizers. Nanocrystals were fully characterized by dynamic light scattering, laser diffraction, transmission electron microscopy, thermal analysis (thermogravimetry and derivative thermogravimetry, and differential scanning calorimetry), and X-ray powder diffraction revealing an acceptable polydispersity index, changes in the crystalline state with hydrate formation and z-average of 100-200 nm, a remarkable 200-time reduction compared to the OA raw material (44.3 μm). Furthermore, saturation solubility study showed an improvement of 13 times higher than the micronized powder. In addition, cytotoxicity assay revealed mild toxicity for the FB and FC formulations prepared with povacoat®. OA nanocrystal platform can deliver innovative products allowing untapped the versatile potential of this drug substance candidate.

Recently, several approaches have been reported to improve the dissolution rate and bioavailability of furosemide, a class IV drug. However, to the best of our knowledge, none of them proposed nanocrystals. In the last decade, nanocrystals successfully addressed solubility issues by increasing surface area and saturation solubility, both leading to an increase in the dissolution rate of poor water soluble drugs. The preparation of furosemide nanocrystals was by a rotation revolution mixer method. Size distribution and morphology were performed using laser diffraction and scanning electron microscopy, respectively. In addition, differential scanning calorimetry, thermogravimetry, X-ray powder diffraction (XRD) and low frequency shift-Raman spectroscopy allowed investigating the thermal properties and crystalline state. Solubility saturation and intrinsic dissolution rate (IDR) studies were conducted. The thermal analysis revealed lower melting range for the nanocrystals comparing to furosemide. Moreover, a slight crystalline structure change to the amorphous state was observed by XRD and confirmed by low frequency shift Raman. The particle size was reduced to 231 nm with a polydispersity index of 0.232, a 30-fold reduction from the original powder. Finally, the saturation solubility and IDR showed a significant increase. Furosemide nanocrystals showed potential for development of innovative formulations as an alternative to the commercial products.

The present work describes the development and characterization of a nanostructured mesoporous SBA-15 silica loaded with prednicarbate, a corticosteroid widely used in the treatment for atopic dermatitis, and the assessment of its in vitro release profile in comparison with a conventional cream formulation. The inclusion of prednicarbate in the SBA-15 pores was confirmed by the respective 24 and 16 % decrease in the surface area (S BET) and mesopores volume (V), in combination with supporting data obtained by thermal analysis (TG and DSC), FTIR spectroscopy, X-ray diffraction, and elemental analysis. Additionally, it has been shown through X-ray diffraction and DSC that the encapsulated molecules remain in an amorphous state, and the protective function of the loading was demonstrated through thermogravimetry by the decrease in the rate of the thermal decomposition reaction of the drug-loaded material (Δm 600–850 °C). Finally, the HPLC–MS/MS method developed was proven to be precise and accurate for the determination of prednicarbate in the receiving fluid samples collected during the in vitro release test using Franz diffusion cells.

The use of flubendazole (FBZ) in the treatment of lymphatic filariasis and onchocerciasis (two high incidence neglected tropical diseases) has been hampered by its poor aqueous solubility. A material consisting of binary flubendazole/maleic acid crystals (FBZ/MA), showing considerably improved solubility and dissolution rate relative to flubendazole alone, has been prepared in this work through solvent assisted mechanical grinding. The identification of FBZ/MA as a binary crystalline compound with salt character (proton transfer from MA to FBZ) relied on the combined results of powder X-ray diffraction, Raman spectroscopy, attenuated total reflection Fourier transform infrared spectroscopy (ATR-FTIR), X-ray photoelectron spectroscopy (XPS), thermogravimetry (TG), and differential scanning calorimetry (DSC). Isothermal solution microcalorimetry studies further suggested that the direct formation of FBZ/MA from its precursors in the solid state is thermodynamically favored. A comparison of the in silico pha...

For many years, the idea of analyzing atom-atom contacts in amorphous drug-polymer systems has been of major interest, because this method has always had the potential to differentiate between amorphous systems with domains and amorphous systems which are molecular mixtures. In this study, local structure of ionic and noninonic interactions were studied by High-Energy X-ray Diffraction and Pair Distribution Function (PDF) analysis in amorphous solid dispersions of lapatinib in hypromellose phthalate (HPMCP) and hypromellose (HPMC-E3). The strategy of extracting lapatinib intermolecular drug interactions from the total PDF x-ray pattern was successfully applied allowing the detection of distinct nearest neighbor contacts for the HPMC-E3 rich preparations showing that lapatinib molecules do not cluster in the same way as observed in HPMC-P, where ionic interactions are present. Orientational correlations up to nearest neighbor molecules at about 4.3 Å were observed for polymer rich samples; both observations showed strong correlation to the stability of the systems. Finally, the superior physical stability of 1:3 LP:HPMCP was consistent with the absence of significant intermolecular interactions in (∆"Equation missing") in the range of 3.0 to 6.0 Å, which are attributed to C-C, C-N and C-O nearest neighbor contacts present in drug-drug interactions.

Esculetin, a natural coumarin derived from herbs, has shown different potential pharmacological activities. However, the poor aqueous solubility of esculetin may limit its therapeutic efficacy. Nanocrystal is a promising dosage form to overcome this drawback by enhancing drug saturation solubility. Hence, a laboratory-scale wet-bead milling approach was employed to develop an esculetin nanocrystal formulation. Povacoat™ was selected as a stabilizer after screening different surfactants and polymers. Design of experiments was applied to identify and understand the relationship between process parameters and formulation compositions at the stage of formulation optimization. Furthermore, the optimized formulation was solidified using two different approaches (spray-drying and freeze-drying) and characterized by dynamic light scattering, laser diffraction, transmission electron microscopy, scanning electron microscopy, thermal analysis, and X-ray powder diffraction. An esculetin-Povacoat™ nanocrystal formulation that maintained a 200 nm particle size for 180 days was successfully obtained with specific critical process parameters and formulation composition within the design space.

Buparvaquone (BPQ), a veterinary drug, was formulated as nanostructured lipid carriers (NLC) for leishmaniases treatment. The formulation design addressed poor water solubility of BPQ and lack of human drug delivery system. The DSC/TG and microscopy methods were used for solid lipids screening. Softisan® 154 showed highest BPQ solubility in both methods. The BPQ solubility in liquid lipids using HPLC revealed Miglyol® 812 as the best option. Response surface methodology (RSM) was used to identify the optimal Softisan154 : Miglyol 812 ratios (7 : 10 to 2 : 1) and Kolliphor® P188 and Tween® 80 concentration (>3.0% w/w) aiming forz-average in the range of 100–300 nm for macrophage delivery. The NLC obtained by high-pressure homogenization showed lowz-averages (z-average. Therefore, these drug delivery systems have the potential to improve the availability of affordable medicines due to the low cost of raw materials, using well established, reliable, and feasible scale-up technology.

Made available in DSpace on 2015-05-15T13:30:17Z (GMT). No. of bitstreams: 0 Previous issue date: 2013Bitstream added on 2015-05-15T13:56:23Z : No. of bitstreams: 1 ISSN2157-9431-2013-04-03-283-287.pdf: 599400 bytes, checksum: 1c2a2010ff829211ff619ab90a71b608 (MD5) Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) LNLS (Brazilian Synchrotron Light Laboratory) Tibolone, a synthetic steroid, is used in the treatment of natural or surgical menopause disturbs resultant of estrogenic deficiency. Isotibolone (Δ4-tibolone) is one of the three active metabolic degradation products of tibolone that displays progestagenic effects on carcinoma cell growth and gene regulation. Isotibolone can be present in raw material of tibolone due to some inadequate synthesis or storage. Its presence is necessary to be identified and quantified in active pharmaceutical ingredients (API), before its use in the manufacturing of medicines. After a recent study on the crystal structure determination of isotibolone, quantitative phase analyses of both tibolone and isotibolone in raw materials and tablets became possible to be conducted. X-ray powder diffraction is one recommended tool for this purpose, but it can be highly frustrating due to the extreme peak overlap when conventional laboratory equipments are used. In this work we show that the use of Brazilian Synchrotron Light Source X-ray powder diffraction data and the Rietveld method can be successfully applied to identify and quantify the isotibolone in two samples of tibolone raw materials. Universidade Estadual Paulista Júlio de Mesquita Filho, Departamento de Físico-Química, Instituto de Química de Araraquara, Araraquara, R. Prof. Francisco Degni 55, Quitandinha, CEP 14800-060, SP, Brasil Departamento de Físico-Química, Instituto de Química, Universidade Estadual Paulista, Araraquara, Brazil. FAPESP: 2008/10537-3 FAPESP: 2010/ 06849-0) CNPq: 476335/2008-6 CNPq: 309811/2009-0 CNPq: 306293/ 2009-9 CNPq: 477296/2011-4

T– – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – – –

Tibolone is used for hormone reposition of postmenopause women and isotibolone is considered the major degradation product of tibolone. Isotibolone can also be present in tibolone API raw materials due to some inadequate synthesis. Its presence is then necessary to be identified and quantified in the quality control of both API and drug products. In this work we present the indexing of an isotibolone X-ray diffraction pattern measured with synchrotron light (λ=1.2407 Å) in the transmission mode. The characterization of the isotibolone sample by IR spectroscopy, elemental analysis, and thermal analysis are also presented. The isotibolone crystallographic data are a=6.8066 Å, b=20.7350 Å, c=6.4489 Å, β=76.428°, V=884.75 Å3, and space group P21, ρo=1.187 g cm−3, Z=2.

The aim of this study was to use DSC and X-ray diffraction measurements to determine the pore size and pore wall thickness of highly ordered SBA-15 materials. The DSC curves showed two endothermic events during the heating cycle. These events were due to the presence of water inside and outside of mesopores. The results of pore radius, wall thickness and pore volume measurements were in good agreement with the results obtained by nitrogen adsorption measurement, XRD and transmission electron microscopy.

Single crystal growth of lapatinib free base was induced by immersion of a copper wire into a supersaturated methanolic aqueous solution yielding monoclinic anhydrous plates (space group P21/c, Form 1) and needles of a previously unknown channel hydrate (in P42212). Also, a new method has been developed herein to obtain anhydrous Form 1 via acid–base reaction of lapatinib ditosylate and sodium methoxide, avoiding the usage of an aqueous solution and hydrate formation. Anhydrous Form 2 as well as new solvates were produced via solution mediated transformation experiments, including a dichloromethane solvate with a powder X-ray diffraction pattern similar to that of anhydrous Form 2. Differential scanning calorimetry and solution equilibrium experiments helped to elucidate the interconversion pathways between Form 1, Form 2, and the solvates.

The mesoporous materials in particular the Mobil Composition of Matter No. 41 (MCM-41) and Santa Barbara Amorphous-15 (SBA-15) are considered promising as devices for controlled drug release, because of properties such as hexagonal arrangement, high surface area and non-cytotoxic properties. The materials were synthesized under hydrothermal method and efavirenz (EFZ) was used for testing of controlled release. The material obtained was ordered and had high surface area even after of the incorporation of the drug. The test of the release was made with capsules and the reading was made by UV/Vis with the time interval during two hours to evaluation the efficiency of the dissolution profile of the drug.

The encapsulation of natural ingredients, such as rutin, can offer improvements in sun protection effectiveness. This strategy can provide enhanced flavonoid content and produces an improved bioactive compound with new physical and functional characteristics. As an alternative to common synthetic-based sunscreens, rutin-entrapped gelatin nanoparticles (GNPs) were designed and associated with ethylhexyl dimethyl PABA (EHDP), ethylhexyl methoxycinnamate (EHMC) and methoxydibenzoylmethane (BMDBM) in sunscreen formulations. The purpose of this study was to develop rutin-loaded gelatin nanoparticles and characterize their physicochemical, thermal, functional and safety properties. Rutin-loaded gelatin nanoparticles increased antioxidant activity by 74% relative to free-rutin (FR) solution. Also, this new ingredient upgraded the Sun Protection Factor (SPF) by 48%, indicating its potential as a raw material for bioactive sunscreens. The safety profile indicated that GNPs and glutaraldehyde (GTA) decreased HaCaT cell viability in a concentration/time-dependent manner. However, both blank nanoparticles (B-NC) and rutin-loaded nanoparticles (R-NC) had good performance on skin compatibility tests. These results functionally characterized rutin-loaded nanoparticles as a safe SPF enhancer in sunscreens, especially in association with UV filters.

Submitted by Vitor Silverio Rodrigues (vitorsrodrigues@reitoria.unesp.br) on 2014-05-27T11:26:56Z No. of bitstreams: 0Bitstream added on 2014-05-27T14:47:45Z : No. of bitstreams: 1 2-s2.0-84864851294.pdf: 2055476 bytes, checksum: bfbc1d756505b93c0ecb4b68a9071efa (MD5) Made available in DSpace on 2014-05-27T11:26:56Z (GMT). No. of bitstreams: 0 Previous issue date: 2012-08-15 O polimorfismo pode ocasionar desvios de qualidade durante o processo produtivo e influenciar o desempenho dos medicamentos. Por isso, o entendimento do fenômeno e suas implicações abre um campo amplo de possibilidades a serem exploradas na área farmacêutica, incluindo o surgimento de novos paradigmas e ferramentas na garantia da qualidade de medicamentos. Este trabalho apresenta uma introdução aos aspectos básicos do fenômeno do polimorfismo e suas implicações na produção e controle de medicamentos, com ênfase no polimorfismo dos fármacos. Palavras-chave: Polimorfismo de fármacos. Caracterização no estado sólido. Cristalografia de policristais. ABSTRACT Polymorphism can cause quality deviations during the production of medicines and can influence their effectiveness. Therefore, an understanding of this phenomenon and its implications opens a wide field of possibilities to be explored in the pharmaceutical field, including the emergence of new paradigms and tools for the quality assurance of medicines. This paper presents an introduction to basic aspects of the polymorphism phenomenon and its implications for the production and control of medicines, with emphasis on drug polymorphs. Keywords: Polymorphism of drugs. Solid State Characterization. Crystallography of Polycrystals. Polymorphism can cause quality deviations during the production of medicines and can influence their effectiveness. Therefore, an understanding of this phenomenon and its implications opens a wide field of possibilities to be explored in the pharmaceutical field, including the emergence of new paradigms and tools for the quality assurance of medicines. This paper presents an introduction to basic aspects of the polymorphism phenomenon and its implications for the production and control of medicines, with emphasis on drug polymorphs. Departamento de Farmácia Faculdade de Ciências Farmacêuticas Universidade de São Paulo, São Paulo Farmanguinhos Fundação Oswaldo Cruz, Rio de Janeiro, RJ Instituto de Química UNESP, Araraquara, SP Instituto de Química Universidade de São Paulo, São Paulo, SP Instituto de Química UNESP, Araraquara, SP

Tibolona é um esteróide sintético muito utilizado na terapia de reposição hormonal em mulheres na pós-menopausa, o qual possui a propriedade de se cristalizar em dois grupos espaciais (polimorfismo), dependendo do solvente de cristalização. O objetivo desse trabalho foi obter as diferentes modificações polimórficas desse esteróide sintético e caracterizá-las pelas típicas técnicas sensíveis à estrutura, tais quais TG, DSC, difratometria de raios X pelo método do pó, microscopia Raman, espectroscopia FTIR, microscopia óptica com luz polarizada e microscopia eletrônica de varredura. Os resultados confirmam que duas formas polimórficas puras da tibolona foram cristalizadas: forma I, monoclínica, obtida pela recristalização em acetona e água, e forma II, triclínica, recristalizada em tolueno ou hexano. Foram detectadas diferenças substanciais comparando-se os polimorfos no que se refere às suas propriedades de estado sólido. As análises microscópicas permitiram a perfeita distinção entre os polimorfos, pois ambos apresentam birrefringência, mas possuem morfologia e propriedades ópticas distintas. Os resultados da espectroscopia vibracional confirmam a existência de diferenças conformacionais. A difratometria de raios X pelo método do pó, aliada ao refinamento pelo método de Rietveld, mostrou-se uma técnica adequada para análise quantitativa de misturas dos polimorfos de tibolona. Os estudos de termogravimetria mostraram que os cristais monoclínicos apresentam maior estabilidade térmica que os triclínicos. Pela calorimetria exploratória diferencial foi possível caracterizar a menor estabilidade térmica dos cristais triclínicos, com a presença de três eventos endotérmicos nesses cristais, na faixa de 144 a 170 ºC. Análises por microscopia Raman, difratometria de raios X em altas temperaturas e DSC no modo modulado, mostraram que não há evidências de transições polimórficas relacionadas a esses três eventos térmicos, mas de alterações na estrutura química da tibolona. Estudos dinâmicos e isotérmicos de interação tibolona e excipientes por TG, DSC e cromatogradia líquida de alta eficiência (CLAE) indicaram maior suscetibilidade à degradação da forma triclínica que da forma monoclínica. Foi observado que a ação do excipiente palmitato de ascorbila sobre a estabilidade da tibolona depende da forma polimórfica utilizada. O estudo também mostrou que a compactação reduz a estabilidade química de ambas as formas cristalinas da tibolona. Fatores como preparo de amostra, condições experimentais e ocorrência de misturas de fases, os quais foram capazes de introduzir artefatos nos resultados de estudos de sistemas polimórficos, foram revisados e caracterizados. Tibolone is a synthetic steroid widely used in hormone replacement therapy in postmenopausal women presenting the property of crystallizing in two space groups (polymorphism), depending on the solvent used in the crystallization procedure. The aim of this work was to obtain different polymorphic modifications of the synthetic steroid tibolone and to characterize them by means of typical structure-sensitive analytical techniques, such as Thermogravimetry (TG), Differential Scanning Calorimetry (DSC), X-ray powder diffractometry (XRPD), Raman microscopy, FTIR spectroscopy, Polarizated Light Microscopy and Scanning Electron Microscopy (SEM). The results confirm that two pure polymorphic forms for tibolone were crystallized: Form I, monoclinic, obtained by recrystallisation from acetone and water and Form II, triclinic, recrystallised from tolune or hexane. Substantial differences were detected comparing the polymorphs with regard to their solid-state properties. Microscopic analysis enabled the perfect distinction between polymorphs, since both present birefringence, but have different morphology and optical properties. Results from vibrational spectroscopy, confirmed the existence of conformational differences. X-ray powder diffractometry allied to the refinement by Rietveld method has shown to be an appropriate technique for quantitative analysis of tibolone polymorphs mixtures. Studies of thermogravimetric analysis showed that the monoclinic form present greater thermal stability than the triclinic one. By differential scanning calorimetry it was possible to characterize the lower thermal stability of the triclinic crystalline form, with the presence of three endothermic events in these crystals ranging from 144 to 170ºC. Raman microscopy, high temperature X-ray diffractometry and modulated DSC analysis showed no evidence of polymorphic transitions related these three thermal events, but changes in chemical structure of tibolone instead. Also, tibolone-excipients dynamic and isothermal interaction studies by TG, DSC and High Performance Liquid Chromatography (HPLC) indicated that the triclinic tibolone form presents a greater susceptibility to chemical degradation than the monoclinic form. The excipient ascorbil palmitate was shown to affect the tibolone stability differently depending on the polymorphic form used. This study also showed that compactation decreases the chemical stability of both crystalline forms of tibolone. Factors such as sample preparation, experimental conditions and the occurrence of phase mixtures, which were able to introduce artifacts in the results of studies of polymorphic systems, were reviewed and characterized.

Isotibolone is frequently found as an impurity in tibolone, a drug used for hormone reposition of post-menopause women, due to some inadequate tibolone synthesis or as a result of degradation during drug storage. The presence of isotibolone impurities should be detected and quantified in active pharmaceutical ingredient products of tibolone before its use in the manufacturing of medicaments. The X-ray powder diffraction technique offers the possibility of quantifying isotibolone amounts at different stages of drug production and storage, from the chemical synthesis to the final formulation. In the course of a study involving the quantitative analysis of isotibolone by X-ray powder diffraction, the authors determined the structure of the title compound using a recently developed approach (A. Gomez and S. Kycia, J. Appl. Crystallogr. 2011, 44, 708–713). The structure is monoclinic, space group P21 (4), with unit cell parameters a = 6.80704(7) A, b = 20.73858(18) A, c = 6.44900(6) A, β = 76.4302(5)°, V = 884.980(15) A3 and two molecules per unit cell (Z = 2). The molecules are hydrogen bonded in the ab plane forming layers that are held together in the crystal by van der Waals interactions along the c-axis.

The antiparasitic niclosamide has shown promising anticancer activity in preclinical studies against several types of cancer, such as colorectal and prostate. Thus, the objective of this work was to develop innovative formulations for the repositioning of niclosamide as an anticancer agent. In chapter I, a critical review of the literature on the physicochemical properties of the drug was carried out, in addition the results of clinical studies against colorectal and prostate cancer. Besides, a review was carried out on studies that developed formulations containing this drug, as well as hypotheses to improve the biopharmaceutical performance of this molecule. In chapter II, the development of solid amorphous dispersion containing niclosamide was carried out. Drug/polymer solutions were acoustic levitated and characterized by synchrotron X-ray light. This set allowed fast, high quality measurements, as well as the identification of niclosamide recrystallization. Plasdone® and Soluplus® demonstrated better properties to form amorphous dispersions, with the latter showing superior solubility enhancement. The study showed that the developed formulation increased the apparent saturation solubility of niclosamide in water by two times. In chapter III the objective was the development, physicochemical characterization and in vitro anticancer activity of a niclosamide nanoemulsion, having HCT-116 cells as a cellular model. Preliminary results indicated Capmul® MCM C8 as the best liquid lipid for the system, but the first nanoemulsions containing this lipid were not stable to justify its usage. On the other hand, Miglyol® 812 indicated to be a suitable liquid lipid for the system. The niclosamide nanoemulsion (~200 nm) with Miglyol® 812 and poloxamer 188 was stable for 56 days, with a monomodal particle size distribution. Cell viability assay against HCT-116 cells demonstrated that niclosamide cytotoxicity is time and concentration dependent. Results herein obtained encourage further research to understand and optimize niclosamide performance as an anticancer drug substance. O antiparasitário niclosamida tem apresentado promissora atividade anticâncer em estudos pré- clínicos contra diversos tipos de câncer, como coloretal e próstata. Assim, o objetivo deste trabalho foi desenvolver formulações inovadoras para o reposicionamento da niclosamida como agente anticâncer. No capítulo I foi realizada revisão crítica da literatura sobre as propriedades físico-químicas do fármaco, além de resultados de estudos clínicos da niclosamida contra câncer de coloretal e de próstata. Além disso, foi feita revisão sobre estudos que desenvolveram formulações contendo esse fármaco, bem como hipóteses para melhorar o desempenho biofarmacêutico dessa molécula. No capítulo II foi realizado o desenvolvimento de dispersão solida amorfa contendo niclosamida. Soluções de fármaco/polímero foram levitadas em levitador acústico e caracterizadas por raios-X de luz síncrotron. Este conjunto permitiu medições rápidas e de alta qualidade, bem como identificação de recristalização da niclosamida. Plasdone® e Soluplus® demonstraram melhores propriedades para formar as dispersões amorfas, com o último apresentando aumento de solubilidade superior. O estudo mostrou que a formulação desenvolvida aumentou em duas vezes a solubilidade aparente de saturação da niclosamida em água. No capítulo III o objetivo foi o desenvolvimento, a caracterização físicoquímica e atividade anticâncer in vitro de uma nanoemulsão de niclosamida, tendo células HCT-116 como modelo celular. Resultados preliminares indicaram o Capmul® MCM C8 como o melhor lipídio líquido para o sistema, mas as primeiras nanoemulsões contendo este lipídio não foram estáveis para justificar seu uso. Por outro lado, Miglyol® 812 indicou ser um lipídio líquido adequado para o sistema. A nanoemulsão de niclosamida (~200 nm) com Miglyol® 812 e poloxâmero 188 foi estável por 56 dias, com distribuição monomodal do tamanho de partícula. O ensaio de viabilidade celular contra células HCT-116 demonstrou que a citoxicidade da niclosamida é dependente do tempo e da concentração. Os resultados aqui obtidos encorajam mais pesquisas para entender e otimizar o desempenho da niclosamida como uma substância anticancerígena.

A baixa solubilidade aquosa dos insumos farmacêuticos ativos (IFA) é um grande desafio no desenvolvimento de formulações farmacêuticas, pois pode resultar em biodisponibilidade insuficiente e variável. Diversas estratégias de modificação do estado sólido dos compostos ativos, têm sido propostas para incrementar a solubilidade de fármacos pouco solúveis em água. Dentre as estratégias abordadas a ispersão sólida (DS) é uma das formas mais promissoras de aumentar a solubilidade, dissolução e a biodisponibilidade de IFAs com baixa solubilidade aquosa. O efavirenz (EFV) é um inibidor não nucleosídeo da transcriptase reversa (NNRTI) e um dos componentes da terapia antirretroviral de alta atividade (HAART), sendo parte da primeira linha de tratamento de infecções do vírus HIV tipo 1. O antirretroviral está classificado como pertencente à classe II do SCB, e exibe baixa solubilidade aquosa (solubilidade menor que 10 µg/mL) e alta permeabilidade com absorção dependente da taxa de dissolução, resultando em biodisponibilidade oral baixa e variável. A administração de fármacos pouco solúveis na forma de DS é um método atraente para aumentar a biodisponibilidade in vivo. Neste estudo, um método de triagem rápida por evaporação de solvente foi empregado para preparar DS de EFV, variando-se proporções em misturas compostas pelos carreadores, polivinilpirrolidona K-28/32 (PVP K-28/32), copovidona (CoPVP), hidroxipropilmetilcelulose ftalato (HPMCP-50, HPMCP-55 e HPMCP-55s), poloxâmero 188 (P188) e poloxâmero 407 (P407). A solubilidade das DS foi avaliada por meio do método do equilíbrio (shake-flask), onde selecionou-se os polímeros P188 e P407 que conduziram a uma elevada capacidade de saturação em meio aquoso, superior a 1.000 vezes ao fármaco puro. As propriedades físico-químicas e do estado sólido das amostras foram avaliadas por meio de calorimetria exploratória diferencial (DSC); termogravimetria (TG); espectroscopia do infravermelho com transformada de Fourier (FTIR), difratometria de raios X pelo método do pó (DRXP) e ensaios de dissolução com emprego do aparato IV USP. Os resultados de DRXP demonstraram que os carreadores P188 e P407 foram capazes de estabilizar o EFV na forma amorfa nas DS, fato esse evidenciado pela ausência de picos característicos do antirretroviral. The low aqueous solubility of the active pharmaceutical ingredient (API) is a major challenge in the development of pharmaceutical formulations as it may result in insufficient and variable bioavailability. Several strategies for modifying the solid-state of the active compounds have been proposed to increase solubility of drugs that are poorly soluble in water. Among the strategies approaches, solid dispersion (SD) is one of the most promising ways to increase solubility, dissolution and bioavailability of APIs with low aqueous solubility. Efavirenz (EFV) is a non-nucleoside reverse transcriptase inhibitor (NNRTI) and one of the components of highly active antiretroviral therapy (HAART), being part of the first line of treatment of type 1 HIV virus infections. The antiretroviral is classified as belonging to BCS class II, and exhibits low aqueous solubility (solubility less than 10 µg / mL) and high permeability with dissolution ratedependent absorption, resulting in low and variable oral bioavailability. Drug delivery of poorly aqueous soluble drugs in form SD is an appealing method to increase in vivo bioavailability. In this study, a fast screening method of solvent evaporation method was used to prepare EFV SD, varying the proportions in mixtures composed by the carriers polyvinylpyrrolidone K-28/32 (PVP K-28/32), copovidone (CoPVP), hydroxypropylmethylcellulose phthalate (HPMCP-50, HPMCP-55 e HPMCP-55s), poloxamer 188 (P188) e poloxamer 407 (P407). The solubility of the samples was evaluated by the method of equilibrium (shake-flask), wherein the polymers P188 and P407 were selected due to the capacity to promote high saturation in aqueous medium, 1,000 times superior to the pure drug. The physicochemical and solid-state properties of the samples were evaluated by differential scanning calorimetry (DSC); thermogravimetry (TG); Fourier transform infrared spectroscopy (FTIR), X-ray powder diffraction (XRPD) and dissolution assays using the IV USP apparatus. The results of XRPD demonstrated that the carriers P188 and P407 were able to stabilize the EFV in amorphous form in the SD, a fact evidenced by the absence of characteristic peaks of the antiretroviral.

The study of the polymorphism of lercanidipine hydrochloride (LRC) has revealed a significative impact on solubility with a strong dependence on buffer type, pH, and ionic strength. For the first time, unexpected changes in the solubility ratio between two polymorphic forms of LRC (forms I and II) depending on the media composition were identified, and its potential consequences to the pharmacokinetic performance were evaluated through physiologically based pharmacokinetic (PBPK) modeling using GastroPlus(TM); the results suggest that in cases of low stomach acidity, form II is potentially less bioavailable than form I. Phosphate buffer showed to promote less solubility variation in the concentration range of 0.01-0.1 mol·L-1 and favored solubility increase for both forms in the 2-3.5 pH range when compared to a citric acid buffer. Solid-state characterization of both polymorphs accompanied by polythermal solubility experiments carried out in ethanol and acetonitrile permitted to establish the thermodynamic relationship between the two polymorphs as monotropic. Furthermore, forced degradation was applied to determine thermal and photostability of each form, determining form I as the less chemically stable. Determination LRC form II crystalline structure was accomplished based on the successful obtainment of its single crystal, while structural data of LRC form I was estimated by applying single-value decomposition approach to its X-ray powder diffraction scans. A investigação do polimorfismo do cloridrato de lercanidipina (LRC) revelou um impacto significativo na solubilidade com forte dependência do tipo de tampão, pH e força iônica. Pela primeira vez, mudanças inesperadas na relação de solubilidade entre duas formas polimórficas de LRC (formas I e II), dependendo da composição do meio, foram identificadas e suas conseqüências potenciais para o desempenho farmacocinético foram avaliadas através de modelagem farmacocinética (PBPK) usando GastroPlus(TM); os resultados sugerem que, em casos de baixa acidez estomacal, a forma II é potencialmente menos biodisponível que a forma I. O tampão fosfato mostrou promover menor variação de solubilidade na faixa de concentração de 0.01-0.1 mol·L-1 e aumento de solubilidade favorecido para ambas as formas em pH 2-3,5 quando comparado com um tampão de ácido cítrico. A caracterização em estado sólido de ambos os polimorfos e experimentos politermais de solubilidade realizados em etanol e acetonitrila permitiram estabelecer a relação termodinâmica de estabilidade entre os dois polimorfos como monotrópica. Além disso, a degradação forçada foi aplicada para determinar as propriedades térmicas e fotoestáveis de cada forma, determinando a forma I como menos quimicamente estável. A determinação da estrutura cristalina da forma II de LRC foi realizada com base na obtenção de seu monocristal, enquanto os dados estruturais da forma I de LRC foram estimados aplicando uma abordagem de decomposição de valor único para suas varreduras de difração de raios X.

Os nanocristais são partículas de fármacos cristalinos, com tamanho médio na faixa de submicrons, geralmente entre 200 e 500 nm, estabilizados por agentes estéricos ou eletrostáticos adsorvidos na superfície das partículas do fármaco. Sua dimensão reduzida proporciona propriedades especiais, como a adesividade às mucosas e o aumento de área superficial e da solubilidade de saturação, o que melhora significativamente a biodisponibilidade de fármacos pouco solúveis em água. Outra aplicação emergente dos nanocristais é na melhoria da entrega e da retenção de fármacos em tecidos e células tumorais. Estudos demonstraram que o flubendazol é um fármaco capaz de induzir a morte celular em tumores malignos e retardar o seu crescimento, por meio da alteração que provoca na estrutura dos microtúbulos e pela inibição da polimerização da tubulina. Foi demonstrada sua atividade antiproliferativa em linhagens de leucemia, mieloma, câncer intestinal, câncer de mama e neuroblastoma. O flubendazol é também um fármaco eficaz contra os helmintos, demonstrando atividade superior na eliminação dos vermes adultos, quando comparado com a dietilcarbamazina. Embora o flubendazol pareça ser uma molécula promissora, é um fármaco praticamente insolúvel em água (0,005 mg/mL). Para atingir o efeito terapêutico desejado, é necessário o desenvolvimento de uma formulação com melhores solubilidade e biodisponibilidade. Nesse sentido, o presente trabalho apresenta o preparo e a caracterização físico-química de nanocristais de flubendazol por meio da microfluidização. Foram realizados ensaios exploratórios para avaliar a performance de diferentes agentes estabilizantes nas suspensões: o polissorbato 80, o polaxamer 188 e o D-α tocoferol polietilenoglicol 1.000 succinato (TPGS). A avaliação da distribuição do tamanho de partícula foi realizada por espalhamento de luz laser (LLS), espalhamento de luz dinâmica (DLS), análise de rastreamento de nanopartículas (NTA) e microscopia eletrônica de varredura (MEV). A utilização do TPGS favoreceu a obtenção de uma nanossuspensão com o menor diâmetro hidrodinâmico médio das partículas, de 253,9 ± 3,0 nm. Nos estudos exploratórios, também foram determinados os parâmetros ótimos de moagem do microfluidizador, sendo estabelecidos: 35.000 psi de pressão, temperatura do produto de 30°C (± 5°C) e tempo de recirculação de 2 horas/100 gramas. Objetivando alcançar o menor diâmetro hidrodinâmico médio dos nanocristais, executou-se um planejamento estatístico no qual foi avaliada a influência da concentração de flubendazol (% p/p) e de TPGS (% p/p) na formulação. A análise revelou a significativa influência da concentração do TPGS na redução do tamanho de partícula e na estabilidade físico-química da nanossuspensão. Ensaios complementares de solubilidade demonstraram que o nanocristal proporcionou incremento na solubilidade de 2,3 e 3,2 e 5,2 vezes em HCl 0,1 N, tampão fosfato pH 6,8 e tampão fosfato salino pH 7,4, respectivamente. No ensaio de dissolução conduzido em HCl 0,1 N e 0,1% TPGS, observou-se significativo incremento, de 41% de fármaco dissolvido após 60 minutos, quando comparado com o flubendazol micronizado. As características do estado sólido do nanocristal foram avaliadas por meio de análise térmica (calorimetria exploratória diferencial e termogravimetria) e difratometria de raios X, não sendo observadas significativas alterações da estrutura cristalina. O presente trabalho também avaliou a efetividade dos nanocristais de flubendazol em tumores de pulmão, demonstrando sua expressiva capacidade de retardar o crescimento e diminuir o tamanho desses tumores em camundongos xenotransplantados. Nanocrystals are drug particles with an average size in the sub-micron range, generally between 200 and 500 nm, stabilized by steric or electrostatic agents adsorbed on the surface of the drug particles. The reduced size provides special properties such as mucosal adhesiveness, increase in surface area and saturation solubility, which significantly improves the bioavailability of poorly water-soluble drugs. Another emerging application of nanocrystals is in the enhancement of drug delivery and retention in tumor tissues. Studies have shown that flubendazole is a drug capable of inducing cell death in malignant tumors and decelerating their growth, by altering the structure of the microtubules and inhibiting the tubulin polymerization. Antiproliferative activity has been demonstrated in leukemia, myeloma, intestinal cancer, breast cancer and neuroblastoma lines. In addition, flubendazole is also an effective drug against helminths, demonstrating superior activity in eliminating adult worms when compared to diethylcarbamazine. Although flubendazole appears to be a promising molecule, it is an insoluble drug in water (0.005 mg / mL). To achieve the desired therapeutic effect, it is necessary the development of a formulation with better solubility and bioavailability. In this context, the present research reports the physico-chemical preparation and characterization of flubendazole nanocrystals through microfluidization. Exploratory experiments were carried out to evaluate the performance of different stabilizing agents in formulations: polysorbate 80, polaxamer 188 and D-α tocopherol polyethylene glycol 1000 succinate (TPGS). The determination of the particle size distribution determination was performed by laser light scattering (LLS), dynamic light scattering (DLS), nanoparticle scanning (NTA) and scanning electron microscopy (SEM). The use of TPGS favored the preparation of a nanosuspension with the lowest mean hydrodynamic size of the particles, of 253.9 ± 3 nm. In the exploratory studies, the optimum grinding parameters were also determined: 35,000 psi of microfluidizer pressure, product temperature of 30 ° C (± 5 ° C) and recirculation time of 2 hours for each 100 grams of suspension. In order to reach the lowest average hydrodynamic diameter, a statistical design was applied in which the influence of flubendazole concentration (% w / w) and TPGS (% w / w) on the formulation was evaluated. The analysis revealed a significant influence of TPGS concentration on the particle size reduction and on the physicochemical stability of the nanosuspension. Complementary solubility tests showed that the nanocrystal provided an increase in solubility of 2.3, 3.2 and 5.2-fold in 0.1 N HCl, phosphate buffer pH 6.8 and phosphate buffer saline pH 7.4, respectively. In the dissolution test performed in 0.1 N HCl with 0.1% TPGS, a 41% increase of the drug dissolved after 60 minutes was achieved, when compared to micronized flubendazole. The solid-state characteristics of the nanocrystal were accessed through thermal analysis (differential scanning calorimetry and thermogravimetry) and X-ray diffraction and the results indicated that the crystal structure was not significantly altered. This research also evaluated the action of flubendazole nanocrystals in lung tumors, demonstrating expressive ability to retard growth and decrease the size of these tumors in xenotransplanted mice.

No contexto de qualidade, segurança e eficácia dos medicamentos, os produtos de degradação surgem com um crescente foco regulatório no Brasil e no mundo. Para análise confiável dos medicamentos, métodos indicativos de estabilidade devem ser utilizados, visando a avaliação qualitativa e quantitativa das impurezas e dos produtos de degradação neles contidos. O cloridrato de propafenona é utilizado no tratamento de arritmias supraventriculares e ventriculares, apresentando-se como bloqueadores dos canais de sódio, além de ser um betabloqueador. O cloridrato de pioglitazona é um agente anti-hiperglicemiante que atua primariamente diminuindo a resistência à insulina, no tratamento da Diabetes tipo 2. Os métodos oficiais descritos nas farmacopeias, muitas vezes, não fornecem informações a respeito de análise de impurezas farmacêuticas e de produtos de degradação. Assim sendo, deve-se verificar se os métodos são indicativos da estabilidade, antes de utilizá-los para analisar os produtos de degradação. A presente pesquisa tem como objetivo avaliar amostras simuladas dos medicamentos citados, após serem submetidos a condições de estresse; determinar os principais produtos de degradação através dos métodos descritos na Farmacopeia Americana e avaliar se tais métodos são indicativos de estabilidade, assim como realizar balanço de massa. Foi realizado um delineamento fatorial 32 dos meios de degradação avaliando-se a variação do tempo e da intensidade e a capacidade de detecção e quantificação de produtos de degradação presentes. Os fatores considerados no delineamento foram degradação ácida, alcalina, meio oxidativo com peróxido de hidrogênio, e temperatura/umidade além da fotoestabilidade. O cloridrato de propafenona apresentou degradação nos estresses ácidos, oxidativos e em temperatura/umidade. No meio alcalino e a exposição a luz (branca/UV), a magnitude da degradação foi amena. Houve um balanço de massas entre os métodos de doseamento e de impurezas, mostrando-se que o método é indicativo de estabilidade. O principal produto de degradação, no meio ácido e oxidativo, foi identificado utilizando o método de LC-MS. O cloridrato de pioglitazona apresentou degradação em meios básicos, oxidativos assim como em exposição à luz e elevada temperatura/umidade. A hidrólise ácida não apresentou impacto significativo. Os métodos de doseamento e de impurezas não apresentaram balanço de massa, mostrando-se que o método não é indicativo de estabilidade. As análises in silico, com o software Zeneth®, foi utilizada para estabelecer correlações entre o processo de degradação e os plausíveis produtos formados. Assim, conclui-se que os dados de estresses obtidos, neste trabalho, podem servir como suporte nos estudos de estabilidade, bem como contribuir na definição das condições de transporte e armazenamento do cloridrato de propafenona e cloridrato de pioglitazona. In the context of quality, safety and efficacy of pharmaceuticals, degradation products ascend with a growing regulatory focus in Brazil and in the world. For reliable analysis of pharmaceutical products, stability indicative methods must be used, aiming at qualitative and quantitative analysis of impurities and degradation products contained therein. Propafenone HCl is used in the treatment of supraventricular and ventricular arrhythmias and has sodium channel blocking capacity, besides its betareceptor blocking activity. Pioglitazone HCl is an anti-hiperglicemiante agent that acts primarily by reducing insulin resistance in the treatment of type 2 diabetes. The official methods described in the Pharmacopoeias often do not provide information regarding the analysis of pharmaceutical impurities and degradation products. Therefore, it important to verified whether the methods are stability indicative or not, before being use in the analysis of degradation products. The objective of this research is to evaluate simulated samples of cited pharmaceuticals, after submission to stress conditions. To determine the main degradation products through the methods described in the American Pharmacopoeia and assess whether such methods are indicative of stability by mass balance approach. A factorial design (32) of the degradation mediums was carried out to evaluate impact of time of contact and variable intensity. On the outer side, the ability of the method to detect and quantify degradation products was also assessed. The degradation medium factors considered in the design were, acid, alkaline, oxidant medium using hydrogen peroxide, temperature/humidity and photostability. Propafenone hydrochloride presented degradation in acid, oxidative and temperature/humidity stress conditions. In the alkaline medium and exposure to light (white/UV), the extent of degradation was mild. There was a mass balance between the assay method and impurity method, illustrating that the method is stability indicative. The main degradation product, in the acidic and oxidative medium, was identified using the LC-MS method. Pioglitazone hydrochloride presented degradation in basic, oxidative means as well as on exposure to light and elevated temperature/humidity conditions. Acidic hydrolysis has no significant impact. The assay and impurity methods did not show mass balance, elucidating that the method is not stability indicative. In silico analysis, with the Zeneth® software, was used to establish correlations between the degradation process and the plausible degradation pathway and products. Thus, it is concluded that the data obtained in degradation studies, in this work, may serve as support in the stability studies, as well as subsidize to define transport and storage conditions for propafenone HCl and pioglitazone HCl.

O flubendazol (FB) é um agente anti-helmíntico benzimidazólico cuja potencialidade foi demonstrada para uso no tratamento da filariose linfática e da oncocercose em humanos. As formulações atualmente comercializadas, entretanto, atuam apenas em parasitas do trato gastrointestinal, uma vez que, praticamente, não são absorvidas por via oral em decorrência da baixa solubilidade do fármaco. Assim, observa-se a necessidade da busca de alternativas que melhorem a solubilidade do FB e viabilizem o desenvolvimento de formulações orais de efeito sistêmico. Uma das tecnologias que vem se destacando no mercado farmacêutico nas últimas décadas para a produção de dispersões sólidas amorfas para melhoria de solubilidade é a extrusão a quente; esta representa uma potencial solução para o problema apresentado, constituindo-se o objeto de estudo do presente trabalho. Para tal, foram selecionados os polímeros copovidona e HPMCAS LG, além dos adjuvantes HPC EF e estearato de magnésio. Inicialmente os componentes individuais e misturas binárias de FB e excipientes foram caracterizados por DSC e TG, mostrando-se compatíveis com o fármaco em questão. Misturas entre o fármaco, polímero e adjuvantes para a extrusão a quente foram planejadas por delineamento experimental e o processo conduzido em extrusora dupla rosca. Parâmetros como a temperatura das zonas de aquecimento, velocidade de alimentação e das roscas da extrusora foram mantidos constantes durante todo o processo, de modo a avaliar o impacto de cada material e sua porcentagem na fórmula. A copovidona mostrou-se altamente extrusável, sendo que o HPMCAS LG, para os parâmetros utilizados, não permitiu a obtenção de extrusados com o FB. Todos os testes feitos com a copovidona, exceto o com alta carga de FB, pois nesta condição não foi possível obter extrusados, foram avaliados por meio de DSC e difratometria de raios-X pelo método do pó, durante um ano em temperatura ambiente e, após 30 dias, em condição de estabilidade acelerada (40°C/75% U.R.), com resultados positivos relativos à amorfização do fármaco. Adicionalmente, ensaios de dissolução foram realizados em meio HCl pH 1.2 indicaram melhoria expressiva da solubilidade, porém de forma distinta para cada formulação proposta. Desta forma, o processo de extrusão a quente com a copovidona mostrou-se uma alternativa viável e eficiente para promover o aumento da dissolução do FB, por meio da obtenção de uma dispersão sólida amorfa estável. Flubendazole (FB) is a benzimidazole anthelmintic agent that has recently demonstrated effectiveness for the treatment of lymphatic filariasis and onchocerciasis in humans. However, the formulations currently commercialized act only on parasites of the gastrointestinal tract, since they are not orally absorbed due to the poor drug solubility. Thus, there is a need to seek alternatives to improve FB solubility and enable the development of oral formulations with systemic effect. Hot melt extrusion (HME) is a technology that has been outstanding on the pharmaceutical market in recent decades aiming to produce amorphous solid dispersion for solubility enhancement. Aside from that, this technique can be considered a potential alternative to the presented drug. Therefore, the purpose of this study was to prepare a solid dispersion using copovidone and HPMCAS LG as the polymers and HPC EF and magnesium stearate as the adjuvants. Initially, the individual components and drug/excipients binary mixtures were characterized by differential scanning calorimetry (DSC) and thermogravimetry (DTG) to evaluate the thermal behavior and compatibility with FB. Through these tests, it was possible to verify that the polymers and adjuvants chosen were compatible with FB. Then, the mixtures of drug, polymer and adjuvant were designed statistically and the process was performed in a twin-screw extruder; the temperature of the heating zones, screw speed, and feed screw speed were kept constant for all tests to evaluate the impact of each material and its percentage on getting an achievable solid dispersion. Copovidone was highly extrudable and the HPMCAS LG, for the determined parameters, did not allow obtaining extrudates for FB. The extruded materials were evaluated by DSC and X-ray powder diffraction and presented positive results concerning amorphization of the drug, except the tests with high drug loading. Stability tests were performed at room temperature for one year and accelerated condition (40° C/75% RH) for 30 days showing, for almost all tests, optimistic results regarding keeping FB amorphous. In order to evaluate the improvement of the solubility of the drug, a comparative dissolution test of the extrudates and the pure FB was carried out at HCl pH 1.2. At different levels, all extrudates showed expressive improvement on the solubility when compared to pure FB. In conclusion, HME process can be considered a viable alternative to obtain stable solid amorphous dispersion of FB and copovidone.

A nanotecnologia tem sido empregada como plataforma para o desenvolvimento de formas farmacêuticas com maior eficácia e segurança. A redução do tamanho de partículas em escala nanométrica permite conferir ao material propriedades inovadoras que têm sido exploradas em inúmeras aplicações, principalmente na indústria farmacêutica. Essa nova característica permite aumentar a biodisponibilidade oral de fármacos pouco solúveis em água. Os nanocristais apresentam como vantagens o aumento da solubilidade de saturação e da velocidade de dissolução. Tais propriedades são decorrentes da sua maior área superficial. Além disso, os nanocristais apresentam excelente adesão em superfícies biológicas. Essa característica resulta não apenas em uma melhor biodisponibilidade, mas também em redução na variação da biodisponibilidade de fármacos pouco solúveis em água. A malária é uma doença negligenciada prevalente nos países emergentes e afeta mais de 210 milhões de pessoas no mundo. Dentre as terapias medicamentosas para o tratamento da malária, o artemeter, derivado da artemisinina, apresenta potente atividade esquizonticida na fase hepática e na fase eritrocítica. Esse fármaco, amplamente utilizado no tratamento da malária, apresenta baixa solubilidade em água limitando sua biodisponibilidade oral. Tendo em vista a melhoria dessa característica, foram utilizados os métodos de moagem a alta energia, homogeneização a alta pressão e moagem via úmida, em escala reduzida para a obtenção de nanocristais. Esse último método foi aquele que permitiu a redução das partículas em escala nanométrica. O método por moagem a alta energia (MAE) revelou, nas condições experimentais do presente trabalho, 10% (D0,1) da população das partículas com diâmetro menor ou igual a 3,504 ± 0,19 µm, 50% (D0,5) menor ou igual a 14,225 ± 0,34 µm e 90% (D0,9) menor ou igual a 57,306 ± 5,72 µm. O diâmetro hidrodinâmico médio foi 25,01 ± 2,08 µm, sendo que o fator limitante na redução do tamanho da partícula foi a densidade do artemeter. Resultados similares foram obtidos empregando método de homogeneização a alta pressão. Diferentes tensoativos foram avaliados empregando o método selecionado, a moagem via úmida em escala reduzida. O agente estabilizante soluplus® foi aquele que favoreceu a redução do tamanho das partículas. Tal característica foi observada por meio de análise térmica. Essa análise permitiu determinar o grau de amorfização mínima, assim como, a presença de fortes ligações moleculares entre o fármaco e diferentes polímeros. A utilização do método por moagem via úmida em escala reduzida permitiu a obtenção de nanocristais de artemeter (formula R2-MUR), com diâmetro hidrodinâmico médio (DHM) igual a 342 ± 16,3 nm, índice de polidispersão (IP) de 0,23 ± 0,01 e distribuição monomodal de tamanho. Essa preparação otimizada foi obtida por meio de planejamento de experimentos por superfície de resposta tendo como variáreis independentes as concentrações de artemeter e do agente estabilizante (Soluplus®) além do tempo de moagem. As respostas foram o DHM e o IP, determinados utilizando espalhamento de luz dinâmica (DLS). Adicionalmente, as avaliações empregando calorimetria exploratória diferencial (DSC) e difração de raio X (DRX) revelaram que não houve alteração na estrutura cristalina do artemeter e interação entre o fármaco e os excipientes. O presente trabalho permitiu a obtenção de nanocristais de artemeter com solubilidade de saturação até 2,0 e 1,8 vezes maior em água e tampão McIlvaine (pH 2,5) respectivamente, comparada ao fármaco micronizado. Além disso, a preparação liofilizada foi estável após armazenamento por três meses a temperatura de 25 e 4 °C. Nanotechnology has been used as a platform for the development of pharmaceutical forms with greater effectiveness and safety. The reduction of particle size on a nanometric scale enables innovative properties to the material. These properties have been exploited in numerous applications, mainly in the pharmaceutical industry. This novel feature allows increasing the oral bioavailability of poorly water-soluble drugs. Nanocrystals have advantages such as increased saturation solubility and dissolution rate. These properties are due to their greater surface area. In addition, nanocrystals exhibit excellent adhesion on biological surfaces. This characteristic results not only in a better bioavailability but also in a reduction in the bioavailability variation of poorly water-soluble drugs. Malaria is a neglected disease prevalent in emerging countries and affects more than 210 million people worldwide. Among the medicinal therapies for the treatment of malaria, artemisinin-derived, artemether has potent schizonticidal activity in the liver and erythrocyte phases. This drug, widely used in the treatment of malaria, presents low solubility in water limiting its oral bioavailability. In order to improve this characteristic, the methods of high energy milling, high-pressure homogenization and wet milling on a reduced scale were used to obtain nanocrystals. This last method was the one that allowed the reduction of the artemether particles in nanoscale. The high energy milling method revealed, in the experimental conditions of the present study, 10% (D0,1) of the population of particles with a diameter less than or equal to 3,504 ± 0,19 µm, 50% (D0,5) less than or equal to 14.225 ± 0.34 µm and 90% (D0.9) less than or equal to 57.306 ± 5.72 µm. The mean hydrodynamic diameter was 25.01 ± 2.08 µm, being the limiting factor in the reduction of particle size the density of the artemether. Similar results were obtained using a high-pressure homogenization method. Different surfactants were evaluated using the selected method, wet milling on a reduced scale. The stabilizing agent soluplus® was the one that favored the reduction of the particle size. This characteristic was observed by thermal analysis. This analysis allowed determining the degree of minimum amorphization, as well as the presence of strong molecular bonds between the drug and some polymers. The wet milling on a reduced scale method allowed obtaining artemether nanocrystals (formula R2-MUR) with a mean hydrodynamic diameter (MHD) of 342 ± 16.3 nm, polydispersity index (PdI) of 0,23 ± 0.01 and monomodal distribution. These preparations were obtained through the response surface methodology (RSM) having as independent variables the concentrations of artemether and stabilizing agent (Soluplus®) and the milling time. MHD and PdI were performed using dynamic light scattering (DLS). In addition, evaluations using differential scanning calorimetry (DSC) and X-ray diffraction (XRD) revealed that there was no change in the crystal structure of the artemether and interaction between the drug and the excipients. The present work allowed obtaining of artemether nanocrystals with saturation solubility up to 2.0 and 1.8 times higher in water medium and McIlvaine buffer (pH 2.5), respectively, compared to the micronized drug. In addition, the lyophilized preparation was stable after storage for three months at 25 and 4 ° C.