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1.
Phys Chem Chem Phys ; 22(3): 1583-1590, 2020 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-31894786

RESUMO

While water is the solvent of choice for the lyophilization of pharmaceuticals, tert-butyl alcohol (TBA) along with water can confer several advantages including increased solubility of hydrophobic drugs, decreased drying time, improved product stability and reconstitution characteristics. The goal of this work was to generate the phase diagram and determine the eutectic temperature and composition in the "water rich" region (0.0 to 25.0% w/w TBA) of TBA-water mixtures. Solutions of different compositions were frozen and characterized by low temperature differential scanning calorimetry and powder X-ray diffractometry (XRD). The thermal events observed during warming, and their characterization by XRD, enabled the generation of phase boundaries as well as the eutectic temperature and composition. While TBA crystallized as a dihydrate in frozen solutions, on heating, the dihydrate transformed to a heptahydrate. TBA heptahydrate and ice (22.5% w/w TBA) formed a eutectic at ∼-8 °C.


Assuntos
Química Farmacêutica/métodos , Liofilização , Preparações Farmacêuticas/química , Água/química , terc-Butil Álcool/química
2.
J Chem Phys ; 152(2): 024107, 2020 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-31941292

RESUMO

The primary goal of this work is to assess the effect of excluded volume interactions on the diffusion controlled release of drug molecules from a spherical, neutral, inert, and cross-linked device of nanometric size. To this end, coarse-grained simulations of the release process were performed. In this way, the inner structure and topology of the polymer network can be explicitly taken into account as well. Our in silico experiments reveal that the boundary condition of constant surface concentration is not appropriate for nanogels. In particular, the predictions based on the perfect sink condition clearly overestimate the fraction of drug released. In addition, these simulations provide values for the release exponent that depends on both the diameter of drug molecules and the number of drug molecules loaded in the matrix, which clearly contrasts with the classical prediction of a constant release exponent. Consequently, the widely used classification of drug release mechanisms based on this kinetic exponent must be extended to include new situations.


Assuntos
Liberação Controlada de Fármacos , Simulação de Dinâmica Molecular , Preparações Farmacêuticas/química , Preparações de Ação Retardada , Difusão , Interações Hidrofóbicas e Hidrofílicas , Polímeros/química , Propriedades de Superfície
3.
Chemistry ; 26(2): 390-395, 2020 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-31596010

RESUMO

Dearomatisation of indole derivatives to the corresponding isatin derivatives has been achieved with the aid of visible light and oxygen. It should be noted that isatin derivatives are highly important for the synthesis of pharmaceuticals and bioactive compounds. Notably, this chemistry works excellently with N-protected and protection-free indoles. Additionally, this methodology can also be applied to dearomatise pyrrole derivatives to generate cyclic imides in a single step. Later this methodology was applied for the synthesis of four pharmaceuticals and a pesticide called dianthalexin B. Detailed mechanistic studies revealed the actual role of oxygen and photocatalyst.


Assuntos
Indóis/química , Luz , Praguicidas/química , Preparações Farmacêuticas/química , Pirróis/química , Catálise , Imidas/química , Praguicidas/síntese química , Preparações Farmacêuticas/síntese química
4.
Chemistry ; 26(1): 33-48, 2020 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-31599057

RESUMO

The ability to modify biologically active molecules such as antibodies with drug molecules, fluorophores or radionuclides is crucial in drug discovery and target identification. Classic chemistry used for protein functionalisation relies almost exclusively on thermochemically mediated reactions. Our recent experiments have begun to explore the use of photochemistry to effect rapid and efficient protein functionalisation. This article introduces some of the principles and objectives of using photochemically activated reagents for protein ligation. The concept of simultaneous photoradiosynthesis of radiolabelled antibodies for use in molecular imaging is introduced as a working example. Notably, the goal of producing functionalised proteins in the absence of pre-association (non-covalent ligand-protein binding) introduces requirements that are distinct from the more regular use of photoactive groups in photoaffinity labelling. With this in mind, the chemistry of thirteen different classes of photoactivatable reagents that react through the formation of intermediate carbenes, electrophiles, dienes, or radicals, is assessed.


Assuntos
Preparações Farmacêuticas/química , Proteínas/química , Animais , Anticorpos/química , Linhagem Celular Tumoral , Radioisótopos de Cobre/química , Reação de Cicloadição , Humanos , Marcação por Isótopo , Ligantes , Metano/análogos & derivados , Metano/química , Camundongos , Camundongos Nus , Neoplasias/diagnóstico por imagem , Tomografia Computadorizada de Emissão de Fóton Único , Transplante Heterólogo , Raios Ultravioleta
5.
Chemistry ; 26(1): 49-88, 2020 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-31483909

RESUMO

Drugs in the chemical space beyond the rule of 5 (bRo5) can modulate targets with difficult binding sites while retaining cell permeability and oral absorption. Reviewing the syntheses of bRo5 drugs approved since 1990 highlights synthetic chemistry's contribution to drug discovery in this space. Initially, bRo5 drugs were mainly natural products and semi-synthetic derivatives. Later, peptidomimetics and de novo designed compounds, that include up to seven chiral centres and macrocyclic rings became dominant. These drugs are prepared by total synthesis, sometimes by routes of more than 25 steps with stereocentres originating from the chiral pool, or being installed by chiral induction or enzymatic resolution. Interestingly, ring-closing metathesis proved to be the method of choice for macrocyclisation in hepatitis C virus protease inhibitors. We conclude that structural simplification, planning of synthetic routes regarding incorporation of stereocentres and macrocyclisation, as well as incorporation of structural knowledge and consideration of chameleonic properties in design, should facilitate drug discovery in bRo5 space.


Assuntos
Descoberta de Drogas , Preparações Farmacêuticas/síntese química , Proteínas de Bactérias/química , Proteínas de Bactérias/metabolismo , Sítios de Ligação , Hepacivirus/enzimologia , Compostos Macrocíclicos/síntese química , Compostos Macrocíclicos/química , Compostos Macrocíclicos/metabolismo , Peptidomiméticos , Preparações Farmacêuticas/química , Preparações Farmacêuticas/metabolismo , Inibidores de Proteases/síntese química , Inibidores de Proteases/química , Inibidores de Proteases/metabolismo , Ribossomos/química , Ribossomos/metabolismo , Proteínas Virais/química , Proteínas Virais/metabolismo
6.
Chemosphere ; 239: 124730, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31726518

RESUMO

The impact of electrolytes on the adsorption of emerging pollutants: pharmaceuticals onto layered materials: a raw clay mineral and its nonionic and cationic organoclay derivatives was studied. The selected pharmaceuticals: amoxicillin, norfloxacin, sulfamethoxazole, metoprolol, carbamazepine, and trimethoprim show different electric charges: zwitterionic, anionic, cationic and neutral and hydrophobic character (different LogP). Without any salts, the set of complementary data obtained by UV and infrared spectroscopies, X-ray diffraction points out the importance of the electric charge which represents a key parameter in both the spontaneity and feasibility of the adsorption. In contrast, the hydrophobicity of the analytes plays a minor role but determines the magnitude of the adsorbed amount of pharmaceuticals onto organoclays. With a dual hydrophilic and hydrophobic behavior, nonionic organoclay appears to be the most polyvalent material for the removal of the pharmaceuticals. In the presence of electrolytes (NaCl at a concentration of 1 × 10-2 mol L-1), both nonionic and cationic organoclays show a decrease of their efficiencies, whereas the adsorption is particularly enhanced for Na-Mt except for the cationic species (trimethoprim and metoprolol). Thus, in realistic experimental conditions close to those of natural effluents, raw clay mineral appears as the most appropriate sorbent for the studied pharmaceuticals while it raises the question of the usefulness of organoclays in water remediation strategy.


Assuntos
Eletrólitos/química , Recuperação e Remediação Ambiental/métodos , Preparações Farmacêuticas/análise , Poluentes do Solo/análise , Solo/química , Poluentes Químicos da Água/análise , Adsorção , Amoxicilina/análise , Amoxicilina/química , Carbamazepina/análise , Carbamazepina/química , Cátions/análise , Interações Hidrofóbicas e Hidrofílicas , Metoprolol/análise , Metoprolol/química , Norfloxacino/análise , Norfloxacino/química , Preparações Farmacêuticas/química , Poluentes do Solo/química , Sulfametoxazol/análise , Sulfametoxazol/química , Trimetoprima/análise , Trimetoprima/química , Água/química , Poluentes Químicos da Água/química , Difração de Raios X
7.
Eur J Med Chem ; 185: 111813, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31732255

RESUMO

Unbound tissue-to-plasma partition coefficients (Kpuu) were determined for 56 structurally diverse compounds in rats following intravenous infusion. Five tissues were included in the study: white adipose, brain, heart, liver, and skeletal muscle. The rank ordering of the median tissue Kpuu values was: liver (4.5) > heart (1.8) > adipose (1.2) > skeletal muscle (0.6) > brain (0.05), with liver being most enriched and brain most impaired. The median Kpuu values of acids and zwitterions were lower than those of bases and neutrals in all tissues but liver. Selective tissue distribution was observed, dependent upon chemotype, which demonstrated the feasibility of targeting or restricting drug exposure in certain tissues through rational design. Physicochemical attributes for Kpuu were identified using recursive partitioning, which further classified compounds with enriched or impaired tissue distribution. The attributes identified provided valuable insight on design principles for asymmetric tissue distribution to improve efficacy or reduce toxicity.


Assuntos
Compostos Orgânicos/farmacocinética , Preparações Farmacêuticas/química , Animais , Relação Dose-Resposta a Droga , Infusões Intravenosas , Masculino , Modelos Moleculares , Estrutura Molecular , Compostos Orgânicos/administração & dosagem , Compostos Orgânicos/química , Preparações Farmacêuticas/administração & dosagem , Ratos , Ratos Wistar , Relação Estrutura-Atividade , Distribuição Tecidual
8.
Spectrochim Acta A Mol Biomol Spectrosc ; 224: 117339, 2020 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-31344573

RESUMO

An analytical investigation was carried out to study the treatment and amplification of the spectral signals produced by critical concentrations with high accuracy and precision using two advanced approaches. The factorized-spectrum approach was applied through two novel methods which were: absorptivity centering technique via both: factorized zero order absorption spectrum (ACT-FSD0ΔA) and factorized ratio spectrum (ACT-FSRΔP). The proposed methods were found to be linear in the ranges of (15-100 µg/mL) and (3-40 µg/mL) for ASP and MTO, respectively. Those methods were compared to the methods following the geometrical standard addition approach: ratio H-point standard addition method (RHPSAM) and geometrical induced amplitude modulation (GIAM). The approaches were applied for the determination of the minor component metoclopramide in its mixture with the major component aspirin in the challengeable ratio of (1,90) respectively in a white multicomponent system. The results obtained from the proposed approaches were statistically compared with each other. The methods were validated according to ICH guidelines where the results were found to be within the acceptable limits. The methods were found to be accurate and reliable for the determination of metoclopramide critical concentration besides aspirin concentration. The results of single factor ANOVA analysis indicated that there is no significant difference among the developed methods. These methods provided simple resolution of this binary combination from synthetic mixtures and pharmaceutical preparation and can be conveniently adopted for routine quality control analysis.


Assuntos
Preparações Farmacêuticas/análise , Processamento de Sinais Assistido por Computador , Espectrofotometria/métodos , Aspirina/análise , Aspirina/química , Modelos Lineares , Metoclopramida/análise , Metoclopramida/química , Modelos Químicos , Modelos Estatísticos , Preparações Farmacêuticas/química , Reprodutibilidade dos Testes
10.
Photochem Photobiol Sci ; 18(12): 2921-2930, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31691716

RESUMO

Boron nitride (BN) nanosheets are promising support materials for catalysts. A series of TiO2-BN enabled electrospun nanofibers were synthesized for the photocatalytic treatment of ibuprofen and secondary wastewater effluent under visible light. X-ray photoelectron spectroscopy confirmed the existence of B-O-Ti bonds between the BN nanosheets and TiO2 nanofibers, resulting in energy rearrangement, narrowed band gaps, and enhanced light utilization efficiency of the TiO2-BN nanocomposites in the visible light spectrum. Transient photocurrent measurements revealed that the BN enhanced the transport of photogenerated holes from the bulk TiO2 nanofibers to its surface, resulting in more efficient separation and less recombination of the charge carriers. A kinetic study of ibuprofen degradation indicated the enhanced photocatalytic performance of TiO2-BN catalysts with a higher BN content in the nanocomposites. The kinetic rate constant of the TiO2-10% BN catalysts was 10 times higher than that of the pure TiO2 nanofibers. The degradation of organic contaminants in wastewater followed the same trend as ibuprofen and improved with increasing BN content. The stability of the TiO2-BN nanocomposites as an effective solar photocatalyst was demonstrated by multiple cycles of wastewater treatment. The results proved that TiO2-BN is an appealing photocatalyst under visible light.


Assuntos
Compostos de Boro/química , Luz , Nanofibras/química , Preparações Farmacêuticas/química , Titânio/química , Eliminação de Resíduos Líquidos/métodos , Catálise , Ibuprofeno/química , Oxirredução , Poluentes Químicos da Água/química
11.
Nature ; 575(7782): 336-340, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31723273

RESUMO

Organoboron reagents are important synthetic intermediates that have a key role in the construction of natural products, pharmaceuticals and organic materials1. The discovery of simpler, milder and more efficient approaches to organoborons can open additional routes to diverse substances2-5. Here we show a general method for the directed C-H borylation of arenes and heteroarenes without the use of metal catalysts. C7- and C4-borylated indoles are produced by a mild approach that is compatible with a broad range of functional groups. The mechanism, which is established by density functional theory calculations, involves BBr3 acting as both a reagent and a catalyst. The potential utility of this strategy is highlighted by the downstream transformation of the formed boron species into natural products and drug scaffolds.


Assuntos
Compostos de Boro/química , Compostos de Boro/síntese química , Boro/química , Produtos Biológicos/síntese química , Produtos Biológicos/química , Teoria da Densidade Funcional , Descoberta de Drogas , Indóis/química , Compostos Organometálicos/química , Preparações Farmacêuticas/síntese química , Preparações Farmacêuticas/química
12.
Eur J Pharm Biopharm ; 145: 113-120, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31682903

RESUMO

Lipid-based drug delivery systems (LBDDS) are highly relevant as pharmaceutical formulations significantly enhancing the bioavailability of active pharmaceutical ingredients (APIs). These formulations often are complex mixtures of APIs, various lipids, and other excipients (e.g. surfactants). In their simplest form, LBDDS contain one API being dissolved in a pure lipid, which often is a triglyceride (TG). In this work, solubilities of the APIs indomethacin, ibuprofen, and fenofibrate in pure TGs of different chain lengths (C chain 8-18) and degree of saturation were investigated. Solubilities of APIs in TGs were measured via differential scanning calorimetry, hot-stage microscopy, high-performance liquid chromatography, and Raman spectroscopy. The influence of fatty-acid chain length and degree of saturation on the API solubility in the TGs was investigated. APIs showed a higher solubility in saturated (wIBU = 10.5 wt% at 25 °C in tricaprylin) TGs compared to unsaturated ones (wIBU = 4.0 wt% at 25 °C in triolein). The fatty-acid chain length of TGs only slightly affects the solubility of ibuprofen and fenofibrate, but strongly influences the eutectic temperature of the API/TG mixtures. API solubilities in TGs and TG mixtures (mixtures of tricaprylin and tricaprin) were successfully modeled using the Perturbed-Chain Statistical Associating Fluid Theory (PC-SAFT) accounting for the intermolecular API/TG interactions providing a deep understanding of the energetic and structural impact of the TGs on API solubility.


Assuntos
Preparações Farmacêuticas/química , Solubilidade/efeitos dos fármacos , Triglicerídeos/química , Varredura Diferencial de Calorimetria/métodos , Química Farmacêutica/métodos , Composição de Medicamentos/métodos , Sistemas de Liberação de Medicamentos/métodos , Excipientes/química , Fenofibrato/química , Ibuprofeno/química , Indometacina/química , Lipídeos/química
13.
Nature ; 574(7779): 516-521, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31645723

RESUMO

Methods for selective C-H bond functionalization have provided chemists with versatile and powerful toolboxes for synthesis, such as the late-stage modification of a lead compound without the need for lengthy de novo synthesis1-5. Cleavage of an sp3 C-H bond via hydrogen atom transfer (HAT) is particularly useful, given the large number of available HAT acceptors and the diversity of reaction pathways available to the resulting radical intermediate6-17. Site-selectivity, however, remains a formidable challenge, especially among sp3 C-H bonds with comparable properties. If the intermediate radical could be further trapped enantioselectively, this should enable highly site- and enantioselective functionalization of C-H bonds. Here we report a copper (Cu)-catalysed site- and enantioselective allylic C-H cyanation of complex alkenes, in which a Cu(II)-bound nitrogen (N)-centred radical plays the key role in achieving precise site-specific HAT. This method is shown to be effective for a diverse collection of alkene-containing molecules, including sterically demanding structures and complex natural products and pharmaceuticals.


Assuntos
Carbono/química , Cobre/química , Hidrogênio/química , Alcenos/química , Produtos Biológicos/química , Catálise , Teoria da Densidade Funcional , Nitrogênio/química , Oxirredução , Preparações Farmacêuticas/química , Especificidade por Substrato
15.
J Chem Theory Comput ; 15(11): 6025-6035, 2019 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-31596078

RESUMO

Despite the numerous computational efforts on estimating acid dissociation constant (pKa's), an accurate estimation of pKa's of bio-organic molecules in the aqueous medium is still a challenge. The major difficulty lies in the accurate description of the aqueous environment and the cost and accuracy of quantum mechanical (QM) methods. Herein, we report a well-defined quantum chemical protocol for accurately calculating pKa's of a wide range of bio-organic molecules in aqueous media. The performance of our method has been assessed using test sets containing molecules with a range of sizes and a variety of functional groups, including alcohols, phenols, amines, and carboxylic acids, and obtained an impressive mean absolute accuracy of 0.5 pKa units. For the smaller molecules, we use a high-level QM method (CBS-QB3) and a calibrated explicit-implicit solvation model that yields accurate pKa values for a range of functional groups. For the larger molecules, we combine this approach with an efficient error-cancellation scheme that eliminates the systematic errors in different density functional methods to yield accurate pKa values for simple to complex molecular systems. Our protocol is efficient, applicable to large molecules, covers all the common functional groups present in bio-organic molecules, and should find widespread applications in diverse research areas including drug-protein binding, catalysis, and chemical synthesis.


Assuntos
Compostos Orgânicos/química , Proteínas/química , Água/química , Ácidos Carboxílicos/química , Cinética , Preparações Farmacêuticas/química , Preparações Farmacêuticas/metabolismo , Fenóis/química , Proteínas/metabolismo , Teoria Quântica
16.
Chem Commun (Camb) ; 55(85): 12869-12872, 2019 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-31599274

RESUMO

A hierarchical USY zeolite has been produced using the surfactant-templating method and used as a catalyst for the production of two important active pharmaceutical ingredients. The presence of intracrystalline mesoporosity in the zeolite results in a significant increase in both the activity (up to 30 fold increase in TOF) and reusability for Friedel-Crafts alkylation and aldol condensation steps.


Assuntos
Nanoestruturas/química , Preparações Farmacêuticas/química , Tensoativos/química , Zeolitas/química , Catálise
17.
Chem Pharm Bull (Tokyo) ; 67(10): 1144-1151, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31582634

RESUMO

Definitive screening design (DSD) is a new class of small three-level experimental design that is attracting much attention as a technical tool of a quality by design (QbD) approach. The purpose of this study is to examine the usefulness of DSD for QbD through a pharmaceutical study on the preparation of ethenzamide-containing orally disintegrating tablet. Model tablets were prepared by directly compressing the mixture of the active pharmaceutical ingredient (API) and excipients. The five evaluated factors assigned to DSD were: the contents of API (X1) and lubricant (X2), and the compression force (X3) of the tableting process, the mixing time (X4), and the filling ratio of powder in the V-type mixer (X5). After tablet preparation, hardness and disintegration time were measured. The same experiments were performed by using the conventional design of experiments [i.e., L8 and L16 orthogonal array designs and central composite design (CCD)]. Results showed that DSD successfully clarified how various factors contribute to tablet properties. Moreover, the analysis result from DSD agreed well with those from the L8 and L16 experiments. In additional experiments, response surfaces for tablet properties were created by DSD. Compared with the response surfaces created by CCD, DSD could produce reliable response surfaces for its smaller number of experiments. We conclude that DSD is a powerful tool for implementing pharmaceutical studies including the QbD approach.


Assuntos
Desenho de Drogas , Preparações Farmacêuticas/química , Composição de Medicamentos , Avaliação Pré-Clínica de Medicamentos , Preparações Farmacêuticas/administração & dosagem , Propriedades de Superfície , Comprimidos/administração & dosagem , Comprimidos/química
19.
Ecotoxicol Environ Saf ; 185: 109696, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31585393

RESUMO

Current risk assessment in many countries, including European Union, is still placing focus on single substances rather than their mixtures, although mixtures are commonly found in the environment. To overcome this problem and gain new insights, six pharmaceuticals, namely: azithromycin (AZM), erythromycin (ERM), carbamazepine (CBA), oxytetracycline (OTC), dexamethasone (DXM), and diclofenac (DCF), were selected in order to analyze their combined toxicity in binary mixtures. Overall, 45 binary mixtures were analyzed. Single component toxicities were determined as well, for modelling purpose. Two most common mathematical models for the description of mixture toxicities were applied: concentration addition (CA) and independent action (IA) model. Comparison of the predicted and experimentally obtained toxicities provided information about the modes of toxicity action in the mixtures. OTC-DCF binary mixture indicated synergism with respect to additive behavior (CA model). All other binary combinations containing OTC or DCF were acting very similarly: the synergism with respect to additive behavior was observed for OTC-CBA and DCF-CBA combinations, while OTC-AZM, OTC-ERM, DCF-AZM and DCF-ERM exhibited antagonistic behavior with respect to CA model. All the remaining binary mixtures indicated additive behavior. The applicability of IA model as a proof of independent toxic action of the components was confirmed in cases of DCF-AZM, DCF-ERM, and OTC-AZM mixtures.


Assuntos
Sinergismo Farmacológico , Modelos Teóricos , Preparações Farmacêuticas/química , Poluentes Químicos da Água/química , Poluentes Químicos da Água/toxicidade , Aliivibrio fischeri/efeitos dos fármacos , Relação Dose-Resposta a Droga , Estrutura Molecular , Testes de Toxicidade
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