RESUMO
Prenylated stilbenoids such as arachidin-1 and arachidin-3 are stilbene derivatives that exhibit multiple pharmacological activities. We report an elicitation strategy using different combinations of cyclodextrin, hydrogen peroxide, methyl jasmonate and magnesium chloride to increase arachidin-1 and arachidin-3 production in peanut hairy root cultures. The treatment of hairy root cultures with cyclodextrin with hydrogen peroxide selectively enhanced arachidin-1 yield (132.6 ± 20.4 mg/L), which was 1.8-fold higher than arachidin-3. Similarly, cyclodextrin combined with methyl jasmonate selectively enhanced arachidin-3 yield (178.2 ± 6.8 mg/L), which was 5.5-fold higher than arachidin-1. Re-elicitation of the hairy root cultures further increased the levels of arachidin-1 and arachidin-3 by 24% and 42%, respectively. The ethyl acetate extract of the culture medium was consecutively fractionated by normal- and reversed-phase column chromatography, followed by semi-preparative HPLC purification on a C18 column to yield arachidin-1 with a recovery rate of 32% and arachidin-3 with a recovery rate of 39%, both at higher than 95% purity. This study provided a sustainable strategy to produce high-purity arachidin-1 and arachidin-3 using hairy root cultures of peanuts combined with column chromatography and semi-preparative HPLC.
Assuntos
Ciclodextrinas , Estilbenos , Acetatos , Arachis/química , Ciclodextrinas/análise , Ciclopentanos , Hemiterpenos , Peróxido de Hidrogênio/análise , Cloreto de Magnésio , Oxilipinas , Raízes de Plantas/química , Estilbenos/análise , Estilbenos/farmacologiaRESUMO
MAIN CONCLUSION: Peanut cultivars are known to produce stilbene compounds. Transcriptional control plays a key role in the early stages of the stress response mechanism, involving both PR-proteins and stilbene compounds. In this study, the production of stilbenoid compounds, especially prenylated, was investigated in two cultivars of peanut hairy root lines, designated as K2-K599 and T9-K599 elicited with a combination of chitosan (CHT), methyl jasmonate (MeJA), and cyclodextrin (CD): CHT + MeJA + CD. The antioxidant activities and stilbenoid content of both K2-K599 and T9-K599 hairy root lines increased significantly during the elicitation period. The T9-K599 hairy root line expressed higher ABTS and FRAP antioxidant activities than the K2-K599 line while the latter exhibited greater total phenolic content than the former at all-time points. Additionally, the K2-K599 line exhibited more stilbene compounds, including trans-resveratrol, trans-arachidin-1, and trans-arachidin-3 than the T9-K599 line, which showed statistically significant differences at all-time points. Gene expression of the enzyme involved in the stilbene biosynthesis pathway (PAL, RS, RS3) was observed, responding early to elicitor treatment and the metabolic production of a high level of stilbenoid compounds at a later stage. The antioxidant enzyme (CuZn-SOD, APX, GPX) and pathogenesis-related protein (PR; PR4A, PR5, PR10, chitinase) genes were strongly expressed after elicitor treatment at 24 h and decreased with an increasing elicitation time. Investigation of the response mechanism illustrates that the elicitor treatment can affect various plant responses, including plant cell wall structure and integrity, antioxidant system, PR-proteins, and secondary plant metabolites at different time points after facing external environmental stimuli.
Assuntos
Quitosana , Ciclodextrinas , Fabaceae , Estilbenos , Acetatos , Antioxidantes/metabolismo , Arachis/genética , Quitosana/análise , Quitosana/metabolismo , Ciclodextrinas/análise , Ciclodextrinas/metabolismo , Ciclopentanos , Fabaceae/metabolismo , Oxilipinas , Raízes de Plantas/metabolismo , Estilbenos/metabolismoRESUMO
Cyclodextrins (CDs) are highly respected for their ability to form inclusion complexes via host-guest noncovalent interactions and, thus, ensofance other molecular properties. Various molecular modeling methods have found their applications in the analysis of those complexes. However, as showed in this review, molecular dynamics (MD) simulations could provide the information unobtainable by any other means. It is therefore not surprising that published works on MD simulations used in this field have rapidly increased since the early 2010s. This review provides an overview of the successful applications of MD simulations in the studies on CD complexes. Information that is crucial for MD simulations, such as application of force fields, the length of the simulation, or solvent treatment method, are thoroughly discussed. Therefore, this work can serve as a guide to properly set up such calculations and analyze their results.
Assuntos
Ciclodextrinas/análise , Ciclodextrinas/química , Simulação de Dinâmica Molecular , Estrutura MolecularRESUMO
Cyclodextrin (CD) has been widely used as a solubilizing agent for poorly water-soluble drugs. In the present study, the effect of CD on the amorphous drug solubility and the maximum thermodynamic activity of the drug in the aqueous phase when the drug concentration exceeded the liquid-liquid phase separation (LLPS) concentration was investigated using three chemically diverse CDs, ß-cyclodextrin (ß-CD), dimethyl-ß-CD (DM-ß-CD), and hydroxypropyl-ß-CD (HP-ß-CD). The amorphous solubility of ibuprofen (IBP) increased substantially linearly with the increase in the CD concentration due to IBP/CD complex formation. Surprisingly, although the crystalline solubility of IBP in the ß-CD solution reached a plateau at ß-CD concentrations above 3 mM (BS-type solubility diagram) because of the limited crystalline solubility of the IBP/ß-CD complex, the amorphous solubility of IBP increased linearly even when the ß-CD concentration was higher than 3 mM. The amorphous solubility of IBP in CD solutions was influenced primarily by the phase separation of the IBP-supersaturated solution to the aqueous phase and the other phase mainly composed of IBP, namely, the IBP-rich phase, via LLPS. NMR spectroscopy revealed that DM-ß-CD was distributed into the IBP-rich phase when the IBP concentration exceeded its amorphous solubility, while ß-CD and HP-ß-CD showed minimal mixing with the IBP-rich phase. NMR diffusometry showed that the maximum free IBP concentration was reduced in the DM-ß-CD solution compared to that in the buffer. The mixing of DM-ß-CD with the IBP-rich phase reduced the chemical potential of IBP in the IBP-rich phase, which in turn reduced the maximum thermodynamic activity of IBP in the aqueous phase. In contrast, the maximum free IBP concentration was unchanged when ß-CD or HP-ß-CD was present. The hydrophobic nature of the DM-ß-CD substituent may contribute to its partitioning into the IBP-rich phase. The present study highlights the impact of CD on the maximum thermodynamic activity of drugs as well as the apparent amorphous solubility of the drug. This aspect should be considered for improving the effective absorption of poorly water-soluble drugs.
Assuntos
Ciclodextrinas/análise , Ciclodextrinas/química , Excipientes/química , Imageamento por Ressonância Magnética/métodos , Química Farmacêutica , Interações Hidrofóbicas e Hidrofílicas , Ibuprofeno/análise , Ibuprofeno/química , SolubilidadeRESUMO
The human immunodeficiency virus (HIV) impacts up to 37 million people globally, of which 1.8 million are children. To date, there is no cure for HIV, although treatment options such as antiretroviral therapy (ART) are available. ART, which involves a patient taking a combination of antiretrovirals, is being used to treat HIV clinically. Despite the effectiveness of ART, there is currently no palatable pediatric formulation to treat HIV in children, which has hindered patient compliance and overall treatment efficacy. In addition, anti-HIV therapeutics are often poorly water-soluble, and hence have poor bioavailability. In the present study, we developed a pediatric-friendly formulation for anti-HIV therapeutics with improved dissolution characteristics of the therapeutic agents. Lopinavir (LPV) and ritonavir (RTV), available as FDA-approved fixed-dose combination products, were chosen as model ART drugs, and the formulation and processing parameters of spray-dried cyclodextrin (CD)-based LPV and RTV complexes were studied. Results showed that the spray-dried complexes exhibited enhanced dissolution profiles in comparison to pure drugs, particularly spray-dried ß-CD complexes, which showed the most favorable dissolution profiles. This current formulation with enhanced dissolution and taste-masking ability through the use of cyclodextrin has the potential to address the unmet need for the development of suitable pediatric formulations.
Assuntos
Fármacos Anti-HIV/análise , Fármacos Anti-HIV/síntese química , Ciclodextrinas/análise , Ciclodextrinas/síntese química , Desenvolvimento de Medicamentos/métodos , Secagem por Atomização , Fármacos Anti-HIV/uso terapêutico , Criança , Ciclodextrinas/uso terapêutico , Composição de Medicamentos/métodos , Infecções por HIV/tratamento farmacológico , Humanos , Espectroscopia de Ressonância Magnética/métodos , Pediatria/métodos , Difração de Raios X/métodosRESUMO
Enantiomeric drugs are widely used and play important roles in pharmaceuticals. Ion mobility spectrometry coupled with mass spectrometry technology provides a unique method for distinguishing the enantiomeric drugs, enantiomeric identification, and quantitation in the gas phase. In this study, enantiomeric molecules of ibuprofen and flurbiprofen were clearly recognized by forming host-guest complex ions using trapped ion mobility time-of-flight mass spectrometry. Ternary complex ions can be produced easily by electrospray ionization of the mixed solutions of ibuprofen, cyclodextrins, and CaCl2 , LiCl, or NaCl, as well as flurbiprofen, cyclodextrins, and CaCl2 . The relative contents of different chiral ibuprofens in a mixed solution were also quantitatively measured. This new method is a simple, effective, and a convenient enantioselective analysis method.
Assuntos
Complexos de Coordenação/análise , Ciclodextrinas/análise , Flurbiprofeno/análise , Ibuprofeno/análise , Cálcio/análise , Cátions/análise , Espectrometria de Mobilidade Iônica , Lítio/análise , Estrutura Molecular , Sódio/análise , EstereoisomerismoRESUMO
A novel matrix-assisted laser desorption/ionization time-of-flight mass spectrometric method (MALDI-TOF MS) for determination of highly sensitive small molecular compounds was developed based on molybdenum disulfide nanosheets hybridized with ultrathin graphitic carbon nitride (MoS2/g-C3N4) as the matrix. With this approach, the synergistic effects of MoS2 and g-C3N4 enhance the UV absorption of MoS2/g-C3N4, increase both desorption and ionization efficiency in LDI MS, and induce higher signal-to-noise ratio of analytes when compared with the bare MoS2 and g-C3N4 matrix in the determination of amino acids, antibiotics, neutral oligosaccharides, uric acid, and polyethylene glycols (PEGs). The detection limits of these small molecular compounds are in the ranges 0.1 to 10 µg mL-1, 1*10-3 to 1.0 µg mL-1, 1.0 to 10 µg mL-1, and 2*10-4 µg mL-1, respectively, and the polydispersity index of these PEGs is less than 1.02. Moreover, high salt tolera`nce and homogeneous deposition on the spot results in good reproducibility. The relative standard deviations (RSDs) of shot-to-shot and spot-to-spot (n = 15) of these compounds are less than 10.1% and 12.5%, respectively. With MoS2/g-C3N4, the uric acid in complicated biological samples can be directly determined in combination with LDI-TOF MS. We synthesized MoS2/g-C3N4 nanohybrid as an efficient matrix for MALDI-TOF MS analysis of small molecules as well as quantitative detection of uric acid in human urine.
Assuntos
Dissulfetos/química , Grafite/química , Espectrometria de Massas/métodos , Molibdênio/química , Nanoestruturas/química , Compostos de Nitrogênio/química , Ácido Úrico/urina , Aminoácidos/análise , Antibacterianos/análise , Ciclodextrinas/análise , Humanos , Limite de Detecção , Polietilenoglicóis/análise , Reprodutibilidade dos TestesRESUMO
The negatively charged cyclodextrins (CDs) play an important role in chiral analysis due to the additional electrostatic effect beyond the host-guest inclusion, especially in enantioanalysis of positively charged and electrically neutral analytes. This review presents recent advances in application of anionic CDs for enantioanalysis during the past five years. Firstly, the synthesis approaches of random substitution and single isomers of anionic CDs are briefly discussed. The main part focuses on the chiral analysis using anionic CDs in various analytical techniques, including capillary electrophoresis, high-performance liquid chromatography, capillary electrochromatography, counter current chromatography, nuclear magnetic resonance, etc. Particular attention is given to the capillary electrophoresis application since charged CDs could be used as a carrier of enantiomers by virtue of their self-mobility and offer an easy adjustment of the enantiomer migration order. Finally, future opportunities are also discussed in the conclusion of this review.
Assuntos
Ânions/química , Técnicas de Química Sintética , Ciclodextrinas , Eletrocromatografia Capilar/métodos , Cromatografia Líquida de Alta Pressão/métodos , Distribuição Contracorrente/métodos , Ciclodextrinas/análise , Ciclodextrinas/síntese química , Eletroforese Capilar/métodos , Humanos , Espectroscopia de Ressonância Magnética/métodos , Estrutura Molecular , Eletricidade Estática , EstereoisomerismoRESUMO
Noncovalent complexes between cyclodextrin (CD) and divalent metal cations drew growing attentions due to their applications in the pharmaceutical industry for molecular recognition. In this study, gas-phase binding of noncovalent complexes between α-, or γ-CD and divalent metal cations was investigated by electrospray ionization mass spectrometry (ESI-MS), demonstrating the formation of 1:1 stoichiometric noncovalent complexes. The binding of the complexes were furtherly confirmed by collision-induced dissociation (CID) with tandem mass spectrometry. The CID revealed the fragmentation pattern were strongly dependent on the electronic configuration of the cations and the charge separation reaction frequently took place in the cyclodextrin-complexes with transition metal cations. For the non-covalent complexes of α-CD with Mg2+, Ca2+, Sr2+ or Ba2+ at a collision energy of 25 eV, the fragments attributed to [α-CD + cation-nGlucose unit]2+ were observed (named series A). However, for the γ-CD complexes with transition metal cations Co2+, Ni2+, Cu2+ or Zn2+, apart from fragments of series A, it were observed fragment ions of [γ-CD + cation-nGlucose unit]+ (named series B), together with the Glucose unit (m/z 163.2) and its products with loss of H2O (m/z 145.2 and 126.8). The CID performed at a collision energy from 10 to 50 eV showed that the binding strength of complexes increase in the order of [α-CD + Mg]2+, [α-CD + Ca]2+, [α-CD + Sr]2+ and [α-CD + Ba]2+. Through mass spectrometric titrations, the values of dissociation constant Kd (in µmolâ¢L-1) for the complexes of α-CD with Ca2+ or Ni2+ were obtained, which were 4.30 and 4.26, respectively.
Assuntos
Ciclodextrinas/análise , Metais Alcalinoterrosos/análise , Metais Pesados/análise , Cátions/análise , Espectrometria de MassasRESUMO
Cyclodextrin (CD) is a conical compound used in food and pharmaceutical industry to complexation of hydrophobic substances. It is a product of microbial enzymes which converts starch into CD during their activity. We aim to detect CD using active-electrode biosensor of SnO2. They were grown on active electrode by the VLS method. The CD consists of several glucose units which have hydroxyl groups which tend to bind to interface states present in nanowires changing their conductivity. Experimental results of electrical conductivity at different CD concentrations are presented. A model that describes the influence of adsorbed glucose on nanowires and its electrical properties is also presented. Some general observations are performed on the applicability of the CD adsorption method by the nanowire-based biosensor.
Assuntos
Técnicas Biossensoriais , Ciclodextrinas/análise , Glucosiltransferases/metabolismo , Nanofios/química , Compostos de Estanho/química , Bacillus/enzimologia , Eletricidade , Eletrodos , Nanofios/ultraestrutura , Fatores de TempoRESUMO
An important and well-designed solution to overcome some of the problems associated with new drugs is provided by the molecular encapsulation of the drugs in the cyclodextrins (CDs) cavity, yielding corresponding inclusion complexes (ICs). These types of non-covalent complexes are of current interest to the pharmaceutical industry, as they improve the solubility, stability and bioavailability of the guest molecules. This review highlights several methods for cyclodextrin ICs preparation and characterization, focusing mostly on the mass spectrometry (MS) studies that have been used for the detection of noncovalent interactions of CDs inclusion complexes and binding selectivity of guest molecules with CDs. Furthermore, the MS investigations of several ICs of the CD with antifungal, antioxidants or fluorescent dyes are presented in greater details, pointing out the difficulties overcome in the analysis of this type of compounds.
Assuntos
Química Farmacêutica/métodos , Ciclodextrinas/análise , Espectrometria de Massas , SolubilidadeRESUMO
Chiral separation is an important process in the chemical and pharmaceutical industries. From the analytical chemistry perspective, chiral separation is required for assessing the fit-for-purpose and the safety of chemical products. Capillary electrophoresis, in the electrokinetic chromatography mode is an established analytical technique for chiral separations. A water-soluble chiral selector is typically used. This review therefore examines the use of various chiral selectors in electrokinetic chromatography during 2017â»2018. The chiral selectors were both low and high (macromolecules) molecular mass molecules as well as molecular aggregates (supramolecules). There were 58 papers found by search in Scopus, indicating continuous and active activity in this research area. The macromolecules were sugar-, amino acid-, and nucleic acid-based polymers. The supramolecules were bile salt micelles. The low molecular mass selectors were mainly ionic liquids and complexes with a central ion. A majority of the papers were on the use or preparation of sugar-based macromolecules, e.g., native or derivatised cyclodextrins. Studies to explain chiral recognition of macromolecular and supramolecular chiral selectors were mainly done by molecular modelling and nuclear magnetic resonance spectroscopy. Demonstrations were predominantly on drug analysis for the separation of racemates.
Assuntos
Eletroforese Capilar , Substâncias Macromoleculares/análise , Substâncias Macromoleculares/química , Ciclodextrinas/análise , Ciclodextrinas/química , Eletroforese Capilar/métodos , Espectroscopia de Ressonância Magnética , Micelas , Modelos Moleculares , Peso Molecular , Açúcares/análiseRESUMO
The aim of the current study was to evaluate the physicochemical properties of a solid dispersion of coenzyme Q10 (CoQ10)/cyclodextrin metal organic frameworks-1 (CD-MOF-1). As a result of the powder X-ray diffraction (PXRD), it was confirmed that the CD-MOF-1 was changed from the α form to the ß form by evaporation (EVP). A diffraction peak due to melting of CoQ10 disappeared the EVP (CoQ10/CD-MOF-1 = 1/2). The structure of this complex is presumed to be similar to the ß form of CD-MOF-1. As a result of the differential scanning calorimetry (DSC), the endothermic peak due to the melting of CoQ10 disappeared the EVP (CoQ10/CD-MOF-1 = 1/2). As a result of the near-infrared (NIR) absorption spectroscopy, findings suggested the hydrogen bond in formation between the CH group in the isoprene side chains of CoQ10 and the OH group of CD-MOF-1. Therefore, the formation of crystal solid dispersion in CoQ10/CD-MOF-1 was suggested. As a result of the dissolution test in distilled water, the EVP (CoQ10/CD-MOF-1 = 1/2) had better dissolution in comparison to CoQ10 alone. Furthermore, also in fasted state simulated intestinal fluid (FaSSIF) in vivo, the EVP (CoQ10/CD-MOF-1 = 1/2) had better dissolution in the human body than CoQ10 alone. From the results of 2D-nuclear overhauser effect spectroscopy (NOESY) NMR spectroscopy, CD-MOF-1 could not include the benzoquinone ring of CoQ10. It was confirmed that the isoprene side chain was included. Therefore, it was suggested that CD-MOF-1 useful as a novel drug carrier for CoQ10.
Assuntos
Ciclodextrinas/síntese química , Portadores de Fármacos/síntese química , Solventes/síntese química , Ubiquinona/análogos & derivados , Varredura Diferencial de Calorimetria/métodos , Ciclodextrinas/análise , Ciclodextrinas/metabolismo , Portadores de Fármacos/análise , Portadores de Fármacos/metabolismo , Solubilidade , Solventes/análise , Solventes/metabolismo , Espectroscopia de Infravermelho com Transformada de Fourier/métodos , Ubiquinona/análise , Ubiquinona/síntese química , Ubiquinona/metabolismo , Difração de Raios X/métodosRESUMO
Nesta pesquisa avaliou-se o efeito do colesterol sobre o sêmen de garanhões da raça Nordestina sobre a qualidade espermática. Vinte ejaculados de dois garanhões foram diluídos com BotuSemen e colesterol carreado pela ciclodextrina (CCC) adicionado no sêmen: controle, 0,75mg de CCC e 1,0mg de CCC/120x106 sptz/mL, e incubado a 26°C/15min. O sêmen foi diluído 1:5 (v/v) com diluente Lactose-gema de ovo e resfriado a 5°C/2h, envasado em palhetas de 0,5mL, e acondicionado sob vapor de nitrogênio líquido, e depois imersos. As amostras foram descongeladas (37 °C/30s) e avaliadas. As variáveis foram avaliadas com ANOVA e teste de Tukey (P<0,05). A motilidade total e progressiva foi maior (P<0,05) no sêmen tratado com CCC comparado as amostras do grupo controle, e CCC promoveu maior percentual (P<0,05) de motilidade total e progressiva durante as 3 horas de incubação. A percentagem de espermatozoides com viabilidade e integridade foi maior (P<0,05) no sêmen tratado com CCC (81,47 e 86,07%) comparado ao controle (72,12 e 70,19%). O número de espermatozoides reativos ao teste hiposmótico foi maior (P<0,05) nas amostras de sêmen tratadas com CCC comparado ao controle. Adição de colesterol no sêmen de garanhões Nordestino melhora a qualidade espermática apos a criopreservação.(AU)
In the study effect of cholesterol was evaluated on the sperm quality of Nordestina stallion breed. Twenty semen samples were used from two stallions, diluted with BotuSemen extender and cholesterol add as follows: control, 0.75mg of cholesterol-loaded cyclodextrin (CLC) and 1.0mg of CLC/120x106 sperm/mL, and incubated for 15 min at 22°C. The samples were diluted 1:5 with lactose-yolk egg extender and cooled to 5°C over two hours, loaded into 0.5mL straws and frozen in static liquid nitrogen vapor before being plunged into nitrogen. Samples were thawed (37°C/30s) and analyzed. The variables were analyzed by ANOVA and means compared by Tukey test (P<0.05). Higher percentages of total and progressive motile was higher for sperm treated with CLC compared to control, and CLC promoted higher percentages (P<0.05) of total and progressive motility for the 3 hours of incubation. The percentage of viability and plasma membrane integrity of spermatozoa were higher (P<0.05) in sperm treated with CLC compared to the control group. The number of spermatozoa reacted to hypoosmotic test was higher (P<0.05) in sperm treated with CLC than control. Addition of CLC in the semen of Nordestina stallion breed improve the sperm quality after cryopreservation.(AU)
Assuntos
Animais , Preservação do Sêmen/veterinária , Colesterol/administração & dosagem , Ciclodextrinas/análise , LongevidadeRESUMO
Functional siRNAs (luciferase and PLK1) have been conjugated to ß-cyclodextrin and the ability of the conjugates to retain gene knockdown activity has been assessed by delivery to cancer cell lines using various formulations. Initially two formulations used complexation with polycations, namely Lipofectamine 2000 and an amphiphilic polycationic cyclodextrin. Gene knockdown results for human glioblastoma cells (U87) and prostate cancer cells (PC3, DU145) showed that conjugation to the cyclodextrin did not reduce gene silencing by the RNA. A third mode of delivery involved formation of targeted nanoparticles in which the conjugate was first complexed with adamantyl-PEG-ligands (targeting ligand RVG peptide or dianisamide) by adamantyl inclusion in the cyclodextrin cavities of the conjugates, followed by charge neutralisation with the cationic polymer chitosan. Enhanced knockdown was achieved by these ligand-targeted formulations. In summary, while this study illustrated the gene silencing efficacy of a simple cyclodextrin-siRNA conjugate it is envisaged that future studies will explore the use of conjugates with a modified cyclodextrin which would be self-delivering. Detailed data such as stability, lysosomal escape etc. will then be reported for each conjugate, since this will be appropriate for conjugates which are intended to exploit, rather than merely demonstrate, the concept. The present paper was intended to demonstrate the viability and generality of this novel concept.
Assuntos
Ciclodextrinas/síntese química , Sistemas de Liberação de Medicamentos/métodos , Inativação Gênica/efeitos dos fármacos , RNA Interferente Pequeno/síntese química , Linhagem Celular Tumoral , Ciclodextrinas/administração & dosagem , Ciclodextrinas/análise , Inativação Gênica/fisiologia , Humanos , RNA Interferente Pequeno/administração & dosagem , RNA Interferente Pequeno/análiseRESUMO
A method for the enantioseparation of radezolid (RAD), an analogue of a truly new class of antibacterial agents, oxazolidinones, was developed based on capillary electrokinetic chromatography using a cyclodextrin as a chiral pseudophase (CD-cEKC). The mechanism of RAD separation, together with its precursor, were investigated to directly define the relationship between the oxazolidinone structure and the complexation process. During the development of the method, anionic single isomer cyclodextrins were tested. They were ranked in order from hydrophilic to hydrophobic as follows: heptakis-(2,3-dihydroxy-6-sulfo)-ß-cyclodextrin (HS-ß-CD), heptakis-(2,3-diacetyl-6-sulfo)-ß-cyclodextrin (HDAS-ß-CD) and heptakis-(2,3-dimethyl-6-sulfo)-ß-cyclodextrin (HDMS-ß-CD). Experiments were performed at pH values of 2.5, 6.6, 8.2 and 9.6. The cyclodextrins that had an acetyl or methyl group at the C2 and C3 positions, referred to as HDAS-ß-CD and HDMS-ß-CD, respectively, exhibited partial and baseline separation of enantiomers in a low pH buffer. However, higher temperatures were required for HDAS-ß-CD and acetonitrile addition was required for HDMS-ß-CD. During the experiments, different organic solvents, varying in their amphiprotic or aprotic nature, were tested. The best results for the separation of enantiomers using the CD-cEKC method were obtained with 40mM HDMS-ß-CD dissolved in a 50mM phosphate buffer (pH 2.5) with the addition of acetonitrile (65:35, v/v) at 27°C, reversed polarity and a voltage equal to 28kV. The apparent binding constants for each enantiomer to HDAS-ß-CD or HDMS-ß-CD were calculated. Finally, the stereochemistry of (S) and (R)-RAD and the behaviour of selected complex formations were established using electronic circular dichroism.
Assuntos
Eletrocromatografia Capilar/métodos , Dicroísmo Circular/métodos , Ciclodextrinas/química , Ciclodextrinas/metabolismo , Oxazolidinonas/química , Oxazolidinonas/metabolismo , Ciclodextrinas/análise , Oxazolidinonas/análise , EstereoisomerismoRESUMO
This report, which is a sequence of a series of reviews, records the most important chiral selectors (CSs) applied in CE. It highlights the CSs that were used during the period 2014 to mid-2016. In this review, method developments, validations, and pharmaceutical along with biomedical applications are presented. The different CSs include CDs, antibiotics, cyclofructants, linear and branched oligo- and polysaccharides, and polymeric surfactants. In addition, the advantages of these CSs, along with their chiral recognition mechanisms, and their performance, are discussed.
Assuntos
Eletroforese Capilar/métodos , Animais , Antibacterianos/análise , Ciclodextrinas/análise , Humanos , Polissacarídeos/análise , Estereoisomerismo , Tensoativos/análiseRESUMO
The aim of this study was to evaluate hot-melt extrusion (HME) as a continuous process to form cyclodextrin (CD) inclusion complexes in order to increase the solubility and dissolution rate of itraconazole (ITZ), a class II model drug molecule of the Biopharmaceutics Classification System. Different CD derivatives were tested in a 1:1 (CD:ITZ) molar ratio to obtain CD ternary inclusion complexes in the presence of a polymer, namely Soluplus® (SOL). The CD used in this series of experiments were ß-cyclodextrin (ßCD), hydroxypropyl-ß-cyclodextrin (HPßCD) with degrees of substitution of 0.63 and 0.87, randomly methylated ß-cyclodextrin (Rameb®), sulfobutylether-ß-cyclodextrin (Captisol®) and methyl-ß-cyclodextrin (Crysmeb®). Rheology testing and mini extrusion using a conical twin screw mini extruder were performed to test the processability of the different CD mixtures since CD are not thermoplastic. This allowed Captisol® and Crysmeb® to be discarded from the study due to their high impact on the viscosity of the SOL/ITZ mixture. The remaining CD were processed by HME in an 18mm twin screw extruder. Saturation concentration measurements confirmed the enhancement of solubility of ITZ for the four CD formulations. Biphasic dissolution tests indicated that all four formulations had faster release profiles compared to the SOL/ITZ solid dispersion. Formulations of HPßCD 0.63 and Rameb® even reached 95% of ITZ released in both phases after 1h. The formulations were characterized using thermal differential scanning calorimetry and attenuated total reflectance infra-red analysis. These analyses confirmed that the increased release profile was due to the formation of ternary inclusion complexes.
Assuntos
Química Farmacêutica/métodos , Ciclodextrinas/análise , Ciclodextrinas/síntese química , 2-Hidroxipropil-beta-Ciclodextrina , Reologia , Difração de Raios X/métodos , beta-Ciclodextrinas/análise , beta-Ciclodextrinas/síntese químicaRESUMO
BACKGROUND: Cyclodextrins (CDs), as one type of the novel pharmaceutical excipients, have been widely used in drug delivery and pharmaceutical industry. Over the past decades, a large amount of molecular modeling studies in CDs were reported for profound understanding of structural, dynamic and energetic features of CDs systems. Thus, this review is focused on qualitative and quantitative analysis of research outputs on molecular modeling in CDs. METHODS: The original data were collected from Web of Science and analyzed by scientific knowledge mapping tools, including Citespace, Science of Science, VOSviewer, GPSvisualizer and Gephi software. Scientific knowledge mapping, as an emerging approach for literature analysis, was employed to identify the knowledge structure and capture the development of the science in a visual way. RESULTS: The results of analysis included research outputs landscape, collaboration patterns, knowledge structure and research frontiers shift with time. China had the largest contributions to the publication number in this area, while USA dominated the high quality research outputs. International collaboration between USA and Europe was much stronger than that within Asia. J American Chemical Society, as one of the most important journals, played a pivotal role in linking different research fields. Furthermore, seven important thematic clusters were identified by the research cluster analysis with visualization tools and demonstrated from three different perspectives including: (1) the mostly-used CD molecules: ß-Cyclodextrin, (2) preferred modeling tools: docking calculation and molecular dynamic, (3) hot research fields: structural properties, solubility, chiral recognition and solidstate inclusion complexes. Moreover, research frontier shift in the past three decades was traced by detecting keywords bursts with high citation. CONCLUSION: The current review provided us a macro-perspective and intellectual landscape to molecular modeling in CDs.
Assuntos
Ciclodextrinas/análise , Indústria Farmacêutica , Modelos Moleculares , SoftwareRESUMO
Three advanced methods, high performance affinity chromatography (HPAC), surface plasmon resonance (SPR) and surface plasmon resonance imaging (SPRi) were compared and evaluated for determining the drug-cyclodextrin (CD) interactions herein. In total, 18 sparingly soluble drugs were selected for this comparative study. The three methods share a unique connection in the working principles and strategies. The same strategies of CD fixation onto solid phase were used in HPAC and SPR for the measurements, whereas, the SPR and SPRi share identical working principles. However, whilst these relationships are evident, no strong correlation was found between kinetic constants obtained from the three methods: Four drugs, namely, prednisolone, pseudolaric acid B, diazepam and gramisetron failed to show any response on SPR, whereas, the kinetics parameters from SPRi and HPAC were successfully measured. From a comparative review of all the kinetic data, random results without any trends were observed (ka, kd and KA) regardless of the relationships between the three methods: It is apparent that the measurement conditions (volume, flow rate, buffers), non-specific adsorption and experimental procedures had a strong impact on the generated data. The relative advantages and limitations of each method are critically presented on the basis of generated data. This comparative study provides a basis to further upgrade these techniques for confident measurement of drug-CDs interactions.