Ângelo Rocha

Design of controlled release systems for THEDES—Therapeutic deep eutectic solvents, using supercritical fluid technology

Deep eutectic solvents (DES) can be formed by bioactive compounds or pharmaceutical ingredients. A therapeutic DES (THEDES) based on ibuprofen, a non-steroidal anti-inflammatory drug (NSAID), and menthol was synthesized and its thermal behavior was analyzed by differential scanning calorimetry (DSC). A controlled drug delivery system was developed by impregnating a starch:poly-ϵ-caprolactone polymeric blend (SPCL 30:70) with the menthol:ibuprofen THEDES in different ratios (10 and 20 wt%), after supercritical fluid sintering at 20 MPa and 50 °C. The morphological characterization of SPCL matrices impregnated with THEDES was performed by scanning electron microscopy (SEM) and micro-computed tomography (micro-CT). Drug release studies were carried out in a phosphate buffered saline. The results obtained provide important clues for the development of carriers for the sustainable delivery of bioactive compounds.

Ion Jelly Conductive Properties Using Dicyanamide-Based Ionic Liquids

The thermal behavior and transport properties of several ion jellys (IJs), a composite that results from the combination of gelatin with an ionic liquid (IL), were investigated by dielectric relaxation spectroscopy (DRS), differential scanning calorimetry (DSC), and pulsed field gradient nuclear magnetic resonance spectroscopy (PFG NMR). Four different ILs containing the dicyanamide anion were used: 1-butyl-3-methylimidazolium dicyanamide (BMIMDCA), 1-ethyl-3-methylimidazolium dicyanamide (EMIMDCA), 1-butyl-1-methylpyrrolidinium dicyanamide (BMPyrDCA), and 1-butylpyridinium dicyanamide (BPyDCA); the bulk ILs were also investigated for comparison. A glass transition was detected by DSC for all materials, ILs and IJs, allowing them to be classified as glass formers. Additionally, an increase in the glass transition temperature upon dehydration was observed with a greater extent for IJs, attributed to a greater hindrance imposed by the gelatin matrix after water removal, rendering the IL less mobile. While crystallization is observed for some ILs with negligible water content, it was never detected for any IJ upon thermal cycling, which persist always as fully amorphous materials. From DRS measurements, conductivity and diffusion coefficients for both cations (D+) and anions (D-) were extracted. D+ values obtained by DRS reveal excellent agreement with those obtained from PFG NMR direct measurements, obeying the same VFTH equation over a large temperature range (ΔT ≈ 150 K) within which D+ varies around 10 decades. At temperatures close to room temperature, the IJs exhibit D values comparable to the most hydrated (9%) ILs. The IJ derived from EMIMDCA possesses the highest conductivity and diffusion coefficient, respectively, ∼10(-2) S·cm(-1) and ∼10(-10) m(2)·s(-1). For BMPyrDCA the relaxational behavior was analyzed through the complex permittivity and modulus formalism allowing the assignment of the detected secondary relaxation to a Johari-Goldstein process. Besides the relevant information on the more fundamental nature providing physicochemical details on ILs behavior, new doorways are opened for practical applications by using IJ as a strategy to produce novel and stable electrolytes for different electrochemical devices.

Development of antimicrobial Ion Jelly fibers

We report a method to obtain electrospun fibers based on ionic liquids and gelatin, exhibiting antimicrobial properties.

Synthesis of choline sulfonate buffers and their effect on cytochrome c dissolution and oxidation state

Seven choline sulfonates with buffering properties were prepared in good yields (74–94%) and high purity by reacting choline hydroxide with different Goods buffers. Choline sulfonate buffers containing hydroxyl group-rich cations appeared to be liquid at room temperature. The dissolution of cytochrome c in the synthesized choline sulfonates was investigated. It was found that complete solubilisation of this heme protein in most of the choline sulfonate buffers can be obtained through addition of 21–31% (w/w%) water. In these hydrated choline sulfonates, cyt c is solubilised in its reduced form.

Synthesis and characterization of acetylated amylose and development of inclusion complexes with rifampicin

Amylose (AM) tends to form single helical inclusion complexes with suitable agents. These complexes are considered promising biomaterial carrier since the guest molecules can be released later, leading to many applications, especially in the pharmaceutical industry. Rifampicin (RIF) has long been recognized as an active drug against Mycobacterium tuberculosis, however, the administration of RIF in high dosages can originate unwanted side-effects. Due to the fact that the use of native amylose (AM) in the formation of complexes is limited by their low water solubility, it was acetylated with a medium degree of substitution (DS), allowing solubilizing (0.5gL-1) acetylated amylose (AMA) in water at neutral pH, in opposition to that observed with native amylose (trace solubility). The resulting acetylated amylose was characterized by means of Fourier Transform Infrared (FT-IR) spectroscopy and Scanning Electron Microscopy (SEM). FT-IR results indicated that the acetylation of anhydroglucose units of amylose corresponds to a low DS, whereas SEM results suggested that the smooth surfaces of amylose granules were changed into rougher surfaces after acetylation. Ultraviolet absorption spectroscopy (UV-vis) analysis confirmed the formation and allowed the quantification of both native (AM-RIF) and acetylated (AMA-RIF) amylose inclusion complexes. Their characterization in solution was performed by dynamic light scattering (DLS) and zeta potential (ZP) measurements. The average size of inclusion complexes as determined by DLS, ranged between 70 and 100nm. Besides, ZP analysis showed that both complexes are more stable in the presence of RIF. This study may lead to the development of an effective method for the preparation of amylose inclusion complexes, which is beneficial to their further application in drug delivery systems.

Enzymatic Kinetic Resolution of Secondary Alcohols Using an Ionic Anhydride Generated In Situ

We developed a method for the resolution of secondary alcohols using an ionic anhydride acylating agent prepared directly in the reaction medium containing the biocatalyst Candida antarctica lipase B (CALB). NMR studies showed that mixing all components at the same time does not interfere with the coupling reaction or the enzymatic activity. After optimization of the reaction conditions, the method allowed the resolution of a number of substrates in very high conversions (46-48 %) and enantiomeric ratios (E>170) along with an easy recovery of both enantiomers without the need for preparative chromatographic separation. Additionally, both the starting ionic acid and the biocatalyst could be recovered and reused up to nine cycles without significant loss of enantioselectivity.

Studies on the dynamic resolution of Crizotinib intermediate

Crizotinib is an anti-cancer agent approved for treatment of non-small cell lung carcinoma. Retrosynthetic analysis revels 1-(2,6-dichloro-3-fluorophenyl)ethanol as an important intermediate, which can be made available by different biocatalytic approaches. Herein we report our results on the kinetic and dynamic resolution towards the desired chiral intermediate for Crizotinib synthesis. The results obtained show that very good conversions and high selectivity could be obtained for the kinetic resolution (45% conv. and E>200) while dynamic kinetic resolution under continuous-flow conditions afforded the desired product in 57% conversion and 98% e.e.