The preparation and characterization of multi-component systems in drug pre-formulation

The supramolecular derivatisation, via co-crystallization and cyclodextrin (CD) inclusion of three active pharmaceutical ingredients (APIs), was attempted with the aim of generating new solid forms with potential pharmaceutical application. The APIs under investigation included allopurinol (used for the treatment of gout and kidney stones), 6-thioguanine (used to treat acute myelogenous leukaemia) and valproic acid (for treatment of epilepsy and bipolar disorders). Allopurinol and 6-thioguanine were fairly intractable, yielding very limited results following co-crystallization trials with a series of co-formers. However, a new polymorph of one of the co-formers, namely isonicotinamide, was discovered serendipitously and thoroughly characterized using thermal analysis and single crystal X-ray diffraction. Phase solubility studies with a variety of CDs showed that the poor aqueous solubility of allopurinol and 6-thioguanine was not significantly modified in the presence of CD solutions. However, a more accurate aqueous solubility value for 6-thioguanine was achieved, namely 0.078 ± 0.003 mg.cm-3 at 25 o C. Six new CD complexes of valproic acid (VAL) were isolated by kneading and/or coprecipitation methods and characterized by thermal analysis, powder X-ray diffraction and spectroscopic (1H NMR and FT-IR) techniques. The six CD complexes (with host-guest stoichiometries in parentheses) included -CD·VAL (2:1), -CD·VAL (1:1), -CD·VAL (4:3), DMB·VAL (1:1), TMB·VAL (1:1) and TMA·VAL (1:1). The -CD·VAL, -CD·VAL, and -CD·VAL complexes were assessed for their ability to alter the aqueous solubility of the drug at 23 o C. The SCD/So ratios for these CD complexes (SCD being the solubility of VAL in the form of the CD complex and So the solubility of pure VAL) were 0.39, 0.42 and 0.41 respectively and thus CD complexation reduced the aqueous solubility of valproic acid. Single crystal X-ray structures of four of the CD-valproic acid complexes were determined, those with native CDs featuring fully disordered guest molecules, while those with permethylated -CD and dimethylated -CD revealed the modes of inclusion of the drug unequivocally

In vitro studies of dermally absorbed Cu(II) tripeptide complexes as potential anti-inflammatory drugs

Copper(II) complexes have anti-inflammatory properties which can alleviate the symptoms of rheumatoid arthritis (RA) and thus control the progression of the disease. In this study two tripeptides, namely sarcosyl-L-leucyl-phenylalanine (Sar-Leu-Phe) and glycyl-L-leucyl-phenylalanine (Gly-Leu-Phe) were studied as potential chelators, which would increase the bioavailability of copper(II) through dermal absorption. Glass electrode potentiometry was used to measure the solution thermodynamics of copper(II), nickel(II) and zinc(II) with Gly-Leu-Phe and Sar-Leu-Phe, at 25 0.01 °C and an ionic strength of 0.15 M (NaCl). The terminal amine of both tripeptides was found to have the same basicity, but the methyl group on the terminal amine decreased the stability constants of the copper(II) ligand species by 0.38 to 1.67 log units. It increased the stability constants of the zinc(II) ligand species by 0.13 to 1.07 log units and it also increased the stability constant of the NiL2H-1 species by 1.3 to 1.4 log units, while not affecting the NiL species. The solution structures of the complexes were determined spectroscopically using Ultraviolet-visible spectrophotometry, Infrared spectroscopy and 1H NMR spectroscopy. The copper(II) complexes tend more towards a square planar geometry, rather than the expected tetragonally distorted octahedral geometry. All the nickel(II) species, were square planar, except for the ML species, which was octahedral. The ligand coordinated to the metal ion via an amine-N, two amide-Ns, two carbonyl-Os and a carboxyl-O. The postulated coordination modes were validated using quantum mechanical calculations. Two methods were used to study percutaneous skin absorption, namely octanol/water partition coefficients and Franz cell permeation

Coarse grained model for exploring voltage dependent ion channels

AbstractThe relationship between the membrane voltage and the gating of voltage activated ion channels and other systems have been a problem of great current interest. Unfortunately, reliable molecular simulations of external voltage effects present a major challenge, since meaningful converging microscopic simulations are not yet available and macroscopic treatments involve major uncertainties in terms of the dielectric used and other key features. This work extends our coarse grained (CG) model to simulations of membrane/protein systems under external potential. Special attention is devoted to a consistent modeling of the effect of external potential due to the electrodes, emphasizing semimacroscopic description of the electrolytes in the solution regions between the membranes and the electrodes, as well as the coupling between the combined potential from the electrodes plus the electrolytes and the protein ionized groups. We also provide a clear connection to microscopic treatment of the electrolytes and thus can explore possible conceptual problems that are hard to resolve by other current approaches. For example, we obtain a clear description of the charge distribution in the entire electrolyte system, including near the electrodes in membrane/electrodes systems (where continuum models do not seem to provide the relevant results). Furthermore, the present treatment provides an insight on the distribution of the electrolyte charges before and after equilibration across the membrane, and thus on the nature of the gating charge. The different aspects of the model have been carefully validated by considering problems ranging for the simple Debye–Huckel, and the Gouy–Chapman models to the evaluation of the electrolyte distribution between two electrodes, as well as the effect of extending the simulation system by periodic replicas. Overall the clear connection to microscopic descriptions combined with the power of the CG modeling seems to offer a powerful tool for exploring the balance between the protein conformational energy and the interaction with the external potential in voltage activated channels. To illustrate these features we present a preliminary study of the gating charge in the voltage activated Kv1.2 channel, using the actual change in the electrolyte charge distribution rather than the conventional macroscopic estimate. We also discuss other special features of the model, which include the ability to capture the effect of changes in the protonation states of the protein residues during the close to open voltage induced transition. This article is part of a Special Issue entitled: Membrane protein structure and function

Multiple lift tube pumps boost refrigeration capacity in absorption plants

The technology of the diffusion absorption refriger-ator is receiving renewed attention due to its ability to use exclusively, low-grade heat to produce cool-ing or heating. Its capacity, however, has been large-ly restricted to small domestic-type units because of the flow rate limitations imposed by its single lift-tube pump. To increase its refrigeration capacity, a multiple lift-tube bubble pump can be used, in order to increase the volume flow rates of the fluids, which are directly related to the amount of refriger-ant produced. Testing on a diffusion absorption plant using a multiple lift tube bubble pump, and the effects of additional tubes on the system’s per-formance have been recorded. Although a full range of heat inputs could not be implemented, because of the limitations of the components of the unit itself, it was observed that the refrigeration cooling capacity was increased without a significant drop in Coefficient of Performance (COP). It was concluded that the multiple lift tube bubble pump has no limitation to the fluid flow rate and depends solely on the amount of heat input. This gives the freedom to design the lift tube pump according to the refrigeration demand of the unit, and not the other way round which is the current approach by the manufacturers world wide

Comparison between two different solution-pumping methods in absorption refrigeration machines

This paper presents a pumping method in absorp-tion refrigeration where a vapour-driven pump is to replace the electricity-driven pump. The vapour pump is driven by a fraction of the generator’s hot, high-pressure, vapour mixture. The refrigerator is thus exclusively heat-powered and rendered inde-pendent of the availability of electricity as the main energy source. The design and operation of the vapour pump is presented. The results obtained by a computer simulation program show a decrease in performance (COP), which is confirmed by the data obtained from a 1 kW cooling capacity refrigerator. Peak performances occur at higher generator tem-peratures when compared to a cycle using an elec-tricity-driven pum

Comparison between two different solution-pumping methods in absorption refrigeration machines

This paper presents a pumping method in absorp-tion refrigeration where a vapour-driven pump is to replace the electricity-driven pump. The vapour pump is driven by a fraction of the generator’s hot, high-pressure, vapour mixture. The refrigerator is thus exclusively heat-powered and rendered inde-pendent of the availability of electricity as the main energy source. The design and operation of the vapour pump is presented. The results obtained by a computer simulation program show a decrease in performance (COP), which is confirmed by the data obtained from a 1 kW cooling capacity refrigerator. Peak performances occur at higher generator tem-peratures when compared to a cycle using an elec-tricity-driven pum

A car air-conditioning system based on an absorption refrigeration cycle using energy from exhaust gas of an internal combustion engine

Energy from the exhaust gas of an internal combus-tion engine is used to power an absorption refriger-ation system to air-condition an ordinary passenger car. The theoretical design is verified by a unit that is tested under both laboratory and road-test condi-tions. For the latter, the unit is installed in a Nissan 1400 truck and the results indicate a successful pro-totype and encouraging prospects for future devel-opment

Native Cyclodextrins as Complexation Agents for Pterostilbene: Complex Preparation and Characterization in Solution and in the Solid State

Pterostilbene (3,5-dimethoxy-4′-hydroxystilbene, PTB) is a natural dietary stilbene, occurring primarily in blueberries and Pterocarpus marsupium heartwood. The interest in this compound is related to its different biological and pharmacological properties, such as its antioxidant, anti-inflammatory, and anticarcinogenic activities and its capacity to reduce and regulate cholesterol and blood sugar levels. Nevertheless, its use in therapy is hindered by its low aqueous solubility; to overcome this limitation we studied the feasibility of the use of cyclodextrins (CDs) as solubility-enhancing agents. CDs are natural macrocyclic oligomers composed of α-d-glucose units linked by α-1,4 glycosidic bonds to form torus-shaped molecules, responsible for inclusion complex formation with organic molecules. In particular, the aim of this study was to evaluate the feasibility of complexation between PTB and native CDs using various preparative methods. The isolated solid products were characterized using differential scanning calorimetry (DSC), simultaneous thermogravimetric/DSC analysis (TGA/DSC), Fourier transform infrared (FT-IR) spectroscopy, and X-ray diffraction (XRD) on powder and single crystals. The results indicated little or no evidence of the affinity of PTB to complex with α-CD using the kneading method. However, with β-CD and γ-CD thermal analysis revealed an interaction which was also corroborated by FT-IR and 1H-NMR spectroscopy. With β-CD, a hydrated complex of PTB was isolated and its characterization by single-crystal XRD revealed, for the first time, the mode of inclusion of the PTB molecule in the cavity of a CD. To complement the solid-state data, liquid-phase studies were carried out to establish the effect of CDs on the aqueous solubility of PTB and to determine the complex stoichiometries and the association constants for complex formation. Phase-solubility studies showed AL-type profiles for α- and β-CD and a BS profile for γ-CD, with K1:1 values of 1144, 4950, and 133 M−1 for α-CD·PTB, β-CD·PTB, and γ-CD·PTB, respectively. The stoichiometry of CD·PTB complexes, determined by Job’s method, revealed for each system a 1:1 molar ratio. The dissolution rate of PTB was approximately doubled just by employing simple physical mixtures, but the best performance was achieved by products obtained via kneading and co-precipitation, which effected the complete dissolution of PTB in 40 and 20 min for β-CD and γ-CD, respectively

Aqueous Solution Equilibria and Spectral Features of Copper Complexes with Tripeptides Containing Glycine or Sarcosine and Leucine or Phenylalanine

Copper(II) complexes of glycyl-L-leucyl-L-histidine (GLH), sarcosyl-L-leucyl-L-histidine (Sar-LH), glycyl-L-phenylalanyl-L-histidine (GFH) and sarcosyl-L-phenylalanyl-L-histidine (Sar-FH) have potential anti-inflammatory activity, which can help to alleviate the symptoms associated with rheumatoid arthritis (RA). From pH 2–11, the MLH, ML, MLH-1 and MLH-2 species formed. The combination of species for each ligand was different, except at the physiological pH, where CuLH-2 predominated for all ligands. The prevalence of this species was supported by EPR, ultraviolet-visible spectrophotometry, and mass spectrometry, which suggested a square planar CuN4 coordination. All ligands have the same basicity for the amine and imidazole-N, but the methyl group of sarcosine decreased the stability of MLH and MLH-2 by 0.1–0.34 and 0.46–0.48 log units, respectively. Phenylalanine increased the stability of MLH and MLH-2 by 0.05–0.29 and 1.19–1.21 log units, respectively. For all ligands, 1H NMR identified two coordination modes for MLH, where copper(II) coordinates via the amine-N and neighboring carbonyl-O, as well as via the imidazole-N and carboxyl-O. EPR spectroscopy identified the MLH, ML and MLH-2 species for Cu-Sar-LH and suggested a CuN2O2 chromophore for ML. DFT calculations with water as a solvent confirmed the proposed coordination modes of each species at the B3LYP level combined with 6-31++G**