L. A. E. Batista de Carvalho

s-cis and s-trans Conformers of formic, thioformic and dithioformic acids. An ab initio study

Ab initio SCF-MO calculations have been carried out for formic, thioformic and dithioformic acids using the 6–31G* basis set. Fully optimized geometries, atomic charges, relative stabilities and harmonic force fields for s-cis and s-trans conformers of these molecules have been determined and the effects of oxygen-by-sulphur substitution analysed. A realistic description of the molecular charge distribution can be reached by introducing a quantum-mechanical correction to the Mulliken atomic charges, derived from the ‘charge’-‘charge flux’-‘overlap’(CCFO) model. Unlike reported theoretical results, the present ab initio calculations yield relative stabilities of the thioformic acid conformers in agreement with experiment [s-cis(thiol) > s-trans(thiol) > s-cis(thione) > s-trans(thione)]. The success of these ab initio calculations should be partially ascribed to the inclusion of polarization functions on all non-hydrogen atoms.

Role of Cellulose Ether Polymers on Ibuprofen Release from Matrix Tablets

Cellulose derivatives are the most frequently used polymers in formulations of pharmaceutical products for controlled drug delivery. The main aim of the present work was to evaluate the effect of different cellulose substitutions on the release rate of ibuprofen (IBP) from hydrophilic matrix tablets. Thus, the release mechanism of IBP with methylcellulose (MC25), hydroxypropylcellulose (HPC), and hydroxypropylmethylcellulose (HPMC K15M or K100M) was studied. In addition, the influence of the diluents lactose monohydrate (LAC) and β-cyclodextrin (β-CD) was evaluated. Distinct test formulations were prepared containing: 57.14% of IBP, 20.00% of polymer, 20.29% of diluent, 1.71% of talc lubricants, and 0.86% of magnesium stearate as lubricants. Although non-negligible drug-excipient interactions were detected from DSC studies, these were found not to constitute an incompatibility effect. Tablets were examined for their drug content, weight uniformity, hardness, thickness, tensile strength, friability, porosity, swelling, and dissolution performance. Polymers MC25 and HPC were found to be unsuitable for the preparation of this kind of solid dosage form, while HPMC K15M and K100M showed to be advantageous. Dissolution parameters such as the area under the dissolution curve (AUC), the dissolution efficiency (DE20 h), dissolution time (t 50%), and mean dissolution time (MDT) were calculated for all the formulations, and the highest MDT values were obtained with HPMC indicating that a higher value of MDT signifies a higher drug retarding ability of the polymer and vice-versa. The analysis of the drug release data was performed in the light of distinct kinetic mathematical models—Kosmeyer-Peppas, Higuchi, zero-, and first-order. The release process was also found to be slightly influenced by the kind of diluent used.

CONFORMATIONAL STUDY OF 1,2-DIAMINOETHANE BY COMBINED AB INITIO MO CALCULATIONS AND RAMAN SPECTROSCOPY

Abstract A conformational analysis of the linear polyamine 1,2-diaminoethane was performed by both Raman spectroscopy and ab initio SCF-MO methods (with and without inclusion of water solvent effects). Ten different conformers were detected by ab initio calculations, the most stable ones being TGG′ and GGG′. When considering the solvent, the conformations having a higher dipole moment were found to be favoured over the less polar ones. The Raman spectra of this amine obtained for the pure liquid, the aqueous solution and the solid sample, allowed to conclude that its conformational preferences are determined by the relative importance of intra- versus intermolecular hydrogen bonds.

Influence of Cellulose Ether Mixtures on Ibuprofen Release: MC25, HPC and HPMC K100M

The influence of cellulose ether derivatives on ibuprofen release from matrix tablets was investigated. Raman spectroscopy and differential scanning calorimetry (DSC) experiments were used, in order to examine the compatibility between the matrix components: both excipients and ibuprofen. While both the DSC and Raman results did not detect any incompatibilities, DSC revealed the existence of some drug:excipient interactions, reflected by variations in the hydration/dehydration processes. Formulations containing mixtures of polymers with both low and high viscosity grades—methylcellulose (MC25) or hydroxypropylcellulose (HPC), and hydroxypropylmethylcellulose (HPMC K100M), respectively—were prepared by a direct compression method (using 20, 25, and 30% of either MC25 or HPC). The tablets were evaluated for their drug content, weight uniformity, hardness, thickness, tensile strength, friability, porosity, surface area, and volume. Parameters such as the mean dissolution time (MDT) and the dissolution efficiency (DE) were calculated in all cases. The solid formulations presently studied demonstrated a predominantly Fickian diffusion release mechanism.

Molecular structure and properties of thioacetic acid

Abstract Ab initio SCF-MO calculations have been carried out for thioacetic acid using the 3–21G and 4–31G basis sets. Energies and structures of several conformations of the two tautomeric forms of this molecule (the thiol and thion forms) determined by gradient geometry refinement are reported, and some conformationally dependent local geometry trends discussed. The results are compared with available data on acetic and dithioacetic acids in order to assess the effects of the substitution of oxygen by sulphur on molecular properties. It is shown that the O(H)→S(H) substitution originates important changes in the molecular properties, which can be correlated with the greater conjugating ability of the oxygen atom. On the other hand, the calculations indicate that the O=→S=substitution causes minor changes in the relative conformational energies, although other properties may be significantly affected. Charges on atoms, dipole moments and ionization potentials are also presented and compared with the available experimental values.

A comparative ab initio MO study of internal rotations in ethylamine and n-propylamine

Abstract A comparative ab initio study of the internal rotations in ethylamine and n-propylamine using a 3-21G(N * ) basis set and fully optimized geometries is presented. For n-propylamine, the NH 2 rotation about the :N-C bond, for a trans skeleton, and the rotations about the C1-C2 bond, for trans and gauche orientations of the nitrogen lone pair, are considered.

Conformational studies by Raman spectroscopy and statistical analysis of gauche interactions in n-butylamine

Abstract Raman spectra of n -butylamine recorded at different temperatures show pairs of bands whose temperature-dependent intensities clearly suggest their assignment to different conformers in simultaneous equilibria. Normal coordinate analysis and i.r. spectra of n -butylamine are also used to assign the spectra. These vibrational data are interpreted and correlated with structural information obtained from a statistical analysis of gauche skeletal arrangements in n -butylamine at different temperatures.

Conformational studies of n-propylamine by combined ab initio MO calculations and Raman spectroscopy

Abstract The results of ab initio SCF-MO calculations performed with a 3-21G(N*) basis set, for fully optimized geometries of five conformations of n -propylamine, are presented. The calculated relative order of total energies for these conformers is TT≈GG′>TG>GT>GG. At 300 K, the Boltzmann distribution of populations is 18, 37, 20, 19 and 7%, respectively. Raman spectra of n -propylamine and n -propylamine-N- d 2 in the liquid phase exhibit a number of bands whose temperature-dependent intensities clearly suggest the occurrence of different conformers in simultaneous equilibria. Deuteration of the amine group originates pairs of Raman bands at 428 and 440 cm −1 and at 863 and 885 cm −1 . The bands at 428 and 885 cm −1 are favoured by reduction of temperature. Normal coordinate calculations permit the assignment of the Raman and i.r. spectra in good agreement with experimental evidence. Among the five possible conformers of n -propylamine, it is possible to detect the presence of at least three conformations in the liquid phase, corresponding to the skeletal trans (TT and GT) and at least one of the skeletal gauche (TG, GG or GG′) forms. In the solid phase, only the bands ascribed to the TT form were observed. The ab initio results for the isolated molecule show that the all- trans conformation, TT, and the conformation GG′ have the smallest energies. On the other hand, the vibrational results for the liquid and solid phases indicate that the all- trans conformation, TT, is the more populated form. In addition, this conformer presents the highest calculated dipole moment, in good agreement with the liquid phase Raman spectroscopic results which point out that this conformation is favoured by polar solvents. Intermolecular interactions operating in the liquid n -propylamine, possibly of the hydrogen bonding type, are responsible for altering the relative order of conformational stability as predicted by the ab initio SCF-MO results for the isolated molecule.

A molecular mechanics force field for conformational analysis of aliphatic acyclic amines

An improved molecular mechanics force field for conformational and vibrational studies of aliphatic acyclic amines is developed. The resulting force field reproduces molecular structures adequately and provides a good fit for energy differences between conformers and barriers to internal rotation for a large number of amines. In addition, vibrational frequencies are calculated in good agreement with available experimental data. When compared with existent force fields for amines, the present force field is considerably more simple and gives rise to calculated properties in closer agreement with experiment.

Determination of preferred conformations of ibuprofen in chloroform by 2D NOE spectroscopy

Solution of an anti-inflammatory drug ibuprofen ((RS)-2-(4-isobutylphenyl) propionic acid) in chloroform was studied by nuclear magnetic resonance spectroscopy. A set of 2D NOESY spectra was analyzed in order to obtain atom-atom distances. Since ibuprofen is known to exist as an ensemble of different conformations, these distances are averaged over the ensemble. To compare experimental and calculated distances, three models of averaging were concerned. Our data allowed to determine the dominant conformers of ibuprofen dissolved in chloroform. The population of conformers in the saturated solution leads to a certain crystal morphology formed within the nucleation process. Observed and calculated (13)C chemical shifts (at the DFT/B3LYP/6-311+G(2d,p) level) were in good agreement.