Determination of preferred conformations of ibuprofen in chloroform by 2D NOE spectroscopy (original) (raw)
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Journal of Pharmaceutical Sciences, 2008
A thorough conformational analysis of ibuprofen [2-(4-isobutylphenyl) propionic acid] was carried by out, using density functional theory (DFT) calculations coupled to optical vibrational spectroscopy (both Raman and FTIR). Eight different geometries were found to be energy minima. The relative orientations of the substituent groups in the ibuprofen molecule, which can be considered as a para-substituted phenyl ring, were verified to hardly affect its conformational stability. The internal rotations converting the calculated conformers of ibuprofen were studied and the intramolecular interactions governing the conformational preferences of the molecule were analyzed by quantitative potential energy deconvolution using Fourier type profiles. The harmonic vibrational frequencies and corresponding intensities were calculated for all the conformers obtained, leading to the assignment of the spectra, and evidencing the sole presence of one of the lowest energy conformers in the solid state. Vibrational spectroscopic proof of intermolecular hydrogen bonds between the carboxylic groups of adjacent ibuprofen molecules, leading to the formation of dimers, was also obtained.
Chirality, 2007
In this work, we describe an NMR-based method that utilizes an orientation media composed of the chiral polypeptide liquid crystal poly-g-benzyl-L-glutamate (PBLG) dissolved in CDCl 3 , to measure the 1 H-1 H, 1 H-13 C and 13 C-13 C residual dipolar couplings (RDCs) of (R) and (S)-ibuprofen. Calculated RDCs, obtained from the lowest energy conformers, are then compared with the experimentally measured RDCs to predict the stereochemistry of each enantiomer. Excellent agreement between calculated and experimental RDCs was found when the lowest energy structure of each enantiomer, obtained in a simulated PBLG/CDCl 3 environment, was used to back-calculate the RDCs. This method is generally useful for small molecular weight molecules that possess either one or two chiral centers, are soluble in low viscosity organic solvents, and will not crystallize (Clegg, Crystal Structure Analysis. Principles and Practice. New York: Oxford University Press; 2002) or cannot be derivatized with a Mosher's reagent (Dale and Mosher, J Am Chem Soc 1973;95:512-519). Chirality 19:741-750, 2007. V V C 2006 Wiley-Liss, Inc.
Pharmaceutical Research, 2005
Purpose. The aim of this study was to investigate, at a molecular level, the structural and dynamic properties of the acidic and sodium salt forms of ibuprofen and their solid dispersions with Eudragit RL-100, obtained by two different preparation methods (physical mixtures and coevaporates), which may affect the release properties of these drugs in their dispersed forms. Methods. 1 H and 13 C high-resolution solid-state nuclear magnetic resonance techniques, including single-pulse excitation magic-angle spinning, cross-polarization magic-angle spinning, and other selective 1D spectra, as well as more advanced 2D techniques Frequency Switched Lee-Goldburg HETeronuclear CORrelation (FSLG-HETCOR) and Magic Angle Spinning -J-Heteronuclear Multiple-Quantum Coherence (MAS-J-HMQC) and relaxation time measurements were used. Results. A full assignment of 13 C resonances and precise 1 H chemical shift values were achieved for the first time for the two forms of ibuprofen that showed very different interconformational dynamic behavior; drug-polymer interactions were observed and characterized in the coevaporates of the two forms but were much stronger for the acidic form. Conclusions. A combined analysis of several high-resolution solid-state nuclear magnetic resonance experiments allowed the investigation of the structural and dynamic properties of the pure drugs and of the solid dispersions with the polymer, as well as of the degree of mixing between drug and polymer and of the chemical nature of their interaction. Such information could be related to the in vitro drug release profiles observed for the tested coevaporates.
Linear models for prediction of ibuprofen crystal morphology based on hydrogen bonding propensities
Fluid Phase Equilibria, 2009
Solvents have a significant impact on the final crystal form of organic solids during solution crystallization. The use of polarity scales such as Hildebrand solubility parameter and dielectric constant for solvent selection often proves too generalized and do not provide enough insights into the solvent-solute intermolecular interactions directly affecting crystal growth and morphology. This paper addresses the challenging task of selecting an appropriate single component solvent property index that most accurately and sufficiently characterizes crystal morphology. Cooling crystallization experiments were carried out in a wide range of solvents using ibuprofen as a model pharmaceutical compound. Subsequently, optical microscope images were used for quantitative characterization of morphology. Linear models that correlate ibuprofen crystal morphology with pure solvent properties were developed. Our results show that, in general, there is a negative linear correlation between crystal aspect ratio (morphology) and a given solvent index. Some correlations revealed significant deviations which were explained with the help of infrared spectroscopic measurements. The "acceptance number" was identified as an index that significantly captures the ibuprofen-solvent hydrogen bonding intermolecular interactions. Predictions, using model based on acceptance number, were found to compare very well with experimentally determined aspect ratio data from the open literature. Finally, based on insights gained from this work, a flowchart which serves as a useful solvent selection guideline for crystallization of ibuprofen is proposed.
Cloud point, fluorimetric and 1H NMR studies of ibuprofen-polymer systems
Journal of Molecular Structure, 2014
h i g h l i g h t s Much interest has been shown on interactions between amphiphilic drugs and polymers in a variety of fields, such as pharmaceuticals and bioscience. The 1 H NMR spectroscopy was used in the present investigation to probe the molecular investigation between ibuprofen and polymers. Aggregation number depends strongly on polymer percentage. g r a p h i c a l a b s t r a c t Average aggregation numbers of the total ensemble of ibuprofen micelles formed in solution, N agg , as a function of the polymer percentage.
Journal of Crystal Growth, 2017
, which was generated from ibuprofen molecule by molecular simulation. The predicted crystal structures of ibuprofen with space group P2 1 /c has the lowest total energy and the largest density, which is nearly indistinguishable with experimental result. In addition, the XRD patterns for predicted crystal structure are highly consistent with recrystallization from solvent of ibuprofen. That indicates that the simulation can accurately predict the crystal structure of ibuprofen from the molecule. Furthermore, based on this crystal structure, we predicted the crystal habit in vacuum using the attachment energy (AE) method and considered solvent effects in a systematic way using the modified attachment energy (MAE) model. The simulation can accurately construct a complete process from molecule to crystal structure to morphology prediction. Experimentally, we observed crystal morphologies in four different polarity solvents compounds (ethanol, acetonitrile, ethyl acetate, and toluene). We found that the aspect ratio decreases of crystal habits in this ibuprofen system were found to vary with increasing solvent relative polarity. Besides, the modified crystal morphologies are in good agreement with the observed experimental morphologies. Finally, this work may guide computer-aided design of the desirable crystal morphology.
Pharmaceutical Research, 2006
Purpose. Investigation of the conformational and molecular dynamic properties of the acidic and sodium salt forms of Flurbiprofen and their solid dispersions with Eudragit \ RL100, obtained by two different preparation methods (physical mixtures and coevaporates), and of the mixing degree between the two components in the dispersions. Materials and Methods. 1 H and 13 C high-resolution solid state NMR techniques, including Single Pulse Excitation-MAS, CP-MAS, FSLG-HETCOR; low-resolution 1 H FID analysis; 1 H spin-lattice relaxation time measurements. Results. Conformational, molecular packing and dynamic differences were observed between the two pure forms of flurbiprofen, as well as between the pure drugs and the corresponding coevaporates. In the coevaporates of the two flurbiprofen forms, drug and polymer appear intimately mixed; their chemical interactions were detected and characterized. Conclusions. A combined analysis of several 13 C and 1 H high-and low-resolution solid state NMR experiments allowed the investigation of the conformational and dynamic properties of the pure drugs and of the solid dispersions with the polymer, as well as of the degree of mixing between drug and polymer and of the chemical nature of their interaction. Such information could be compared to the in vitro drug release profiles given by these solid dispersions.
Journal of Chemical Physics, 2018
In this paper, the molecular dynamics of a series of ester derivatives of ibuprofen (IBU), in which the hydrogen atom from the hydroxyl group was substituted by the methyl, isopropyl, hexyl, and benzyl moieties, has been investigated using Broadband dielectric (BD), Nuclear magnetic resonance (NMR), and Raman spectroscopies. We found that except for benzyl IBU (Ben-IBU), an additional process (slow mode, SM) appears in dielectric spectra in all examined compounds. It is worth noting that this relaxation process was observed for the first time in non-modified IBU (a Debye relaxation). According to suggestions by Affouard and Correia [J. Phys. Chem. B. 114, 11397 (2010)] as well as further studies by Adrjanowicz et al. [J. Chem. Phys. 139, 111103 (2013)] on Met-IBU, it was attributed to synperiplanar-antiperiplanar conformational changes within the molecule. Herein, we have shown that with an increasing molecular weight of the substituent, the relaxation times of the SM become longer and its activation energy significantly increases. Moreover, this new relaxation mode was found to be broader than a simple Debye relaxation in Iso-IBU and Hex-IBU. Additional complementary NMR studies indicated that either there is a significant slowdown of the rotation around the O= =C− −O− −R moiety or this kind of movement is completely suppressed in the case of Ben-IBU. Therefore, the SM is not observed in the dielectric loss spectra of this compound. Finally, we carried out isothermal experiments on the samples which have a different thermal history. Interestingly, it turned out that the relaxation times of the structural processes are slightly shorter with respect to those obtained from temperature dependent measurements. This effect was the most prominent in the case of Hex-IBU, while for Ben-IBU, it was not observed at all. Additional time-dependent measurements revealed the ongoing equilibration manifested by the continuous shift of the structural process, until it finally reached its equilibrium position. Further Raman investigations showed that this effect may be related to the rotational/conformational equilibration of the long hexyl chains. Our results are the first ones demonstrating that the structural process is sensitive to the conformational equilibration occurring in the specific highly viscous systems.
Journal of molecular …, 2006
Mid-, far-infrared, and Raman vibrational spectra of Ibuprofen [2-(4-isobutylphenyl) propionic] acid, Naproxen [6-methoxy-a-methyl-2naphthalene acetic] acid and Tolmetin [1-methyl-5-(4-methylbenzoyl)-1H-pyrrole-2-acetic] acid have been measured at room and low temperatures and analyzed by means of ab initio calculations. The conformational space of these compounds has been scanned using molecular dynamics and complemented with functional density calculations that optimize the geometry of the lowest-energy conformers of each species as obtained in the simulations. The vibrational frequencies were assigned using functional density calculations. The Molecular Electrostatic Potential Maps were obtained and analyzed and the corresponding topological study was performed in the Bader's theory (atoms in molecules) framework.