Amorphous Solid Forms of Ranolazine and Tryptophan and Their Relaxation to Metastable Polymorphs.

Different methods were explored for the amorphization of ranolazine, a sparingly soluble anti-anginal drug, such as mechanochemistry, quench-cooling, and solvent evaporation from solutions. Amorphous phases, with Tg values lower than room temperature, were obtained by cryo-milling and quench-cooling. New forms of ranolazine, named II and III, were identified from the relaxation of the ranolazine amorphous phase produced by cryo-milling, which takes place within several hours after grinding. At room temperature, these metastable polymorphs relax to the lower energy polymorph I, whose crystal structure was solved in this work for the first time. A binary co-amorphous mixture of ranolazine and tryptophan was produced, with three important advantages: higher glass transition temperature, increased kinetic stability preventing relaxation of the amorphous to crystalline phases for at least two months, and improved aqueous solubility. Concomitantly, the thermal behavior of amorphous tryptophan obtained by cryo-milling was studied by DSC. Depending on experimental conditions, it was possible to observe relaxation directly to the lower energy form or by an intermediate metastable crystalline phase and the serendipitous production of the neutral form of this amino acid in the pure solid phase.

Introduction to Pharmaceutical Co-amorphous Systems Using a Green Co-milling Technique.

The concept of co-amorphous systems is introduced in an integrated laboratory experiment, designed for advanced chemistry students, using solvent-free, environmentally friendly mechanochemistry. The dual-drug naproxen-cimetidine co-amorphous system (NPX-CIM) is investigated as an example of the emergent field of medicinal mechanochemistry. Students are trained in solid-state characterization techniques including X-ray powder diffraction, Fourier-transform infrared spectroscopy, and thermal analysis by differential scanning calorimetry. This lab experiment also provides an opportunity to discuss the relevance of different solid forms of pharmaceutics, emphasizing particular properties of disordered materials. This experiment can easily fit the curriculum of any Chemistry or Pharmacy master level degree in courses dealing with instrumental analysis, solid state chemistry, or green chemistry, for classes of 6 to 18 students, in a 5-h lab session. Suggestions to adapt it to the use of a single characterization technique are provided.

Dual Photochemistry of Benzimidazole.

Monomers of benzimidazole trapped in an argon matrix at 15 K were characterized by vibrational spectroscopy and identified as 1H-tautomers exclusively. The photochemistry of matrix-isolated 1H-benzimidazole was induced by excitations with a frequency-tunable narrowband UV light and followed spectroscopically. Hitherto unobserved photoproducts were identified as 4H- and 6H-tautomers. Simultaneously, a family of photoproducts bearing the isocyano moiety was identified. Thereby, the photochemistry of benzimidazole was hypothesized to follow two reaction pathways: the fixed-ring and the ring-opening isomerizations. The former reaction channel results in the cleavage of the NH bond and formation of a benzimidazolyl radical and an H-atom. The latter reaction channel involves the cleavage of the five-membered ring and concomitant shift of the H-atom from the CH bond of the imidazole moiety to the neighboring NH group, leading to 2-isocyanoaniline and subsequently to the isocyanoanilinyl radical. The mechanistic analysis of the observed photochemistry suggests that detached H-atoms, in both cases, recombine with the benzimidazolyl or isocyanoanilinyl radicals, predominantly at the positions with the largest spin density (revealed using the natural bond analysis computations). The photochemistry of benzimidazole therefore occupies an intermediate position between the earlier studied prototype cases of indole and benzoxazole, which exhibit exclusively the fixed-ring and the ring-opening photochemistries, respectively.

Dihydrofolate Reductase Inhibitors: The Pharmacophore as a Guide for Co-Crystal Screening.

In this work, co-crystal screening was carried out for two important dihydrofolate reductase (DHFR) inhibitors, trimethoprim (TMP) and pyrimethamine (PMA), and for 2,4-diaminopyrimidine (DAP), which is the pharmacophore of these active pharmaceutical ingredients (API). The isomeric pyridinecarboxamides and two xanthines, theophylline (THEO) and caffeine (CAF), were used as co-formers in the same experimental conditions, in order to evaluate the potential for the pharmacophore to be used as a guide in the screening process. In silico co-crystal screening was carried out using BIOVIA COSMOquick and experimental screening was performed by mechanochemistry and supported by (solid + liquid) binary phase diagrams, infrared spectroscopy (FTIR) and X-ray powder diffraction (XRPD). The in silico prediction of low propensities for DAP, TMP and PMA to co-crystallize with pyridinecarboxamides was confirmed: a successful outcome was only observed for DAP + nicotinamide. Successful synthesis of multicomponent solid forms was achieved for all three target molecules with theophylline, with DAP co-crystals revealing a greater variety of stoichiometries. The crystalline structures of a (1:2) TMP:THEO co-crystal and of a (1:2:1) DAP:THEO:ethyl acetate solvate were solved. This work demonstrated the possible use of the pharmacophore of DHFR inhibitors as a guide for co-crystal screening, recognizing some similar trends in the outcome of association in the solid state and in the molecular aggregation in the co-crystals, characterized by the same supramolecular synthons.

Vibrationally Induced Conformational Isomerization and Tunneling in Pyrrole-2-Carboxylic Acid.

The conformational behavior of carboxylic acids has attracted considerable attention, as it can be used as a gateway for the study of more complex phenomena. Here, we present an experimental and computational study of pyrrole-2-carboxylic acid (PCA) conformational space and the vibrational characterization of the compound by infrared spectroscopy. The possibility of promoting conformational transformations using selective vibrational excitation of the 2ν(OH) and 2ν(NH) stretching overtones is explored. Two conformers, exhibiting the cis configuration of the COOH group (O═C-O-H dihedral angle near 0°) and differing by the orientation of the carboxylic group with respect to the pyrrole ring (i.e., showing either a cis or a trans NCC═O arrangement), were found to coexist initially for the compound isolated in a cryogenic nitrogen matrix, in an 86:14 ratio, and were characterized by infrared spectroscopy. A third conformer, with the COOH group in the trans configuration, was produced, in situ, by narrowband near-infrared (NIR) excitation of the most stable PCA form (with a cis NCC═O moiety). The photogenerated PCA conformer was found to decay back to the most stable PCA form, by H-atom quantum mechanical tunneling, with a characteristic half-life time of ∼10 min in the nitrogen matrix at 10 K. Tunneling rates were theoretically estimated and compared for the observed isomerization of pyrrole-2-carboxylic acid and for the structurally similar furan-2-carboxylic acid. This comparison showcases the effect of small modifications in the potential energy surface and the implications of quantum tunneling for the stability of short-living species.

UV-induced radical formation and isomerization of 4-methoxyindole and 5-methoxyindole.

Monomers of 4-methoxyindole and 5-methoxyindole trapped in low-temperature xenon matrices (15-16 K) were characterized by IR spectroscopy, in separate experiments. Each compound was shown to adopt the most stable 1H-tautomeric form. The photochemistry of the matrix-isolated compounds was then investigated by exciting the matrices with narrowband UV light with λ ≤ 305 nm. Two main photoproducts, similar for each compound, have been detected: (1) 4-methoxy- or 5-methoxy-indolyl radical, resulting from cleavage of the N-H bond; (2) 3H-tautomers (4-methoxy- or 5-methoxy-) with the released hydrogen atom reconnected at the C3 ring carbon atom. The presence of the two types of photoproducts in the UV-irradiated matrices was confirmed by comparison of their B3LYP/6-311++G(d,p) calculated IR spectra with the experimental spectra emerging upon the irradiations. The mechanism of the observed phototransformations was elucidated by Natural Bond Orbital and Natural Resonance Theory computations on the methoxy-substituted indolyl radicals resulting from the N-H bond cleavage. The highest natural atomic spin densities were predicted at the C3 and N1 positions of the indolyl ring, corresponding to a predominance of the resonance structures with the radical centres located at these two atoms. As a whole, the obtained experimental and theoretical data allowed establishing a general pattern for the photochemistry of methoxyindoles under matrix-isolation conditions.

Synthesis of new metalloporphyrin triads: efficient and versatile tripod optical sensor for the detection of amines.

Zinc and manganese complexes of porphyrin triads have been synthesized and are shown to be efficient as highly sensitive and selective tripod optical sensors for amines at the picomolar level.

Conformational cooling dynamics in matrix-isolated 1,3-butanediol.

The complete conformational space of monomeric 1,3-butanediol has been characterized theoretically, and 73 unique stable conformers were found at the MP2/6-311++G(d,p) level. These were classified into nine families whose members share the same heavy atom backbone configurations and differ in the hydrogen atom orientations. The first and third most populated backbone families are governed by the formation of an intramolecular hydrogen bond; however, the second precludes this type of interaction and was frequently overlooked in previous studies. Its stability is determined by the relatively high entropy of its main conformers. The hydrogen bonding of four of the most important conformers was characterized by means of atoms in molecules (AIM, also known as QTAIM) and natural bond orbital (NBO) analyses. Using appropriate isodesmic reactions, hydrogen bonding energy stabilizations of 12-14 kJ mol(-1) have been found. Experimentally, monomeric molecules of 1,3-butanediol were isolated in low-temperature inert matrixes, and their infrared spectra were analyzed from the viewpoint of the conformational distribution. All the relevant transition states for the conformational interconversion reaction paths were characterized at the same level of theory to interpret the conformational cooling dynamics observed in the low-temperature matrixes. The energy barriers for rotation of the OH groups were calculated to be very low (<3 kJ mol(-1)). These barriers were overcome in the experiments at 10 K (Ar matrix), in the process of matrix deposition, and population within each family was reduced to the most stable conformers. Further increase in the substrate temperature (up to 40 K, Xe matrix) resulted in conformational cooling where the medium-height barriers (approximately 13 kJ mol(-1)) could be surmounted and all conformational population converted to the ground conformational state. Remarkably, this state turned to consist of two forms of the most stable hydrogen bonded family, which were predicted by calculations to be accidentally degenerated and were found in the annealed matrix in equal amounts. All of these experimentally observed conformational cooling processes were analyzed and supported by full agreement with the theoretical calculations.

Structure of isolated 1,4-butanediol: combination of MP2 calculations, NBO analysis, and matrix-isolation infrared spectroscopy.

Theoretical calculations at the MP2 level, NBO and AIM analysis, and matrix-isolation infrared spectroscopy have been used to investigate the structure of the isolated molecule of 1,4-butanediol (1,4-BDO). Sixty-five structures were found to be minima on the potential energy surface, and the three most stable forms are characterized by a folded backbone conformation leading to the formation of an intramolecular H-bond. To better characterize the intramolecular interactions and particularly the hydrogen bonds, natural bond orbital analysis (NBO) was performed for the four most stable conformers, and was further complemented with an atoms-in-molecules (AIM) topological analysis. Infrared spectra of 1,4-BDO isolated in low-temperature argon and xenon matrixes show a good agreement with a population-weighted mean theoretical spectrum, and the spectral features of the conformers expected to be trapped in the matrixes were observed experimentally. Annealing the xenon matrix from 20 to 60 K resulted in significant spectral changes, which were interpreted based on the barriers to intramolecular rotation. An estimation of the intramolecular hydrogen bond energy was carried out following three different methodologies.

Hydration of cyclohexylamines: CPCM calculation of hydration Gibbs energy of the conformers.

This work presents a theoretical study on the hydration of cyclohexylamine and isomers of cyclohexyldiamine. All possible conformers were fully optimized in solution using the conductor-like polarizable continuum model (CPCM) and density functional theory. Values of the Gibbs energy of solvation, its respective contributions (electrostatic, nonelectrostatic and conformational change), and the relative Gibbs energy of the conformers in aqueous solution and gas phase are reported. From these values and the Boltzmann populations of the conformers in both phases, the weighted mean values of DeltaG(solv) for the compounds are calculated. Three structural features were found to be important for the hydration of these compounds: the distance between the two NH2 groups (proximity disfavors hydration), their position relative to the ring (equatorial is preferred over axial), and the orientation of the nitrogen lone-pairs (gauche is more favorable to hydration than trans). In the particular case of vicinal cyclohexyldiamines, in addition to these two factors, the relative orientation of one group to the other should also be taken into account.

Conformational study of monomeric 2,3-butanediols by matrix-isolation infrared spectroscopy and DFT calculations.

The FT-IR spectra of two diastereomers of 2,3-butanediol, (R,S) and (S,S), isolated in low-temperature argon and xenon matrixes were studied, allowing the identification of two different conformers for each compound. These conformers were characterized by a +/-gauche arrangement around the O-C-C-O dihedral angle, thus enabling the establishment of a very weak intramolecular hydrogen bond of the O...H-O type. No other forms of these compounds were identified in matrixes, despite the fact that these four conformers had calculated relative energies from 0 to 5.1 kJ mol(-1) and were expected to be thermally populated from 50 to 6% in the gaseous phase of each compound. The nonobservation of additional conformers was explained in terms of low barriers to intramolecular rotation, resulting in the conformational relaxation of the compounds during deposition of the matrixes. The barriers to internal rotation of the OH groups were computed to be less than 4 kJ mol(-1) and are easily overcome in matrixes within the family of conformers with the same heavy atom backbone. The barriers for intramolecular rearrangement of the O-C-C-O dihedral angle in both diastereomers were calculated to range from 20 to 30 kJ mol(-1). Interconversions between the latter conformers were not observed in matrixes, even after annealing up to 65 K. Energy calculations, barriers, and calculated infrared spectra were carried out at the DFT(B3LYP)/6-311++G theory. Additional MP2/6-311++G calculations of energies and vibrational frequencies were performed on the most relevant conformers. Finally, independent estimations of the hydrogen-bond enthalpy in the studied molecules were also obtained based on theoretical structural data and from vibrational frequencies (using well-established empirical correlations). The obtained values for -DeltaH for both diastereomers of 2,3-butanediol amount to ca. 6-8 kJ mol(-1).

Stepwise conformational cooling towards a single isomeric state in the four internal rotors system 1,2-butanediol.

The present work explores the possibilities of the matrix isolation technique in the structural characterisation of highly flexible molecules. To date, most studies of this type were carried out on molecules with three or less internal degrees of freedom and a few (less than 10) possible conformations. The molecule of 1,2-butanediol has four conformationally relevant three-fold rotational axes, which can result in 81 possible conformations. A detailed theoretical study, at the MP2 and DFT(B3LYP) levels of theory with the 6-311 + + G(d,p) basis set, revealed that more than 20 conformers of 1,2-butanediol have relative energies in a 0-10 kJ mol(-1) range and contribute appreciably to the gas phase equilibrium at room temperature. This fact renders conformational studies of the system extremely difficult under normal conditions. However, the method of matrix isolation permits the reduction of the number of populated conformational states in the experiment at low temperature due to the effect known as conformational cooling: low energy barriers promote the relaxation of the higher energy local minima into more stable structures. As a result of massive conformational cooling occurring upon matrix deposition, only five conformers of 1,2-butanediol were retained in the samples at 10 K. These conformers were identified using a combination of FTIR spectroscopy and extensive theoretical calculations of vibrational spectra. Annealing of the matrices up to 50 K resulted in the extreme case of conformational cooling related with the depopulation of all conformers into the most stable unique structure. The observed transformations were rationalized in terms of barriers to intramolecular rotation.