L-Leucine is an essential amino acid which has been focusing a lot of investigations on its phase transition sequence for more than fifty years. Combining Raman spectroscopy and X-ray diffraction experiments provides a new interpretation of the second order phase transition extending between 270 and 360 K as a displacive incommensurate-normal phase transition. A soft mode was clearly detected from low-frequency Raman investigations which exhibits the temperature dependence (A·(TC-T)1/2) typical of the temperature behavior of the amplitudon, an excitation specific to incommensurate phases. Simultaneously to the softening of the amplitudon, several very weakly intense X-ray reflections vanish upon heating at 360 K, and thereby are interpreted as satellite reflections. This incommensurability was described as resulting from the freezing of thermally activated hydrophobic side-chain rotations upon cooling in disordered orientations. Raman investigations were also performed on the isomeric amino acid L-norleucine previously identified as undergoing a normal-incommensurate phase transition around 200 K. Comparison of both studies suggests that the temperature behavior of thermally activated local motions generates lattice instabilities. Loss of periodicity can result from the freezing of rotations of molecular moieties in disordered orientations, or from the enhancement of anharmonicity of these rotations. This could be a general phenomenon in hydrophobic amino acids with direct consequences on their applications in the life science area.

The crystal structure of a new cocrystal of carbamazepine (systematic name: 5H-dibenzo[b,f]azepine-5-carboxamide, C15H12N2O) and DL-tartaric acid (C4H6O6), obtained by liquid-assisted grinding, was solved by powder X-ray diffraction (PXRD). The high-resolution PXRD pattern of this new phase was recorded at room temperature thanks to synchrotron experiments at the European Synchrotron Radiation Facility (Grenoble, France). The starting structural model was generated by a Monte-Carlo simulated annealing method. The final structure was obtained through Rietveld refinement and an energy minimization simulation was used to estimate the H-atom positions. The stability of the proposed structure as a function of temperature was also assessed from molecular dynamics simulations. The symmetry is monoclinic (space group P21/c) and contains eight molecules per unit cell, namely, four DL-tartaric acid and four carbamazepine molecules.

The mechanism of devitrification of racemic ibuprofen (RS-IBP, C13H18O2) was analyzed by low-wavenumber Raman spectroscopy (LWRS). This study shows the capabilities of LWRS to provide detailed new structural information, with respect to X-ray diffraction data, on the atypical crystallization process of a molecular material (RS-IBP) composed of a majority of hydrogen atoms. The conversions of Raman intensity into reduced intensity and Raman susceptibility were presented. The combination of these two types of spectrum representation reflecting the fast relaxational dynamics and the structural organization, respectively, has clearly revealed the high degree of disorder of Phase II. Additionally, Phase II was described as an early transient and metastable step of crystallization toward Phase I, from a deeply quenched liquid state. Analyzing the isothermal and nonisothermal crystallization has revealed two types of conversion of Phase II into Phase I, a solid-solid transformation and a crystallization of Phase I after melting of Phase II, respectively.

Two new crystalline polymorphs of the widely used antifungal drug griseofulvin (phases II and III), which originate from the crystallization of the melt, have been detected recently. The crystal structure of phase II of griseofulvin {systematic name: (2S,6'R)-7-chloro-2',4,6-trimethoxy-6'-methyl-3H,4'H-spiro[1-benzofuran-2,1'-cyclohex-2-ene]-3,4'-dione}, C17H17ClO6, has been solved by powder X-ray diffraction (PXRD). The PXRD pattern of this new phase was recorded at room temperature using synchrotron radiation. The starting structural model was generated by a Monte Carlo simulated annealing method. The final structure was obtained through Rietveld refinement with soft restraints for interatomic bond lengths and angles, except for the aromatic ring, where a rigid-body constraint was applied. The symmetry is orthorhombic (space group P212121) and the asymmetric unit contains two molecules.

Valsartan is an antihypertensive drug, recognized to be marketed in an amorphous state, different from that obtained by quenching the liquid state below Tg. This is an unusual and very original situation, given that the amorphous state is unstable. Low-wavenumber Raman spectroscopy and X-ray diffraction investigations were carried out on the various solid-state forms of valsartan. It was found that the marketed form is not amorphous and can be described in terms of mesophase in which the long-range order of the stable crystal is limited on the lengthscale of tens nanometers, inducing a melting temperature lower than that of the stable crystalline state, inherent to the crystallite size. This unusual physical state of a marketed drug was correlated to the relative population of cis–trans conformers, preventing the development of the hydrogen-bond network distinctive of the long-range order in the crystalline state.

In this work, three monomeric forms of arabinitol, usually named arabitol, and their dimeric species have been structural and vibrationally studied by using the micro-Raman spectra in the solid phase accomplished with theoretical calculations based on the theory of the functional of the density (DFT). The hybrid B3LYP method was used for all the calculations together with the 6-31G* and 6-311++g** basis sets. Two different L structures with minima energies were predicted in accordance to the two polymorphic structures revealed by recent X-ray diffraction experiments. The studies by natural bond orbital (NBO) calculations reveals high stabilities of the L form as compared with the D one but the topological properties by using the atoms in molecules (AIM) suggest a higher stability of the D form due to a strong H bond interactions. The scaled mechanical force fields (SQMFF) procedure was used to perform the complete vibrational assignments for the monomeric forms and their dimer. On the other hand, the similarity in the gap values computed for the three forms of arabitol with those observed for sucrose, trehalose, maltose and lactose in gas phase at the same level of theory could partially explain the sweetening property of this alcohol. In addition, the influences of the size of the basis set on some properties were evidenced.

Kinetics of isothermal crystallization of l-arabitol were analyzed from the undercooled liquid state within micron-sized droplets from micro-Raman spectroscopy. This study reveals that crystallization slightly above Tg is controlled by stochastic heterogeneous nucleation inherent to the droplet size. Microscopic Raman investigations performed in droplets give the unique opportunity to analyze the pure metastable Form II of l-arabitol. It was found that Form II is characterized by a molecular packing more compact than that of the stable Form I, inherent to strong intermolecular hydrogen bonding. Kinetics laws obtained by analyzing several droplets at different temperatures, reveal the transient character of Form II, quasi systematically detected during the crystallization process of form I. Form II appears as the first step of crystallization prior to successive short-living metastable states which is necessary to achieve a complete crystallization in Form I. It was found that the kinetics of conversion between the metastable states (Form II) into Form I is dependent on the amount of strong hydrogen bonding distinctive of Form II.

The physical state of amorphous powder obtained by cryomilling forms I and III of carbamazepine (CBZ) were analyzed from low-wavenumber Raman spectroscopy investigations and compared to that of the quenched liquid. This analysis has shown subtle structural modifications between the amorphous states prepared by melt-quenching and cryomilling polymorphs I and III of CBZ. Moreover, two different non-isothermal crystallization mechanisms from these two different types of amorphous states were revealed, in agreement with calorimetric analyzes. Raman spectroscopy and differential scanning calorimetry experiments performed on cryomilled forms I and III of CBZ, provide information on the bimodal crystallization, observed upon heating several amorphous organic crystalline materials produced by milling. This study clearly shows that milling gives the opportunity to explore new amorphous states which cannot be achieved using the classical melt-quenching method.

This study shows the contribution of Raman spectroscopy to carefully describe the mechanism of solid-state transformation at the molecular level, by simultaneously monitoring the molecular reorganization and the water escape during the dehydration kinetics. Dehydration of monohydrate caffeine was analyzed at various temperatures. In-situ low- and high-frequency Raman investigations provide information on the long-range and local arrangement of caffeine molecules, during the dehydration kinetics and in the anhydrate state. The nature of the anhydrate was determined, from the analysis in the low-frequency region, as metastable and transient between both polymorphic forms of anhydrous caffeine. It was shown that changing the temperature mainly induces structural reorganization of caffeine molecules in the hydrate state, leading to an anhydrate more or less transformed in form I of anhydrous caffeine.

The crystallization process of l-arabitol was investigated using differential scanning calorimetry (DSC) and X-ray diffraction. In order to estimate the temperature range where the rates of nucleation and growth reach their maximum, we have applied an experimental protocol consisting in a succession of quenching of the liquid at different temperatures followed by a heating ramp. It enabled us to show that the nucleation and growth domains were clearly separated and a metastable polymorph of lower melting point was obtained. The conditions for the appearance of this form have been studied in detail. The crystallization kinetic of the undercooled liquid at T=0°C, followed by X-ray diffraction, has permitted to show that the stable form was obtained after the transient metastable form.

X-ray powder diffraction patterns of n-butanol at 110 K and the isothermal transformation above the glass transition temperature of the supercooled liquid into the glacial state were recorded with a laboratory diffractometer. The starting structural model of the crystalline stable phase was found by a Monte-Carlo simulated annealing method. The final structure was obtained through Rietveld refinements with soft restraints on the interatomic bond lengths and angles. The cell is triclinic with space group P1 and contains two molecules. The width of the Bragg peaks is interpreted by a phenomenological microstructural approach in terms of anisotropic strain effects. The study of the hydrogen bonds by Raman spectroscopy shows the existence of two main kinds of hydrogen bonds in the crystal, in agreement with the structure obtained by diffraction. The glacial state resulting from an abortive crystallization is composed of microcrystallites of the stable phase coexisting with non-transformed supercooled liquid. Crystalline features of the glacial state were determined as closely connected to the microstructural description of the crystal, leading to information about the origin of the glacial state.

Raman spectroscopy and X-ray diffraction experiments were performed in the liquid, undercooled liquid, and glassy states of n-butanol. Clear correlated signatures are obtained below the melting temperature, from both temperature dependences of the low-wavenumber vibrational excitations and the intermediate-range order characterized by a prepeak detected in the different amorphous states. It was found that these features are related to molecular associations via strong hydrogen bonds, which preferentially develop at low temperature, and which are not compatible with the long-range order of the crystal. This study provides information on structural heterogeneities developing in hydrogen-bonded liquids, associated to the undercooled regime and the inherent glass transition. The analysis of the isothermal abortive crystallization, 2 K above the glass transition temperature, has given the opportunity to analyze the early stages of the crystallization and to describe the origin of the frustration responsible for an uncompleted crystallization.

Low-frequency Raman investigations were carried out upon pressurizing and grinding both crystalline forms of anhydrous caffeine at room temperature. These investigations have led to the detection of metastable states under stress. Upon moderated hydrostatic compression, only form I transform into a metastable state characterized by a Raman band-shape resembling that of form II. Above 2GPa, both pressurized forms convert into an identical disordered state, suggesting a pressure-induced amorphization. In contrast to hydrostatic compression, grinding induces transformation of each phase into the other, leading to an intermediate state only stabilized under long enough grinding. The origin of these metastable states induced by stress was related to the disordered nature of both crystalline forms of caffeine and the stability conditions at room temperature of form I.

Powder X-ray diffraction patterns of the commercial phase of L-arabinitol were recorded with a laboratory diffractometer. The starting structural model was found by a Monte-Carlo simulated annealing method. The final structure was obtained through Rietveld refinements with soft restraints on the interatomic bond lengths and bond angles. H atoms of hydroxyl groups were localized by minimization of the crystalline energy. The cell is triclinic with the space group P1 and contains two molecules. The crystalline cohesion is achieved by an important network of O-H···O hydrogen bonds.

It has been previously reported that α-lactose could be totally amorphized by ball milling. In this paper we report a detailed investigation of the structural and microstructural changes by which this solid state amorphization takes place. The investigations have been performed by Powder X-ray Diffraction, Solid State Nuclear Magnetic Resonance ((13)C CP-MAS) and Differential Scanning Calorimetry. The results reveal the structural complexity of the material in the course of its amorphization so that it cannot be considered as a simple mixture made of a decreasing crystalline fraction and an increasing amorphous fraction. Heating this complexity can give rise to a fully nano-crystalline material. The results also show that chemical degradations upon heating are strongly connected to the melting process.

Low- and high-frequency Raman experiments in the 5–200cm−1 and 600–1800cm−1 ranges were carried out in the crystalline and amorphous states of ibuprofen. Low-frequency investigations indubitably reveal the existence of a molecular disorder in the metastable phase (phase II), through the observation of quasielastic contribution below 30cm−1, and the absence of phonon peaks in the Raman susceptibility which mimics the density of vibrational states of an amorphous state. High-frequency Raman spectra indicate a local order in phase II similar to that in the glassy state. Both dynamic and static molecular disorder could contribute to the Raman signatures of the disorder in crystalline phase II. Raman investigations suggest that phase II can be considered as a transient metastable state in the devitrification process of ibuprofen upon heating from a far from equilibrium state toward the stable phase I.

Raman investigations are carried out both in crystalline forms of caffeine and during the isothermal transformation of the orientationally disordered form I into the stable form II at 363 K. The time dependence of the Raman spectrum exhibits no significant change in the intramolecular regime (above 100 cm(-1)), resembling the spectrum of the liquid state. By contrast, significant changes are observed below 100 cm(-1), and the low-frequency spectra of forms I and II are observed to be different from that of the liquid. The temperature dependence of the 5-600 cm(-1) spectrum gives information on the static disorder through the analysis of collective motions, while information on dynamic disorder are obtained from the study of the 555 cm(-1) band corresponding to internal vibrations in the pyrimidine ring. This analysis indubitably reveals that form II is also orientationally disordered with a local molecular arrangement that mimics that in form I and the liquid state. The comparison of the low-frequency spectra recorded in theophylline and form II of caffeine allows one to describe the stable form of caffeine from the packing arrangement of anhydrous theophylline with the consideration of reorientational molecular disorder.

Annealing of the quenched ibuprofen at 258 K yielded a new crystalline form, called phase II. Powder X-ray diffraction patterns of this phase II were recorded with a laboratory diffractometer equipped with an INEL G3000 goniometer and a curved position-sensitive detector CPS120. The starting structural model was found by a Monte-Carlo simulated annealing method. The final structure was obtained through Rietveld refinements with rigid-body constraints for the phenyl group and soft restraints on the other interatomic bond lengths and bond angles. The cell volume is 5% larger than that of the conventional phase I at 258 K. It is also shown that the orientation of the propanoic acid group is drastically changed with respect to phase I, leading to strong modifications of the orientation of the O—H...O hydrogen bonds with respect to the chains of dimers. These structural considerations could explain the metastable character of this phase II.

Powder X-ray diffraction patterns of the stable anhydrous form of alpha-lactose and of a mixture of alpha-lactose monohydrate with hygroscopic anhydrous alpha-lactose were recorded at room temperature. The starting structural models were found by a Monte-Carlo simulated annealing method. The final structures were obtained through Rietveld refinements with soft restraints on interatomic bond lengths and bond angles and crystalline energy minimisation to locate the H atoms of the hydroxyl groups. The stable form of alpha-lactose is triclinic with space group P1, Z = Z'=2, a = 7.6522 (2), b = 19.8637 (5), c = 4.9877 (1) angstrom, alpha = 92.028 (1), beta = 106.261 (1), gamma = 97.153 (1)degrees, V = 720.18 (3) angstrom 3. For hygroscopic anhydrous alpha-lactose, the symmetry is monoclinic, space group P21, Z = 2, Z' = 1, a = 7.7795 (3), b = 19.6931 (7), c = 4.9064 (1) angstrom, beta = 103.691 (2)degrees, V = 730.32 (4) A3.