Molecular structure of ketoprofen-polyvinylpyrrolidone solid dispersions prepared by different amorphization methods.

Amorphous solid dispersions (ASDs) are a widely studied formulation approach for improving the bioavailability of poorly water-soluble pharmaceuticals. Yet, a complete understanding remains lacking for how specific processing methods may influence ASDs' molecular structure. We prepare ketoprofen/polyvinylpyrrolidone (KTP/PVP) ASDs, ranging from 0-75 wt% KTP, using five different amorphization techniques: melt quenching, rotary evaporation with vacuum drying, spray drying, and acoustic levitation with either a premixed solution or in situ mixing of separate co-sprayed solutions. The co-spray levitation approach enables on-demand compositional changes in a containerless processing environment, while requiring minimal pharmaceutical material (∼1 mg). The structure of all ASDs are then compared using high-energy X-ray total scattering. X-ray pair distribution functions are similar for most ASDs of a given composition (Rx = 0.4-2.5%), which is consistent with them having similar intramolecular structure. More notably, differences in the X-ray structure factors for the various amorphization routes indicate differing extents of molecular mixing, a direct indication of their relative stability against crystallization. Melt quenching, spray drying, and levitation of premixed solutions exhibit some degree of molecular mixing, while the co-sprayed levitation samples have molecular arrangements like those of KTP/PVP physical mixtures. These findings illustrate how X-ray total scattering can be used to benchmark amorphous forms prepared by different techniques.

Plutonium oxide melt structure and covalency.

Advances in nuclear power reactors include the use of mixed oxide fuel, containing uranium and plutonium oxides. The high-temperature behaviour and structure of PuO2-x above 1,800 K remain largely unexplored, and these conditions must be considered for reactor design and planning for the mitigation of severe accidents. Here, we measure the atomic structure of PuO2-x through the melting transition up to 3,000 ± 50 K using X-ray scattering of aerodynamically levitated and laser-beam-heated samples, with O/Pu ranging from 1.57 to 1.76. Liquid structural models consistent with the X-ray data are developed using machine-learned interatomic potentials and density functional theory. Molten PuO1.76 contains some degree of covalent Pu-O bonding, signalled by the degeneracy of Pu 5f and O 2p orbitals. The liquid is isomorphous with molten CeO1.75, demonstrating the latter as a non-radioactive, non-toxic, structural surrogate when differences in the oxidation potentials of Pu and Ce are accounted for. These characterizations provide essential constraints for modelling pertinent to reactor safety design.

Microgravity effects on nonequilibrium melt processing of neodymium titanate: thermophysical properties, atomic structure, glass formation and crystallization.

The relationships between materials processing and structure can vary between terrestrial and reduced gravity environments. As one case study, we compare the nonequilibrium melt processing of a rare-earth titanate, nominally 83TiO2-17Nd2O3, and the structure of its glassy and crystalline products. Density and thermal expansion for the liquid, supercooled liquid, and glass are measured over 300-1850 °C using the Electrostatic Levitation Furnace (ELF) in microgravity, and two replicate density measurements were reproducible to within 0.4%. Cooling rates in ELF are 40-110 °C s-1 lower than those in a terrestrial aerodynamic levitator due to the absence of forced convection. X-ray/neutron total scattering and Raman spectroscopy indicate that glasses processed on Earth and in microgravity exhibit similar atomic structures, with only subtle differences that are consistent with compositional variations of ~2 mol. % Nd2O3. The glass atomic network contains a mixture of corner- and edge-sharing Ti-O polyhedra, and the fraction of edge-sharing arrangements decreases with increasing Nd2O3 content. X-ray tomography and electron microscopy of crystalline products reveal substantial differences in microstructure, grain size, and crystalline phases, which arise from differences in the melt processes.

Probing Molecular Packing of Amorphous Pharmaceutical Solids Using X-ray Atomic Pair Distribution Function and Solid-State NMR.

The structural investigation of amorphous pharmaceuticals is of paramount importance in comprehending their physicochemical stability. However, it has remained a relatively underexplored realm primarily due to the limited availability of high-resolution analytical tools. In this study, we utilized the combined power of X-ray pair distribution functions (PDFs) and solid-state nuclear magnetic resonance (ssNMR) techniques to probe the molecular packing of amorphous posaconazole and its amorphous solid dispersion at the molecular level. Leveraging synchrotron X-ray PDF data and employing the empirical potential structure refinement (EPSR) methodology, we unraveled the existence of a rigid conformation and discerned short-range intermolecular C-F contacts within amorphous posaconazole. Encouragingly, our ssNMR 19F-13C distance measurements offered corroborative evidence supporting these findings. Furthermore, employing principal component analysis on the X-ray PDF and ssNMR data sets enabled us to gain invaluable insights into the chemical nature of the intermolecular interactions governing the drug-polymer interplay. These outcomes not only furnish crucial structural insights facilitating the comprehension of the underlying mechanisms governing the physicochemical stability but also underscore the efficacy of synergistically harnessing X-ray PDF and ssNMR techniques, complemented by robust modeling strategies, to achieve a high-resolution exploration of amorphous structures.

The local ordering of polar solvents around crystalline carbon nitride nanosheets in solution.

The crystalline graphitic carbon nitride, poly-triazine imide (PTI) is highly unusual among layered materials since it is spontaneously soluble in aprotic, polar solvents including dimethylformamide (DMF). The PTI material consists of layers of carbon nitride intercalated with LiBr. When dissolved, the resulting solutions consist of dissolved, luminescent single to multilayer nanosheets of around 60-125 nm in diameter and Li+ and Br- ions originating from the intercalating salt. To understand this unique solubility, the structure of these solutions has been investigated by high-energy X-ray and neutron diffraction. Although the diffraction patterns are dominated by inter-solvent correlations there are clear differences between the X-ray diffraction data of the PTI solution and the solvent in the 4-6 Å-1 range, with real space differences persisting to at least 10 Å. Structural modelling using both neutron and X-ray datasets as a constraint reveal the formation of distinct, dense solvation shells surrounding the nanoparticles with a layer of Br-close to the PTI-solvent interface. This solvent ordering provides a configuration that is energetically favourable underpinning thermodynamically driven PTI dissolution. This article is part of the theme issue 'Exploring the length scales, timescales and chemistry of challenging materials (Part 2)'.

Molecular interactions in short-chain perfluoroalkyl carboxylic acids and aqueous solutions.

The presence of short-chain per- and polyfluoroalkyl substances in water poses a major health and environmental challenge. Here, we have performed high-energy small- and wide-angle X-ray scattering measurements on CF3[CF2]nCOOH (where n = 1, 2, 3 represents the chain length) and their aqueous solutions at 10% mole concentrations to characterize their molecular interactions at the atomic and nanometer length scales. The experimental wide-angle structure factors have been modelled using Empirical Potential Structural Refinement. The oxygen-oxygen partial X-ray pair distribution functions show that the coordination number between the hydroxyl oxygen on the acid and surrounding oxygen water molecules increases significantly with acid chain length, rising from 3.2 for n = 1 to 4.1 for n = 3. The small-angle scattering is dominated by a sharp, high-intensity peak at Q1 ∼ 0.2 Å-1 and a smaller peak at Q2 = 1.2 Å-1 for n = 3, both of which decrease with decreasing chain length. The Q2 peak is attributed to groups of adjacent non-bonded acid molecules, and Q1 has contributions from both correlations between acid molecules and water-water interactions. In all cases, the models show nanoscale aggregation occurs in the form of denser channels of winding hydrogen-bonded chains, approximately 20 water molecules in length, surrounding clusters of acid molecules. This article is part of the theme issue 'Exploring the length scales, timescales and chemistry of challenging materials (Part 2)'.

Mapping the structural trends in zinc aluminosilicate glasses.

The structure of zinc aluminosilicate glasses with the composition (ZnO)x(Al2O3)y(SiO2)1-x-y, where 0 ≤ x < 1, 0 ≤ y < 1, and x + y < 1, was investigated over a wide composition range by combining neutron and high-energy x-ray diffraction with 27Al magic angle spinning nuclear magnetic resonance spectroscopy. The results were interpreted using an analytical model for the composition-dependent structure in which the zinc ions do not act as network formers. Four-coordinated aluminum atoms were found to be in the majority for all the investigated glasses, with five-coordinated aluminum atoms as the main minority species. Mean Al-O bond distances of 1.764(5) and 1.855(5) Å were obtained for the four- and five-coordinated aluminum atoms, respectively. The coordination environment of zinc was not observed to be invariant. Instead, it is dependent on whether zinc plays a predominantly network-modifying or charge-compensating role and, therefore, varies systematically with the glass composition. The Zn-O coordination number and bond distance were found to be 4.36(9) and 2.00(1) Å, respectively, for the network-modifying role vs 5.96(10) and 2.08(1) Å, respectively, for the charge-compensating role. The more open coordination environment of the charge-compensator is related to an enhanced probability of zinc finding bridging oxygen atoms as nearest-neighbors, reflecting a change in the connectivity of the glass network comprising four-coordinated silicon and aluminum atoms as the alumina content is increased.

The structure of molten calcium ferrite under various redox conditions.

Laser-heated melts based on the 43CaO-57Fe2O3-x eutectic, close to the calcium ferrite (CF) composition, were measured with high-energy X-ray diffraction using aerodynamic levitation over a range of redox states controlled by CO/CO2 gas atmospheres. The iron-oxygen coordination number was found to rise from 4.4 ± 0.3 at 15% Fe3+ to 5.3 ± 0.3 at 87% Fe3+. Empirical potential structure refinement modelling was used to obtain the ferric and ferrous partial pair distribution functions. It was found that the Fe2+ iron-oxygen coordination number is consistently approximately 10% higher in CF than in pure iron oxide, while Fe3+ is essentially identical in all but the most oxygen-rich environments (where it is higher in CF compared with FeOx). The model also shows calcium octahedra to be the dominant species across all redox environments, although the population of CaO7 increases with the availability of oxygen at the expense of CaO4 and CaO5. This article is part of the theme issue 'Exploring the length scales, timescales and chemistry of challenging materials (Part 1)'.

Decoding the Atomic Structure of Ga2Te5 Pulsed Laser Deposition Films for Memory Applications Using Diffraction and First-Principles Simulations.

Neuromorphic computing, reconfigurable optical metamaterials that are operational over a wide spectral range, holographic and nonvolatile displays of extremely high resolution, integrated smart photonics, and many other applications need next-generation phase-change materials (PCMs) with better energy efficiency and wider temperature and spectral ranges to increase reliability compared to current flagship PCMs, such as Ge2Sb2Te5 or doped Sb2Te. Gallium tellurides are favorable compounds to achieve the necessary requirements because of their higher melting and crystallization temperatures, combined with low switching power and fast switching rate. Ga2Te3 and non-stoichiometric alloys appear to be atypical PCMs; they are characterized by regular tetrahedral structures and the absence of metavalent bonding. The sp3 gallium hybridization in cubic and amorphous Ga2Te3 is also different from conventional p-bonding in flagship PCMs, raising questions about its phase-change mechanism. Furthermore, gallium tellurides exhibit a number of unexpected and highly unusual phenomena, such as nanotectonic compression and viscosity anomalies just above their melting points. Using high-energy X-ray diffraction, supported by first-principles simulations, we will elucidate the atomic structure of amorphous Ga2Te5 PLD films, compare it with the crystal structure of tetragonal gallium pentatelluride, and investigate the electrical, optical, and thermal properties of these two materials to assess their potential for memory applications, among others.

AL4GAP: Active learning workflow for generating DFT-SCAN accurate machine-learning potentials for combinatorial molten salt mixtures.

Machine learning interatomic potentials have emerged as a powerful tool for bypassing the spatiotemporal limitations of ab initio simulations, but major challenges remain in their efficient parameterization. We present AL4GAP, an ensemble active learning software workflow for generating multicomposition Gaussian approximation potentials (GAP) for arbitrary molten salt mixtures. The workflow capabilities include: (1) setting up user-defined combinatorial chemical spaces of charge neutral mixtures of arbitrary molten mixtures spanning 11 cations (Li, Na, K, Rb, Cs, Mg, Ca, Sr, Ba and two heavy species, Nd, and Th) and 4 anions (F, Cl, Br, and I), (2) configurational sampling using low-cost empirical parameterizations, (3) active learning for down-selecting configurational samples for single point density functional theory calculations at the level of Strongly Constrained and Appropriately Normed (SCAN) exchange-correlation functional, and (4) Bayesian optimization for hyperparameter tuning of two-body and many-body GAP models. We apply the AL4GAP workflow to showcase high throughput generation of five independent GAP models for multicomposition binary-mixture melts, each of increasing complexity with respect to charge valency and electronic structure, namely: LiCl-KCl, NaCl-CaCl2, KCl-NdCl3, CaCl2-NdCl3, and KCl-ThCl4. Our results indicate that GAP models can accurately predict structure for diverse molten salt mixture with density functional theory (DFT)-SCAN accuracy, capturing the intermediate range ordering characteristic of the multivalent cationic melts.

Structure of amorphous materials in the NASICON system Na1+xTi2SixP3-xO12.

The structure of glasses in the sodium (Na) super-ionic conductor (NASICON) system Na1+xTi2SixP3-xO12withx= 0.8 andx= 1.0 was explored by combining neutron and high-energy x-ray diffraction with29Si,31P and23Na solid-state nuclear magnetic resonance (NMR) spectroscopy. The29Si magic angle spinning (MAS) NMR spectra reveal that the silica component remains fully polymerized in the form of Si4units, i.e. the silicon atoms are bound to four bridging oxygen atoms. The31P{23Na} rotational echo adiabatic passage double resonance (REAPDOR) NMR data suggest that the31P MAS NMR line shape originates from four-coordinated Pnunits, wheren= 1, 2 or 3 is the number of bridging oxygen atoms per phosphorus atom. These sites differ in their31P-23Na dipolar coupling strengths. The results support an intermediate range order scenario of a phosphosilicate mixed network-former glass in which the phosphate groups selectively attract the Na+modifier ions. Titanium takes a sub-octahedral coordination environment with a mean Ti-O coordination number of 5.17(4) forx= 0.8 and 4.86(4) forx= 1.0. A mismatch between the P-O and Si-O bond lengths of 8% is likely to inhibit the incorporation of silicon into the phosphorus sites of the NASICON crystal structure.

Insights on the dissolution of water in an albite melt at high pressures and temperatures from a direct structural analysis.

The water dissolution mechanism in silicate melts under high pressures is not well understood. Here we present the first direct structure investigation of a water-saturated albite melt to monitor the interactions between water and the network structure of silicate melt at the molecular level. In situ high-energy X-ray diffraction was carried out on the NaAlSi3O8-H2O system at 800 °C and 300 MPa, at the Advanced Photon Source synchrotron facility. The analysis of the X-ray diffraction data was augmented with classical Molecular Dynamics simulations of a hydrous albite melt, incorporating accurate water-based interactions. The results show that metal-oxygen bond breaking at the bridging sites occurs overwhelmingly at the Si site upon reaction with H2O, with subsequent Si-OH bond formation and negligible Al-OH formation. Furthermore, we see no evidence for the dissociation of the Al3+ ion from the network structure upon breaking of the Si-O bond in the hydrous albite melt. The results also indicate that the Na+ ion is an active participant in the modifications of the silicate network structure of the albite melt upon water dissolution at high P-T conditions. We do not find evidence for the Na+ ion dissociating from the network structure upon depolymerization and subsequent formation of NaOH complexes. Instead, our results show that the Na+ ion persists as a structure modifier with a shift away from Na-BO bonding to an increase in the extent of Na-NBO bonding, in parallel with pronounced depolymerization of the network. Our MD simulations show that the Si-O and Al-O bond lengths are expanded by about 6% in the hydrous albite melt compared to those of the dry melt at high P-T conditions. The changes in the network silicate structure of a hydrous albite melt at high pressure and temperature, as revealed in this study, must be considered in the advancement of water dissolution models of hydrous granitic (or alkali aluminosilicate) melts.

Structure of diopside, enstatite, and magnesium aluminosilicate glasses: A joint approach using neutron and x-ray diffraction and solid-state NMR.

Neutron diffraction with magnesium isotope substitution, high energy x-ray diffraction, and 29Si, 27Al, and 25Mg solid-state nuclear magnetic resonance (NMR) spectroscopy were used to measure the structure of glassy diopside (CaMgSi2O6), enstatite (MgSiO3), and four (MgO)x(Al2O3)y(SiO2)1-x-y glasses, with x = 0.375 or 0.25 along the 50 mol. % silica tie-line (1 - x - y = 0.5) or with x = 0.3 or 0.2 along the 60 mol. % silica tie-line (1 - x - y = 0.6). The bound coherent neutron scattering length of the isotope 25Mg was remeasured, and the value of 3.720(12) fm was obtained from a Rietveld refinement of the powder diffraction patterns measured for crystalline 25MgO. The diffraction results for the glasses show a broad asymmetric distribution of Mg-O nearest-neighbors with a coordination number of 4.40(4) and 4.46(4) for the diopside and enstatite glasses, respectively. As magnesia is replaced by alumina along a tie-line with 50 or 60 mol. % silica, the Mg-O coordination number increases with the weighted bond distance as less Mg2+ ions adopt a network-modifying role and more of these ions adopt a predominantly charge-compensating role. 25Mg magic angle spinning (MAS) NMR results could not resolve the different coordination environments of Mg2+ under the employed field strength (14.1 T) and spinning rate (20 kHz). The results emphasize the power of neutron diffraction with isotope substitution to provide unambiguous site-specific information on the coordination environment of magnesium in disordered materials.

Transient Mesoscopic Immiscibility, Viscosity Anomaly, and High Internal Pressure at the Semiconductor-Metal Transition in Liquid Ga2Te3.

Gallium tellurides appear to be promising phase-change materials (PCMs) of the next generation for brain-inspired computing and reconfigurable optical metasurfaces. They are different from the benchmark PCMs because of sp3 gallium hybridization in both cubic Ga2Te3 and amorphous pulsed laser deposition (PLD) films. Liquid Ga2Te3 also shows a viscosity η(T) anomaly just above melting when η(T) first increases and only then starts decreasing. We used high-energy X-ray diffraction to observe a transient mesoscopic immiscibility that suggested dense metallic liquid droplets in a semiconducting melt. The η(T) shape was consistent with this finding. A vanishing first sharp diffraction peak that also shifts to a higher Q indicates a high internal pressure in the metallic melt, which produces a remarkable asymmetry of the Ga-Te nearest neighbor distances and is reminiscent of high-pressure rhombohedral Ga2Te3. The observed phenomena provide a realistic scenario for a fast, multilevel SET-RESET response, which also unravels similar trends in the purported density-driven liquid polyamorphism of water, phosphorus, sulfur, and other materials.

Phase separation in mullite-composition glass.

Aluminosilicates (AS) are ubiquitous in ceramics, geology, and planetary science, and their glassy forms underpin vital technologies used in displays, waveguides, and lasers. In spite of this, the nonequilibrium behavior of the prototypical AS compound, mullite (40SiO2-60Al2O3, or AS60), is not well understood. By deeply supercooling mullite-composition liquid via aerodynamic levitation, we observe metastable liquid-liquid unmixing that yields a transparent two-phase glass, comprising a nanoscale mixture of AS7 and AS62. Extrapolations from X-ray scattering measurements show the AS7 phase is similar to vitreous SiO2 with a few Al species substituted for Si. The AS62 phase is built from a highly polymerized network of 4-, 5-, and 6-coordinated AlOx polyhedra. Polymerization of the AS62 network and the composite morphology provide essential mechanisms for toughening the glass.

Octahedral oxide glass network in ambient pressure neodymium titanate.

Rare-earth titanates form very fragile liquids that can be made into glasses with useful optical properties. We investigate the atomic structure of 83TiO2-17Nd2O3 glass using pair distribution function (PDF) analysis of X-ray and neutron diffraction with double isotope substitutions for both Ti and Nd. Six total structure factors are analyzed (5 neutron + 1 X-ray) to obtain complementary sensitivities to O and Ti/Nd scattering, and an empirical potential structure refinement (EPSR) provides a structural model consistent with the experimental measurements. Glass density is estimated as 4.72(13) g cm-3, consistent with direct measurements. The EPSR model indicates nearest neighbor interactions for Ti-O at [Formula: see text] = 1.984(11) Å with coordination of [Formula: see text] = 5.72(6) and for Nd-O at [Formula: see text] = 2.598(22) Å with coordination of [Formula: see text] = 7.70(26), in reasonable agreement with neutron first order difference functions for Ti and Nd. The titanate glass network comprises a mixture of distorted Ti-O5 and Ti-O6 polyhedra connected via 71% corner-sharing and 23% edge-sharing. The O-Ti coordination environments include 15% nonbridging O-Ti1, 51% bridging O-Ti2, and 32% tricluster O-Ti3. This structure is highly unusual for oxide glasses melt-quenched at ambient pressure, as it consists of Ti-Ox predominantly in octahedral (with nearly no tetrahedral) coordination.

Structural Phase Transitions between Layered Indium Selenide for Integrated Photonic Memory.

The primary mechanism of optical memoristive devices relies on phase transitions between amorphous and crystalline states. The slow or energy-hungry amorphous-crystalline transitions in optical phase-change materials are detrimental to the scalability and performance of devices. Leveraging an integrated photonic platform, nonvolatile and reversible switching between two layered structures of indium selenide (In2 Se3 ) triggered by a single nanosecond pulse is demonstrated. The high-resolution pair distribution function reveals the detailed atomistic transition pathways between the layered structures. With interlayer "shear glide" and isosymmetric phase transition, switching between the α- and ß-structural states contains low re-configurational entropy, allowing reversible switching between layered structures. Broadband refractive index contrast, optical transparency, and volumetric effect in the crystalline-crystalline phase transition are experimentally characterized in molecular-beam-epitaxy-grown thin films and compared to ab initio calculations. The nonlinear resonator transmission spectra measure of incremental linear loss rate of 3.3 GHz, introduced by a 1.5 µm-long In2 Se3 -covered layer, resulted from the combinations of material absorption and scattering.

Structures of glasses created by multiple kinetic arrests.

X-ray scattering has been used to characterize glassy itraconazole (ITZ) prepared by cooling at different rates. Faster cooling produces ITZ glasses with lower (or zero) smectic order with more sinusoidal density modulation, larger molecular spacing, and shorter lateral correlation between the rod-like molecules. We find that each glass is characterized by not one, but two fictive temperatures Tf (the temperature at which a chosen order parameter is frozen in the equilibrium liquid). The higher Tf is associated with the regularity of smectic layers and lateral packing, while the lower Tf with the molecular spacings between and within smectic layers. This indicates that different structural features are frozen on different timescales. The two timescales for ITZ correspond to its two relaxation modes observed by dielectric spectroscopy: the slower δ mode (end-over-end rotation) is associated with the freezing of the regularity of molecular packing and the faster α mode (rotation about the long axis) with the freezing of the spacing between molecules. Our finding suggests a way to selectively control the structural features of glasses.

Hot-melt extrudability of amorphous solid dispersions of flubendazole-copovidone: An exploratory study of the effect of drug loading and the balance of adjuvants on extrudability and dissolution.

The FDA-approved anthelmintic flubendazole has shown potential to be repositioned to treat cancer and dry macular degeneration; however, its poor water solubility limits its use. Amorphous solid dispersions may overcome this challenge, but the balance of excipients may impact the preparation method and drug release. The purpose of this study was to evaluate the influence of adjuvants and drug loading on the development of an amorphous solid dispersion of flubendazole-copovidone by hot-melt extrusion. The drug, copovidone, and adjuvants (magnesium stearate and hydroxypropyl cellulose) mixtures were statistically designed, and the process was performed in a twin-screw extruder. The study showed that flubendazole and copovidone mixtures were highly extrudable, except when drug loading was high (>40%). Furthermore, magnesium stearate positively impacted the extrusion and was more effective than hydroxypropyl cellulose. The extruded materials were evaluated by modulated differential scanning calorimetry and X-ray powder diffraction, obtaining positive amorphization and physical stability results. Pair distribution function analysis indicated the presence of drug-rich domains with medium-range order structure and no evidence of polymer-drug interaction. All extrudates presented faster dissolution (HCl, pH 1.2) than pure flubendazole, and both adjuvants had a notable influence on the dissolution rate. In conclusion, hot-melt extrusion may be a viable option to obtain stable flubendazole:copovidone amorphous dispersions.

The Structure of Liquid and Glassy Carbamazepine.

To enhance the solubility of orally administered pharmaceuticals, liquid capsules or amorphous tablets are often preferred over crystalline drug products. However, little is known regarding the variation in bonding mechanisms between pharmaceutical molecules in their different disordered forms. In this study, liquid and melt-quenched glassy carbamazepine have been studied using high energy X-ray diffraction and modeled using Empirical Potential Structure Refinement. The results show significant structural differences between the liquid and glassy states. The liquid shows a wide range of structures; from isolated molecules, to aromatic ring correlations and NH-O hydrogen bonding. Upon quenching from the liquid to the glass the number of hydrogen bonds per molecule increases by ~50% at the expense of a ~30% decrease in the close contact (non-bonded) carbon-carbon interactions between aromatic rings. During the cooling process, there is an increase in both singly and doubly hydrogen-bonded adjacent molecules. Although hydrogen-bonded dimers found in the crystalline states persist in the glassy state, the absence of a crystalline lattice also allows small, hydrogen-bonded NH-O trimers and tetramers to form. This proposed model for the structure of glassy carbamazepine is consistent with the results from vibrational spectroscopy and nuclear magnetic resonance.