In Situ Cocrystallization via Spray Drying with Polymer as a Strategy to Prevent Cocrystal Dissociation.

The aim of the present study was to investigate how different polymers affect the dissociation of cocrystals prepared by co-spray-drying active pharmaceutical ingredient (API), coformer, and polymer. Diclofenac acid-l-proline cocrystal (DPCC) was selected in this study as a model cocrystal due to its previously reported poor physical stability in a high-humidity environment. Polymers investigated include polyvinylpyrrolidone (PVP), poly(1-vinylpyrrolidone-co-vinyl acetate) (PVPVA), hydroxypropyl methyl cellulose, hydroxypropylmethylcellulose acetate succinate, ethyl cellulose, and Eudragit L-100. Terahertz Raman spectroscopy (THz Raman) and powder X-ray diffraction (PXRD) were used to monitor the cocrystal dissociation rate in a high-humidity environment. A Raman probe was used in situ to monitor the extent of the dissociation of DPCC and DPCC in crystalline solid dispersions (CSDs) with polymer when exposed to pH 6.8 phosphate buffer and water. The solubility of DPCC and solid dispersions of DPCC in pH 6.8 phosphate buffer and water was also measured. The dissociation of DPCC was water-mediated, and more than 60% of DPCC dissociated in 18 h at 40 °C and 95% RH. Interestingly, the physical stability of the cocrystal was effectively improved by producing CSDs with polymers. The inclusion of just 1 wt % polymer in a CSD with DPCC protected the cocrystal from dissociation over 18 h under the same conditions. Furthermore, the CSD with PVPVA was still partially stable, and the CSD with PVP was stable (undissociated) after 7 days. The superior stability of DPCC in CSDs with PVP and PVPVA was also demonstrated when systems were exposed to water or pH 6.8 phosphate buffer and resulted in higher dynamic solubility of the CSDs compared to DPCC alone. The improvement in physical stability of the cocrystal in CSDs was thought to be due to an efficient mixing between polymer and cocrystal at the molecular level provided by spray drying and in situ gelling of polymer. It is hypothesized that polymer chains could undergo gelling in situ and form a physical barrier, preventing cocrystal interaction with water, which contributes to slowing down the water-mediated dissociation.

Low-Frequency Raman Spectroscopy of Pure and Cocrystallized Mycophenolic Acid.

The aqueous solubility of solid-state pharmaceuticals can often be enhanced by cocrystallization with a coformer to create a binary cocrystal with preferred physical properties. Greater understanding of the internal and external forces that dictate molecular structure and intermolecular packing arrangements enables more efficient design of new cocrystals. Low-frequency (sub-200 cm-1) Raman spectroscopy experiments and solid-state density functional theory simulations have been utilized together to investigate the crystal lattice vibrations of mycophenolic acid, an immunosuppressive drug, in its pure form and as a cocrystal with 2,2'-dipyridylamine. The lattice vibrations primarily consist of large-amplitude translations and rotations of the crystal components, thereby providing insights into the critical intermolecular forces governing cohesion of the molecular solids. The simulations reveal that despite mycophenolic acid having a significantly unfavorable conformation in the cocrystal as compared to the pure solid, the cocrystal exhibits greater thermodynamic stability over a wide temperature range. The energetic penalty due to the conformational strain is more than compensated for by the strong intermolecular forces between the drug and 2,2'-dipyridylamine. Quantifying the balance of internal and external energy factors in cocrystal formation indicates a path forward in the development of future mycophenolic acid cocrystals.

Exploring the Solid-State Landscape of Carbamazepine during Dehydration: A Low Frequency Raman Spectroscopy Perspective.

The solid-state landscape of carbamazepine during its dehydration was explored using Raman spectroscopy in the low- (-300 to -15, 15 to 300) and mid- (300 to 1800 cm-1) frequency spectral regions. Carbamazepine dihydrate and forms I, III, and IV were also characterized using density functional theory with periodic boundary conditions and showed good agreement with experimental Raman spectra with mean average deviations less than 10 cm-1. The dehydration of carbamazepine dihydrate was examined under different temperatures (40, 45, 50, 55, and 60 °C). Principal component analysis and multivariate curve resolution were used to explore the transformation pathways of different solid-state forms during the dehydration of carbamazepine dihydrate. The low-frequency Raman domain was able to detect the rapid growth and subsequent decline of carbamazepine form IV, which was not as effectively observed by mid-frequency Raman spectroscopy. These results showcased the potential benefits of low-frequency Raman spectroscopy for pharmaceutical process monitoring and control.

Low-Frequency Vibrational Spectroscopy and Quantum Mechanical Simulations of the Crystalline Polymorphs of the Antiviral Drug Ribavirin.

Crystal polymorphism is a common phenomenon in pharmaceutical solids and a critical issue when considering the formulation of therapeutics since multiple polymorphs may form during drug manufacturing. Low-frequency vibrational spectroscopy is sensitive to polymorphic content, and in this work, terahertz time-domain spectroscopy and low-frequency Raman spectroscopy were utilized in the study of crystalline ribavirin, a widely applicable antiviral. Characteristic spectra with numerous peaks in the sub-200 cm-1 region were obtained of the more common polymorph of ribavirin (Form II). Solid-state density functional theory (ss-DFT) simulations were then used to optimize the crystal structure of this polymorph and calculate the frequencies and spectral intensities of the lattice vibrations in the low-frequency region. The near-harmonic thermal behavior of the sample with cooling enabled excellent agreement between experiment and theory to be achieved, emphasizing the quality of the applied model, and the observed spectral peaks could be assigned to specific atomic motions in the solid. Form I and Form II polymorphs of ribavirin were both investigated with ss-DFT to understand the different aspects governing the relative stabilities of these solids. The ss-DFT simulations of the polymorph energies revealed that Form II is more stable at all temperatures due to a stronger cohesive energy than Form I; however, ribavirin in Form I has a significantly lower conformational energy. The finding of monotropism appears to conflict with the reported enantiotropism of the ribavirin polymorphs but ultimately confirms that crystal defects in the real samples greatly affect the thermodynamic relationship of the crystals.

In Situ Observation of the Structure of Crystallizing Magnesium Sulfate Heptahydrate Solutions with Terahertz Transmission Spectroscopy.

Terahertz time-domain spectroscopy in a transmission geometry combined with visual analysis was used to investigate the crystallization process of MgSO4 solution. Careful spectral analysis of both a feature at 1.6 THz and the overall magnitude of absorption allowed the extraction of information about the liquid phase before and during crystallization, aiding the investigation of solvation dynamics and the behavior of molecular species at phase boundaries. The method was reproducibly applied to a number of measurements on a series of solutions of three chosen concentrations at different temperatures. When increasing temperature at the end of the measurement, the dissolution of crystals was observed as well. The temperature-dependent absorption data of the semicrystalline systems were converted to the solvent concentrations using a recently developed method. Solutions of a series of concentrations were also investigated in the temperature range of 4-25 °C. The results were compared to the theoretical calculated values, and the consistent differences proved the existence of a hydration shell around the salt ions whose behavior is different from bulk water. Future work will focus on triggering nucleation at specific positions in order to study the very beginning of the crystallization process. MgSO4 heptahydrate is used as a model system in this study, while the concept and the setup can be applied to other systems.

Study on Hydration and Dehydration of Ezetimibe by Terahertz Spectroscopy with Humidity-Controlled Measurements and Theoretical Analysis.

Understanding the solid-state transitions of active pharmaceutical ingredients (APIs) is essential for quality control since differences in their forms affect the bioavailability of APIs. Terahertz (THz) frequency-domain spectroscopy is suitable for such an application since it can sensitively probe the lattice phonon modes originating in the crystal structures. THz absorption spectra were obtained for ezetimibe (EZT) and ezetimibe monohydrate (EZT-MH), which have similar crystalline structures and belong to the same space group. The observed absorption spectrum of EZT matched well with the solid-state density functional theory (ss-DFT)-simulated spectrum for the structures at 0 K and room temperature (modeled using constrained unit cell volumes). However for EZT-MH, the ss-DFT spectrum of the room-temperature structure showed better correlation with the experimental THz spectrum than that of the simulated spectrum of the 0 K structures, suggesting that the EZT-MH crystal has greater anharmonic character. Gibbs free-energy curves were calculated, and EZT-MH was found to be more stable than pure EZT and water in a broad temperature range. The hydrate stability may be influenced by the existence of more hydrogen bonds in EZT-MH. The hydration and dehydration of EZT in a pure API tablet and formulation tablets were monitored using a THz spectrometer with a humidity-controlled sample chamber. The effect of the excipient in the formulation tablet on hydration was successfully confirmed by showing that the solid-state transition of the API with excipients is significantly slower than that without it. Under a relative humidity of 60%, hydration of EZT in a pure EZT tablet occurred in 200 min, while the hydration of EZT in a formulation tablet was 50 times slower.

Photocatalytic turnover of CO2 under visible light by [Re(CO)3(1-(1,10) phenanthroline-5-(4-nitro-naphthalimide))Cl] in tandem with the sacrificial donor BIH.

Optimized photocatalytic conversion of CO2 requires new potent catalysts that can absorb visible light. The photocatalytic reduction of CO2 using rhenium(i) has been demonstrated but suffers from low turnover. Herein, we describe a [Re(CO)3(1-(1,10)phenanthroline-5-(4-nitro-naphthalimide))Cl] photocatalyst, which when combined with the sacrificial donor 1,3-dimethyl-2-phenyl-2,3-dihydro-1H-benzo[d]imidazole, results in selective production of formic acid and a high turnover number of 533 and turnover frequency of 356 h-1. Single-crystal X-ray diffraction and DFT studies are also discussed.

New Insights into the Crystallographic Disorder in the Polymorphic Forms of Aspirin from Low-Frequency Vibrational Analysis.

Terahertz time-domain spectroscopy (THz-TDS) is applied to two polymorphs of acetylsalicylic acid (aspirin), and the experimental spectra are compared to lattice dynamical calculations using high accuracy density functional theory. The calculations confirm that forms I and II have very close energetic and thermodynamic properties and also that they show similar spectral features in the far-infrared region, reflecting the high degree of similarity in their crystal structures. Unique vibrational modes are identified for each polymorph which allow them to be distinguished using THz-TDS measurements. The observation of spectral features attributable to both polymorphic forms in a single sample, however, provides further evidence to support the hypothesis that crystalline aspirin typically comprises intergrown domains of forms I and II. Differences observed in the baseline of the measured THz-TDS spectra indicate a greater degree of structural disorder in the samples of form II. Calculated Gibbs free-energy curves show a turning point at 75 K, inferring that form II is expected to be more stable than form I above this temperature as a result of its greater vibrational entropy. The calculations do not account for any differences in configurational entropy that may arise from expected structural defects. Further computational work on these structures, such as ab initio molecular dynamics, would be very useful to further explore this perspective. Here, aspirin is a model system to show how the additional insight from the low-frequency vibrational information complements the structural data and allows for quantitative thermodynamic information of pharmaceutical polymorphs to be extracted. The methodology is directly applicable to other polymorphic systems.

[Re(CO)3(5-PAN)Cl], a rhenium(I) naphthalimide complex for the visible light photocatalytic reduction of CO2.

A rhenium(i) naphthalimide complex [Re(CO)3(5-PAN)Cl] (Re(5-PAN); 5-PAN = 1-(1,10-phenanthroline)-4-nitro-naphthalimide) was synthesized, characterized, and evaluated as a photocatalyst for CO2 reduction. Characterization included use of MALDI-ToF mass spectrometry, FT-IR, RAMAN, 1H and 13C NMR, elemental analysis, electronic absorption and emission spectroscopy, single crystal X-ray diffraction, DFT and cyclic voltammetry. Photocatalytic (406 nm) reduction of 13CO2 to formate (H13COO) in the presence of this catalyst was tracked via13C NMR. Results support Re5-PAN (φ = 0.021) functioning as a catalyst for the reduction of CO2 (maximum turn-over 48-50 at 300 equiv. triethylamine as the sacrificial electron donor).

Simulation and Assignment of the Terahertz Vibrational Spectra of Enalapril Maleate Cocrystal Polymorphs.

The identification of crystalline drug polymorphs using terahertz vibrational spectroscopy is a powerful approach for the nondestructive and noninvasive characterization of solid-state pharmaceuticals. However, a complete understanding of the terahertz spectra of molecular solids is challenging to obtain because of the complex nature of the low-frequency vibrational motions found in the sub-3 THz (sub-100 cm-1) range. Unambiguous assignments of the observed spectral features can be achieved through quantum mechanical solid-state simulations of crystal structures and lattice vibrations utilizing the periodic boundary condition approach. The terahertz spectra of two polymorphs of enalapril maleate are presented here to demonstrate that even large pharmaceuticals can be successfully modeled using solid-state density functional theory, including cocrystalline solids comprised of multiple distinct species. These simulations enable spectral assignments to be made, but also provide insights into the conformational and cohesion energies that contribute to the polymorph stabilities. The results reveal that the Form II polymorph of enalapril maleate is the more stable of the two under ambient conditions, and that this stability is driven by a greater intermolecular cohesion energy as compared to Form I.

Identifying and explaining vibrational modes of quinacridones via temperature-resolved terahertz spectroscopy: absorption experiments and solid-state density functional theory simulations.

Quinacridone and its substituted analogs are pigments widely used in art and industry. The temperature dependence of the crystal structures of two quinacridone polymorphs (ß and γ), along with the common variant 2,9-dimethylquinacridone, were investigated using powder X-ray diffraction and terahertz spectroscopy. These were then compared with solid-state density functional theory simulations of both structures and vibrations. X-ray patterns were collected at eight temperatures in the range 13-298 K and terahertz spectra at fifteen temperatures in the range 20-300 K. Simulations were at absolute zero and at appropriate expansions to model room temperature. It was found that some of the powder X-ray diffraction features in only ß-quinacridone (15.7°, 19.7° and 31.2° at 13 K) underwent anomalous shifting with temperature change. We attribute this to the unique coplanar hydrogen bonding pattern of ß-quinacridone compared to the other solids, with the unusual diffraction peaks originating from crystallographic planes perpendicular to the a axis intermolecular hydrogen bonds. This observation coincides with a contraction of the a axis with heating and results from its relatively weak N-HO hydrogen bonds and significant C-HH-C repulsions. Associated with this anomalous contraction, for ß-quinacridone only spectral peaks are seen to increase in energy with temperature.

Quantitative Analysis of Minium and Vermilion Mixtures Using Low-Frequency Vibrational Spectroscopy.

Low-frequency vibrational spectroscopy offers a compelling solution for the nondestructive and noninvasive study of pigments in historical artifacts by revealing the characteristic sub-200 cm-1 spectral features of component materials. The techniques of terahertz time-domain spectroscopy (THz-TDS) and low-frequency Raman spectroscopy (LFRS) are complementary approaches to accessing this spectral region and are valuable tools for artifact identification, conservation, and restoration. In this investigation of historical pigments, pure and mixed samples of minium (Pb3O4) and vermilion (HgS) were studied using a combination of THz-TDS and LFRS experiments to determine the limits of detection (LOD) and quantitation (LOQ) for each compound with both methods. The measurements were also supported using solid-state density functional theory simulations of the pigment structures and vibrations, enabling spectral peaks to be assigned to specific atomic motions in these solids. The THz-TDS LOD was found to be similar for both minium and vermilion at 6% by mass on average. In comparison, LFRS was found to be more sensitive to both pigments, particularly to the presence of vermilion with an LFRS LOD of 0.2%. These results demonstrate that low-frequency vibrational spectroscopy can be used for successful quantitative analysis of pigment mixtures and provide reliable new data for use in heritage science.

Mapping the polymorphic transformation gateway vibration in crystalline 1,2,4,5-tetrabromobenzene.

The thermosalient behavior of 1,2,4,5-tetrabromobenzene (TBB) is related to a temperature-induced polymorphic structural change. The mechanism behind the phase transition has been investigated in this work using low-frequency (10-250 cm-1) Raman spectroscopy and solid-state density functional theory simulations. Careful adjustments of the probing laser power permitted thermal control of the polymorph populations and enabled high-quality Raman vibrational spectra to be obtained for both the ß (low temperature) and γ (high temperature) forms of TBB. Numerous well-defined vibrational features appear in the Raman spectra of both polymorphs which could be assigned to specific motions of the solid-state TBB molecules. It was discovered that the lowest-frequency vibration at 15.5 cm-1 in ß-TBB at 291 K is a rotational mode that functions as a gateway for inducing the polymorphic phase transition to γ-TBB, and serves as the initiating step in the storage of mechanical strain for subsequent macroscopic release. Computationally mapping the potential energy surface along this vibrational coordinate reveals that the two TBB polymorphs are separated by a 2.40 kJ mol-1 barrier and that γ-TBB exhibits an enhanced cohesion energy that stabilizes its structure.

Anomalous Temperature Dependence of the Lowest-Frequency Lattice Vibration in Crystalline γ-Aminobutyric Acid.

Crystalline γ-aminobutyric acid (GABA) exhibits unusual thermal behavior in a low-frequency lattice vibration that occurs at 37.2 cm-1 at 290 K but decreases dramatically by 34.0% when the sample is cooled to 78 K. Lattice vibrations in molecular crystals are indicators of intermolecular force characteristics, and the extraordinary temperature sensitivity of this vibration offers new insight into the local environment within the solid. Solid-state density functional theory simulations of the GABA crystal have found this anomalous frequency shift is based in unexpected differences in the strengths of the intermolecular hydrogen bonds that are cursorily the same. This was accomplished through mapping of the potential energy surfaces governing the terahertz-frequency motions of the GABA solid and use of the quasi-harmonic approximation to model the response of all the lattice vibrations to temperature-induced unit cell volume changes brought about through the anharmonic character of the intermolecular interactions. The analysis reveals that the vibration in question is rotational in nature and involves the significant distortion of a specific weak intermolecular N-H···O hydrogen bond in the crystal that results in its unique thermal response.

Terahertz Spectroscopy and Quantum Mechanical Simulations of Crystalline Copper-Containing Historical Pigments.

Terahertz spectroscopy, a noninvasive and nondestructive analytical technique used in art conservation and restoration, can provide compelling data concerning the composition and condition of culturally valuable and historical objects. Terahertz spectral databases of modern and ancient artists' pigments exist but lack explanations for the origins of the unique spectral features. Solid-state density functional theory simulations can provide insight into the molecular and intermolecular forces that dominate the observed absorption features as well as reveal deviations from simple harmonic vibrational behavior that can complicate these spectra. The characteristic terahertz spectra of solid azurite, malachite, and verdigris are presented here, along with simulations of their crystalline structures and sub-3.0 THz lattice vibrations. The powerful combination of theory and experiment enables unambiguous spectral assignment of these complex materials and highlights the challenges that anharmonic peak broadening in organic-containing materials may present in the construction of reference pigment databases.

Methyl-rotation dynamics in metal-organic frameworks probed with terahertz spectroscopy.

In ZIF-8 and its cobalt analogue ZIF-67, the imidazolate methyl-groups, which point directly into the void space, have been shown to freely rotate - even down to cryogenic temperatures. Using a combination of experimental terahertz time-domain spectroscopy, low-frequency Raman spectroscopy, and state-of-the-art ab initio simulations, the methyl-rotor dynamics in ZIF-8 and ZIF-67 are fully characterized within the context of a quantum-mechanical hindered-rotor model. The results lend insight into the fundamental origins of the experimentally observed methyl-rotor dynamics, and provide valuable insight into the nature of the weak interactions present within this important class of materials.

Optical Properties of Meloxicam in the Far-Infrared Spectral Region.

One of the most commonly used nonsteroidal anti-inflammatory active pharmaceutical ingredient called Meloxicam has been characterized spectroscopically both by Terahertz (THz) time domain spectroscopy (THz-TDS) and by Fourier Transform Infrared (FTIR) spectroscopy in far-IR regions of electromagnetic spectrum; 0.2 THz to 20 THz. While many relatively sharp features are observed in the far-IR range between 2 THz to 20 THz as expected for being an organic substance, very distinct and relatively strong absorption bands are also observed at 1.00, 1.66, 2.07 and 2.57 THz in the THz range. These well separated, defined, and fairly strong spectral features can be used for discrimination and quantification of Meloxicam in drug analysis. Frequency dependent refractive index of the drug was determined in a range of 0.2 THz and 2.7 THz, where an almost constant index was observed with an average index of 1.75. Powder XRD, and solid-state Density Functional Theory (SS-DFT) calculations were utilized to determine the crystalline form of the Meloxicam sample in its enolic crystalline form. Single molecule DFT calculations were also performed in all four possible structures of Meloxicam. In addition, the capability of THz waves transmission through common packaging materials is demonstrated for possibility of future on-site analysis. The results suggest that drug analysis will be possible to perform not only at every stage of manufacturing without destruction but also directly at the shelf of a market after development of portable THz technologies.

The significance of the amorphous potential energy landscape for dictating glassy dynamics and driving solid-state crystallisation.

The fundamental origins surrounding the dynamics of disordered solids near their characteristic glass transitions continue to be fiercely debated, even though a vast number of materials can form amorphous solids, including small-molecule organic, inorganic, covalent, metallic, and even large biological systems. The glass-transition temperature, Tg, can be readily detected by a diverse set of techniques, but given that these measurement modalities probe vastly different processes, there has been significant debate regarding the question of why Tg can be detected across all of them. Here we show clear experimental and computational evidence in support of a theory that proposes that the shape and structure of the potential-energy surface (PES) is the fundamental factor underlying the glass-transition processes, regardless of the frequency that experimental methods probe. Whilst this has been proposed previously, we demonstrate, using ab initio molecular-dynamics (AIMD) simulations, that it is of critical importance to carefully consider the complete PES - both the intra-molecular and inter-molecular features - in order to fully understand the entire range of atomic-dynamical processes in disordered solids. Finally, we show that it is possible to utilise this dependence to directly manipulate and harness amorphous dynamics in order to control the behaviour of such solids by using high-powered terahertz pulses to induce crystallisation and preferential crystal-polymorph growth in glasses. Combined, these findings provide compelling evidence that the PES landscape, and the corresponding energy barriers, are the ultimate controlling feature behind the atomic and molecular dynamics of disordered solids, regardless of the frequency at which they occur.

Quantification of cation-anion interactions in crystalline monopotassium and monosodium glutamate salts.

Crystalline salt compounds composed of metal cations and organic anions are becoming increasingly popular in a number of fields, including the pharmaceutical and food industries, where such formulations can lead to increased product solubility. The origins of these effects are often in the interactions between the individual components in the crystals, and understanding these forces is paramount for the design and utilisation of such materials. Monosodium glutamate monohydrate and monopotassium glutamate monohydrate are two solids that form significantly different structures with correspondingly dissimilar dynamics, while their chemistry only differs in cation identity. Crystals of each were characterised experimentally with single-crystal X-ray diffraction and terahertz time-domain spectroscopy and theoretically using solid-state density functional theory simulations, in order to explain the observed differences in their bulk properties. Specifically, crystal orbital overlap and Hamiltonian population analyses were performed to examine the role that the individual interactions between the cation and anion played in the solid-state structures and the overall energetic profiles of these materials.

Concomitant polymorphism and the martensitic-like transformation of an organic crystal.

Crystalline polymorphism is a phenomenon that occurs in many molecular solids, resulting in a diverse range of possible bulk structures. Temperature and pressure can often be used to thermodynamically control which crystal form is preferred, and the associated transitions between polymorphic phases are often discontinuous and complete. N-Methyl-4-carboxypyridinium chloride is a solid that undergoes an apparent continuous temperature-dependent phase transition from an orthorhombic to a monoclinic polymorph. However, a hybrid characterization approach using single-crystal X-ray diffraction, terahertz time-domain spectroscopy, and solid-state density functional theory reveals the transformation to be actually a slowly changing ratio of the two discrete polymorphic forms. The potential energy surface of this process can be directly accessed using terahertz radiation, and the data show that a very low barrier (43.3 J mol-1) exists along the polymorph transformation coordinate.