Characterization of organic crystals for second-harmonic generation.

Second-harmonic generation (SHG) is a common technique with many applications. Common inorganic single-crystalline materials used to produce SHG light are effective using short IR/visible wavelengths but generally do not perform well at longer, technologically relevant IR wavelengths such as 1300, 1550, and 2000 nm. Efficient SHG materials possess many of the same key material properties as terahertz (THz) generators, and certain single-crystalline organic THz generation materials have been reported to perform at longer IR wavelengths. Consequently, this work focuses on characterizing three efficient organic THz generators for SHG, namely, DAST (trans-4-[4-(dimethylamino)-N-methylstilbazolium] p-tosylate), DSTMS (4-N,N-dimethylamino-4'-N'-methylstilbazolium 2,4,6-trimethylbenzenesulfonate), and the recently discovered generator PNPA ((E)-4-((4-nitrobenzylidene)amino)-N-phenylaniline). All three of these crystals outperform the beta-barium borate (BBO), an inorganic material commonly used for SHG, using IR pump wavelengths (1200-2000 nm).

Temporal Profile of Nonresonant Sum-Frequency Signal from Single-Crystal Silicon Depends on Crystal Orientation.

Proper analysis of vibrational sum-frequency generation (VSFG) spectra requires that the nonresonant contribution be dealt with correctly. This work shows that the temporal profile of the nonresonant SFG response varies with crystal facing and sample orientation for single-crystal Si and is significantly different than what is observed with polycrystalline Au. These considerations will affect the use of time-delay methods to experimentally suppress the nonresonant signal in broadband SFG measurements. Time-resolved or phase-sensitive SFG measurements will also need to properly account for these effects in post-processing.

The 2018 Nobel Prize in Physics: optical tweezers and chirped pulse amplification.

The 2018 Nobel Prize in Physics was awarded to Arthur Ashkin (prize share ½), Gérard Mourou (prize share »), and Donna Strickland (prize share ») for "groundbreaking inventions in the field of laser physics." This feature article summarizes the development of "optical tweezers and their application to biological systems" by Arthur Ashkin, as well as the Mourou/Strickland method of "generating high-intensity, ultrashort optical pulses" known as chirped pulse amplification. Further developments are also briefly discussed.

Surface Spectroscopic Signatures of Mechanical Deformation in High-Density Polyethylene (HDPE).

High-density polyethylene (HDPE) has been extensively studied, both as a model for semi-crystalline polymers and because of its own industrial utility. During cold drawing, crystalline regions of HDPE are known to break up and align with the direction of tensile load. Structural changes due to deformation should also manifest at the surface of the polymer, but until now, a detailed molecular understanding of how the surface responds to mechanical deformation has been lacking. This work establishes a precedent for using vibrational sum-frequency generation (VSFG) spectroscopy to investigate changes in the molecular-level structure of the surface of HDPE after cold drawing. X-ray diffraction (XRD) was used to confirm that the observed surface behavior corresponds to the expected bulk response. Before tensile loading, the VSFG spectra indicate that there is significant variability in the surface structure and tilt of the methylene groups away from the surface normal. After deformation, the VSFG spectroscopic signatures are notably different. These changes suggest that hydrocarbon chains at the surface of visibly necked HDPE are aligned with the direction of loading, while the associated methylene groups are oriented with the local C2v symmetry axis roughly parallel to the surface normal. Small amounts of unaltered material are also found at the surface of necked HDPE, with the relative amount of unaltered material decreasing as the amount of deformation increases. Aspects of the nonresonant SFG response in the transition zone between necked and undeformed polymer provide additional insight into the deformation process and may provide the first indication of mechanical deformation. Nonlinear surface spectroscopy can thus be used as a noninvasive and nondestructive tool to probe the stress history of a HPDE sample in situations where X-ray techniques are not available or not applicable. Vibrational sum-frequency generation thus has great potential as a platform for material state awareness (MSA) and should be considered as part of a broader suite of tools for such applications.

Polarization and phase characteristics of nonresonant sum-frequency generation response from a silicon (111) surface.

Silicon (111) [Si(111)] surfaces both with and without a thin film of polystyrene are investigated with sum-frequency generation (SFG) spectroscopy with s-polarized visible and p-polarized infrared inputs. On uncoated Si, the nonresonant polarization changes from s to p, with the maximum signal in each polarization component repeating every 60° of sample rotation. With polystyrene on Si(111), the resonant features go in and out of phase with the nonresonant signal every 120°. The resonant response is only s polarized, as expected; however, the nonresonant response again switches between s and p polarizations. Implications for proper collection and interpretation of SFG spectra from crystalline substrates are discussed.

The solid-state continuum: a perspective on the interrelationships between different solid-state forms in drug substance and drug product.

OBJECTIVE: The objective of the review is to provide an overview of the nomenclature used in the solid-state continuum and relate these to the development of drug substances and drug products. KEY FINDINGS: The importance of a rational approach to solid-state form selection, including integrated decision making (ensuring equal weight is given to the needs of the drug substance and the drug product), is vital for the effective development of a drug candidate. For example, how do secondary processing considerations influence the selection of drug substance solid-state form and resulting formulation, and how can drug substance solid-state form be used to optimise secondary processing? Further, the potential use of 'crystal' engineering to optimise stability, purity and optical resolutions, and the linked regulatory requirements, will be discussed. SUMMARY: The nomenclature used in the solid-state continuum, which contains a large number of different crystalline and non-crystalline forms, for example, amorphous systems, was reviewed. Further, the significant role of the drug substance within the solid oral dose form from a physicochemical perspective was covered.

Plasma treatment of polystyrene thin films affects more than the surface.

Plasma treatment of polymer materials introduces chemical functionalities and modifies the material to make the native hydrophobic surface more hydrophilic. It is generally assumed that this process only affects the surface of the material. We used vibrationally resonant sum-frequency generation spectroscopy to observe changes in the orientation of phenyl groups in polystyrene (PS) thin films on various substrates before and after plasma treatment. VR-SFG selectively probes regions of broken symmetry, such as surfaces, but can also detect the emergence of anisotropy. On dielectric substrates, such as fused silica, the spectroscopic peak corresponding to the symmetric stretching (ν2) mode of the phenyl rings was undetectable after plasma treatment, showing that surface phenyl rings were altered. This peak also diminished on conducting substrates, but the intensity of another peak corresponding to the same mode in a bulklike environment increased significantly, suggesting that plasma treatment induces partial ordering of the bulk polymer. This ordering is seen on conducting substrates even when the polymer is not directly exposed to the plasma. Annealing reverses these effects on the polystyrene bulk; however, the surface phenyl rings do not return to the orientation observed for untreated films. These results call into question the assumption that the effects of plasma treatment are limited to the free surface and opens up other possibilities for material modification with low-temperature plasmas.

Role of nonresonant sum-frequency generation in the investigation of model liquid chromatography systems.

In vibrationally resonant sum-frequency generation (VR-SFG) spectra, the resonant signal contains information about the molecular structure of the interface, whereas the nonresonant signal is commonly treated as a background and has been assumed to be negligible on transparent substrates. The work presented here on model chromatographic stationary phases contradicts this assumption. Model stationary phases, consisting of functionalized fused-silica windows, were investigated with VR-SFG spectroscopy, both with and without experimental suppression of the nonresonant response. When samples are moved from CD(3)OD to D(2)O, the VR-SFG spectrum was found to change over time when the nonresonant signal was present but not when the nonresonant signal was suppressed. No effect was seen when the solvent was changed and pressurized to 900 psi. These results suggest that the response to the new solvent manifests primarily in the nonresonant response, not the resonant response. Any structural changes caused by the new solvent environment appear to be minor. The nonresonant signal is significant and must be properly isolated from the resonant signal to ensure a correct interpretation of the spectral data. Curve-fitting procedures alone are not sufficient to guarantee a proper interpretation of the experimental results.

Back-surface gold mirrors for vibrationally resonant sum-frequency (VR-SFG) spectroscopy using 3-mercaptopropyltrimethoxysilane as an adhesion promoter.

Back-surface mirrors are needed as reference materials for vibrationally resonant sum-frequency generation (VR-SFG) probing of liquid-solid interfaces. Conventional noble metal mirrors are not suitable for back-surface applications due to the presence of a metal adhesion layer (chromium or titanium) between the window substrate and the reflective metal surface. Using vapor deposited 3-mercaptopropyltrimethoxysilane (MPTMS) as a bi-functional adhesion promoter, gold mirrors were fabricated on fused silica substrates. These mirrors exhibit excellent gold adhesion as determined by the Scotch(®) tape test. They also produce minimal spectroscopic interference in the C-H stretching region (2800-3000 cm(-1)), as characterized by VR-SFG. These mirrors are thus robust and can be used as back-surface mirrors for a variety of applications, including reference mirrors for VR-SFG.

Multilayer polymer microchip capillary array electrophoresis devices with integrated on-chip labeling for high-throughput protein analysis.

It is desirable to have inexpensive, high-throughput systems that integrate multiple sample analysis processes and procedures, for applications in biology, chemical analysis, drug discovery, and disease screening. In this paper, we demonstrate multilayer polymer microfluidic devices with integrated on-chip labeling and parallel electrophoretic separation of up to eight samples. Microchannels were distributed in two different layers and connected through interlayer through-holes in the middle layer. A single set of electrophoresis reservoirs and one fluorescent label reservoir address parallel analysis units for up to eight samples. Individual proteins and a mixture of cancer biomarkers have been successfully labeled on-chip and separated in parallel with this system. A detection limit of 600 ng/mL was obtained for heat shock protein 90. Our integrated on-chip labeling microdevices show great potential for low-cost, simplified, rapid, and high-throughput analysis.

The Role of Configurational Entropy in Amorphous Systems.

Configurational entropy is an important parameter in amorphous systems. It is involved in the thermodynamic considerations, plays an important role in the molecular mobility calculations through its appearance in the Adam-Gibbs equation and provides information on the solubility increase of an amorphous form compared to its crystalline counterpart. This paper presents a calorimetric method which enables the scientist to quickly determine the values for the configurational entropy at any temperature and obtain the maximum of information from these measurements.

Applying thermodynamic and kinetic parameters to predict the physical stability of two differently prepared amorphous forms of simvastatin.

Converting drugs from the crystalline to the amorphous state has gained increasing interest in the past decades as a potential method to overcome solubility issues of poorly water soluble drugs. A variety of techniques exist to convert the crystalline state of a drug to its amorphous form, including solution based, heat based and solid - solid conversion based methods. Inherent to the amorphous state, regardless of its preparation technique, is its physical instability and tendency to recrystallize. In this study, quench-cooled and cryo-milled simvastatin were compared with regards to their configurational thermodynamic parameters (entropy, enthalpy and Gibbs free energy) and mobility (relaxation times calculated using the Adam-Gibbs and Kohlrausch-Williams-Watts method). Stability studies showed quench-cooled simvastatin to be more stable than cryo-milled simvastatin. This was reflected in the calculated parameters although their absolute values did not agree with the stability behaviour. Relaxation time parameters of tau = 6.9 x 10(4) s for quench-cooled and tau = 1.7 x 10(4) s for cryo-milled simvastatin were calculated. The results from this study suggested that differences in the physical stability of amorphous forms prepared by different techniques are reflected in their mobility and thermodynamic parameters. Even though the predictive capabilities of these parameters for a set of different drugs may be limited, they can serve as a predictive tool for physical stability assessment if differently prepared amorphous forms of the same drug are investigated.

Correlating thermodynamic and kinetic parameters with amorphous stability.

Poor physical stability is one of the single most important factors limiting the widespread use of the amorphous state in pharmaceutics. The purpose of this study is to move away from the case study approach by investigating thermodynamic and kinetic parameters as potential predictors of physical stability of amorphous drugs for a larger sample set (12 drugs). The relaxation time, fragility index and configurational thermodynamic properties (enthalpy, entropy and Gibbs free energy) were calculated and correlated to the actual stability behaviour, obtained for 12 drugs. Below the glass transition temperature the relaxation time and fragility showed no correlation with the observed physical stability. All drugs were calculated to be 'fragile'. However, variation in the fragility index existed, with values spanning from 8.9 to 21.3, manifesting themselves as differences in the temperature dependencies of the relaxation times. A reasonable correlation between the thermodynamic parameters and the stability above T(g) was found, with the configurational entropy exhibiting the strongest correlation (r(2)=0.685). However, it could also be shown that below T(g) no clear relationship between the various factors determined and physical stability exists, indicating that stability predictions on the basis of relaxation time alone may be inadequate.

Shock wave induced decomposition of RDX: quantum chemistry calculations.

Quantum chemical calculations on single molecules were performed to provide insight into the decomposition mechanism of shocked RDX. These calculations complement time-resolved spectroscopy measurements on shock wave compressed RDX crystals (previous paper, this issue). It is proposed that unimolecular decomposition is the primary pathway for RDX decomposition in its early stages and at stresses lower than approximately 10 GPa. This decomposition leads to the generation of broadband emission from 350 to 850 nm. Chemiluminescence from (2)B1 and (2)B2 excited states of NO2 radicals is associated with a major portion of the experimentally observed emission spectrum (>400 nm). The remaining portion (<400 nm) of the emission spectrum primarily results from excited HONO intermediates. It is proposed that for stresses higher than 10 GPa, bimolecular reactions between radical decomposition products and unreacted RDX molecules become the dominant pathway. This radical assisted homolysis pathway is cyclic and leads to the acceleration of decomposition, with increased production of low energy NO2 radicals. These radicals produce emission that is stronger in the long wavelength portion of the spectrum. Finally, a comprehensive chemical decomposition mechanism is put forward that is consistent with the experimental observations of shock-induced emission in RDX crystals.

Shock wave induced decomposition of RDX: time-resolved spectroscopy.

Time-resolved optical spectroscopy was used to examine chemical decomposition of RDX crystals shocked along the [111] orientation to peak stresses between 7 and 20 GPa. Shock-induced emission, produced by decomposition intermediates, was observed over a broad spectral range from 350 to 850 nm. A threshold in the emission response of RDX was found at about 10 GPa peak stress. Below this threshold, the emission spectrum remained unchanged during shock compression. Above 10 GPa, the emission spectrum changed with a long wavelength component dominating the spectrum. The long wavelength emission is attributed to the formation of NO2 radicals. Above the 10 GPa threshold, the spectrally integrated intensity increased significantly, suggesting the acceleration of chemical decomposition. This acceleration is attributed to bimolecular reactions between unreacted RDX and free radicals. These results provide a significant experimental foundation for further development of a decomposition mechanism for shocked RDX (following paper in this issue).

Melt extrusion and spray drying of carbamazepine and dipyridamole with polyvinylpyrrolidone/vinyl acetate copolymers.

AIM: Carbamazepine and dipyridamole are class II compounds (BCS) whose oral bioavailability is limited by poor solubility. The use of glass solutions to improve the bioavailability of this class of compound has been an area of research for a number of years. The influence of polymer parameters (Tg, hydrophilicity, solubility parameter, and ability to hydrogen bond) on glass solution properties is investigated. METHODS: Carbamazepine and dipyridamole glass solutions are prepared with PVP/VA 64 and PVP/VA 37 by spray drying and melt extrusion. The products are then characterized by XRPD, thermal, and spectroscopic methods. Yield, physical stability, and dissolution profiles are also assessed. RESULTS: The properties of the polymer greatly influenced the ability to produce glass solutions. With decreases in Tg and hydrophilicity, melt extrusion became the more viable of the two preparative techniques. Although glass solutions were successfully prepared, the greater the difference in component solubility parameter, the less physically stable the formulation. CONCLUSION: Consideration must be given to the characteristics of the polymer when selecting for glass solution formulation. Although a number of process parameters can be varied for melt extrusion and spray drying, their ability to overcome fundamental differences in the physical parameters discussed is limited.

Shock wave-induced phase transition in RDX single crystals.

The real-time, molecular-level response of oriented single crystals of hexahydro-1,3,5-trinitro-s-triazine (RDX) to shock compression was examined using Raman spectroscopy. Single crystals of [111], [210], or [100] orientation were shocked under stepwise loading to peak stresses from 3.0 to 5.5 GPa. Two types of measurements were performed: (i) high-resolution Raman spectroscopy to probe the material at peak stress and (ii) time-resolved Raman spectroscopy to monitor the evolution of molecular changes as the shock wave reverberated through the material. The frequency shift of the CH stretching modes under shock loading appeared to be similar for all three crystal orientations below 3.5 GPa. Significant spectral changes were observed in crystals shocked above 4.5 GPa. These changes were similar to those observed in static pressure measurements, indicating the occurrence of the alpha-gamma phase transition in shocked RDX crystals. No apparent orientation dependence in the molecular response of RDX to shock compression up to 5.5 GPa was observed. The phase transition had an incubation time of approximately 100 ns when RDX was shocked to 5.5 GPa peak stress. The observation of the alpha-gamma phase transition under shock wave loading is briefly discussed in connection with the onset of chemical decomposition in shocked RDX.

Preparation of glass solutions of three poorly water soluble drugs by spray drying, melt extrusion and ball milling.

The aim of this study was to investigate the influence of the manufacturing process on the physicochemical properties of three poorly water soluble compounds (carbamazepine, dipyridamole, and indomethacin) when processed with a polymer (polyvinylpyrrolidone K30 (PVP)) at a 1:2 drug to polymer ratio. Melt extrusion, spray drying, and ball milling techniques were used to prepare glass solutions. Product homogeneity, dissolution, physical stability, and drug/polymer interactions were investigated. Particular attention was paid to solid phase analysis using XRPD, modulated temperature DSC, optical microscopy, and Raman microscopy and the importance of using a combination of techniques was demonstrated. The latter technique when applied to freshly ball milled samples exhibited the presence of drug and polymer rich areas, indicating that complete glass solution formation had not occurred. The three compounds produced products with differing physical stability with indomethacin proving the most physically stable. These differences in physical stability were attributed to hydrogen bonding of drug and polymer. The manufacturing technique did not influence physical stability, but it did affect dissolution. The dissolution of the spray-dried material was generally poor, compared to melt extruded and ball milled products. This was probably due to rapid dissolution of PVP from the small particles of the spray-dried products.

The influence of thermal and mechanical preparative techniques on the amorphous state of four poorly soluble compounds.

A number of studies in the literature have reported on the use of different preparative techniques to convert crystalline pharmaceutical compounds into the amorphous form. However, very few direct comparisons of different preparative techniques using the same drugs are available. The purpose of this study was to determine the influence of two techniques: quench cooling and ball milling on four structurally diverse pharmaceutical drugs. Dipyridamole, carbamazepine, glibenclamide, and indomethacin were converted to the amorphous form by (a) quench cooling of the drug melt and (b) ball milling. The chemical purity and physical form of the products was determined using diffractometric, spectroscopic, and thermal analytical techniques. Products were analysed immediately post preparation and after storage under different stability conditions. Quench cooling of the melt resulted in amorphous conversion of all four compounds. However with glibenclamide, quench cooling resulted in unacceptable chemical degradation whereas ball milling of glibenclamide resulted in a change in the keto-enol tautomerism at the aryl amide moiety of this drug. Ball milling resulted in predominantly amorphous products for all compounds except carbamazepine. Ball milling of carbamazepine resulted in a polymorphic transition of the starting material to form III. Physical stability studies showed that irrespective of preparative technique and storage conditions all samples showed at least partial reversion to the crystalline state after storage. Quench cooling of drug melts may be of use as a preparative technique however it can result in chemical degradation. Ball milling may also be of use as a preparative technique however its effectiveness is dependent on the unit cell structure of the compound.

Ultrafast dynamics of shock compression of molecular monolayers.

Femtosecond laser-driven approximately 1 GPa shock waves are used to compress monolayers of hydrocarbon chains. Vibrational sum-frequency generation spectroscopy probes the orientation of the terminal methyl groups. With an odd number (15) of carbon atoms, shock compression is an elastic process that causes the methyl groups to tilt. With an even number (18) of carbon atoms, shock compression is viscoelastic, creating single and double gauche defects. When the shock unloads, single gauche defects remain while double defects relax in 30 ps to single-defect states with more upright methyl groups.