Scott J. Toth

Effect of Substrates on Naproxen-Polyvinylpyrrolidone Solid Dispersions Formed via the Drop Printing Technique

Solid dispersions have been used to improve the bioavailability of poorly water-soluble drugs. However, drug solid-state phase, compositional uniformity, and scale-up problems are issues that need to be addressed. To allow for highly controllable products, the drop printing (DP) technique can provide precise dosages and predictable compositional uniformity of active pharmaceutical ingredients in two-/three-dimensional structures when integrated with edible substrates. With different preparation conditions, DP was conducted to fabricate naproxen (NAP)-polyvinylpyrrolidone solid dispersions with chitosan and hydroxypropyl methylcellulose films as the substrate. Scanning electron microscopy, X-ray diffraction, second harmonic generation microscopy, and atomic force microscopy analyses were performed to characterize the microstructure and spatial distribution of NAP in the solid dispersions. The results identified that composition, temperature, and substrate type all had an impact on morphology and crystallization of samples. The surface energy approach was combined with classical nucleation theory to evaluate the affinity between the nucleus of NAP and substrates. Finally, the collective results of the drug were correlated to the release profile of NAP within each sample.

Impact of Polymers on the Precipitation Behavior of Highly Supersaturated Aqueous Danazol Solutions

The phase behavior of supersaturated solutions of a relatively hydrophobic drug, danazol, was studied in the absence and presence of polymeric additives. To differentiate between phase separation to a noncrystalline phase and phase separation to a crystalline phase, an environmentally sensitive fluorescent probe was employed. Induction times for crystallization in the presence and absence of polymeric additives were studied using a combination of ultraviolet and fluorescence spectroscopy. It was found that, when danazol was added to aqueous media at concentrations above the amorphous solubility, liquid-liquid phase separation was briefly observed prior to crystallization, resulting in a short-lived, drug-rich noncrystalline danazol phase with an initial size of around 500 nm. The addition of polymers was found to greatly extend the lifetime of the supersaturated two phase system, delaying the onset of crystallization from a few minutes to a few hours. Below a certain threshold danazol concentration, found to represent the amorphous solubility, only crystallization was observed. Thus, although the addition of polymers was unable to prevent danazol from precipitating once a threshold concentration was exceeded, they did inhibit crystallization, leading to a solution with prolonged supersaturation. This observation highlights the need to determine the structure of the precipitating phase, since it is linked to the resultant solution concentration time profile.

Integrated nonlinear optical imaging microscope for on-axis crystal detection and centering at a synchrotron beamline

Nonlinear optical (NLO) instrumentation has been integrated with synchrotron X-ray diffraction for combined single-platform analysis, examining the viability of NLO microscopy as an alternative to the conventional X-ray raster scan for the purposes of sample centering. Second-harmonic generation microscopy and two-photon excited ultraviolet fluorescence microscopy were evaluated for crystal detection, and assessed by X-ray raster scanning.

Crystallization and Dissolution Behavior of Naproxen/Polyethylene Glycol Solid Dispersions

The crystallization kinetics of naproxen (NAP) in NAP/polyethylene glycol (NAP/PEG) solid dispersions prepared at different crystallization temperatures was studied by in situ small-angle X-ray scattering/wide-angle X-ray scattering (SAXS/WAXS). It was found that the crystallization rate of NAP was faster at 25 °C in comparison to 40 °C. This resulted in different sizes of NAP domains, and consequently impacted the dissolution behavior. The sizes of NAP domains prepared at 40 °C were larger than those at 25 °C, as determined with surface area analysis, utilizing second-order nonlinear optical imaging of chiral crystals (SONICC). Consistent with this observation, the corresponding dissolution rate of the NAP/PEG dispersion prepared at 40 °C was indeed slower than that prepared at 25 °C. The microstructure of the NAP/PEG solid dispersions and the dissolution behavior also showed a dependence on the chemical composition of the solid dispersions.

Nonlinear optical imaging for sensitive detection of crystals in bulk amorphous powders

The primary aim of this study was to evaluate the utility of second-order nonlinear imaging of chiral crystals (SONICC) to quantify crystallinity in drug-polymer blends, including solid dispersions. Second harmonic generation (SHG) can potentially exhibit scaling with crystallinity between linear and quadratic depending on the nature of the source, and thus, it is important to determine the response of pharmaceutical powders. Physical mixtures containing different proportions of crystalline naproxen and hydroxyl propyl methyl cellulose acetate succinate (HPMCAS) were prepared by blending and a dispersion was produced by solvent evaporation. A custom-built SONICC instrument was used to characterize the SHG intensity as a function of the crystalline drug fraction in the various samples. Powder X-ray diffraction (PXRD) and Raman spectroscopy were used as complementary methods known to exhibit linear scaling. SONICC was able to detect crystalline drug even in the presence of 99.9 wt % HPMCAS in the binary mixtures. The calibration curve revealed a linear dynamic range with a R(2) value of 0.99 spanning the range from 0.1 to 100 wt % naproxen with a root mean square error of prediction of 2.7%. Using the calibration curve, the errors in the validation samples were in the range of 5%-10%. Analysis of a 75 wt % HPMCAS-naproxen solid dispersion with SONICC revealed the presence of crystallites at an earlier time point than could be detected with PXRD and Raman spectroscopy. In addition, results from the crystallization kinetics experiment using SONICC were in good agreement with Raman spectroscopy and PXRD. In conclusion, SONICC has been found to be a sensitive technique for detecting low levels (0.1% or lower) of crystallinity, even in the presence of large quantities of a polymer.

Selective imaging of active pharmaceutical ingredients in powdered blends with common excipients utilizing two-photon excited ultraviolet-fluorescence and ultraviolet-second order nonlinear optical imaging of chiral crystals.

Second order nonlinear optical imaging of chiral crystals (SONICC) and two-photon excited fluorescence measurements [both autofluorescence and two-photon excited UV-fluorescence (TPE-UVF)] were assessed for the selective detection of APIs relative to common pharmaceutical excipients. Active pharmaceutical ingredients (APIs) compose only a small percentage of most tabulated formulations, yet the API distribution within the tablet can affect drug release and tablet stability. Complementary measurements using either UV-SONICC (266 nm detection) or TPE-UVF were shown to generate signals >50-fold more intense for a model API (griseofulvin) than those produced by common pharmaceutical excipients. The combined product of the measurements produced signals >10(4)-fold greater than the excipients studied. UV-SONICC or TPE-UVF produced greater selectivity than analogous measurements with visible-light detection, attributed to the presence of aromatic moieties within the API exhibiting strong one and two photon absorption at ~266 nm. Complementary SONICC and fluorescence measurements allowed for the sensitive detection of the three-dimensional distribution of tadalafil within a Cialis tablet to a depth of >140 μm.

Parts per Million Powder X-ray Diffraction

Here we demonstrate the use of second harmonic generation (SHG) microscopy-guided synchrotron powder X-ray diffraction (PXRD) for the detection of trace crystalline active pharmaceutical ingredients in a common polymer blend. The combined instrument is capable of detecting 100 ppm crystalline ritonavir in an amorphous hydroxypropyl methylcellulose matrix with a high signal-to-noise ratio (>5000). The high spatial resolution afforded by SHG microscopy allows for the use of a minibeam collimator to reduce the total volume of material probed by synchrotron PXRD. The reduction in probed volume results in reduced background from amorphous material. The ability to detect low crystalline loading has the potential to improve measurements in the formulation pipeline for pharmaceutical solid dispersions, for which even trace quantities of crystalline active ingredients can negatively impact the stability and bioavailability of the final drug product.

Water–solid interactions in amorphous maltodextrin-crystalline sucrose binary mixtures

Abstract Amorphous and crystalline solids are commonly found together in a variety of pharmaceutical and food products. In this study, the influence of co-formulation of amorphous maltodextrins (MDs) and crystalline sucrose (S) on moisture sorption, deliquescence, and glass transition (Tg) properties of powder blends was investigated. Individual components and binary mixtures of four different molecular weight MDs with sucrose in 1:1 w/w ratios were exposed to various relative humidity (RH) environments and their equilibrium and dynamic moisture contents were monitored. The deliquescence point (RH0) and dissolution behavior of sucrose alone and in blends was also monitored by polarized light microscopy and second harmonic generation imaging. In S:MD blends, the deliquescence RH of sucrose was lower than the RH0 of sucrose alone, and synergistic moisture sorption also occurred at RHs lower than the RH0. Intimate contact of sucrose crystals with the amorphous MDs resulted in complete dissolution of sucrose at RH < RH0. When blends were stored at conditions exceeding the Tg of the individual MDs (25 °C and 60%, 49% and 34%RH for MD21, MD29 and MD40, respectively), the Tg of the blends was lower than that of individual MDs. Thus, co-formulation of amorphous MDs with crystalline sucrose sensitizes the blend to moisture, potentially leading to deleterious changes in the formulation if storage conditions are not adequately controlled.

Imaging local electric fields produced upon synchrotron X-ray exposure.

Significance Exposure to high-energy X-rays, experienced during X-ray diffraction experiments for determining atomic structures, can potentially create large local electric fields from photoelectron ejection. Under cryogenic conditions, these fields may persist indefinitely. Mapping of electric fields is important for a complete understanding of damage mechanisms involved in X-ray measurements, for potential effects on the quality and interpretation of X-ray data, and for possible direct impact on diffraction resolution through the piezoelectric effect. Mapping of electric fields may also be useful in retaining a record of locations of X-ray exposure. In this paper, electric-field induced second harmonic generation imaging is explored in simulation and experiment. It provides insight into the position and distribution of local electric fields within an X-ray exposed sample. Electron–hole separation following hard X-ray absorption during diffraction analysis of soft materials under cryogenic conditions produces substantial local electric fields visualizable by second harmonic generation (SHG) microscopy. Monte Carlo simulations of X-ray photoelectron trajectories suggest the formation of substantial local electric fields in the regions adjacent to those exposed to X-rays, indicating a possible electric-field–induced SHG (EFISH) mechanism for generating the observed signal. In studies of amorphous vitreous solvents, analysis of the SHG spatial profiles following X-ray microbeam exposure was consistent with an EFISH mechanism. Within protein crystals, exposure to 12-keV (1.033-Å) X-rays resulted in increased SHG in the region extending ∼3 μm beyond the borders of the X-ray beam. Moderate X-ray exposures typical of those used for crystal centering by raster scanning through an X-ray beam were sufficient to produce static electric fields easily detectable by SHG. The X-ray–induced SHG activity was observed with no measurable loss for longer than 2 wk while maintained under cryogenic conditions, but disappeared if annealed to room temperature for a few seconds. These results provide direct experimental observables capable of validating simulations of X-ray–induced damage within soft materials. In addition, X-ray–induced local fields may potentially impact diffraction resolution through localized piezoelectric distortions of the lattice.

Linear fitting of multi-threshold counting data with a pixel-array detector for spectral X-ray imaging.

Experiments and modeling are described to perform spectral fitting of multi-threshold counting measurements on a pixel-array detector. An analytical model was developed for describing the probability density function of detected voltage in X-ray photon-counting arrays, utilizing fractional photon counting to account for edge/corner effects from voltage plumes that spread across multiple pixels. Each pixel was mathematically calibrated by fitting the detected voltage distributions to the model at both 13.5 keV and 15.0 keV X-ray energies. The model and established pixel responses were then exploited to statistically recover images of X-ray intensity as a function of X-ray energy in a simulated multi-wavelength and multi-counting threshold experiment.