Chemical mapping of hydration and dehydration process of theophylline in tablets using terahertz pulsed imaging

The purpose of this research is to investigate the topographical pattern of hydration and dehydration (also known as pseudo-polymorphic change) of drug substance in drug product using terahertz (THz) pulsed imaging. Emphasis is placed on (1) applicability of THz pulsed imaging and (2) kinetic analysis in the pseudo-polymorphic change. Either anhydrous or monohydrated form of theophylline was used as the drug substance, leading to initially anhydrous or monohydrated tablets. These tablets were stored at 25°C to keep the relative humidity constant at 84% (anhydrous tablets) or 45% (monohydrated tablets), respectively. The THz pulsed imaging was confirmed to enable visualization that the hydration of the anhydrous form or the dehydration of the monohydrated form began on the surface of the tablets and gradually progressed to the core side in the tablets with storage. Kinetic studies indicated that these pseudo-polymorphic changes followed the phase boundary mechanism. Since the other imaging techniques has been scarcely achieved to show the topographical pattern of pseudo-polymorphic change of drug substances in drug products directly and visually, it is considered that THz pulsed imaging has a potential ability to solve complicated issues in pharmaceutical development.     

Do amorphous troglitazones prepared from two diastereomer-pairs have the same molecular mobility and crystallization rate at the surface?

The surface of amorphous compounds crystallizes faster compared to the bulk. This suggests that molecules at the surface have high molecular mobility. Crystallization behavior is affected by various factors including molecular weight and glass transition temperature (T(g)). In this study, we focus on troglitazone which is composed of diastereomers, RR/SS and RS/SR, as model compound, because each diastereomer has the same molecular weight and similar chemical structure. Troglitazone is isolated into each diastereomer, and both amorphous prepared from RR/SS and RS/SR showed similar T(g) (around 60°C). The surface relaxation of each amorphous troglitazone prepared from two diastereomers, RR/SS and RS/SR, was determined to compare surface molecular mobility, using inverse gas chromatography under dry conditions. As a result, amorphous prepared from RS/SR, showed the shorter surface relaxation time at 40°C (temperature below T(g)), which means it has higher molecular mobility than that from RR/SS at the surface although both have the same molecular weight and similar T(g). Microscopy analysis was conducted to observe the crstallization behavior at the surface of amorphous troglitazone in conditions of high temperature and humidity. Micrographs showed that crystallization area at the surface of amorphous prepared from RS/SR, which showed the shorter surface relaxation time, increased faster than that of the amorphous prepared from RR/SS. Although the reason for the difference in the surface relaxation time of each amorphous troglitazone could not be determined, factors such as the difference of configuration might affect the difference.     

Synthesis of Chiral Labtb and Visualization of Its Enantiomeric Excess by Induced Circular Dichroism Imaging

Crystalline particles of a microporous, robust, and chiral metal–organic framework (MOF) were synthesized and their enantiomer excess (ee) was visualized for each microparticle by CD imaging. Labtb, a thermally and chemically robust MOF, was employed in this study because it shows a chiral space group. Although Labtb has been obtained as a racemic conglomerate, enantioselective synthesis of Labtb was achieved via a chiral precursor complex consisting of lanthanum and homochiral phenylalanine. Methyl orange (MO) was introduced into the micropores of chiral Labtb, which showed a strong induced CD signal for the absorption band of MO chromophores. High ee of the chiral Labtb was revealed by microscopic CD observation at the particle-level. This result provides a facile way to obtain a robust MOF that has chiral nanospace.     

Development of a rapid process monitoring method for dry-coated tableting process by using near-infrared spectroscopy

A nondestructive transmittance near-infrared (NIR) method for detecting off-centered cores in dry-coated (DC) tablets was developed as a monitoring system in the DC tableting process. Caffeine anhydrate was used as a core active pharmaceutical ingredient (API), and DC tablets were made by the direct compression method. NIR spectra were obtained from these intact DC tablets using the transmittance method. The reference assay was performed with HPLC. Calibration models were generated by partial least squares (PLS) regression and principal component regression (PCR) utilizing external validations. Hierarchical cluster analysis (HCA) of the results confirmed that NIR spectroscopy correctly detected off-centered cores in DC tablets. We formulated and used the Centering Index (CI) to evaluate the precision of core alignment and generated an NIR calibration model that could correctly predict this index. The principal component (PC) 1 loading vector of the final calibration model indicated that it could specifically detect the misalignment of tablet cores. The model also had good linearity and accuracy. The CIs of unknown sample tablets predicted by the final calibration model and those calculated through the HPLC analysis were closely parallel with each other. These results demonstrate the validity of the final calibration model and the utility of the transmittance NIR spectroscopic method developed in this study as a monitoring system in DC tableting process.     

Miscibility of polymer blends studied by a simplified method of data analysis using light heating modulated temperature DSC

A simple method of application of light heating modulated temperature DSC to a study of miscibility of polymer blends has been developed. In this method only the sample was measured and the standard materials were not used. The total heat flow, the complex heat capacity, the reversing and non-reversing heat flows were obtained as values measured from those quantities in hypothetical glassy state at T>T_g. The values of the hypothetical glassy state were calculated by extrapolation from T<T_g. The present method gives relative values but useful information can be obtained from the results. Some results from miscible and immiscible polymer blends are shown. This revised version was published online in July 2006 with corrections to the Cover Date.     

Solid State Radical Recombination and Charge Transfer across the Boundary between Indomethacin and Silica under Mechanical Stress

A composite of indomethacin (IM) and SiO₂ was prepared in a solid state by cogrinding. Dehydration was observed as a consequence of a chemical reaction between silanol groups of SiO₂ and carboxyl groups of IM. Several specific radical species found on separately ground SiO₂ disappeared preferentially after cogrinding as a result of their recombination. These chemical interactions under mechanical stress bring about a charge transfer, as confirmed by X-ray photoelectron spectroscopy, leading to Si-O-C bridging bond formation at the IM/SiO₂ interface.     

Growth of Cu(AlxGa1−x)SSe pentenary alloy crystals by iodine chemical vapor transport method

Single crystals of Cu(Al_xGa_1−x)SSe pentenary alloys were successfully grown by the vapor transport technique using iodine as a transport agent. Systematic measurements of the basic crystal properties were carried out using powder X-ray, photoluminescence (PL), photoreflectance (PR), and Van der Pauw methods. Dependence of the lattice constants, exciton transition energies, and PL peak energies on Al composition, x, were examined in detail. The lattice constants obeyed Vegard's law. A quadratic dependence of exciton transition energies on x was found. The broadening parameters in the PR spectrum increase monotonically with increasing x, the results showing that the crystal quality degrades with increasing x. Exciton-related PL peaks were found for 0 ≤ x ≤ 0.77 at 77 K.