Naoki Wakiyama

Stability of amorphous indomethacin compounded with silica

The stability of indomethacin (IM) compounded with SiO(2) either by co-grinding or by melt-quenching was examined by recrystallization kinetics under the conditions 30 degrees C and 11% relative humidity. A decrease of the recrystallization rate with and without an appreciable induction period was observed in both compounds. Higher stability of amorphous IM compounded with SiO(2) was attained by prolonged co-grinding than by melt-quenching. This was explained by the stronger chemical interaction at the interface between IM and SiO(2) by co-grinding, as revealed by (29)Si and (13)C solid state NMR. Incomplete co-grinding with the rest of the crystalline state, however, made the amorphous state appreciably unstable, since the remaining crystallites serve as seeds for recrystallization.

Comparison between polyvinylpyrrolidone and silica nanoparticles as carriers for indomethacin in a solid state dispersion.

States of interaction between indomethacin (IM) and polyvinylpyrrolidone (PVP) in an amorphous solid dispersion prepared by co-grinding were compared with those between IM and silica nanoparticles. Changes in the carbon chemical states of the solid dispersions were evaluated based on the chemical shift in the 13C-CP/MAS-NMR. Hydrogen bonds between the amide carbonyl of PVP particles and the carboxyl groups of IM molecules were formed by co-grinding. Despite the wide difference in carrier properties, the apparent equilibrium solubility (AES) of IM in the ground IM-PVP mixture was predicted by solid state NMR on the basis of the relationship previously established for IM with SiO(2). This indicates that AES is affected solely by the state of IM, irrespective of the carrier species, and despite carrier-dependent chemical interactions.

Stabilization of amorphous indomethacin by co-grinding in a ternary mixture.

Mechanochemical amorphization of indomethacin (IM) was substantially enhanced by grinding with SiO(2), talc and a Mg(OH)(2)-SiO(2) mixture. The rates of the mechanochemical amorphization were in the order of Mg(OH)(2)-SiO(2) mixture>talc>SiO(2). Amorphous state stability of IM compounded with the carrier was examined by crystallization behavior under the condition of 30 degrees C and 11% relative humidity. Superiority of the binary mixture as a carrier was explained in terms of the mechanically induced strong acidic sites of the carrier.

Fc domain mediated self-association of an IgG1 monoclonal antibody under a low ionic strength condition

Recently, we reported that IgG1 monoclonal antibody A (MAb A) underwent liquid-liquid phase separation and separated into light and heavy phases under a low ionic strength condition. The liquid-liquid phase separation was induced due to self-association of MAb A in the heavy phase when the initial concentration of MAb A was between the two critical concentrations [Nishi et al., Pharm. Res., 27, 1348-1360 (2010)]. Here, we determined the interaction site of MAb A by using proteolytic Fab and Fc fragments of MAb A. The mean hydrodynamic diameter of the Fc fragment increased in a low ionic strength buffer, and furthermore the SPR measurement detected interactions of the Fc fragment with both whole MAb A and the Fc fragment, whereas the Fab fragment interacted with neither whole MAb A nor the Fc fragment. No binding was detected under an isotonic ionic strength condition. Zeta potential of MAb A was significant positive below pH 5.5 and negative above pH 6.5. Between pH 5.5 and 6.5 where the phase separation is significantly induced, MAb A had only a small positive or negative net charge. The isothermal titration calorimetry dilution method revealed that dissociation of MAb A accompanied endothermic heat changes, suggesting that intermolecular interactions among MAb A molecules were attributed to the enthalpically driven process. These results suggest that liquid-liquid phase separation of MAb A is mediated by a weak electrostatic intermolecular interaction among MAb A molecules mainly at Fc portions.

Prediction of apparent equilibrium solubility of indomethacin compounded with silica by 13C solid state NMR.

The apparent equilibrium solubility (AES) of indomethacin increased by co-grinding with silica. Change in the long- and short range disorder of indomethacin by co-grinding was examined by X-ray powder diffraction and 13C solid state NMR, respectively, to elucidate the increased AES. Since the increase in AES was particularly marked after complete disappearance of X-ray diffraction peaks, we attributed the enhanced AES primarily to the short range disorder on the molecular basis. This was confirmed by a high correlation between the standardized full width at half maximum (SFWHM) of the specific peaks observed by 13C solid state NMR and log (AES). The correlation enables the prediction of AES as well.

Real-time monitoring of lubrication properties of magnesium stearate using NIR spectrometer and thermal effusivity sensor

Real-time monitoring techniques based on an NIR spectrometer and a thermal effusivity sensor for lubrication properties of magnesium stearate (Mg-St) are proposed. The lubrication properties of Mg-St are defined by its concentration distribution and flatting state in a mixture. The concentration distribution of Mg-St significantly affects the absorbance in the NIR wavelength region between 1128 nm and 1240 nm. Thus, the absorbance area in this region after baseline correction was selected as a monitoring index (MI). In laboratory-scale experiments, the difference of Mg-St concentration distribution could be detected by the proposed MI with high sensitivity. In addition, experimental results using spherical mannitol granules confirmed that the changes of the flatting state of Mg-St could also be detected by the proposed MI. Similar experiments with spherical mannitol granules and the thermal effusivity sensor confirmed that effusivity could also be used to detect the changes of the flatting state of Mg-St. The applicability of these monitoring techniques was verified using a 2000 L commercial-scale blender equipped with the NIR spectrometer and the thermal effusivity sensor. The results showed that both lubrication properties could be monitored by the proposed MI, and that the flatting state of Mg-St could be monitored more sensitively by using the effusivity.

Solid phase transition of CS-891 enantiotropes during grinding.

The physical properties of N-[1-(4-methoxyphenyl)-1-methylethyl]-3-oxo-4-aza-5a-androst-1-ene-17beta-carboxamide (CS-891), a novel and orally effective testosterone 5-reductase inhibitor, were investigated by differential scanning calorimetry, powder X-ray diffraction at elevated temperature and single crystal X-ray crystallography. CS-891 was revealed to exist as two enantiotropic forms, a low-temperature stable form (Form A) and a high-temperature stable form (Form B) which reversibly transforms to Form A at around 58 degrees C. The effect of grinding temperature on the transition of CS-891 between the amorphous and the crystalline state during grinding of the eantiotropes was examined. Form A transformed into an amorphous form during the grinding process while the product temperature was kept below the transition temperature. On the other hand, when the product temperature during grinding reached above the transition temperature, Form A transformed into an amorphous form and some of the amorphous form converted back to Form B. Form B crystallized from the amorphous form was physically stable even at below the transition temperature. The amorphous form in equilibrium with Form B exhibited remarkable physical stability in comparison with the amorphous form obtained by continued grinding below the transition temperature.

Verification of model development technique for NIR-based real-time monitoring of ingredient concentration during blending.

There has been a considerable research on the process analytical technology (PAT) and real-time monitoring based on NIR, but the model development is still an important issue and persons in charge have difficulty in building good models. In this study, to realize efficient NIR-based real-time monitoring of ingredient concentration and establish a model development method, we investigated the effect of a calibration set, spectral preprocessing, wavelengths, and other factors on the prediction error through pilot and commercial scale blending experiments. The results confirmed that the small prediction error was realized by a calibration set, including dynamic measurement spectra acquired with the target blender. In addition, the results demonstrated that locally weighted partial least squares (LW-PLS) achieved the smaller prediction error than conventional PLS. The present study has also clarified that spectral preprocessing methods and wavelengths selected to build a model affect the prediction error of ingredient concentration interactively. A wide wavelength range should be selected when the spectral preprocessing does not lessen the effect of baseline variation, while a narrow wavelength range should be selected when it strongly decreases the effect.

Determination for dry layer resistance of sucrose under various primary drying conditions using a novel simulation program for designing pharmaceutical lyophilization cycle.

Dry layer resistance, which is the resistance of dried cake against water vapor flow generated from sublimation, is one of the important parameters to predict maximum product temperature and drying time during primary drying in lyophilization. The purpose of this study was to develop the predictive model of dry layer resistance under various primary drying conditions using the dry layer resistance obtained from a preliminary lyophilization run. When the maximum dry layer resistance was modified under the assumption that the chamber pressure is zero, the modified dry layer resistance, which is defined as specific dry layer resistance, correlated well with the sublimation rate. From this correlation, the novel predictive model including the empirical formula of sublimation rate and specific dry layer resistance is proposed. In this model, the dry layer resistance under various conditions of shelf temperature and chamber pressure was successfully predicted based on the relationship of the sublimation rate and specific dry layer resistance of the edge and center vials obtained from the product temperature in one preliminary cycle run. It is expected that this predictive model could be a practical and useful tool to predict product temperature during primary drying.

Optimization of secondary drying condition for desired residual water content in a lyophilized product using a novel simulation program for pharmaceutical lyophilization.

The aim of this study was to optimize the shelf temperature and the drying time, mainly dependent on the residual water content of a lyophilized product using a novel simulation program for the secondary drying of lyophilization. The simulation program was developed based upon heat transfer formulas, two empirical formulas, and a modified Ficks second law. When a preliminary lyophilization run of secondary drying was carried out, the equilibrium product temperature at the end of secondary drying under various shelf temperatures was accurately predicted by the heat transfer formulas. The apparent diffusion coefficient of water, Deff, and the apparent equilibrium residual water content, We, under the predicted equilibrium product temperature were estimated by two empirical formulas. These estimated Deff and We allow the modified Ficks second law to predict the residual water content in the lyophilized product. Using the developed simulation program, it was verified that the secondary drying condition to achieve the desired residual water content in the lyophilized product was successfully predicted. Therefore, the simulation program can be used to effectively design the secondary drying condition of lyophilization cycles without a trial and error approach.