Katsuhide Terada

Dissolution Improvement and the Mechanism of the Improvement from Cocrystallization of Poorly Water-soluble Compounds

PurposeTo demonstrate improvement in the dissolution of exemestane and megestrol acetate from cocrystallization using various particle sizes and to investigate the mechanism of the improved dissolution.MethodsCocrystal screening was performed by slurry crystallization. The cocrystals were identified and characterized by powder X-ray diffraction, thermal analysis, and single crystal X-ray diffraction. Different particle sizes of each cocrystal were prepared from organic solutions. Solubility and dissolution rates were evaluated using dissolution tests. Transformation behavior of the cocrystals in suspension was analyzed by PXRD and polarization microscopy.ResultsTwo novel cocrystals were obtained: exemestane (EX)/maleic acid (MAL) (cocrystal 1) and megestrol acetate (MA)/saccharin (SA) (cocrystal 2). Cocrystal 1 showed a high dissolution rate even with large particles. Cocrystal 2 showed supersaturation with fine particles. The transformation from cocrystal 1 to EX was observed within 1xa0min in suspension. Cocrystal 2 was transformed to MA within 2–4xa0h.ConclusionsCocrystallizations of EX and MA improved initial dissolution rates compared to the respective original crystals. The mechanism of dissolution enhancement varied. With cocrystal 1, fine particle formation resulted in enhancement, whereas with cocrystal 2, enhancement was due to the maintenance of the cocrystal form and rapid dissolution before transformation to the original crystal.

Evaluation of solid dispersions on a molecular level by the Raman mapping technique

Troglitazone containing two asymmetric carbons has four isomers. Crystalline troglitazone consists of two crystalline diastereomer-pairs, RR/SS and RS/SR, which have different melting points. Using a closed melting method, troglitazone-polyvinylpyrrolidone solid dispersions with various crystallinities were prepared. Raman spectroscopy and its mapping technique were applied to discriminate between the crystalline RR/SS, crystalline RS/SR and amorphous form of troglitazone in solid dispersions. The results of the Raman mapping of solid dispersions showed the co-existence of crystal and amorphous forms, and which diastereomer-pairs remained as crystals, in addition to the distribution of the drug. Moreover, the distribution of PVP could be illustrated from the Raman mapping data. Thus, Raman spectroscopy and its mapping technique are useful tools to evaluate crystal and amorphous states, including discrimination of crystalline diastereomer-pairs in solid dispersions. In addition, by describing the distribution of the drug and the carrier, it could be guessed how drug crystals become amorphous during preparation from the point of view of the distribution of the amorphous form of the drug substance and the carrier.

Effect of the type of lubricant on the characteristics of orally disintegrating tablets manufactured using the phase transition of sugar alcohol

The aim of this study was to evaluate the effect of lubricants on the characteristics of orally disintegrating (OD) tablets manufactured using the phase transition of sugar alcohol. OD tablets were produced by directly compressing a mixture containing lactose-xylitol granules, disintegrant, glidant and lubricant, and subsequent heating. The effect of the type of lubricant on the tablet characteristics was evaluated using magnesium stearate (Mg-St), sodium stearyl fumarate (SSF), and talc as lubricants. The hardness of the tablets increased to ca. 6kp as a result of heating, regardless of the kind of lubricant. The oral disintegration time of the tablets containing Mg-St or SSF increased with an increase in the hardness. In contrast, the oral disintegration time of the tablets containing talc was not changed despite of an increase in hardness. The water absorption rate of the tablets containing talc was much faster than that of the tablets containing other lubricants. The surface free energy measurement showed that the polarity of the tablet components containing talc was remarkably increased by heating. The water absorption rate of the tablets containing talc was also increased by heating. These results indicate that a more hydrophilic surface might be attained by heating the talc. Consequently, talc was demonstrated to be the most desirable lubricant for the preparation of OD tablets based on the principle of the phase transition of sugar alcohol.

Evaluation of Risk and Benefit in the Application of Near-Infrared Spectroscopy to Monitor the Granule Coating Process

The purpose of this article is to study risk and benefit in the application of near-infrared (NIR) spectroscopy to the coating process of granules to monitor the process for determining the coating end point. Cylindrical granules or spherical granules were used as core granules and were coated using a fluidized bed coating apparatus by spraying coating suspension. During the coating run, samples of granules were pulled at regular intervals and amount of talc or lactose, which were the components of the film layer, were estimated by NIR spectroscopy. When the coating layer of granules was thin like the case of the spherical granules, it was possible to monitor and understand the coating process well by an application of NIR spectroscopy, because it was possible to estimate some components in the coating layer simultaneously. However, it was found that as the coating layer became thick like the case of the cylindrical granules, NIR light was scattered by titanium dioxide in the coating layer, and that the increase of the coating layer estimated from NIR spectroscopy showed the misunderstanding saturation. NIR spectroscopy could not be used for the estimation of the granule coating process even if the formulation and amount applied for the coating was same as the spherical granules. When NIR spectroscopy is intended to be used to control granule coating process, it is necessary to check the impacts of the formulation applied for coating, the amount of the coating layer, and the thickness of the coating layer on the estimations.

Applicability of DPI formulations for novel neurokinin receptor antagonist

A novel triple neurokinin receptor antagonist (TNRA) could have pharmaceutical efficacy for asthma and/or chronic obstructive pulmonary disease. TNRA is potentially developed as inhalation medicine. The aim of this investigation was to evaluate the applicability of dry powder inhaler (DPI) formulation for TNRA. DPI formulation containing lactose was used for this feasibility study. Mechanofusion process for surface modification was applied on lactose particles to prepare four different DPI formulations. The mixture of TNRA and lactose was administered to rats intratracheally using an insufflator. The deposition pattern and blood concentration profile of TNRA were evaluated. Although there was no significant difference in deposition on deep lungs between the four formulations, DPI formulations containing mechanofusion-processed lactose showed longer T(max) and t(1/2) and higher AUC(0-infinity) and MRT compared to that containing intact lactose. On the other hand, the contact angle measurement showed that the mechanofusion process decreased the polar part of the surface energy of the lactose. Therefore, the prolongation of the wetting of the formulated powder mixture seemed to delay the dissolution of TNRA deposited in respiratory tract. It was concluded that DPI formulation containing mechanofusion-processed lactose could be suitable for inhalation of TNRA.