Shuichi Yada

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.

Development of a method for the determination of caffeine anhydrate in various designed intact tables by near-infrared spectroscopy: A comparison between reflectance and transmittance technique

Using near-infrared (NIR) spectroscopy, an assay method which is not affected by such elements of tablet design as thickness, shape, embossing and scored line was developed. Tablets containing caffeine anhydrate were prepared by direct compression at various compression force levels using different shaped punches. NIR spectra were obtained from these intact tablets using the reflectance and transmittance techniques. A reference assay was performed by high-performance liquid chromatography (HPLC). Calibration models were generated by the partial least-squares (PLS) regression. Changes in the tablet thickness, shape, embossing and scored line caused NIR spectral changes in different ways, depending on the technique used. As a result, noticeable errors in drug content prediction occurred using calibration models generated according to the conventional method. On the other hand, when the various tablet design elements which caused the NIR spectral changes were included in the model, the prediction of the drug content in the tablets was scarcely affected by those elements when using either of the techniques. A comparison of these techniques resulted in higher predictability under the tablet design variations using the transmittance technique with preferable linearity and accuracy. This is probably attributed to the transmittance spectra which sensitively reflect the differences in tablet thickness or shape as a result of obtaining information inside the tablets.

Prediction of recrystallization behavior of troglitazone/polyvinylpyrrolidone solid dispersion by solid-state NMR

The purpose of this study was to elaborate the relationship between the (13)C CP/MAS NMR spectra and the recrystallization behavior during the storage of troglitazone solid dispersions. The solid dispersions were prepared by either the solvent method or by co-grinding. The recrystallization behavior under storage conditions at 40 degrees C/94% RH was evaluated by the Kolmogorov-Johnson-Mehl-Avrami (KJMA) equation. Solid dispersions prepared by the solvent method or by prolonged grinding brought about inhibition of the nucleation and the nuclei growth at the same time. No differences in the PXRD profiles were found in the samples prepared by the co-grinding and solvent methods, however, (13)C CP/MAS NMR showed significant differences in the spectra. The correlation coefficients using partial least square regression analysis between the PXRD profiles and the apparent nuclei-growth constant or induction period to nucleation were 0.1305 or 0.6350, respectively. In contrast, those between the (13)C CP/MAS NMR spectra and the constant or the period were 0.9916 or 0.9838, respectively. The (13)C CP/MAS NMR spectra had good correlation with the recrystallization kinetic parameters evaluated by the KJMA equation. Consequently, solid-state NMR was judged to be a useful tool for the prediction of the recrystallization behavior of solid dispersions.

Development of a method for nondestructive NIR transmittance spectroscopic analysis of acetaminophen and caffeine anhydrate in intact bilayer tablets

Calibration models for nondestructive NIR analysis of API (active pharmaceutical ingredient) contents in two separate layers of intact bilayer tablets were established. These models will enable the use of NIR transmittance spectroscopy in bilayer tableting processes for the control of API contents in separate layers. Acetaminophen and caffeine anhydrate were used as APIs, and tablets were made by the direct compression method. Their NIR spectra were measured in the transmittance mode. The reference assay was performed by HPLC. Calibration models were generated by the partial least-squares (PLS) regression. The initial calibration generated models with insufficient linearity and accuracy because the fluctuation range of tablet thickness was excessively large and irrelevant information on the thickness fluctuation was included in the models. By narrowing the fluctuation range to determine the proper range for acceptable prediction accuracy, it was confirmed that calibration models with less irrelevant information can be generated when the range was 4.30+/-0.06 mm or narrower. Furthermore, the fluctuation range of 4.30+/-0.06 mm was considered to be empirically valid in covering the fluctuation actually observed in ordinary tableting processes. Thus, the sample tablets within this range were used to generate the final calibration models, and calibration models sufficient in linearity and accuracy were established. In addition, it was proven that controlling the irradiated side was unnecessary. Namely, it is not necessary to keep the same side of sampled tablets for the online NIR analysis during bilayer tableting. It is useful, in order to obtain adequate calibration models, to evaluate the variable factors that affect the linearity and accuracy of the generated models and restrict the range of models or use a subset of prepared samples. Loading vectors, explained variances, and correlation coefficients between components and scores are important for the evaluation of variable factors.

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.

Colonoscopic method for estimating the colonic absorption of extended-release dosage forms in dogs

The purpose of this study was to develop a new method using beagle dogs in order to evaluate the colonic absorption properties of oral extended-release (ER) solid dosage forms. The established method is not only noninvasive and inexpensive but full-sized ER dosage forms are also directly administered to the colons of conscious dogs through the anus with an endoscope and modified bioptome. In the method, it was possible to administer the ER dosage forms into the ascending colon of dogs within 30 s-1 min. The colonic absorption of Voltaren-XR (Diclofenac sodium), Glucophage-XR (metformin), Pacif (morphine hydrochloride), Herbesser-R (diltiazem hydrochloride) and Plendil (felodipine), which are currently on the market, were investigated by this method. The relative bioavailabilities of these ER dosage forms to oral drug solution were 100.3%, 42.5%, 60.6%, 46.3% and 29.8%, respectively. Some of these results reflected the human colonic absorption profiles reported in the literature. This newly developed method could provide researchers with an alternative way to predict the human colon absorption performance of oral ER delivery systems.

Design and evaluation of an extended-release matrix tablet formulation; the combination of hypromellose acetate succinate and hydroxypropylcellulose

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