Hiroaki Nakagami

Effect of crystallinity of microcrystalline cellulose on the compactability and dissolution of tablets

Microcrystalline cellulose (MCC) was pulverized with a vibrational rod mill. The degree of crystallinity of MCC decreased from 65.5 to 12.1% with pulverization time due to mechanochemical effect. Pulverized MCCs were compressed at 155.6 MPa using a compression test apparatus, and the two parameters relating to compactability, the B value and yield pressure, were calculated using a Heckel plot. These values were lowered as the degree of crystallinity of MCC became smaller. These results suggest that the crystal region and the amorphous region in MCC particles may be mainly fractured and deformed plastically during compression, respectively. Then the dissolution test was performed for the acetaminophen-MCC (10:90) tablets. Dissolution profiles showed an interesting phenomenon, namely, the dissolution rate of acetaminophen from MCC tablet decreased when the degree of crystallinity of MCC was in the range from 65.5 to 37.6%, however, it increased markedly when the degree of crystallinity of MCC was in the range from 25.8 to 12.1%. The amount of water absorbed into tablets changed in accord with the dissolution rates of acetaminophen from tablets. The dissolution data indicate that drug release can be modified by changing the degree of crystallinity of MCC.

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 controlled release matrix pellets by annealing with micronized water-insoluble or enteric polymers

The purpose of this study was to develop a new method for preparing controlled release (CR) matrix pellets by annealing with water-insoluble polymers, and to elucidate a relationship between the annealing temperature of the matrix pellets and a glass transition temperature (T(g)) or a minimum film-forming temperature (MFT) of the polymer/plasticizer systems that constituted the matrix pellets. The pellets containing theophylline as a model drug were prepared by the extrusion-spheronization method and subsequent annealing. The pellets were characterized mainly by pellet formation, release studies, and thermal evaluations. It was apparent that the annealing temperature for the CR matrix pellets was related to the T(g) and MFT of the polymer/plasticizer systems. For ethylcellulose (EC) containing 22.7% triethylcitrate (TEC), the annealing temperature required for preparing CR pellets was 80 degrees C, which was more than 20 degrees C higher than the T(g) and MFT of this EC/TEC system. In contrast, hydroxypropylmethylcellulose acetate succinate (HPMCAS) containing 22.7% TEC could be used to prepare CR pellets without heating. The T(g) of this HPMCAS/TEC system was about 60 degrees C and the MFT was lower than 20 degrees C, indicating that water can act as a plasticizer for HPMCAS and that HPMCAS/TEC pellets could be annealed at room temperature. These results suggest that MFT is a better indicator than T(g) for estimating annealing temperature. SEM observation showed that the EC/TEC pellets annealed at 80 degrees C had a matrix structure with coalesced particles. On the contrary, unannealed pellets consisted of individually distinguishable particles. The release rate of drug from the matrix CR pellets was dependent on the drug concentration and polymer to plasticizer ratio.

Evaluation of Infrared-Reflection Absorption Spectroscopy Measurement and Locally Weighted Partial Least-Squares for Rapid Analysis of Residual Drug Substances in Cleaning Processes

The usefulness of infrared-reflection absorption spectroscopy (IR-RAS) for the rapid measurement of residual drug substances without sampling was evaluated. In order to realize the highly accurate rapid measurement, locally weighted partial least-squares (LW-PLS) with a new weighting technique was developed. LW-PLS is an adaptive method that builds a calibration model on demand by using a database whenever prediction is required. By adding more weight to samples closer to a query, LW-PLS can achieve higher prediction accuracy than PLS. In this study, a new weighting technique is proposed to further improve the prediction accuracy of LW-PLS. The root-mean-square error of prediction (RMSEP) of the IR-RAS spectra analyzed by LW-PLS with the new weighting technique was compared with that analyzed by PLS and locally weighted regression (LWR). The RMSEP of LW-PLS with the proposed weighting technique was about 36% and 14% smaller than that of PLS and LWR, respectively, when ibuprofen was a residual drug substance. Similarly, LW-PLS with the weighting technique was about 39% and 24% better than PLS and LWR in RMSEP, respectively, when magnesium stearate was a residual excipient. The combination of IR-RAS and LW-PLS with the proposed weighting technique is a very useful rapid measurement technique of the residual drug substances.

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.

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.

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.

Effect of preparation method on properties of orally disintegrating tablets made by phase transition

In order to evaluate the effect of preparation method on the properties of orally disintegrating (OD) tablets, OD tablets were prepared by compressing a mixture of high melting point sugar alcohol (HMP-SA) and low melting point sugar alcohol (LMP-SA) and subsequent heating. In the direct compression method (DCM) where the LMP-SA was added as a powder, both hardness and disintegration time were increased by decreasing the particle size of the LMP-SA. In the wet granule compression method (WGCM), where the LMP-SA was added as an aqueous binder solution, the tablets became harder with less heating compared to tablets prepared by DCM. Using 1% xylitol as the LMP-SA provided tablets with sufficient hardness when prepared by WGCM, as opposed to DCM where 5% xylitol was necessary to prepare tablets with similar hardness. These results suggest that uniformly distributed LMP-SA on the surface of HMP-SA particles in WGCM might diffuse more easily during the heating process compared to mechanically mixed LMP-SA in DCM, resulting in an increase in tablet hardness even with a short heating time and low content of LMP-SA. In addition, disintegration and hardness stability of the tablets were affected by the LMP-SA content when prepared by WGCM, suggesting that the LMP-SA content should be regulated to assure the stability of OD tablet characteristics.

Dosage form design and in vitro/in vivo evaluation of cevimeline extended-release tablet formulations

The objective of the present work is to develop an extended-release dosage form of cevimeline. Two types of extended-release tablets (simple matrix tablets and press-coated tablets) were prepared and their potential as extended-release dosage forms were assessed. Simple matrix tablets have a large amount of hydroxypropylcellulose as a rate-controlling polymer and the matrix is homogeneous throughout the tablet. The press-coated tablets consisted of a matrix core tablet, which was completely surrounded by an outer shell containing a large amount of hydroxypropylcellulose. The simple matrix tablets could not sustain the release of cevimeline effectively. In contrast, the press-coated tablets showed a slower dissolution rate compared with simple matrix tablets and the release curve was nearly linear. The dissolution of cevimeline from the press-coated tablets was not markedly affected by the pH of the dissolution medium or by a paddle rotating speed over the range of 50-200 rpm. Furthermore, cevimeline was constantly released from the press-coated tablets in the gastrointestinal tract and the steady-state plasma drug levels were maintained in beagle dogs. These results suggested that the designed PC tablets have a potential for extended-release dosage forms.