Formation of Indomethacin-Saccharin Cocrystals during Wet Granulation: Role of Polymeric Excipients.

Formulation of a cocrystal into a solid pharmaceutical dosage form entails numerous processing steps during which there is risk of dissociation. In an effort to reduce the number of unit operations, we have attempted the in situ formation of an indomethacin-saccharin (INDSAC) cocrystal during high-shear wet granulation (HSWG). HSWG of IND (poorly water-soluble drug) and SAC (coformer), with polymers (granulating agents), was carried out using ethanol as the granulation liquid and yielded INDSAC cocrystal granules. Therefore, cocrystal formation and granulation were simultaneously accomplished. Our objectives were to (i) evaluate the influence of polymers on cocrystal formation kinetics during wet granulation and (ii) mechanistically understand the role of polymers in facilitating the cocrystal formation. Polyvinylpyrrolidone (PVP), hydroxypropyl cellulose (HPC), and polyethylene oxide (PEO) were chosen to investigate the influence of soluble polymers. The cocrystal formation kinetics was influenced by the polymer (PVP < HPC < PEO) and its concentration. The interaction of the polymer with cocrystal components inhibited the cocrystal formation. Complete cocrystal formation was observed in the presence of PEO, a polymer which does not interact with IND and SAC.

Bioresorbable zinc hydroxyapatite guided bone regeneration membrane for bone regeneration.

OBJECTIVES: The aim of this study was to investigate the bone regenerative properties of a heat treated cross-linked GBR membrane with zinc hydroxyapatite powders in the rat calvarial defect model over a 6-week period. MATERIAL AND METHODS: In vitro physio-chemical characterization involved X-ray diffraction analysis, surface topology by scanning electron microscopy, and zinc release studies in physiological buffers. Bilateral rat calvarial defects were used to compare the Zn-HAp membranes against the commercially available collagen membranes and the unfilled defect group through radiological and histological evaluation. RESULTS: The synthesized Zn-MEM (100 µm thick) showed no zinc ions released in the phosphate buffer solution (PBS) buffer, but zinc was observed under acidic conditions. At 6 weeks, both the micro-CT and histological analyses revealed that the Zn-MEM group yielded significantly greater bone formation with 80 ± 2% of bone filled, as compared with 60 ± 5% in the collagen membrane and 40 ± 2% in the unfilled control group. CONCLUSION: This study demonstrated the use of heat treatment as an alternative method to cross-linking the Zn-MEM to be applied as a GBR membrane. Its synthesis and production are relatively simple to fabricate, and the membrane had rough surface features on one side, which might be beneficial for cellular activities. In a rat calvarial defect model, it was shown that new bone formation was accelerated in comparison with the collagen membrane and the unfilled defect groups. These results would suggest that Zn-MEM has the potential for further development in dental applications.

Pharmaceutical evaluation of matrix tablets prepared using a fused deposition modelling type three-dimensional printer - Effect of geometrical internal microstructural factors on drug release from enteric-polymer tablets containing rebamipide.

OBJECTIVES: Three-dimensional (3-D) printers are widely expected to provide a novel manufacturing method in the future to make personalized medicines in hospitals. METHODS: Functional filament containing 5-20% drug was prepared with rebamipide (REB; a poorly water-soluble model drug) and hypromellose phthalate (HPMCP; enteric base) at 130-170°C using a biaxial kneading extruder. Several tablet models with various internal structures were designed using computer-aided design. REB-containing 3-D tablets were prepared based on these designs from filament using a fused deposition modelling type 3-D printer. KEY FINDINGS: Physicochemical characteristics of the filament and 3-D tablets were measured by powder X-ray diffraction and differential scanning calorimetry. The results suggested that a part of the crystalline REB dispersed into the HPMCP and transformed into an amorphous form, because crystalline REB was kneaded with melted HPMCP at 130-170°C during the preparation processes of filament and 3-D tablets. The drug-release properties of 3-D tablets were tested in both pH 1.2 and 6.8 buffers. REB was not released from the 3-D tablets at pH 1.2, but HPMCP dissolved at pH 6.8, and then REB was rapidly released from the tablet. CONCLUSIONS: The dissolution of 3-D tablets in the small intestine could be controlled by the tablet geometrical structure.

Real-time monitoring of pharmaceutical properties of medical tablets during direct tableting process by hybrid tableting process parameter-time profiles.

BACKGROUND: Real-time monitoring is required for the pharmaceutical manufacturing process to produce high-quality pharmaceutical products. OBJECTIVE: Changes in the critical tableting process parameters of single-punch tableting machine due to variability in the moisture content of the raw powders were monitored by hybrid tableting pressure-time profiles. METHODS: After mixing of the raw powders, which consisted of theophylline, anhydrous lactose, potato starch and crystalline cellulose, they were stored at 0%, 45%, or 75% relative humidity (RH) for 24 h, respectively. Continuous tablet productions were carried out using the mixed powder samples at 10%, 45%, or 75% RH, respectively. The critical process parameters, such as upper and lower puncture pressures, die wall pressures, and inter-punch distances were recoded with the tableting machine, and then, tablet hardness (H), weight (W) and disintegration time (DT) of the tablets were measured. RESULTS: Hybrid tableting pressure-time profiles were obtained from various critical process parameters, and calibration models to predict pharmaceutical properties were calculated based on the hybrid profiles using a partial-least-squares regression (PLSR) method. In addition, the consistency of the calibration models were verified by constructing robust calibration models. CONCLUSION: Informetrical analysis for tablets based on hybrid tableting pressure-time profiles could evaluate the change of tablet properties dependent on the moisture content in the raw powders during the tableting process. The changes of tableting properties and elasticity were caused by agglomeration of powder particles at moisture content.

Simultaneous quantitative analysis of indomethacin and benzoic acid in gel using ultra-violet-visible spectrophotometry and chemometrics.

BACKGROUND: In order to manufacture pharmaceutical products, real-time monitoring in the manufacturing process is necessary, but large equipment cost is required to achieve it. OBJECTIVE: The aim of this research is to use ultra-violet-visible spectroscopy along with chemometrics procedure to simultaneously carry out quantitative analysis of indomethacin (IMC) and benzoic acid (BA) in the gel during pharmaceutical manufacturing process. METHODS: The gel preparations contained 0.1-1.5% IMC, 0.015-0.225% BA, 2% carbopol® 941 and 95% ethanol solution. The calibration models were constructed using the partial least square regression (PLS). RESULTS: The relationships of the measured and predicted concentrations for both IMC and BA had linear plots. The developed PLS calibration models were used to monitor the IMC and BA concentrations during mixing of the gels by the planetary centrifugal and conventional mixers, respectively. IMC and BA were gradually dispersed, dissolved and completely homogeneous within 30 min by the centrifugal mixer. In contrast, IMC and BA were slowly dispersed, dissolved and completely homogeneous at more than 60 min by the conventional mixer. CONCLUSIONS: The ultra-violet-visible spectrophotometric method couples with multivariate chemometric techniques for quantitative data analysis were successfully applied for the simultaneous determination of major component IMC and trace component BA in the gel.

Mechanochemical effect on swelling and drug release of natural polymer matrix tablets by X-ray computed tomography.

The relationships between the physicochemical properties of milled starch and drug release from tablets were investigated quantitatively using a drug release kinetic method and X-ray computed tomography (XCT). The samples were prepared from raw ß-starch by milling in a planetary ball mill. The tablets, containing 5% theophylline (TH), 94% milled starch, and 1% magnesium stearate, were compressed at 6 kN. The drug-release and gel-forming processes were measured simultaneously using an original dissolution tester with an XCT instrument. Drug release from the tablet was delayed with increasing milling time, because the TH tablet formed a typical gel-layer on the outside of the tablet. The relationship between the crystallinity of milled starch and mean drug release time (MDT) for the TH tablets showed almost a straight inverse proportional relationship. The plots of MDT against area under the curve of the swelling ratio profiles of the TH tablets had a good straight line.