Effects of wet-granulation process parameters on the dissolution and physical stability of a solid dispersion.

This study investigated how the process parameters of wet-granulation affect the properties of solid dispersions (SDs), such as dissolution and physical stability. SDs of nilvadipine (NIL) and hypromellose prepared by spray-drying were wet-granulated and dried under various conditions. The NIL concentration at 4h and area under the curve from dissolution tests were taken to indicate dissolution. Then, the NIL crystallinity calculated from powder X-ray diffraction patterns of SD granules stored at 60°C for 3 months was evaluated to indicate physical stability. A statistical analysis revealed that the amount of granulation liquid (w/w%) and the ratio of water to ethanol in the liquid (v/v%) significantly affected the dissolution property, and that the drying temperature had a significant effect on the physical stability. Although exposure to water makes the wet-granulation process seem less suitable for granulating a SD, the results indicated that the process can be used to develop SD granules by selecting appropriate conditions, such as a lower proportion of granulation liquid, a higher water to ethanol ratio in the liquid, and a higher drying temperature.

Establishment of powder dustiness evaluation method by dustmeter with small amount of pharmaceutical ingredients.

The ratio of high potent materials in the new chemical entities has recently increased in the pharmaceutical industry. Generally, most of them are highly hazardous, but there is little toxicity information about the active pharmaceutical ingredients in the early development period. Even if their handling amount is quite small, the dustiness of high potent powder generated in the manufacturing process has an important impact on worker health; thus, it is important to understand the powder dustiness. The purpose of this study was to establish a method to evaluate the powder dustiness by the consumption of small amount of samples. The optimized measurement conditions for a commercially available dustmeter were confirmed using lactose monohydrate and naproxen sodium. The optimized test conditions were determined: the dustmeter mode, the flow rate, the drum rotation speed, the total measurement time, and sample loaded weight were type I mode, 4 L/min, 10 rpm, 1 min and 1-10 g , respectively. The setup conditions of the dustmeter are considerably valuable to pharmaceutical industries, especially, at the early development stage and especially for expensive materials, because the amount of air-borne dust can be evaluated with accuracy by the consumption of small amount of samples.

Effects of spray drying process parameters on the solubility behavior and physical stability of solid dispersions prepared using a laboratory-scale spray dryer.

PURPOSE: The purpose of this study is to determine the process parameters of the laboratory-scale spray dryer affecting the solubility behavior and physical stability of solid dispersions. METHODS: Solid dispersions of the model drug (nilvadipine or nifedipine) and hypromellose (HPMC) (w/w: 1/1) were prepared using the laboratory-scale spray dryer. As process parameters, nitrogen flow rate, sample concentration and pump speed were investigated. The samples were characterized by dissolution tests, powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), scanning electron microscope (SEM), and nanoscale thermal analysis (Nano-TA). The physical stability was monitored after 7 months storage at 25°C. RESULTS: Solubility behavior and physical stability were improved by setting the low nitrogen flow rate and high sample concentration. DSC showed that the physical state depends on the spray drying conditions, whereas, every sample showed the similar morphology from SEM results. The difference of solubility behavior and physical stability were found to come from the microstructural phase separation of the spray dried particles using a novel analytical technique (Nano-TA). CONCLUSIONS: This study demonstrated that nitrogen flow rate and sample concentration should be the critical parameters for the enhancements of the solubility and physical stability of solid dispersions.

Effects of automated external lubrication on tablet properties and the stability of eprazinone hydrochloride.

We investigated the advantages of an external lubrication technique for tableting. A newly developed external lubricating system was applied to tableting in a rotary tablet press using magnesium stearate. The resulting tablets were compared with tablets produced by the conventional internal lubrication method, in which lubricant is blended before tableting. As a model API, we chose eprazinone hydrochloride, because it is easily hydrolyzed by alkaline lubricant. The amount of lubricant required to prevent sticking with external lubrication was only 1/13th of that required with internal lubrication. External lubrication increased tablet crushing strength by 40%, without prolonging tablet disintegration time, and improved the residual ratio of eprazinone hydrochloride in tablets stored under stress conditions for 4 weeks by 10%. The distribution of lubricant on the surface of externally lubricated tablets was observed by scanning electron microscopy after the preparation by focused ion beam milling. The lubricant had formed a layer on the tablet surface. At the central part of the tablet surface, this layer was much thinner than at the edges, and remained extremely thin even when there was excess magnesium stearate. This is the first report to describe the distribution of lubricant on the surface of externally lubricated tablets.

Phase behavior and phase-transfer catalysis of tetrabutylammonium salts. Interface-mediated catalysis.

The phase behavior and component composition of the coexisting phases in the tetrabutylammonium bromide (TBABr)/benzene/water/NaBr four-component system were strongly influenced by the temperature, TBABr content, and NaBr concentration. The phase-transfer catalytic activity of TBABr for the reaction of decyl methanesulfonate with sodium bromide was closely related to the phase behavior. Under O (oil-rich phase) + L (TBABr-rich liquid phase) + W (aqueous phase) triphase conditions, the influences of temperature and stirring speed on the phase-transfer catalytic activity were small compared with those under O + W biphase conditions. The addition of other quaternary salts that were able to form w/o aggregates in the O phase enhanced the TBABr catalytic activity even under O + W conditions. The relationship between phase behavior and catalytic activity of tetrabutylammonium chloride or iodide (TBACl or TBAI) was also examined. The results strongly suggested that the catalysis of TBAX was attributable to the interfacial reactions of TBAX with the substrate. The interface includes the water-oil microinterface formed in the microemulsion-like L phase as well as the bulk water-oil interface.