Feed factor profile prediction model for two-component mixed powder in the twin-screw feeder.

In continuous pharmaceutical manufacturing processes, it is crucial to control the powder flow rate. The feeding process is characterized by the amount of powder delivered per screw rotation, referred to as the feed factor. This study aims to develop models for predicting the feed factor profiles (FFPs) of two-component mixed powders with various formulations, while most previous studies have focused on single-component powders. It further aims to identify the suitable model type and to determine the significance of material properties in enhancing prediction accuracy by using several FFP prediction models with different input variables. Four datasets from the experiment were generated with different ranges of the mass fraction of active pharmaceutical ingredients (API) and the powder weight in the hopper. The candidates for the model inputs are (a) the mass fraction of API, (b) process parameters, and (c) material properties. It is desirable to construct a high-performance prediction model without the material properties because their measurement is laborious. The results show that using (c) as input variables did not improve the prediction accuracy as much, thus there is no need to use them.

Control of residence time of pharmaceutical powder in a continuous mixer with impeller and scraper.

The control of residence time in a powder mixing process was investigated toward the development of a continuous pharmaceutical manufacturing system. A powder mixer equipped with an impeller and a scraper, which was designed for a continuous granulation machine, was used. The mixing homogeneity and dynamic behavior of the powder in the mixer were investigated by using a tracer, acetaminophen, in impulse- and step-response experiments. The homogeneity of the mixture was guaranteed by the high rotation speed of the impeller, independent of the speed of the scraper. The mean residence time of the powder was controlled by changing the scraper speed. The hold-up weight in the mixer was also changed by the scraper speed. In the measurement of the hold-up weight, the scraper speed also affected the powder filling density. These results confirmed that the scraper equipped in the mixer transported powder towards the exit of the mixer, and that both the scraper's rotation speed and its shape are key parameters for flexibly controlling the residence time of powder in the mixer. These experimental results can provide useful information for adjusting the residence time in order to optimize conditions for the corresponding continuous granulation system.

Determining key parameters of continuous wet granulation for tablet quality and productivity: A case in ethenzamide.

This paper aims to determine key parameters that affect tablet quality and productivity in continuous tablet manufacturing. Experiments were performed based on design of experiments using a continuous high-shear granulator and ethenzamide as the active pharmaceutical ingredient. To guide a systematic and comprehensive parameter analysis, a parameter framework was defined that comprised five input parameters on raw material properties and process parameters, 11 intermediate parameters on granule properties, and 11 output parameters on tablet quality and productivity. The interrelationships were analyzed statistically and were described as matrix functions. The liquid/solid ratio was the key parameter that affected circularity, density, and flowability as the granule properties, and disintegration and dissolution as the tablet quality. The maximum acceptable manufacturing rate that governs productivity was also affected by the liquid/solid ratio. Circularity was found to affect disintegration and dissolution. This result was specific to the setup of the study, but suggested development opportunities for a new process analytical technology system/quality-by-design application based on circularity. In addition, practical findings were obtained as follows: (1) high-speed manufacturing favored a lower liquid/solid ratio, and (2) high circularity slowed down disintegration/dissolution. This obtained knowledge will enhance the applicability of continuous technology in an actual manufacturing environment.

Importance of free water in controlling granule and tablet properties in a novel granulation method, green fluidized bed granulation (GFBG).

In the pharmaceutical field, green fluidized bed granulation (GFBG) is a novel and eco-friendly manufacturing technology used to produce desired granules via simple blending and spraying steps at ambient temperature using a standard fluidized bed granulator. However, the relations between water content and granule and tablet qualities have not yet been elucidated for GFBG. The purpose of this study was to elucidate the influence of different water quantities used in the GFBG process on granule and tablet qualities. In addition, results from the GFBG process were compared with those from the moisture-activated dry granulation (MADG) process. In terms of tablet tensile strength and disintegration time, GFBG had a wider acceptable range for added water quantity (2.0-5.0%) than did MADG. For all added water quantities, the GFBG granules were within the upper limit of water activity (a surrogate of free water amount), which was 0.61 for tensile strength and 0.55 for disintegration time. The air flow in the GFBG process may have reduced the excess free water on the granules during the absorption process. It was concluded that as compared with MADG, GFBG may be a more robust process for manufacturing granules and tablets with superior properties.

Characterization of Amorphous Solid Dispersion of Pharmaceutical Compound with pH-Dependent Solubility Prepared by Continuous-Spray Granulator.

A continuous-spray granulator (CTS-SGR) is a one-step granulation technology capable of using solutions or suspensions. The present research objectives were, (1) to reduce the manufacturing operations for solid dosage formulations, (2) to make amorphous solid dispersion (ASD) granules without pre-preparation of amorphous solids of active pharmaceutical ingredients (API), and (3) to characterize the obtained SGR granules by comprehensive pharmaceutical analysis. Rebamipide (RBM), a biopharmaceutical classification system class IV drug, that has low solubility or permeability in the stomach, was selected as a model compound. Five kind of granules with different concentrations of polyvinylpyrrolidone/vinyl acetate copolymer (PVP-VA) were prepared using a one-step SGR process. All of the SGR granules could be produced in amorphous or ASD form and their thermodynamic stability was very high because of high glass transition temperatures (>178 °C). They were unstable in 20 °C/75%RH; however, their stability was improved according to the proportion of polymer. The carboxy group of RBM was ionized in the granules and interactions appeared between RBM and PVP-VA, with the formation of an ASD confirmed and the solubility was enhanced compared with bulk RBM crystals. The SGR methodology has the possibility of contributing to process development in the pharmaceutical industry.

A large-scale experimental comparison of batch and continuous technologies in pharmaceutical tablet manufacturing using ethenzamide.

This paper compares batch and continuous technologies in terms of product quality and process performance in pharmaceutical tablet manufacturing using ethenzamide as the active pharmaceutical ingredient. Batch and continuous processes using wet granulation were investigated by performing experiments on the scale of 5 and up to 100 kg/lot, using the same raw materials. Three technologies were tested and compared: (i) batch technology using fluidized bed granulation, (ii) batch technology using high shear granulation, (iii) continuous technology using high shear granulation. In the full-scale experiment, in all three technologies including continuous technology, the quality of the tablets fulfilled the target values regarding hardness, active pharmaceutical ingredient content, and dissolution. The granules produced by different technologies, however, presented varying attributes regarding granule size distribution, loose bulk density, or scanning electron microscope images. The process performance, more specifically the yield, was slightly better for batch technologies than for the continuous technology, mainly due to losses in the start-up operation. Notably, this study has shown that continuous technology, which is generally believed to not entail scale-up procedures, could in fact, require parameter adjustment for prolonged operation. The results provided suggestions for improvements to implement large-scale continuous technologies in the pharmaceutical industry.

A novel approach to monitor coating amount by short-wavelength near-infrared spectroscopy using a tracer with a long-chain hydrocarbyl group.

Investigation into the use of near-infrared (NIR) as a Process Analytical Technology has been conducted for in-process monitoring of coating amounts for oral pharmaceutical products. However, the low specificity of NIR spectra has made it time consuming and costly to establish quantitative calibration models for commercial production. Here we revealed that long-chain hydrocarbyl group compounds containing saturated hydrocarbon chains, such as cetyl and stearyl, exhibit specific and strong absorption in the short wavelength (SW)-NIR region (800-1,100 nm) with limited interference from peaks corresponding to other components. To simplify the quantitative model, we used cetanol as a model tracer of coating amount to enhance detection sensitivity and analytical precision. The coating amount on crystalline cellulose granules was determined only from the intensity of NIR absorption at a single wavelength, which was attributed to the tracer. The results showed close agreement with quantitative analyses from gas chromatography and measurement of weight gain. In conclusion, we determined coating amount with considerable accuracy from NIR absorption at a single wavelength in the SW-NIR region using the long-chain hydrocarbyl containing compound as a tracer, thereby eliminating the need for complicated statistics.

Detection of component segregation in granules manufactured by high shear granulation with over-granulation conditions using near-infrared chemical imaging.

The objective of this study was to evaluate the high shear granulation process using near-infrared (NIR) chemical imaging technique and to make the findings available for pharmaceutical development. We prepared granules and tablets made under appropriate- and over-granulation conditions with high shear granulation and observed these granules and tablets using NIR chemical imaging system. We found an interesting phenomenon: lactose agglomeration and segregation of ingredients occurred in experimental tablets when over-granulation conditions, including greater impeller rotation speeds and longer granulation times, were employed. Granules prepared using over-granulation conditions were larger and had progressed to the consolidation stage; segregation between ethenzamide and lactose occurred within larger granules. The segregation observed here is not detectable using conventional analytical technologies such as high pressure liquid chromatography (HPLC) because the content of the granules remained uniform despite the segregation. Therefore, granule visualization using NIR chemical imaging is an effective method for investigating and evaluating the granulation process.