Twin screw granulation – review of current progress

Twin screw granulation (TSG) is a new process of interest to the pharmaceutical community that can continuously wet granulate powders, doing so at lower liquid concentrations and with better product consistency than found by a high shear batch mixer. A considerable body of research has evolved over the short time since this process was introduced but generally with little comparison of results. A certain degree of confidence has been developed through these studies related to how process variables and many attributes of machinery configuration will affect granulation but some major challenges still lay ahead related to scalability, variations in the processing regimes related to degree of channel fill and the impact of wetting and granulation of complex powder formulations. This review examines the current literature for wet granulation processes studied in twin screw extrusion machinery, summarizing the influences of operational and system parameters affecting granule properties as well as strives to provide some practical observations to newly interested users of the technique.     

Proportional control of moisture content of granules by adjusting inlet air temperature in fluidized bed granulation using near-infrared spectroscopy

For process control of fluidized bed granulation process, we investigated proportional (P) moisture content control via adjustment of inlet air temperature in proportion to the difference between measured and target moisture content of granules. Here, we first validated P moisture content control by comparison with bed temperature control. We then confirmed that P moisture content control is effective in maintaining the moisture content, and in minimizing the variance of the particle size of granules following granulation. Furthermore, we observed that when the target temperature was higher than the measured value of inlet air temperature the P moisture content control response was accelerated. In contrast, when the target temperature was less than the measured value of inlet air temperature (<50 °C) the response was delayed. In summary, P moisture content control has good scalability and can be introduced without changing granulation conditions in the development of orally administered pharmaceutical products.     

Dynamic cross-flow filtration: enhanced continuous small-scale solid-liquid separation

Abstract

In a previous study, a small-scale dynamic filtration device (SFD) was analyzed and the basic mechanisms governing the filtration process were characterized. The present work aims at improving the device’s performance in terms of actual production. Various operation modes were tested in order to increase permeate flow and concentration factors (CF), while maintaining a fully continuous production mode. Both, a vacuum-enhanced and a pulsating operation mode, proved to be superior to the currently implemented open-operation mode. For example, for lactose, an increase of the CF could be achieved from 1.7 in open mode to 7.6 in pulsating operation mode. The investigated operation strategy enables process control systems to rapidly react to fluctuating feeds that may occur due to changes in upstream manufacturing steps. As a result, not only filtration performance in terms of permeate rate but also process flexibility can be significantly increased. Overall, vacuum-enhanced operation was shown to be most promising for integration into an industrial environment. The option to elevate achievable concentration factors, ease of flow monitoring as well as the ability to react to changes in the feed conditions allow for effective and efficient continuous small-scale filtration.     

Is the adjustment of the impeller speed a reliable attempt to influence granule size in continuous dry granulation?

As the field of continuous manufacturing of solid pharmaceutics is developing, the interest in implementing continuous granulation methods is growing. Process analytical technology tools should be integrated to ensure the monitoring of the product quality and therefore enforce control strategies.Three single materials which are often used in dry granulation and additionally two formulations, one containing ibuprofen and the other acetaminophen were processed at various process parameters. They all differed in their compaction and fracture behavior. A statistical analysis of the influence of process parameters was executed, to work out which parameters could be used for a granule size control approach in continuous dry granulation. Thereby, the specific compaction force and the impeller speed were found to be significant factors in each design of experiment. However, the impeller speed was evaluated as the only suitable parameter to control granule size, as an impact on granule density is unlikely. Nevertheless, some restrictions such as an upper impeller speed limitation to avoid excessive fines and a lower speed limitation to impede a downturn of the throughput, have to be considered. Furthermore, a decreasing median granule size was observed at higher throughputs for plastically deforming materials and formulations.     

Multivariate process trajectories: capture, resolution and analysis

Modern process analytical chemistry and technology applications are reviewed from the point of view of acquisition, resolution and analysis of trajectories in a designed analytical space.     

The interprocess NIR sampling as an alternative approach to multivariate statistical process control for identifying sources of product-quality variability

We are presenting a new approach of identifying sources of variability within a manufacturing process by NIR measurements of samples of intermediate material after each consecutive unit operation (interprocess NIR sampling technique). In addition, we summarize the development of a multivariate statistical process control (MSPC) model for the production of enteric-coated pellet product of the proton-pump inhibitor class. By developing provisional NIR calibration models, the identification of critical process points yields comparable results to the established MSPC modeling procedure. Both approaches are shown to lead to the same conclusion, identifying parameters of extrusion/spheronization and characteristics of lactose that have the greatest influence on the end-product’s enteric coating performance. The proposed approach enables quicker and easier identification of variability sources during manufacturing process, especially in cases when historical process data is not straightforwardly available. In the presented case the changes of lactose characteristics are influencing the performance of the extrusion/spheronization process step. The pellet cores produced by using one (considered as less suitable) lactose source were on average larger and more fragile, leading to consequent breakage of the cores during subsequent fluid bed operations. These results were confirmed by additional experimental analyses illuminating the underlying mechanism of fracture of oblong pellets during the pellet coating process leading to compromised film coating.     

采用近红外光谱法测定鱼粉的品质

本文比较了用近红外漫反射光谱(NIRS)定量测定和用传统化学方法测定鱼粉中的蛋白质、脂肪和水分含量,结果发现,用近红外漫反射光谱(NIRS)定量测定鱼粉的品质有良好的效果,完全可以替代传统的化学方法。该方法快速、准确且无药品试剂污染,其重现性优于传统化学法。     

Automated wavelength selection for spectroscopic fuel models by symmetrically contracting repeated unmoving window partial least squares

The need for automated quality surveillance of liquid hydrocarbon fuels has driven the development of rapid fuel property modeling from spectroscopic sensor data. The correlation of near-infrared (NIR) and Raman spectroscopic data with jet and diesel fuel properties can be improved by the deliberate selection of continuous wavelength sub-ranges. An automatic wavelength selection strategy would allow for the unsupervised construction of partial least squares (PLS) regression models of increased predictive utility when supervised model construction and maintenance is not feasible. Changeable size moving window partial least squares (CSMWPLS) is one of the most thorough operations suited for this task. Unfortunately, the necessarily large number of PLS model constructions required by an automated version of this procedure limits the evaluation of the predictive ability of the resulting models through full cross-validation results. Presented here is a novel restricted version of the CSMWPLS algorithm in which the initial spectral range selection is accomplished through multiple interval PLS (iPLS) analyses, where analysis windows for the refinement step no longer move, and size changes are limited to a series of symmetric attenuations. It is shown that the proposed algorithm can provide significant PLS model improvements during the course of a fully automated analysis of jet and diesel fuel spectra in less time than an automated CSMWPLS algorithm.     

Near-infrared spectroscopic applications in pharmaceutical particle technology

Abstract

Near-infrared spectroscopy (NIRS) is nowadays an established analytical technique in the pharmaceutical industry. The aim of this review is to present the progress of NIRS in providing useful information for pharmaceutical particle technology. NIR methods are now developed to characterize a wide variety of materials (active pharmaceutical ingredients, excipients, co-processed powders, and physical mixtures) and pharmaceutical dosage forms (conventional, modified drug release technologies, and phytomedicines). This review also provides a number of spectra to illustrate the fundamental understanding of NIRS which has been gained. The sampling that must occur prior to the acquisition of near-infrared spectra is also discussed, as well as developments in monitoring mixing, tableting, and coating. This review will be valuable for product formulation and process engineering specialists.     

Production of composite particles using an innovative continuous dry coating process derived from extrusion

Dry particle coating is used to modify surface properties and monitor the end use properties of powders. These processes are mainly running in batch mode. In certain cases, continuous processes may present interest for specific applications (limitation of investments, stability, versatility…). In this study, the feasibility of dry coating particles by an innovative way derived from the well-known extrusion process was investigated. Adhesion between host and guest particles is induced by mechanical shear stress during processing. A preliminary parametric study on microcrystalline cellulose particles as host particles was carried out in order to determine the operating condition range. Then, coating was successfully performed using talc and a microcrystalline cellulose system, which demonstrates the feasibility of this novel process and led to different morphologies according to the operating conditions.     

The use of near-infrared spectroscopy for the quantitation of a drug in hot-melt extruded films

The objective of the study was to demonstrate the utility of near-infrared spectroscopy (NIRS) for quantitative analysis of a model drug in hot-melt extruded film formulations. Polyethylene oxide (PEO) films with clotrimazole (CT) as a model drug were prepared by hot-melt extrusion (HME) incorporating drug concentrations ranging from 0-20% and analyzed using a Fourier transform near-infrared (FT-NIR) spectrophotometer in the reflectance mode. High performance liquid chromatography (HPLC) was the reference method used for this study. The NIR calibration model derived for CT was composed of 21 frequency ranges that were correlated to the values quantified using the HPLC reference method. The NIR method developed resulted in an assayed CT amount in the film matrix to be within 3.5% of the quantity determined by the reference method. These studies clearly demonstrate that NIRS is a powerful method for the quantitation of active drug substances contained in films produced by HME and warrants further investigation.     

层次分析法预测先进制造技术的应用

提出一个评价受多因素影响的AMT应用概念模型;考虑了系统实施、战略、组织结构和组织文化四个因素对应用AMT的影响,从运作效益、竞争效益以及组织和管理效益三方面来衡量AMT实施的结果.本文用AHP方法对上述模型的预测过程给予分析,由此指导AMT应用的决策制定,确保成功实施AMT.     

Controlling sugar quality on the basis of fluorescence fingerprints using robust calibration

The aim of our study was to highlight the benefits of robust calibration in the context of process control. Two properties were monitored — the color and ash content of sugar samples. It was shown for the data being studied that robust models, constructed using the partial robust M-regression technique, have a better fit to the majority of the data and prediction properties than the classic partial least squares and N-way partial least squares models. In particular, the constructed calibration models were characterized by a root mean square errors improved by 1.60% and 1.82% and a root mean square errors of prediction (for independent test samples) improved by 2.39% and 1.11% compared to classic partial least squares models constructed for color and ash content, respectively.     

A low cost laser-raman spectrometer

A Jobin Yvon-Spex (HR640) monochromator with a notch filter (514·5 nm) and Ar⁺ ion laser has been used to set up a low cost laser Raman spectrometer. The selection and setup of the various optical components used in the present work has been solely carried out in our laboratory. The calibration of the monochromator was established from the studies of various standard mercury lines and the obtained data fitted with the reported data. Raman signals have been recorded for a number of samples e.g. diamond, ruby, carbon tetrachloride (CCI₄), benzene (C₆H₆) and ethanol (C₂H₅OH). The obtained results are found to be in excellent agreement with the reported values for these materials in the literature.