Abstract. The objective of the present study was to investigate the mechanism, kinetics, and factors affecting the polymorphic transformation of nimodipine (NMD) and indomethacin (IMC) during high shear granulation. Granules containing active pharmaceutical ingredient, microcrystalline cellulose, and low-substituted hydroxypropylcellulose were prepared with ethanolic hydroxypropylcellulose solution, and the effects of independent process variables including impeller speed and granulating temperature were taken into consideration. Two polymorphs of the model drugs and granules were characterized by X-ray powder diffraction analysis and quantitatively determined by differential scanning calorimetry. A theoretical kinetic method of ten kinetic models was applied to analyze the polymorphic transformation of model drugs. The results obtained revealed that both the transformation of modification I to modification II of NMD and the transformation of the α form to the γ form of IMC followed a twodimensional nuclei growth mechanism. The activation energy of transformation was calculated to be 7.933 and 56.09 kJ·mol −1 from Arrhenius plot, respectively. Both the granulating temperature and the impeller speed affected the transformation rate of the drugs and, in particular, the high shear stress significantly accelerated the transformation process. By analyzing the growth mechanisms of granules in high-shear mixer, it was concluded that the polymorphic transformation of NMD and IMC took place in accordance with granule growth in a high-shear mixer.
High shear mixers have been widely used in the pharmaceutical industry. There are several advantages of granulation in a high shear mixer: a shorter processing time; a need for less liquid binders compared with fluid bed granulators and, thus, a shorter drying process is obtained; voluminous materials can be densified. Moreover, granulation is performed in a closed system, which can include drying (microwave or vacuum); the porosity of the product can be influenced by the massing time and impact of the impeller; cleaning operations can be carried out easily either manually or by a clean-inplace system. 1) Different phases of growth were identified for high shear granulation: nucleation, fragmentation, densification, exponential growth due to coalescence, and break up.
2)Scale-up of the wet granulation processes from laboratory scale to pilot and production scale is problematic. Even within the same manufacture of machine, liquid requirement and granule properties in terms of granule size distribution and granule porosity might change by scaling-up due to the difference space and impact force between large-scale and small-scale machines. However, in many situations, pharmaceutical researchers have to deal with a shortage of active substances and granulation materials. In order to develop a formulation and study the process effectively, laboratoryscale equipment is used during the early stages of research.
3)Because of the similar structure design to the pilot and production equipments, lab-scale machines are supposed to provide useful information for subsequent granulation in large scale machines of the same type and it is believed that this information will facilitate subsequent large-scale processing. 4,5) High shear granulation is a multivariate process and the product properties are sensitive to changes in the process variables such as impeller speed, chopper speed and kneading time hence it is important to work out the effects of these critical parameters.2,4,6-8) The microcrystalline cellulosebased (MCC-based) system and starch-based system are two main material systems used for high shear granulation; however, researchers usually chose one of the two systems for their investigations. 5,9) Because of the popularity of these two systems and the difficulty in scaling up the process, comparison of the high shear granulating process with the two systems mentioned using lab-scale equipment that is representative of large-scale circumstances is necessary for the application of this technique. In addition, it has been found that the toroidal motion of the wet mass during the granulating process could have marked impact on the product properties and the reproducibility of the manufacturing process.
10)However, few studies report the possibility of maintaining this flow pattern of wet mass by adjusting the process parameters and the raw material.The aims of present study are to compare the manufacturing process for the two main material systems used for high shear granulation and to try to obtain information about p...
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