Rheology, granule growth and granule strength: Application to the wet granulation of lactose–MCC mixtures

Abstract

a b s t r a c tThis study aims at better understanding the wet granulation process of a binary mixture composed of microcrystalline cellulose (water insoluble) and lactose (water soluble). It investigates the effect of formulation (proportion of the different components in the mixture) on the granule growth kinetics, the evolution of granule morphology during granulation, the wet mass consistency and dry granule strength of the end product. Additionally the influence of mixer design has been studied by up scaling the process from the 1.9 L Mi-pro high shear mixer used as the reference scale to a 6 L Diosna P1-6 high shear mixer. The scale-up rules investigated were constant impeller tip speed and constant Froude number. Our results allowed us to draw the following conclusions: -The increase in MCC content is found to increase the optimum binder requirement for granulation, wet mass consistency and dry granule strength.-Granule growth takes place in three distinct stages: wetting, nucleation and growth. These stages can be identified with the help of the recorded torque values during the granulation process or by the evolution of granule size and granule morphology.-The characterization of the starting materials by moisture sorption isotherms brings more insight to the role of each component during the granulation process.-The increase of the granulation scale has little influence on the observed growth mechanism. However bimodality of the granule size distribution is increased, wet mass consistency and dry granule strength are decreased with increasing scale of operation.

Real-time monitoring of granule properties during high shear wet granulation by near-infrared spectroscopy with a chemometrics approach

“…A common method used for monitoring the HSWG process is to monitor a change in the power consumption or torque against the impeller during the manufacturing. 4,5 However, the practical use of this method is hindered by the inuence of the amount, viscosity, and feeding speed of the added binder solution on both the power consumption and torque signals. 6 A focused beam reectance measurement (FBRM) probe can be used to obtain a detailed understanding of the particle size changes during the HSWG process and to determine the end-point properties of formulations.…”

High shear granulation of binary mixtures: Effect of powder composition on granule properties

“…Some of the common mixtures used in the pharmaceutical industries are lactose/micro crystalline cellulose (MCC) [6][7][8], lactose/mannitol [9] and starch/lactose [10][11][12][13][14]. In most granulation applications the raw materials are of comparable bulk densities.…”

Process Simulation and Data Modeling in Solid Oral Drug Development and Manufacture

“…One way to overcome this challenge is to deliver these medicines as a solid solution of amorphous API molecularly dissolved in a glassy polymer. Although some amorphous formulations can have API concentrations over the thermodynamic solubility limit and not crystallize over pharmaceutically relevant timescales due to kinetic stabilization (prevention of crystallization due to restricted mobility of the API in the glassy polymer matrix) it is desirable to have formulations below the thermodynamic solubility limit in order to avoid the risk that the crystallization kinetics may not always be sufficiently inhibited [70,71].…”

“…A first step in model validation is collection of the data that the model predictions will be compared to in order to test their accuracy. In the case of solid solutions of API's dissolved in glassy polymers, this can be much more challenging than, for example, measuring the solubility of an API in a solvent or mixture of solvents to be used in a crystallization [71,91,92]. However, researchers in the field of amorphous API/polymer solid solutions have risen to the challenge and developed methods capable of determining the thermodynamic solubility of API's in these polymer blends.…”

“…However, researchers in the field of amorphous API/polymer solid solutions have risen to the challenge and developed methods capable of determining the thermodynamic solubility of API's in these polymer blends. Typically, Differential Scanning Calorimetry (DSC) is used, sometimes in combination with other supporting techniques such as Powder X-Ray Diffraction (PXRD), Hot Stage Microscopy (HSM), and Infrared spectroscopy (IR) [71,79,88,[91][92][93][94][95]. Use of DSC in combination with improved sample preparation via cryomilling [71,91] and in some cases annealing the sample [92] has been demonstrated to produce results that are sufficiently accurate to be used in design of the amorphous API/polymer solid solution formulations [71].…”