Real-time assessment of critical quality attributes of a continuous granulation process

There exists the intention to shift pharmaceutical manufacturing of solid dosage forms from traditional batch production towards continuous production. The currently applied conventional quality control systems, based on sampling and time-consuming off-line analyses in analytical laboratories, would annul the advantages of continuous processing. It is clear that real-time quality assessment and control is indispensable for continuous production. This manuscript evaluates strengths and weaknesses of several complementary Process Analytical Technology (PAT) tools implemented in a continuous wet granulation process, which is part of a fully continuous from powder-to-tablet production line. The use of Raman and NIR-spectroscopy and a particle size distribution analyzer is evaluated for the real-time monitoring of critical parameters during the continuous wet agglomeration of an anhydrous theophylline− lactose blend. The solid state characteristics and particle size of the granules were analyzed in real-time and the critical process parameters influencing these granule characteristics were identified. The temperature of the granulator barrel, the amount of granulation liquid added and, to a lesser extent, the powder feed rate were the parameters influencing the solid state of the active pharmaceutical ingredient (API). A higher barrel temperature and a higher powder feed rate, resulted in larger granules

Near infrared and Raman spectroscopy for the in-process monitoring of pharmaceutical production processes

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Effect of operating conditions and physico–chemical properties on the wet granulation kinetics in high shear mixer

The wet granulation process is sensitive to changes in product properties and process variables. The optimal process and formulation are based on the knowledge of the granule growth mechanisms and of the effects of product properties and process variables. This paper presents the study of wet granulation of microcrystalline cellulose powder, MCC (Avicel PH101) using high-shear mixer granulator. It aims at understanding the effect of operating parameters (impeller rotational speed, liquid binder flow ate) and of physicochemical properties (viscosity, wettability) of a binder solution on solid particles surfaces, on the agglomeration kinetics. The experiments are carried out with water, aqueous solutions of sodium carboxymethylcellulose, polyvinylpyrrolidone, hydroxypropylméthylcellulose or a non ionic surfactant oxo-C10C6 at a critical micellar concentration. Concerning the process variables the experimental results show that an optimal interval of impeller speed operation exists ranging from 150 to 200 rpm for granule growth. Below, an uncontrollable agglomerate size and localised over-wetting occur, and above granule breakage occurs. Increasing the liquid binder flow rate reduces the extension of the non growth regime, but does not affect the granule mean size. The effect of the physicochemical properties is evaluated using a modified capillary viscous number, Ca′, that we define as the ratio between the viscous forces (μLU) and the work of adhesion Wa=γL(1+cosθ). For Ca′b1, the viscosity of the solution does not significantly affect the granulation process. The dominant forces in the granulation process are the interfacial forces since increasing the work of adhesion enhances the growth kinetics. For Ca′N1.6, the viscous forces predominate and control the granule growth

A STUDY OF FLUID BED GRANULATION OF PRAVASTATIN TABLET USING DESIGN OF EXPERIMENTS

Objective: The objective of this study was to reduce size and weight of pravastatin tablet through quality by design approach; potential factors (spray rate, atomizing pressure, and inlet temperature) which could influence on the production process for critical process parameters of wet granulation using fluid-bed granulator were examined.Methods: The manufacturing process of the reduced weight and size formulation pravastatin tablet involves wet granulation, drying, granulate screening, blending, and tableting. Design of experiments study for wet granulation of the reduced weight/size pravastatin tablet was produced on 11 combinations of three factors (spray rate, atomizing pressure, and inlet temperature), which were chosen through initial risk assessment. The process of wet granulation was rated by measuring four responses: loss on drying (LOD) (%), bulk density (g/ml), product temperature (°C), and dissolution similarity (f2).Results: It was measured that LOD varied from 1.46 to 3.24%, bulk density from 0.34 to 0.51 g/ml, product temperature from 40.12 to 51.69°C, and dissolution (f2) of pravastatin from 52.14 to 58.91. Control strategy for wet granulation production of the reduced weight and size pravastatin tablet by our results demonstrated that the most optimized condition of three factors for wet granulation is spray rate (3–5 g/min), atomizing pressure (about 1 bar), and inlet temperature (65–90°C), respectively. Updated risk assessment and justification by all experimental data safely existed within the range of acceptance criteria were presented.Conclusion: It can be concluded that the ideal ranges of three factors (spray rate, atomizing pressure, and inlet temperature) in wet granulation were successfully identified

Discrete element modelling of fluidised bed spray granulation

A novel discrete element spray granulation model capturing the key features of fluidised bed hydrodynamics, liquid-solid contacting and agglomeration is presented. The model computes the motion of every individual particle and droplet in the system, considering the gas phase as a continuum. Micro scale processes such as particle-particle collisions, droplet-particle coalescence and agglomeration are directly taken into account by simple closure models. Simulations of the hydrodynamic behaviour of a batch granulation process are presented to demonstrate the potential of the model for creating\ud insight into the influence of several key process conditions such as fluidisation velocity, spray rate and spray pattern on powder product characteristics