Monitorgranulationing the wetting phase of fluidized bed granulation process using multi-way methods

Monitoring the wetting phase of fluidized bed granulation process using multi-way methods:The separation of successful from unsuccessful batches

Sanni Matero a ,⁎,Sami Poutiainen b ,Jari Leskinen c ,Satu-Pia Reinikainen d ,Jarkko Ketolainen b ,Kristiina Järvinen b ,Antti Poso a

a

Department of Pharmaceutical Chemistry,University of Kuopio,P.O.Box 1627,FIN-70211,Kuopio,Finland b

Department of Pharmaceutics,University of Kuopio,P.O.Box 1627,FIN-70211,Kuopio,Finland c

Department of Physics,University of Kuopio,P.O.Box 1627,FIN-70211,Kuopio,Finland d

Department of Chemical Technology,Laboratory of Analytical and Inorganic Chemistry,Lappeenranta University of Technology,P.O.Box 20,FIN-53851Lappeenranta,Finland

a b s t r a c t

a r t i c l e i n f o Article history:

Received 25November 2008

Received in revised form 22December 2008Accepted 7January 2009

Available online 29January 2009Keywords:

Fluidized bed granulation Batch process monitoring Multi-way analysis PARAFAC PARAFAC2

Fluidized bed granulation of a pharmaceutical mixture and wet granulation in general is an unpredictable and complex ually the few variables that are known to indicate the granulation end-point are monitored independently but at the same time simultaneously.If one wishes to control the complex process and evaluate how this is affected by different physical and chemical granulation phases and variables measured then multivariate analysis and appropriate controlling tools need to be incorporated into the process line.It is also important to obtain early warnings from the process line when the process is already or about to develop in an unwanted direction.Multivariate tools in conjunction with process variables or spectroscopic data can reveal the latent structure of the process.In this study,multi-way models together with a few process variables have been utilized to distinguish successful batch granulations from unsuccessful runs.The batch-to-batch variation of different runs is handled using the special multi-way data structure of the experiments.

©2009Elsevier B.V.All rights reserved.

1.Introduction

Wet granulation is a very important unit operation in pharmaceu-tical powder processing of oral dosage forms in the pharmaceutical industry.Granulation is used before tabletting in order to achieve better content uniformity and to modify the powder to attain the desired compaction behavior [1,2].Granulation is a complex and dynamic process consisting of overlapping phases,namely wetting and drying,whose extend depend on the applied granulation method and process parameters [1–4].The granulation process is usually carried out in a batch mode,which has its own advantages with respect to quality control but also drawbacks with scalability and ef ficiency [5–7].Two different methods are typically used in wet granulation,high shear mixing granulation and fluidized bed granulation [1,8].In fluidized bed granulation,the wetting and drying phases take place in the same process equipment.In contrast,in high shear granulation,the wetting phase is carried out in a different process vessel than the subsequent fluidized bed drying of granular mass [1].Despite the need to transfer granular mass between the different process phases,high shear granulation is widely used in the pharmaceutical industry because of its ef ficiency in producing dense

granules [1,9]with low porosity.These properties are appropriate for use in subsequent formulation stages such as compression and coating [10,11].However,in spite of the dif ficulties of monitoring and understanding the process [12],fluidized bed granulation can be considered a better method since it yields a narrower granule size distribution,which generally corresponds to more homogeneous granules [2].

The complexity of the fluidized bed granulation process arises from many inter-related variables,such as inlet air humidity and temperature and spray rate of liquid binder that affect on granulation outcome [1,2].Also,batch-to-batch variation in starting materials and process conditions has a strong in fluence on the process.However,the inter-related impact of the critical process variables on the granulation process is still not well understood,and controlling process outcome is still carried out by monitoring individual process variables which may be misleading in many circumstances [13–15].For instance,the tempera-ture difference between inlet air and granular mass (ΔT )has been widely used to monitor the fluidized bed granulation process [16],since the granulation (inlet)air temperature is one of the most important factors affecting the granulation process,alongside with the moisture content of the granular mass [1,2,8,17,18].However,despite this univariate ΔT method being a noteworthy method itself,it is feasible only when the process is in a state of proper fluidization,which depends on among other things that the humidity content of the inlet air does not vary [19].Concentrating on monitoring of ΔT could lead to over-wetting of the bed

Chemometrics and Intelligent Laboratory Systems 96(2009)88–93

⁎Corresponding author.Tel.:+358403553888;fax:+35817162456.E-mail address:sanni.matero@uku.fi(S.

Matero).0169-7439/$–see front matter ©2009Elsevier B.V.All rights reserved.doi:

10.1016/j.chemolab.2009.01.003

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