But, it was observed that sodium stearyl fumarate was the unique lubricant solved the punch sticking problem during experiment studies. Since this problem ...
Modeling of Dexketoprofen Tablets by Using Quality by Design Approach MSc Önder DEMİR¹, Ass. Prof. Dr. Buket AKSU², Prof. Dr. Yıldız ÖZSOY³, Pof. Dr. Ahmet Oğul ARAMAN³ 1Mustafa
Nevzat Pharmaceutical A.S., Department of R&D, İstanbul, Turkey 2Santa Farma Pharmaceutical A.S., Department of Corporate Affairs, Istanbul, Turkey 3Istanbul University, Faculty of Medicine, Department of Pharmaceutical Technology, Istanbul, Turkey
INTRODUCTION
RESULTS AND DISCUSSION
Quality by design (QbD) encompasses designing and developing formulations and manufacturing processes which ensures predefined product specifications. An important part of QbD is to understand how process and formulation parameters affect the product characteristics and subsequent optimization of these parameters should be identified in order to monitor these parameters online in the production process [1]. In this study, development, understanding, control strategy and specifications of formulation and manufacturing process of immediaterelease film coated tablets containing Dexketoprofen Trometamol were determined by using Quality by Design approach. Design of Experiment (DoE) was formed for formulation development via Minitab software. Results of the experiments were firstly analyzed by Minitab software capable of linear regression modeling. These results were then assessed via Artificial Neural Network (ANN) and Gene Expression Programming (GEP) modules of INForm software capable of non-linear modeling.
THE RESULT OF DoE TRIALS
MATERIALS AND METHODS
Dexketoprofen trometamol, Starch 1500-LM, Avicel PH102, Aerosil 200, The parameters that may affect the Critical Quality Primojel, Precirol ATO 5, Compritol Attributes 888 ATO, sodium stearyl fumarate (PRUV) and Opadry White 03J280000 coating mixture were used as formulation ingredients. GEA SP 15 mixer, Korsch eccentrically tablet pressing machine, Glatt SIEB GS 60 milling granulator, 30 and 40 mesh manual sieve, Glatt GMPCI Minicoater coating machine were used as process equipments. Minitab 17.1.0 (LEAD Technologies, Inc) and INForm V5.1 (Intelligensys) were used as evaluation softwares.
General Full Factorial DoE Application Software: Minitab 17.1.0 Number of factors: 3 Number of trials: 18 Number of based block: 1 Number of total block: 1 Replications: 1 Levels of factor: 2; 3; 3
MODELLING RESULTS The optimized formulation result obtained in Minitab software
The optimized formulation parameter results obtained in INForm ANN software
The optimized formulation parameter obtained in INForm GEP software
results
Minitab Design Table (Randomized) Factors A: Slug compression Yes (1); No (2)
B: Lubricant amount
%1.5 (1); %2.5 (2); %3.5 (3)
C: Lubricant Type Gl. Distearate (1); Gl. Dibehenate (2); S. Stearil Fumarat (3)
Response Variables (CQAs) Carr’s index (%), Disintigration (min.), Weight Deviation (%RSD), Friability (%)
MODELLING PARAMETERS OF MINITAB and INForm The parameters of “Response Optimizer” in Minitab software
INForm ANN and GEP modules optimization parameters
DECISION MAKING OF OPTIMUM FORMULATON PARAMETERS As a result of modelling studies, it was determined that slug compression should be implemented as a production method, glyceryl dibehenate should be used as lubricant type. The amount of lubricant should be between %2.03 - %2.50 to provide an optimized formulation. But, it was observed that sodium stearyl fumarate was the unique lubricant solved the punch sticking problem during experiment studies. Since this problem must be solved to produce an acceptable product in the pharmaceutical industry, it is decided to use sodium stearyl fumarate as lubricant type instead of glyceryl dibehenate. Other parameters was held constant.
CONCLUSIONS
Since response variables measured were found to be nonlinear against changing factors in practice, INForm software capable of non-linear modeling was deemed to be more successful with comparison to Minitab software. Optimum formulas found as a result of the modeling studies, were appropriate in terms of chemical and physical tests and solved the sticking problem. Sodium stearyl fumarate was required to be between %2.03 and %2.50 and slug compression was needed for that optimum formulation. ACKNOWLEDGMENTS There is no acknowledgement to be declared on this study. REFERENCES 1. Roy S. Quality by design: A holistic concept of building quality in pharmaceuticals. Int J Pharm Biomed Res 2012, 3(2), 100-108.
