Introduction & Rationale Experimental
Result & Discussion
QbD based Fenofibrate Nanosuspension
Fenofibrate
• Quality based approach for development of Fenofibrate nanosuspension
• Development of Fenofibrate nanosuspension using Planetary Ball Mill process and PVA as stabilizer (Non-infringing Approach)
Patent Physicochemical Properties
BCS class II molecule
Solubility related poor Bioavailability- 36%
Patent listed in orange book-6375968 (Expiry- 2020) Patent claim- Nano precipitation process- SLS as stabilizer
QTPP
QbD Approach
CQA
Risk Assessment
Experimental Design
Control Strategy
Preparation Method
Nanosuspension
Particle size, Polydispersibility index,
Drug loading
Spray Drying
QTPP Element Target Justification
Dosage form Powder(Nanosuspension)
Nanonization to develop pharmaceutical equivalent product
Route of administration
Oral Pharmaceutical equivalent product
Dosage Strength 145 mg Pharmaceutical equivalent product
Stability At least 24 month at RT
To maintain the therapeutic potential during storage
Container closure system
Alu-Alu blister Primary packaging for powder dosage form
Packagingintegrity
Suitable packaging to ensure shelf life of product
Efficacious and Stable formulation
QTPP
QTPP Element Target Is this CQA
Justification
Particle Size(less than 500nm) 400-500nm Yes
To achievebioequivalence
Polydispersibilityindex
0.1-0.3 YesTo maintain stability of nanosuspension
Assay98-102% Yes
To achievetherapeutic equivalence
Drug LoadingMore than 2%
Yes To reduce bulk weight
Cumulative Drug Release
More than 80% in 60min
YesTo achieve Cmax in vivo
CQAs
Risk Assessment Study
Variable Level
-1 0 1
Drug : Stabilizer (ratio) X1 1:0.5 1:1 1:1.5
Milling Speed (rpm) X2 100 200 300
Batch Drug: Stabilizer
ratio
Milling Speed(rpm)
Particle Size(nm)
Milling Speed(rpm)
FNS1 1:0.5 100 827.4 0.901
FNS2 1:0.5 200 811.5 0.745
FNS3 1:0.5 300 754.8 0.833
FNS4 1:1 100 642.9 0.362
FNS5 1:1 200 524.4 0.369
FNS6 1:1 300 427.1 0.208
FNS7 1:2 100 1022 0.402
FNS8 1:2 200 875.2 0.378
FNS9 1:2 300 734.6 0.437
Response Sum of Square
DF Mean Square
F Value
Prob>F
PRESS R2 Adj. r2
Pred r2
ParticleSize
2.48 2 1.248 50.58 0.0002
32897 0.9440
0.9253
0.8756
PDI 0.49 5 0.097 308.64 0.0003
9.369 0.9981
0.9948
0.9870
Mathematical Modelling
ANOVA Results
Graphical Analysis32 Factorial Design
Risk Assessment Study Model Diagnostic Plot
Design Space
Validation
Control Strategy
Conclusion & Future Prospects
References
Particle size: +715.91 – 176.75 X1 – 95.97 X2
PDI: +0.30 – 0.26 X1 – 0.088 X2 – 0.088 X1X2 + 0.027X12
Particle Size: Particle size decrease s with increase in X1 and X2
PDI: PDI decrease with increases in X1 and X2
PDI decreases with increases in X1 and X2
Particle size decreases with increase in X1 and X2
Code Dependent Variable Acceptance limitY1 Particle Size 400-600nmY2 PDI 0.1-0.3
Design Space
Drug Product CQAs
Drug: Stabilizer
(Ratio) Type of
Stabilizerr
Pre-millingTime
Milling Time
Milling Speed
Particle Size High Medium Medium Medium HighPDI High Medium Medium Medium High
Drug loading Medium Medium Low Low LowAssay Low Low Low Low LowStability Low Medium Low Low MediumAttributes with green colors indicates at low risk and no experimentationrequired, attributes with yellow color at medium risk, which based onpreliminary data can be converted to low risk, attributes with red color areat higher risk and need to optimize to convert into lower risk
Factor Attributes/Parameters
Range Studied
Design
Space
Purpose of Control
Drug: Stabilizer (Ratio)
Ratio 1:0.5 to1:2
1:1.5± 5 % To ensure development of stable formulation with desired particle size of 400-600nm and PDI of 0.1-0.3
Milling Speed
Rpm 100-300 rpm
200± 5 %
Milling Time
Hours (h) 1-2h 2h
Finished product quality of developed Fenofibratenanosuspension can be achieved with proposed controlstrategy
QbD BASED DEVELOPMENT OF FENOFIBRATE NANOSUSPENSION: A NON-INFRINGING APPROACH
, Mirani Amit , Gite Sandip, Ghodake Vinod, Patravale Vandana1Department of Pharmaceutical Sciences and Technology, Institute of Chemical Technology,
Matunga, Mumbai-400019
Acknowledgement
The authors are grateful to UGC and DBT for the financial assistance provided for the research work.
A. Bhakay, M. Merwade, E. Bilgili, R.N. Dave, Drug Development Industrial Pharmacy, 2011, 37: 963–976.
B. Anderson, M., Kraber, S., Hansel, H., Klick, S., Beckenbach, R., Cianca-Betancourt, H. 2002. Design Expert® Software Version 6 User’s Guide. MN: Statease Inc..
Anti-Hyperlipidemic Drug
Non infringing formula
Stabilizer- PVA
Non infringing Process-
Planetary Ball Mill
Fenofibrate Nanosuspension
Qbd approach applied
Design Space Generated
Powder dosage form can be converted Tablet/Capsule
dosage form
Para IV approach can be used for filling as generic for Tricor®
No model transformation is required as the lambda value is 1