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