Nanosuspension – An unique tool for

improving the bioavailability of poorly

soluble drugs

Enhancing Drug Bioavailability & Solubility

Boston, MA

Indrajit Ghosh

Principal Scientist

Novartis Pharmaceuticals, NJ.

January 2012 1

Outline

Therapeutical application and benefits of Nanoparticle dosage form

Nanosuspension – At preclinical phase & Clinical phase

Nanosuspension – Formulation design and characterization - Case study 1

Stability approaches– Case study 2

Optimization of process parameters - Case study 3

Scale-up considerations

General risk considerations to human health

2

Benefits of nanoparticle dosage form

3

Main application to BCS Class 2

molecules.

Nanoparticulate dosage form has wide

area of applications – oral, parenteral,

transdermal, inhalation etc, by –

Improving the bioavailability

Decreasing the food effect

Decreasing intra subject variability

Reducing the dose

Increasing adhesiveness with

intestinal membrane.

Reducing gastric irritation

Rainer H. Müller et. al, EJPB

Techniques for producing nanoparticles

Nanosuspensions - Submicron colloidal dispersion systems.

Bottom-up approach (Dow Pharma ; BASF)

Top down approach (Elan’s NanoCrystal ; Sky-ePharma’s Dissocubes technology)

Wet Milling

High Pressure Homogenization

4

Rainer H. Müller et. al, EJPB

Wet media milling

Benefits –

Drug crystallinity remain intact during processing.

No organic solvent.

Unimodal size distribution.

Simple and cost effective

Wet Media milling - comprises mechanical attrition of drug particles using

milling media such as yttrium stabilized zirconium oxide beads of definite size range

(e.g. 0.1-0.5 mm ceramic beads)

5

Theoretical considerations

6

According to Noyes and Whitney, the dissolution velocity

is further enhanced because dc/dt is proportional to the

concentration gradient (cs-cx)/h.

According to Kelvin’s equation, there is an additional effect

of increase in the saturation solubility (Cs) by shifting the

particle size from micron to submicron range.

dC / dt = DA(Cs-C) / h

dX / dt = DA(Cs-X/V) / h

International Journal of Nanomedicine 2008:3(3) 295–309 6

Nanosuspension – Preclinical Phase

During preclinical pharmaceutical development, the API is in tight supply.

Also pre-clinical development is typically characterized by short development time lines

Accelerated feasibility assessment of drugs from research.

7

Nanosuspension – Clinical phase

Instrument: Stirred media mill

Grinding media: Zirconium beads,

0.1 - 0.5 mm

Agitator speed: 1500 - 2500 rpm

Pump speed: 250 rpm

Recirculation: reduces milling time

and decreases particle size

Fpressure, impact

Fshear

8

Nanosuspension – Formulation design and

characterization

9

Formulation effect

Effect of Solubilizer: Vitamin E

TPGS, SLS, Pluronic F68, F127,

DOSS

Effect of stabilizers / suspending

agents: PVP K-30, HPMC 3cps, HPC

EXF

Drug substance properties

Size and size distribution:

Particle charge(zeta

potential):

Morphology by SEM,

TEM, AFM

Crystalline status: By X-

ray, DSC

Surface coverage and

morphology:

SEM,TEM,AFM

Assay, Deg.

Dissolution.

Bulk suspension properties

Rheology

Sedementation rate

Application of Vitamin E TPGS to produce

nanosuspension – Case study 1

Challenges

Morphology – Rod shaped, difficult to mill in

compared to spherical shape, which has more

SA

available for milling.

Wettability – Very poor

DS properties of compound A

Log P (in silico): 3.021, Log D (pH 6.8): 1.27

Solubility at 0.003 mg/ml (in water) (BCS class

II)

10

Particle size of drug substance after 3-4 hours of nanomilling for different formulations.

Particle size reduction of nanosuspension

0

50

100

150

200

250

300

350

400

450

5% Drug with 5% Vitamin ETPGS

5% Drug with 3% Vitamin

ETPGS & 2%

Pluronic F68

5% Drug with 3% Vitamin

ETPGS & 2%

Pluronic F127

5% Drug with 5% Vitamin

ETPGS & 1% SLS

5% Drug with 3% Vitamin

ETPGS & 1% HPMC

5% Drug with 3% Vitamin

ETPGS & 1% PVP

Part

icle

siz

e (n

m)

Composition of Nanosuspension

Particle size distribution profile for nanomilled Compound with different variants

Start 30 min

1 hr 3 hr

The most effective nano range particle size

was observed with 5% Vitamin ETPGS and

also with 5% Vitamin ETPGS and 1%

HPMC 3 cps The “cleavage” and “fracture” mechanism

responsible for particle size reduction.

11

Characterization of crystal properties

XRD

12

Lin

(C

ounts

)

0

100

200

300

400

500

600

2-Theta - Scale

2 10 20 30 40

Drug Substance +Mannitol Freeze dried

Drug Substance

Nanosuspension

Pure drug

Invitro / Invivo drug release from

nanosuspension.

13

The AUC of nanosuspension was increased by about 9 fold and the Cmax

was increased by about 5 fold in compared to coarse suspension.

Indrajit. Ghosh, et. al. International journal of pharmaceutics, 2011

0

200

400

600

800

1000

1200

1400

0 10 20 30 40 50 60

Intralipid coarsesuspension withsalt

Nanosuspensionwith free base

Invitro / Invivo drug release from

nanosuspension.

14

European Journal of Pharmaceutics and

Biopharmaceutics 78 (2011) 441–446

International Journal of Pharmaceutics 408 (2011) 157–

162

Nanomilling - Stability

Stability –

During the milling process due to the change of

Gibbs free energy thermodynamically unstable

nanosuspensions formed which is responsible for

Ostwald ripening and agglomeration phenomenon

or crystal growth during process or during shelf life

due to high particle mobility.

Proper selection of stabilizers are required for

tailoring the particle surface.

Steric stabilization Electrostatic

stabilization

15

Impact crystal structure

No Yes

Crystal growth in nanosuspension

– Case study 2

Compound - A

Initial After 3 months

Time Mean particle size (PCS)

Initial 230.2

1 month 312.0

3 months 477.8

16

The use of polymer along with a

surfactant have synergistic

stabilizing action.

HPMC – Successfully inhibit crystal growth

Because of the absorption of HPMC polymer on the surface of the nuclei the drug

nucleation was inhibited.

17

200

250

300

350

400

450

500

5% Drug with 5%

Vitamin ETPGS

5% Drug with 5%

Vitamin ETPGS and

1% HPMC

5% Drug with 5%

Vitamin ETPGS and

1% PVP

Part

icle

siz

e (

nm

)

Composition of Nanosuspension

Change of particle size of nanomilled compound on

storage

Initial

3 months

HPMC

PVP

Effect of SLS nanocrystal formulation

0

100

200

300

400

500

600

700

800

900

0 1 2 3 4 5 6

Part

icle

siz

e (

nm

)

Time

Particle size distribution profile for nanomilled Compound at different process time

5% Drug with 5% VitaminETPGS

5% Drug with 5% VitaminETPGS & 1% HPMC

5% Drug with 5% VitaminETPGS and 1% SLS

Ostwald ripening was observed with SLS during Nanomilling.

18

Importance of surface hydrophobicity of drug

on dissolution for dried Nanosuspension.

For nano-suspension production, absorption of Vitamin E TPGS on the

surface of drug is very critical.

More hydrophobic compounds will result in more severe and harder-to-

disintegrate agglomerates that will lower the dissolution rate of the product.

J. Pharm. Sci. 35 (2008), 127-135.

19

Optimization of process parameters during

nanomilling of Naproxen – Case study 3

20

RPM - most significant process parameter with a faster RPM produced smaller particles.

Bead size - seem to be a complex parameter. An increase in the specific energy input

(the RPM) combined with a decrease in the media diameter formed finer product in the

shortest time.

Total drug content - did not seem to have significant effect.

0

100

200

300

400

500

600

0 1 2 3 4 5

par

ticl

e s

ize

(nm

)

Time (hrs)

0.1mm, 400RPM, 5% Drug Content: Ratio comparison

1 to 1

2 to 1

4 to 10

200

400

600

800

1000

1200

1400

1600

5%D, 400RPM, 0.1mm bead

5%D, 400RPM, 0.5mm bead

5%D, 150RPM, 0.1mm bead

5%D, 150RPM, 0.5mm bead

Avg

. Par

ticl

e S

ize

(nm

)

Process parameters

Avg. particle size after 4 hours of milling

1:1 (Drug:TPGS)

2:1 (Drug:TPGS)

4:1 (Drug:TPGS)

Indrajit. Ghosh, et. al. AAPS poster, 2011

Combined effect of process parameters &

stabilizer

Although the process parameters determined the success of nanomilling process

in terms of efficiency, however the drug-carrier system was also equally

important for stabilizing the particles during the process by minimizing

agglomeration or crystal growth of drug substance.

0

20

40

60

80

100

120

140

160

180

200

HPMC NS HPC EXF NS PVP NS

Mag

nit

ud

e of

eff

ects

Polymer type

Comparitive effect of process parameters from Pareto Chart on

Particle size after 4 hrs

RPM

Bead Size

Drug load

21

Fragmentation of materials Particle growth through interparticulate collision

Milling time depends upon Drug Morphology

NAP – d50 = 23.632 µm

Compound A – length = 103 – 135 µm

22

Naproxen

Compd. A

Particle size after 4 hrs

milling: Naproxen vs.

Compound - A

Scale-up from planetary mill to stirred media

mill using central composite statistical design

Decrease of polydispersity index (PI)

was observed with milling time of drug

crystals, which confirms that with

prolonged milling time, remaining

larger particles in the nanosuspension

were broken down into smaller

particles.

23

Critical scale-up parameters

Agitator speed (Tip speed)

Bead size

Solid content.

“When the particle size is

decreased, the hardness of the

material is increased”

......resulted to decrease of milling

rate with time.

General Risk Considerations to Human Health

24

NPs cause unique biological effects (including those potentially toxic to humans)

Biological effects can widely vary depending on slight alterations in their physicochemical and surface as well as pharmacological (target / off-target) properties

Each type of NPs must be assessed on its own. FDA: currently no testing requirements specific to NMs, but if research identifies toxicological risks unique to NMs, additional testing requirements may become necessary

R.H. Müller et al.

Conclusion

The wet milling media milling technique is considered to be an attractive

technique in pharmaceutical industries.

It is a very fast process, eliminates the use of organic solvent and thus make

the process eco-friendly.

A significant increase of area under drug concentration / AUC observed

when the drug substance was converted into nanocrystals, probably due to

the increase in dissolution velocity and saturation solubility.

Although the process parameters determined the success of nanomilling

process in terms of efficiency, however the drug-carrier ratio was also

equally important for stabilizing the particles by minimizing agglomeration

or crystal growth.

In this approach, common regulatory approved excipients are generally used,

which give big advantage for the formulation to use in clinical studies and

also to enter regulatory market.

25

Acknowledgements

Sonali Bose, Yogita Krishnamachari, Subash Patel, Glen Biank, Al. Hollywood.

Radha Vippagunta, Frances Liu.

Easter Maulit

Jay Lakshman, Ping Li, Michael Motto, Colleen Ruegger

26

Questions

27

API

Impact

Milling bead

Attrition

Milling bead

Thank you...... Indrajit Ghosh

Principal Scientist & Project Leader

Email: indrajit.ghosh@novartis.com