Design & Characterization of Nanocrystals of Lovastatin for

Solubility & Dissolution Enhancement

Dr. Basavaraj K. NanjwadeDr. Basavaraj K. Nanjwade M. Pharm, PhD.M. Pharm, PhD.

Department of PharmaceuticsDepartment of Pharmaceutics

KLE University’s College of PharmacyKLE University’s College of Pharmacy

Belgaum-590010Belgaum-590010

E-mail: E-mail: bknanjwade@yahoo.co.in

Cell No: 00919742431000Cell No: 00919742431000

Nanocrystal

• Definition: Drug nanocrystals are nanoparticles being composed of

100% drug without any matrix material.

• Methods of production: - Bottom up technology: Precipitation - Top down technology: High pressure homogenization

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Objectives of the study:Objectives of the study:

To increase the drug solubility & dissolution.

To increase the drug bioavailability.

Materials & Methods:Materials & Methods: Materials: Drug: Lovastatin (Kreb’s biochemicals Pvt. Ltd.,

Hyderabad) Solvents: Acetone, Methanol, Acetonitrile

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Method:

• All the formulations were prepared by Precipitation method.

Involves two steps…..

1. Preparation of drug solution in solvent

2. Addition of drug solution to water

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Sr. no.

Code Organic solvent

LVS Concentration in

solvent (mM)

Dilution of LVS solution to water

Volume of LVS solution

(ml)

Volume of water (ml)

1.

2.

3.

4.

5.

6.

F1A

F1BAcetone

3 mM

4 mM

12.3 ml

10.8 ml

615 ml

540 ml

F2A

F2BMethanol

3 mM

4 mM

12.3 ml

10.8 ml

615 ml

540 ml

F3A

F3BAcetonitrile

3 mM

4 mM

12.3 ml

10.8 ml

615 ml

540 ml

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a) Particle morphology

b) Particle size analysis

c) Crystalline state evaluation

- Powder X-ray diffraction (PXRD) - Differential scanning calorimetry (DSC)

d) Solubility determination

e) In vitro release study

f) In vivo evaluation

g) Stability study08/02/2010 6NIPER, Chandigarh

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Pure LVSPure LVS

FF1AA

FF22AA08/02/2010

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579.33 620 584.58

711.85

803.71848.06

0

200

400

600

800

1000

Avg

. p

art

icle

siz

e (

nm

)

F1A F1B F2A F2B F3A F3B

LVS nanocrystal formulation code

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Powder X-Ray diffraction (PXRD):

A

A

A

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Differential scanning calorimetry (DSC):

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A

A

A

Endothermic peak: 175.19˚C

Endothermic peak: 173.92˚C

Endothermic peak: 174.87˚C

Endothermic peak: 174.57˚C

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Sr. No

Mediaused

Solubility in each media (mg/ml)Average ± SD

Pure LVS F1A F1B F2A F2B F3A F3B

1. Distilledwater

0.005±

0.01

0.092±

0.02

0.089±

0.03

0.090±

0.05

0.084±

0.02

0.081±

0.01

0.076±

0.02

2. AcidicbufferPH 1.2

0.007±

0.03

0.148±

0.04

0.136±

0.02

0.131±

0.03

0.129±

0.04

0.097±

0.03

0.089±

0.04

3. Phosphatebuffer PH

7.4

0.008±

0.02

0.176±

0.01

0.161±

0.04

0.173±

0.01

0.154±

0.03

0.134±

0.04

0.105±

0.01

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0

20

40

60

80

100

0 20 40 60 80 100 120 140 160 180

Time (Min.)

% C

um

. dru

g r

elea

sed

F1A F1B F2A F2B F3A F3B Pure LVS

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f)f) In- vivo In- vivo evaluationevaluation In vivo drug release of pure LVS

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0

2

4

6

8

10

0 50 100 150 200 250

Time (Min.)

Pla

sm

a d

rug

co

nc

en

tra

tio

n

(mc

g/m

l)

i.v. control group Oral control group

In vivo drug release of F1A and F2A nanocrystals

0

2

4

6

8

0 100 200 300 400 500

Time (Min.)

Pla

sm

a d

rug

co

ncen

trati

on

(mcg

/ml)

F1A F2A

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Comparison of Bioavailability of LVS nanocrystals

CodeAbsolute

bioavailabilityRelative

bioavailability

Area under curve(0-8) (µg/ml.hrs)

Cmax (µg/ml)Tmax (hrs.)

Oral control group

- - - - - - - - 802.8 5.849± 0.245 2

IV control group

- - - - - - - - 986.7 9.546± 0.094 5*

F1A 0.826 1.015 815.3 6.325± 0.324 2

F2A 0.821 1.010 810.9 5.590± 0.432 2

* Time in minute Values of Cmax are mean ± standard deviation

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Drug content after 30 days storage of F1A

Code Percent drug content at

40C

Percent drug content at 300C±20C / 65%± 5%

RH

Percent drug content at 400C±20C/ 65%± 5%

RH

F1A 66.46% 66.32% 60.54%

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Continued…..Continued…..

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Release study of F1A stored at 40C, at 300C±20C / 65%± 5% RH and at 400C±20C/ 65%± 5% RH

Time (Min.)

% Cumulative LVS release stored at

40C

% Cumulative LVS release stored at

300C±20C / 65%± 5% RH

% Cumulative LVS release stored at

400C±20C/ 65%± 5% RH

15 44.96 45.23 41.03

30 59.16 59.63 54.24

45 70.20 70.86 65.03

60 75.03 75.53 71.26

90 82.97 83.18 79.06

120 87.06 87.45 82.36

150 90.31 90.35 88.65

180 93.76 93.06 89.30

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From the particle morphology by SEM, it was observed that LVS nanocrystals remain crystalline.

Less particle size was observed in case of F1A & F2A as compared to all other.

From PXRD and DSC data, it was observed that F1A , F2A & F3A showed no significant change in crystalline as compared to pure LVS.

Solubility was enhanced due to less particle size & solvent used (acetone & methanol).

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In-vitro release rate studies showed that the maximum drug release was found in the F1A & F2A in the required period of time.

In-vivo relative bioavailability of F1A & F2A was slightly increased as compared to absolute bioavailability.

From stability study data it was revealed that nanocrystals of lovastatin remained more stable at 4ºC. The maximum instability of nanocrystals was observed at 402C.

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THANK YOU….NIPER, Chandigarh 1908/02/2010 E-mail: E-mail: bknanjwade@yahoo.co.in

Cell No: 0091974243100Cell No: 0091974243100