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Design & Characterization of Nanocrystals of Lovastatin for Solubility & Dissolution Enhancement

Dr. Basavaraj K. Nanjwade

M. Pharm, PhD.

Department of Pharmaceutics KLE Universitys College of Pharmacy Belgaum-590010 E-mail: bknanjwade@yahoo.co.in Cell 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: To increase the drug solubility & dissolution. To increase the drug bioavailability.

Materials & Methods:


Materials: Drug: Lovastatin (Krebs 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 Volume of solvent LVS solution (mM) (ml) 3 mM 4 mM 3 mM 12.3 ml 10.8 ml 12.3 ml 10.8 ml 12.3 ml 10.8 ml

Dilution of LVS solution to water Volume of water (ml) 615 ml 540 ml 615 ml 540 ml 615 ml 540 ml
5

1. 2. 3. 4. 5. 6.

F1A F1B F2A F2B F3A F3B


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Acetone

Methanol

4 mM 3 mM 4 mM

Acetonitrile

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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 study
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F1 A Pure LVS

F2 A
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1000 803.71 Avg. particle size (nm) 800 579.33 600 400 200 0 620 584.58 711.85

848.06

F1A

F1B

F2A

F2B

F3A

F3B

LVS nanocrystal formulation code

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Powder X-Ray diffraction (PXRD):


A

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Differential scanning calorimetry (DSC):


Endothermic peak: 174.57C A

Endothermic peak: 174.87C A

Endothermic peak: 173.92C

Endothermic peak: 175.19C

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Sr. No

Media used

Solubility in each media (mg/ml) Average SD

Pure LVS 1. Distilled water

F1A

F1B

F2A

F2B

F3A

F3B

0.005 0.01 0.007 0.03 0.008 0.02

0.092 0.02 0.148 0.04 0.176 0.01

0.089 0.03 0.136 0.02 0.161 0.04

0.090 0.05 0.131 0.03 0.173 0.01

0.084 0.02 0.129 0.04 0.154 0.03

0.081 0.01 0.097 0.03 0.134 0.04

0.076 0.02 0.089 0.04 0.105 0.01

2.

Acidic buffer PH 1.2 Phosphate buffer PH 7.4

3.

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100 80 60 40 20 0 0 20 40 60 80 100 120 140 160 180 Time (Min.) F1A


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% Cum. drug released

F1B

F2A

F2B

F3A

F3B

Pure LVS
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f) In- vivo evaluation


In vivo drug release of pure LVS
10 8 6 4 2 0 0 50 100 150 200 250 Time (Min.) i.v. control group Oral control group Plasma drug concentration (mcg/ml)

Plasma drug concentration (mcg/ml)

In vivo drug release of F1A and F2A 8 nanocrystals


6

0 0 100 200 300 400 500 Time (Min.)

F1A

F2A

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Comparison of Bioavailability of LVS nanocrystals


Absolute Relative bioavailability bioavailability Area under curve(0-8) (g/ml.hrs) Cmax (g/ml) Tmax (hrs.)

Code

Oral control group

------0.826 0.821

------1.015 1.010

802.8 986.7 815.3 810.9

5.849 0.245 9.546 0.094 6.325 0.324 5.590 0.432

2 5* 2 2

IV control group F1A F2A

* 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 300C20C / 65% 5% RH Percent drug content at 400C20C/ 65% 5% RH

F1A

66.46%

66.32%

60.54%

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Continued.. Release study of F1A stored at 40C, at 300C20C / 65% 5% RH and 0 % Cumulative LVS % Cumulative LVS at 400C2 C/ 65% % Cumulative LVS5% RH
Time (Min.) release stored at 40C release stored at 30 C20C / 65% 5% RH
0

release stored at 400C20C/ 65% 5% RH

15 30 45 60 90 120 150 180


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44.96 59.16 70.20 75.03 82.97 87.06 90.31 93.76

45.23 59.63 70.86 75.53 83.18 87.45 90.35 93.06


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41.03 54.24 65.03 71.26 79.06 82.36 88.65 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 4C. The maximum instability of nanocrystals was observed at 402C.
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THANK YOU.
08/02/2010 NIPER, Chandigarh
E-mail: bknanjwade@yahoo.co.in 19