design and characterization of nanocrystals of lovastatin for solubility dissolution enhancement
DESCRIPTION
Design Characterization of Nanocrystal, Dissolution EnhancementTRANSCRIPT
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: [email protected]
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
08/02/2010
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Powder X-Ray diffraction (PXRD):
A
A
A
08/02/2010
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
08/02/2010
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
08/02/2010
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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
08/02/2010
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: [email protected]
Cell No: 0091974243100Cell No: 0091974243100