Dissolution Enhacement Presentation11

8/2/2019 Dissolution Enhacement Presentation11

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Write u r College name


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Studies on Enhancement of

Dissolution Rate of Celecoxib

by Cyclodextrin Complexation

Presented By

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Importance of Bioavailability

Methods for improvement of increase in dissolution

rate and efficiency

Introduction to Non-steroidal Anti-Inflammatory

Drugs(NSAIDS)

Introduction


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BCS Classification System.

Cyclodextrin Complexation.

Non steroidal anti inflammatory drugs.

Celecoxib drug profile.


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To enhance the dissolution rate of Celecoxibby cyclodextrine complexation.

To evaluate CD complexation for enhancingthe dissolution rate Celecoxib.

To prepare and evaluate CD complexation ofCelecoxib in combination with the CD &HP CD.

Objectives of the Investigation


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Dissolution and Bioavailability ofDrug from Solid Dosage Forms


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I. Methods which increase the solubility of drug

II. Methods which increase the surface area of thedrug

Methods available to Enhance thedissolution and Absorption rate of

Poorly Soluble Drugs


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Buffering the PH of the micro environment.

Use of salts of weak acids & weak bases

Use of solvates and hydrates Use of selected polymorphic forms

Complexation

Pro-drug approach Use of surfactants

I. METHODS TO INCREASE THE DISSOLUTIONOF THE DRUG


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Micronization

Use of surfactants

Solvent disposition

Solid dispersions

II.METHODS TO INCREASE THE SURFACEAREA OF THE DRUG


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STRUCTURE OF-CYCLO DEXTRINE

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Property -CD -CD -CD HP-CD MCD SBE--CD TE--CDNumber of

Glucose units

Molecular

Weight

Cavity

diameter. A

Solubility

(200C)

(g/100 ml)

6

972

4.7-5.3

14.5

7

1135

6.0-6.5

1.85

8

1297

7.5-8.3

23.2

7

1390

50.70

7

31.57

7

5.10

7

1723

18x103

CHARATERSTICS OF IMPORTANTCDs

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Improvement of Solubility.

Enhancement of Dissolution Rate &

Bioavailability. Reduce unpleasant taste & side effects.

Improvement of Drug Stability.

Reduction in volatility. As Sustained Release Carrier.

Pharmaceutical Applications ofCyclodextrins


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Salicylates

Aryl alkanoic acids

2-aryl propionic acids

N-aryl anthranillic acids (Mefenamic acid)

Pyrazolidine derivatives

Oxicams (Piroxicam, Meloxicam)

COX-2 inhibitors(Celecoxib)

Non steroidalAnti-inflammatory Drugs


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Indicated for the symptomatic relief of

Rheumatoid arthritis

inflammatory arthoapthies

Psoriatic Arthritis

Acute Gout

Dysmenorrhoea

Meatasataic bonepain Headache

Migraine

Post operative pain

USES


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Class: Benzene sulfonamideIndicationsMild to moderate pain in rheumatoid

arthritis,osteo arthritis, dysmenorrhoea,menorrhagiaDose:100 mg three times daily.Adverse effects:

Skin Rashes,anemia, drowsiness, dizziness.

Celecoxib profile

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Description : White to offWhite crystalline

powder

Solubility : Poorly soluble in Water

Melting Point : 155170 C

Physicochemical Properties


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A Spectrophotometric method based on measurement of

absorbance at 254nm in water containing 1% SLS.

Analytical methods


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Drug sample: Celecoxib

Dilution fluid : Water containing 1%SLS

Spectrophotometer: UV- Analytical Spectro 2060 plus

max 254nm

Estimation of Celecoxib


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Celecoxib

Methanol

-CD

Hydroxypropyl- -CD

Sodium Lauryl Sulphate

All other materials used were of pharmacopoeial grade

Materials

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Kneading method

Co evaporation method

Methods


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Drug and Cyclodextrin were triturated in a mortar with asmall volume of a solvent blend of water-methanol (3:2).

The thick slurry was kneaded for 45 min and then dried at

55 o C until dry. The dried mass was pulverized andsieved through mesh No.120.

Kneading Method


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The aqueous solution of Cyclodextrin was added to thesolution of drug in a solvent blend of water-ethanol (3:2).

The resulting mixture was stirred for 1 hr. andevaporated at a temperature of 55 o C until dry. The dried

mass was pulverized and sieved through mesh No.120.

Co evaporation Method


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Reproducibility

Interference studies

ANALYTICAL METHOD VALIDATION


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Reproducibility of this analytical method was

studied by analyzing six individually weightedsamples of Celecoxib

Reproducibility


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Accurately weighed samples of Celecoxib and polymersor excipients or other materials in 1:1 weight ratio were

mixed thoroughly.

From each sample an accurately weighed powder

equivalent to 10 mg of Celecoxib was assayed by the

above analytical method. The Celecoxib contents were

calculated by measuring the absorbance at 254 nm

Interference Study


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The stock solution was subsequently diluted to a series ofdilutions containing 2,4,6,8 and 10 mg/ml of solution,using distilled water containing 1% sodium laurylsulphate.

The absorbance of these solutions was measured in UV-VIS spectrophotometer at 254nm against same dilutionfluid (1%SLS) as blank.

The absorbance was plotted against concentration ofCelecoxib

Procedure to plot calibration curve


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0

0.2

0.4

0.6

0.8

1

0 2 4 6 8 10 12

Concentration (ug/ml)

Absorbance

Calibration Curve for the Estimation of Celecoxibin Water containing 1% SLS

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DRUG DISSOLUTION FLUIDUSED

Celecoxib Water containing 1% SLS (900 ml)

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Dissolution Studies


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Preparation of Solid complexes

(kneading method, co-evaporation method)

Estimation of Drug Content of Solid DispersionsPrepared inclusion complex of CD

Dissolution Rate Studies on CD

EXPERIMENTAL PROCEDURES


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Time

(min)

Percent Celecoxib Dissolved

CC--CD

1:1 1:2 1:3

5 24.42 74.66 85.69 86.50

10 30.37 97.68 98.04 99.00

20 33.86 99.00 99.82 100.03

30 35.13 100.12 100.01 -

45 37.82 - - -

60 39.41 - - -

90 42.66 - - -

120 45.75 - - -

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Dissolution profiles of Celecoxib Beta-CDcomplexes prepared by kneading method


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0

10

20

30

40

50

60

70

80

90

100

0 20 40 60 80 100 120

Time (Min)

PercentCelecoxibD

issolve

C C-B-CD 1:1 C-B-CD 1:2 C-B-CD 1:3

Dissolution profiles of Celecoxib Beta-CD complexesprepared by kneading method

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0

0.2

0.4

0.6

0.8

1

1.2

1.4

1.6

1.8

2

0 10 20 30 40 50 60 70 80 90 100 110 120

Time (min)

LogPercentMARemaining

Celecoxib C-Beta CD 1:1C-Beta CD 1:2 C-Beta CD 1:3

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First order Dissolution profiles of Celecoxib Beta-CD complexes prepared by kneading method


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Time

(min)


CC--CD

1:1 1:2 1:3

5 24.42 44.6 52.40 59.60

10 30.37 57.70 64.00 71.20

20 33.86 64.40 69.30 77.60

30 35.13 69.70 74.50 81.30

45 37.82 73.80 78.70 84.60

60 39.41 77.20 81.60 87.45

90 42.66 79.80 84.30 90.20

120 45.75 81.60 86.50 94.0035

Dissolution profiles of Celecoxib Beta-CD complexesprepared by

co evaporation method


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Dissolution profiles of Celecoxib C-Beta-CD complexesprepared by

co evaporation method

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First order Dissolution profiles of Celecoxib C-Beta-CDcomplexes prepared by co evaporation method

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Time

(min)


CC-HP--CD

1:1 1:2 1:3

5 24.42 0.53 81.34 0.42 85.24 1.23 98.20 0.68

10 30.37 0.92 96.42 0.20 96.78 0.98 100.45 0.82

20 33.860.58 100.3 0.96 100.060.37 -

30 35.130.27 - - -

45 37.820.54 - - -

60 39.410.74 - - -

90 42.660.35 - - -

120 45.750.87 - - -38

Dissolution profile of Celecoxib and C-HP-Beta-CD Complexation prepared by kneading method


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0

10

20

30

40

50

60

70

80

90

100

0 20 40 60 80 100 120

Time (min)

PercentCelecoxibD

issolved

Celecoxib C-HP-Beta CD 1:1C-HP-Beta CD 1:2 C-HP-Beta CD 1:3

Dissolution profile of Celecoxib and C-HP-Beta-CDComplexation prepared by kneading method

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0

0.2

0.4

0.6

0.8

1

1.2

1.4

1.6

1.8

2

0 10 20 30 40 50 60 70 80 90 100 110 120

Time (min)

LogPercentCelecoxibR

emaining

Celecoxib C-HP Beta CD 1:1C-HP Beta CD 1:2 C-HP Beta CD 1:3

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First order Dissolution profile of Celecoxib and C-HP-Beta-CD Complexation prepared by kneading method

Di l i fil f C l ib d C HP B


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Time

(min)


C

C-HP--CD

1:1 1:2 1:3

5 24.42 58.10 71.20 78.60

10 30.37 70.40 77.43 83.40

20 33.86 75.00 80.90 85.20

30 35.13 78.30 82.85 87.40

45 37.82. 80.50 84.60 89.60

60 39.41 81.30 85.80 90.20

90 42.66 82.00 87.30 92.30

120 45.75 83.90 88.00 93.40

Dissolution profile of Celecoxib and C-HP-Beta-CD Complexation prepared by co evaporation

method

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0

10

20

30

40

50

60

70

80

90

100

0 20 40 60 80 100 120 140

Time (Min)

PercentCelecoxib

Dissolved

C C-HP-beta-CD1:1 C-HP-beta-CD 1:2 C-HP-Beta-CD 1:3

Dissolution profile of Celecoxib and C-HP-Beta-CDComplexation prepared by co evaporation method

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Fi t d Di l ti fil f C l ib d C HP


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0

0.2

0.4

0.6

0.8

1

1.2

1.4

1.6

1.8

2

0 20 40 60 80 100 120 140

Time (Min)

Lo

gPercentCelecoxibrem

aining

C C-HP-Beta -CD 1:1 C-HP-Beta-CD 1:2 C-HP-Beta-CD 1:3

First order Dissolution profile of Celecoxib and C-HP-Beta-CD Complexation prepared by co evaporation

method

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Dissolution parameters of Celecoxib and its


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Solid Inclusion

Complex

Dissolution Parameter

T50

(min)

T90

(min)

DE30

(%)

K1

(min-1)

Celecoxib >120 >120 28.8 0.0035

C- CD (1:1) 3.35 8.33 86.53 0.3764C- CD (1:2) 3.15 7.69 88.73 0.3933C- CD (1:3) 2.89 6.40 89.17 0.4606C-HP- CD (1:1) 3.07 7.87 87.66 0.3330C-HP- CD (1:2) 2.93 7.06 88.4 0.343644

Dissolution parameters of Celecoxib and itscyclodextrine complexes prepared by kneading

method in water containing 1% SLS


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Solid Inclusion

Complex

Dissolution Parameter

T50

(min)

T90

(min)

DE30

(%)

K1

(min-1)

Celecoxib >120 >120 28.8 0.0035

C- CD (1:1) 7.06 >120 54.94 0.0861C- CD (1:2) 4.77 >120 60.25 0.1022C- CD (1:3) 4.19 89.5 67.15 0.1245C-HP- CD (1:1) 4.30 >120 65.33 0.1218C-HP- CD (1:2) 3.51 >120 72.00 0.1489C-HP- CD (1:3) 3.18 60 76.92 0.1796

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Dissolution parameters of Celecoxib and itscyclodextrine complexes prepared by co

evaporation method in water containing 1% SLS


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CD complexes of anti inflammatory drugCelecoxib exhibited several times higher

dissolution rates and DE30

values when compared

to the uncompleted drug.

CD complexes prepared by kneading method

gave higher enhancement in the dissolution rate ofthe drug than the one prepared by co evaporation

method.

CONCLUSIONS

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Overall, HP -CD complexes gave higher dissolution

rates than the -CD .

The higher dissolution rates and DE30 values observed with

Cyclodextrin-CD complexes are due to the Solubilizing

effect of Cyclodextrins by forming inclusion complexes

with Celecoxib in water.

The solubility and dissolution rate of all the antiinflammatory drug studied (Celecoxib) were markedly

enhanced by Complexation with -CD and HP -CD.

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-CD complex of celecoxib (1:3) preparaed by kneading

method exibited 131.6 times increase in the dissolution

rate. -CD complex of celecoxib (1:3) preparaed by co-

evaporation method exhibited 35.6 times increase in the

dissolution rate

HP--CD complex of celecoxib (1:3) prepared by

kneading method exhibited 229.6 fold increase in the

dissolution rate. HP--CD complex of celecoxib (1:3) prepared by co-

evaporation method exhibited 51.3 fold increase in the

dissolution rate.


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Dissolution rate of Celecoxib can be enhanced bycomplexation with -CD and HP -CD.

RECOMMENDATION


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Dissolution Enhacement Presentation11

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