SOLID DISPERSION – AN SOLID DISPERSION – AN APPROACH TOAPPROACH TO

  ENHANCE THE DISSOLUTION ENHANCE THE DISSOLUTION

RATE OFRATE OF  

OLANZAPINEOLANZAPINE

Guided byGuided byProf. T. Satyanarayana Prof. T. Satyanarayana sivaram shankar sivaram shankar Principal Principal Lydia college of pharmacyLydia college of pharmacy

BY U. Aparna Rajeevi M.Pharm., 2nd sem. Regd.no-612270601012

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contents AIM AND OBJECTIVE Introduction Drug profile Review of literature Materials and methods Conclusion References

AIM AND OBJECTIVE• Preparation of solid dispersion using carrier systems by

physical mixture, solvent evapouration,kneading method.

MAIN OBJECTIVE OF PRESENT WORK WAS:• Solubility studies • Construction of standard caliberation curve of

olanzapine in 0.1N HCl • In vitro drug release studies.• Stability studies.•  statistical analysis,data interpretation and conclusion

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Solid dispersion technology is the science of dispersing one or more active ingredients in an inert matrix in the solid stage in order to achieve increased dissolution rate, sustained release of drugs, altered solid state properties, enhanced release of drugs from ointment and suppository bases, and improved solubility and stability.

INTRODUCTION TO SOLID DISPERSION

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INTRODUCTION TO DRUG

• Olanzapine (sold under the brand names Zyprexa, Zypadhera and 

Lanzek.• In combination with fluoxetine, Symbyax) is an  atypical antipsychotic. • Approved by the U.S. Food and Drug

Administration (FDA) for the treatment ofschizophrenia and bipolar disorder.

•  • Olanzapine is structurally is classified as

a thienobenzodiazepine. 

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ABSTRACTOlanzapine is a poorly water soluble drug (BCS CLASS-2) widely prescribed as atypical antipsychotic drug in combination with fluoxetine,symbyax used for treatment of schizophrenia and bipolar disorder in order to increase its solubility and dissolution rate,various solubility enhancement methods in carrier, with different ratios have been investigated.Drug carrier interactions were investigated by FT-IR spectroscopy.The studies were showed that solubility and dissolution rate of olanzapine were distinctively increased in the prepared binary mixture compared to that of pure olanzapine .The increase of dissolution rate was related to the ratio of olanzapine to carrier and the method emplyed. Cogrinding methods were the most effective techniques showing highest dissolution rate.

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TECHNIQUES USED IN PREPARATION OF SOLID

DISPERSION• Solid dispersion technique

involves different methods in that: • Physical mixture, • solvent evapouration,• kneeding method was performed

for olanzapine

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MATERIALS β-cyd, HP- βcyd,poloxomers ,PEG-6000,PEG-4000,were

used as carriers. Dissolution was performed by adjusting dissolution

parameters at 50rpm and temperature 37°c,paddle was used.

U.V has been used to determine the concentraion of the drug at 256nm.

FT-IR spectroscopy was used to evaluate drug-carrier binary mixture.

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SOLU BILITY STUDIES:

It is soluble in acetonitrile,slightly soluble in methanol and dehydrated alcohol and practically insoluble in water.

DETERMINATION OF λ MAX:

10μg/ml in 50%methanol. The solution was scanned in between the

range of 200-400nm.

METHODOLOGY

Construction of caliberation curve

• Further diluted with the 50% methanol.

• From the stock a series of dilutions ranging from 2-10μg/ml prepared.

• Absorbance was measured by using U.V spectroscopy at 256nm.

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Method of Preparation of olanzapine solid dispersion:

• 50mg of drug was takenalong with ingredients such as

• PEG 4000,• PEG 6000,• β-cyd,• HP-βcyd,• poloxomer 188,• poloxomer 237,• poloxomer 407 .

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Code DRUG PEG

4000

PEG

6000

βcyd HP-

βCYD

POLOXOME

R 188

POLOXOME

R 237

POLOXOME

R 407

F1 50mg 50mg * * * * * *

F2 50mg 100mg * * * * * *

F3 50mg * 50mg * * * * *

F4 50mg * 100mg * * * * *

F5 50mg * * 50mg * * * *

F6 50mg * * 100mg * * * *

F7 50mg * * * 50mg * * *

F8 50mg * * * 100mg * * *

F9 50mg * * * * 50mg * *

F10 50mg * * * * 100mg * *

F11 50mg * * * * * 50mg *

F12 50mg * * * * * 100mg

F13 50mg * * * * * * 50mg

F14 50mg * * * * * * 100mg

METHODS OF PREPARATION OF OLANZAPINE SOLID DISPERSION

SYSTEM• Physical mixture: • The carriers and the mixing them in a

glass motor by tirturating.• The resultant physical mixtures was

passed through 44-mesh sieve.• stored in dessicator until used for

further studies.

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• Solvent evapouration method: • The required amount of olanzapine and

the carrier were dissolved in sufficient volume of methanol with continuous stirring.

• The solvent was then completely evapourated at 45⁰c with continuous stirring to obtain dry mass.

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Kneading method: • This physical mixture of the drug and

carrier is tirturated using small quantity of organic solvent and water mixture,usually alcohol and water.

• Advantage of this methd are low temperature requirement for solid dispersion preparation and usage of organic solvent is less.

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Dissolution parameters• MEDIUM: 0.1N HCl IN 900ml bowls• DISSOLUTION APPARATUS 2:PADDLE• SPEED: 50rpm• Temperature:37 +_0.5⁰c.• Time:90minutes

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FT-IR SPECTROSCOPY• The drug –carrier binary mixture of olanzapine

were prepared in the form of KBr pellets.• subjected for scanning from 4000 cm-1 to

1200cm-1 using FTIR spectrophotometer.

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RESULTS

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SL.N0concentration

(µg/ml)Absorbance

at256)1 0 02 2 0.1473 4 0.2864 6 0.4485 8 0.546

Concentration and absorbance obtained for caliberation curve

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Caliberation curve of olanzapine:

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In-vitro dissolution studies of olanzapine-carrier prepared by physical mixture method:

time (min)

βcyd(1:1)

βcyd(1:2)

poloxomer 188(1:1)

poloxomer188(1:2)

poloxomer 407(1:1)

poloxomer 407 (1:2)

0 0 0 0 0 0 0

5 35.172 34.641 43.848 41.382 83.86 83.88

15 92.988 68.643 48.528 92.03 86.4 86.076

30 95.184 75.66 75.238 92.32 94.54 87.73

45 98.226 82.269 77.87 99.34 94.55 90.504

60 99.882 93.817 81.66 100.2 96.09 91.87

90 100 100.4 91.87 100.61 101 99.236

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in-vitro dissolution samples prepared for physical method:

0

20

40

60

80

100

120

0 5 15 30 45 60 90

Perc

enta

ge d

rug

rele

ase

Time(min)

PEG4000(1:1)

PEG 4000(1:2)

PEG 6000(1:1)

PEG6000(1:2)

HP-βCYD(1:1)

HP-βCYD(1:2)

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In-vitro dissolution studies of olanzapine binary mixture prepared by kneading method:

timeHP-βcyd

(1:1)HP-βcyd

(1:2)PEG

4000(1:1)PEG

4000(1:2)PEG

6000(1:1)PEG

6000(1:2)0 0 0 0 0 0 0

5 76.2 57.348 89.76 31.55 87.51 89.83

15 83.4 67.1 96.24 51.54 99.61 90.44

30 85.6 68.49 97.65 81.97 99.612 94.3

45 90.1 69.87 98.44 86.98 99.34 92.3

60 95.22 78.24 99.9 93.56 99.9 100

90 98.01 96.91 100.45 100.69 100.45 100.11

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In-vitro dissolution samples prepared for kneading method

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In-vitro dissolution studies of olanzapine binary mixture

prepared by solvent evapouration method:time(min)

PEG4000(1:1)

PEG 4000(1:2)

PEG 6000(1:1)

PEG6000(1:2)

HP-βCYD(1:1)

HP-βCYD(1:2)

0 0 0 0 0 0 05 84.48 86.13 80.13 89.83 91.73 91.58

15 93.85 90.69 83.82 90.69 92.17 92.4430 95.23 93.55 92.97 95.55 92.77 93.7845 95.79 98.97 95.26 96.95 93.31 95.8160 96.35 100.54 96.96 98.38 98.5 97.2190 100.43 100.98 100.02 100.11 100.13 100.07

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in-vitro dissolution samples prepared for solvent evapouration method

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Percent Release of Pure olanzapine:

sl.no time(min) drug release1 0 02 5 91.623 15 91.644 30 92.475 45 93.076 60 96.357 90 100.64

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Percentage release of pure olanzapine:

Conclusion Dissolution behaviour of pure olanzapine was

studied by using 0.1N HCl.

The obtained data showed that there was linearly increased in dissolution profile of solid dispersion and physical mixture compared to plain drug.

So, it can be concluded that solid dispersion of olanzepine with ploy ethylene glycolin (PEG) increased the solubility of drug.

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REFERENCE• Sekiguchi K, Obi N, “Studies on absorption of eutectic mixtures. I. A

comparison of the behavior of eutectic mixtures of sulphathiazole and that of ordinary sulphathiazole in man”, Chem. Pharm. Bull 1961; 9:866-872.

• Goldberg A, Gibaldi M, Kanig J L, “Increasing dissolution rates and gastrointestinal absorption of drugs via solid solutions and eutectic mixtures III - experimental evaluation of griseofulvin- succinic acid solid solution”, J. Pharm. Sci. 1966; 55:487-492.

• Simonelli AP, Mehta SC and Higuchi WI, Dissolution rates of high energy polyvinylpyrrolidone (PVP)-sulfathiazole co precipitates. J. Pharm. Sci., 1969; 58(5):538-549 .

• Abu TMS. ”Solid dispersion of poorly water soluble drugs: Early promises, subsequent problems and recent breakthroughs.” J. Pharm. Sci 1999; 88:1058-1066.

• Dixit M, Kini AG, Kulkarni PK. Enhancing the aqueous solubility and dissolution of olanzapine usingfreeze-drying. Brazilian Journal of Pharmaceutical Sciences. 2011;47(4):743-9. ASSESSMENT REPORT FOR Olanzapine Glenmark Europe. London: European Medicines AgencyEvaluation of Medicines for Human Use; 2009.

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I was very thankfull to my guide I was heartfully thankfull to my

principal for proving me good facilities for doing my project work.

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