Enhancement of dissolution rate of Indomethacin by melt granulation

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Slide 1:

Enhancement of dissolution rate of Indomethacin by melt granulation technique Nishanth Meghanadh Abhinav Rajesh Hemanth Suresh GUIDANCE :T.NAGA APARNA

Slide 2:

The main objective of present work is to enhance the dissolution rate of poorly water soluble drug like ‘INDOMETHACIN ‘ by using various excipients. AIM OF WORK

Slide 3:

CONTENTS : Introduction Drug profile Excipients profile Experiment methodology Standard curve Preparation of granules Evaluation Results and Discussion Flow property tables Dissolution graphs Conclusion References

Slide 4:

INTRODUTION

Slide 5:

Dissolution : It is a process in which a solid solublises in a given solvent (mass transfer from solid surface to liquid phase). Solubility: Maximum amount of solute dissolved in a given solvent under standard conditions(temperature, pressure and pH)

Slide 6:

BIOPHARMACEUTICS SYSTEM OF CLASSIFICATION (BCS) CLASS SOLUBILITY PERMEABILITY Class – I HIGH SOLUBILITY HIGH PERMEABILITY Class – II LOW SOLUBILITY HIGH PERMEABILITY Class – III HIGH SOLUBILITY LOW PERMEABILITY Class - IV LOW SOLUBILITY LOW PERMEABILITY

Slide 7:

Techniques to improve solubility and dissolution…. Use of co-solvent Hydrotropy method Micronization Nanonization Change in dielectric constant of solvent Use of hydrates or solvates Use of surfactants ,soluble prodrug Porous microparticle technology Solid dispersion Super critical fluid recrystallisation Spray freezing into liquid Selective adsorption on insoluble carriers Evaporative precipitation into aqueous solution(EPAS) Alteration of pH of solvent Functional polymer technology Controlled precipitation technology Inclusion complexes or clathartes Application of ultrasonic waves

Slide 8:

MECHANISM OF INCREASING SOLUBILITY Reduction in particle size (submicron range) Carrier may have a solubilization effect Carrier may enhance wettability, dispersability Formation of metastable dispersion with less activation energy

Slide 9:

SOLID DISPERSION : “a dispersion of one or more active ingredients in an inert carrier or matrix of solid state prepared by melting (fusion), solvent or melting solvent method”. Methods : Melt or fusion method Solvent method Melt adsorption method Lyophilization Technique Melt agglomeration process Extruding method Spray drying Use of surfactant Electro spinning Super critical fluid technology

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ADVANTAGES : Rapid dissolution as compared to tablets and capsules Less pre systemic metabolism (ex. Morphine- tristearin )-saturation of enzymes- less of drug is needed Transformation of liquid to solid- avoid polymorphic changes Protection of drug against decomposition by saliva to allow buccal absorption DISADVANTAGES : Physical and chemical instability Change in crystallinity and decrease in dissolution with ageing Final product is moisture & temperature sensitive & tacky A high content of carrier is required

Slide 11:

Melt granulation is a well known process whereby fine powders are agglomerated by means of a molten binder and processed into spherical or nearly spherical granules of homogeneous size MELT GRANULATION: a)distribution-coalescence b)immersion-nuclei Equipments used :rotating drums or pans, fluid-bed granulators, low-shear mixers such as Z-blade and planetary mixers, and high-shear mixers Mechanism : distribution and immersion

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ADVANTAGES : Sustained released dosage forms Fast release dosage forms Combination of hydrophilic and hydrophobic polymers can be used -(liphophilic binder):glycerol mono stearate -(Hydrophilic binders): PEG and poloxamer DISADVANTAGES: Thermo labile drugs

Slide 13:

SUGARS Dextrose, Sucrose, Galactose, Sorbitol, Maltose, Xylitol, Mannitol . ACIDS Citric acid, succinic acid POLYMERS Poly vinyl pyrrolidone, Poly Ethylene Glycol, HPMC, Methyl Cellulose, Hydroxy Ethyl cellulose, Cyclodextrins SURFACTANTS & MISCELLANEOUS Poloxamer 188, Tweens, Urea, Urethane CARRIERS

Slide 14:

LIST OF POORLY SOLUBLE DRUGS WITH HYDROPHILIC CARIERS CARRIERS DRUGS Polyethylene glycol (PEG) Griseofulvin Polyvinylpyrrolidone (PVP) Flufenamic acid Hydroxypropylmethylcellulose (HPMC) Benidipine Sorbitol Predinisolone

Slide 15:

MARKETED FORMULATIONS OF SOLID DISPERSIONS DRUG NAME BRAND NAME COMPANY NAME INDOMETHACIN INDOMETHACIN EISAI Co RITONAVIR NORVIR ABBOTT LAB AMPRENAVIR AGENERASE GALAXOSMITHKLINE CALCITROL ROCALTROL ROCHE

Slide 16:

DRUG PROFILE

Slide 17:

DRUG PROFILE : INDOMETHACIN: (INDOCAP) Biopharmaceutical classification system: Class – II (high permeability & low solubility) Systematic ( IUPAC ) name: 2-{1-[(4-chlorophenyl)carbonyl]-5-methoxy-2-methyl-1 H -indol-3-yl}acetic acid Chemical data: Formula : C 19 H 16 ClNO 4 Mol. mass 357.787 g.mol -1 Category: NSAID Physical data: Description – White odorless, crystallinepowder Solubility – Soluble in chloroform, ethanol, methanol practically insoluble in water

Slide 18:

Pharmacokinetic data : Bioavailability : 100% (oral), 80–90% (rectal) Protein binding : 99% Metabolism : Hepatic Half-life : 4.5 hours Excretion : Renal60%, faecal33% Mode of action : Nonselective inhibitor of cyclooxygenase (COX 1& 2) Inhibits motility of polymorphonuclear leukocytes uncouples oxidative phosphorylation in cartilaginous hepatic mitochondria

Slide 19:

USES OF INDOMETHACIN : Indomethacin has been found effective in active stages of the following: Moderate to severe rheumatoid arthritis including acute flares of chronic disease. Moderate to severe ankylosing spondylitis. Moderate to severe osteoarthritis. Acute painful shoulder (bursitis and/or tendinitis). Acute gouty arthritis. ADVERSE EFFECTS : Peptic ulcer Edema Hyperkalemia Hypernatremia Hypertension

Slide 20:

CONTRAINDICATIONS : Concurrent peptic ulcer Allergy to other NSAIDs Patients with angioedema Caution: pre-existing bone marrow damage Concurrent with potassium sparing diuretics USUAL DOSAGE FORMS : Tablets or capsules 25 and 50 mg Suppositories 50 and 100 mg modified-release Capsules 75 mg Syrup (25 mg/5ml) Injectable concentrate 50 mg for i.m . injection Spray or gel Patches containing 0.5% by weight 1% topical liquid

Slide 21:

EXCIPIENTS : POLY ETHYLENE GLYCOL (PEG) : Polyethylene glycol is a condensation polymers of ethylene oxide and water It is used to make emulsifying agents and detergents, and as plasticizers, humectants, and lubricants Polyethylene glycol is non-toxic, odorless, neutral, lubricating, nonvolatile and nonirritating PEG-6000 MOL WT : 5000 - 7000 APPEARANCE : white flake colour SPECIFIC GRAVITY - 1.08 -1.09 (50% aq. sol.) pH - 5 – 7 VISCOSITY - 100 cp (50% aq. sol.)

Slide 22:

MICRO CRYSTALLINE CELLULOSE : SODIUM STARCH GLYCOLATE : It is a direct compression filler MCC can be used as a bulking agent, disintegrant, binder, lubricant, and glidant besides being a stability enhancer and a secondary suspending agent Swelling tendencies and excellent water imbibing or wicking action (wet granulation technique) SSG is widely used in oral pharmaceuticals as a disintegrant in capsule and tablet formulations Disintegration occurs by rapid uptake of water followed by rapid and enormous swelling.

Slide 23:

CROSPOVIDONE : Water insoluble synthetic cross-linked homopolymer of N-vinyl-2-pyrrolidinone Exhibit capillary activity and hydration capacity with little tendency to form gels. Tablet disintegrant, dissolution agent, solubility enhancer CROSCARMELLOSE SODIUM CROSCARMELLOSE SODIUM : It is an internally cross-linked sodium carboxymethylcellulose It allows the material to swell and absorb many times its weight in water. Used as disintegrant in pharmaceutical formulations

Slide 24:

EXPERIMENT METHODOLOGY

Slide 25:

PLAN OF WORK Preparation of calibration curve of drug by spectrophotometric method Preparation of melt granules of indomethacin with carrier In-vitro dissolution studies of solid dispersions Selection of drugs and carriers Invitro dissolution studies of pure drug and marketed drug.

Slide 26:

PREPARATION OF SOLUTIONS REQUIRED : PREPARATION OF 0.2M POTASSIUM DIHYDROGENPHOSPHATE : Dissolve 27.2g in 1000ml water PREPARATION OF SODIUMHYDROXIDE(0.2M): Dissolve 8g in 1000ml water. PREPARATION OF PH 7.4 PHOSPHATE BUFFER: 50ml of 0.2M potassium dihydrogenphosphate+39.1ml of 0.2M Naoh+ water sufficient to 200ml PREPARATION OF STOCK SOLUTION : 50 mg 0f pure drug + 50ml ethanol (1000 ug/ml) Prepare different concentrations of drug(2ug,4ug,6ug,8ug,10ug.) from stock solution and record absorbance.

Slide 27:

MELT GRANULATION TECHNIQUE drug polymer Dry blending mixture 30 min 60C m olten mass Solidify & Sieved granules Stored & evaluated

Slide 28:

EVALUATION : Flow properties : Bulk density ( σb ) = Mass / Poured volume Tap density ( σt ) = Mass / Tapped volume Carr’s Index = [( σ t – σ b) / σ t] x 100 Hausner ratio = (σt / (σb) Angle of repose - 1/tan [h/r] Where, h = height of heap r = mean radius of circle Dissolution Studies : Apparatus: USP dissolution apparatus type I (basket)

Slide 29:

Drug :indomethacin Polymer :poly ethylene glycol 6000 Disintegrant: sodiumstarchglycolate(ssg), croscarmellose sodium ( ccs ), crospovidone(cp) Diluent :micro crystalline cellulose Granule code indomethacin peg6000 mcc ssg cp ccs Ind Api ---------- -------- ---------- --------- --------- Indpg 1g 1g -------- --------- --------- ---------- Indmcc 1g 1g 0.5g --------- --------- ---------- Indssg 1g 1g -------- 0.25g --------- --------- Indcp 1g 1g -------- -------- 0.25g -------- Indccs 1g 1g ------- -------- -------- 0.25g

Slide 30:

CAPSULE FILLING MACHINE

Slide 31:

INVITRO DRUG DISSOLUTION STUDIES : Apparatus: USP dissolution apparatus type I (basket) Rotating speed: 100 rpm Buffer : phosphate buffer 7.4 Temperature :37C ±0.2C UV-Spectrophotometer Wavelength :320nm Dissolution rate-hydrophilic character of system

Slide 32:

DISSOLUTION APPARATUS

Slide 33:

Uv visible spectrophotometer

Slide 34:

RESULTS AND DISCUSSIONS

Slide 35:

STANDARD GRAPH OF INDOMETHACIN

Slide 36:

Product code Angle of repose Bulk density Tapped density Carrs index Hausness index Indomethacin 42 0.37 0.53 30.18 1.43 Indpeg 21.5 0.24 0.27 11.11 1.12 Indmcc 20.11 0.26 0.28 8.77 1.09 Indssg 23.68 0.24 0.26 10.03 1.11 Indccs 24.7 0.25 0.28 11.92 1.13 Indcp 25.9 0.24 0.28 12.05 1.13 FLOWABILITY PARAMETERS :

Slide 37:

TABLE: IN VITRO RELEASE STUDY OF INDOMETHACIN AND THEIR PEG MELT GRANULES WITH EXCIPIENTS Product code % release at 30min % release at 50min DE 30 Indocmethacin pure 45.1 57.7 19.2 Indocmethacin mktd 48.66 55.34 24.5 Indocmethacin peg 51.92 65.11 30.02 Indocmethacin mcc 56.87 76.62 32.6 Indocmethacin ssg 64.53 93.84 42.7 Indocmethacin cp 74.74 95.54 44.8 Indocmethacin ccs 99.39 46.5

Slide 38:

Formulation Parameters Zero order First order Hixson Crowell (Q 1/3 -Qt 1/3 ) Ind(pure) K 5.79 -0.08 0.813 r 2 0.67 0.868 0.787 Ind(peg) K 3.85 -0.04 0.113 r 2 0.642 0.861 0.781 Ind(mcc) K 3.76 -0.043 0.107 r 2 0.627 0.820 0.745 Ind(ssg) K 3.02 0.024 0.069 r 2 0.604 0.6922 0.659 Ind(cp) K 3.06 -0.024 0.069 r 2 0.701 0.819 0.78 Ind(ccs) K 2.153 -0.133 0.041 R 2 0.6499 0.7033 0.684 DIFFERENT RELEASE RATE CONSTANTS OF INDOMETHACIN MELT GRANULES

Slide 39:

COMPARISION OF DISSSOLUTION PROFILES OF INDOMETHACIN AND ITS PEG MELTED GRANULES

Slide 40:

CONCLUSION

Slide 41:

CONCLUSION: Melt granulation of indomethacin using polyethylene glycol as carrier is prepared. Dissolution profile of prepared melt granules was compared with plain drug and marketed product. Order of dissolution profiles of drug and melted mixtures : crosscarmellose sodium>cross povidone> sodium starch glycolate>microcrystalline cellulose>polyethylene glycol>pure drug Melt granules prepared by using croscarmellose sodium shows best dissolution profile. The release of Indomethacin from the prepared granules followed first order release kinetics.

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REFERENCES

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WHO GUIDELINES, The Biopharmaceutical Classification System(BCS) Guidance System I.Kanfer,report on international work shop on the biopharmaceutics classification system (BCS):scientific and regulatory aspects in practice ,J Pharma Pharmaceutical sciences5(1)oct,2001,pg no1-4 Ruckmani K, seethamarai R, Jayakar B, “Enhancement of solubility and dissolution of carbamazepine by egg albumin”, Indian drugs, 1999, 36(1): 66-67. James S, James C, “Encyclopedia of pharmaceutical technology’, 2 nd edition, Marcel deccer , New York, 2002, 2669-2669 Soniwala MM, Patel PR, “Dissolution enhancement of rofecoxib ”, Indian J.Pharm.Sci ., 2005;61-62. M.E.Aulton , Pharmaceutics, The design and manufacture of medicines, p.17 Meyer, M., Bioavailability of drugs and bioequivalence. In : Encyclopedia of pharmaceutical technology, vol.2, 1998, New York, Marcel Dekker Inc: 33-58 Leon Lachmann , Herbert A.Libermann , The theory and practice of industrial pharmacy, 3 rd edition, 457- 466.

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Garima Chawla , Arvind K. Basal, “Improved dissolution of a poorly water soluble drug in solid dispersions with polymeric and non-polymeric hydrophilic additives”. Acta pharma , June 2008. Bahar Selen KALAVA, “ Physico chemical characterization and dissolution properties of Cinnarizine solid dispersion”, Turkish J.Pharm Sci 2(2), 51-62, 2005. Martin’s, Physical pharmacy and pharmaceutical sciences, 5th edition, 231-239. Bahar Selen KALAVA, “ Physico chemical characterization and dissolution properties of Cinnarizine solid dispersion”, Turkish J.Pharm Sci 2(2), 51-62, 2005. Vanshiv S.D., “ Physico chemical characterization and in vitro dissolution of Domperidone by solid dispersion technique” Indian J. Pharm Educ.Res.43 (1), Mar-09. J.Akbuga , A.Gursoy and E.Kendi , “The preparation and stability of fast release furosemide PVP solid dispersion:, Drug dev. Ind.Pharm,1988, Vol. 14, 1439-1464 S. Okonogi , T.Oguchi , E.Yonemochi , “Improved dissolution of ofloxacin via solid dispersion”, Int.J.Pharm , 1997, Vol.156, 175-180. Shergil , L and Yu, “Applied biopharmaceutics and pharmacokinetics”, 2nd edition, Appleton-century crofts, Norwalk, C.T, 1985, 193-203.

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Kamal Singh Rathor , Y.S. Tanwar , “Solubility enhancement”, the Indian pharmacist, March, 2008, 31-33. Meka Lingam, Vobalaboina Venkateswarlu , Enhancement of solubility and dissolution rate of poorly water soluble drug using cosolvency and solid dispersion technique, international journal of pharmaceuticalscience and nanotechnology, January-march 2009, 349-356. Chokshi R, Zia H.Hot melt extrusion technique: a review, Iranian J Pharm Res .2004;3;3-16. Schafer T, Holm P, Kristensen HG. Melt granulation in a laboratory scale high shear mixer, Drug Devel Ind Pharm. 1990; 16(8): 1249-1277 Heng WS, Wong TW., Melt processes for oral solid dosage forms, Pharm Tech. 2003;1-6 Evard B, Delattre L. In vitro evaluation of lipid matrices for the development of a sustained release sulfamethazine bolus for lambs, Drug Devl Ind Pharm. 1996; 22 (2): 111-118 Schafer T, Mathiesen C. Melt pelletization in a high shear mixer. IX. Effect of binder particle size, Int J Pharm. 1996; 139:139-148

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THANK YOU