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Project work

1. WELCOME

2. FORMULATION AND EVALUATION OF PIROXICAM DELAYED RELEASE TABLETS Thesis Submitted to JAWAHARLAL NEHRU TECHNOLOGICAL UNIVERSITY ANANTAPUR In partial fulfillment for the award of the degree of MASTER OF PHARMACY IN DEPARTMENT OF PHARMACEUTICS Submitted by PRAVALLIKA SESHACHALA COLLEGE OF PHARMACY,PUTTUR. Under the Guidance of Mr.T.SESHADRI , M.Pharm , Assistant Professor, Department of Pharmaceutics.

3. 1.INTRODUCTION For many decades treatment of acute diseases or chronic illness have been mostly accomplished by delivery of drugs to patients using various pharmaceutical dosage forms including tablets, capsules, suppositories, creams, ointments, liquids, aerosols and injectables . The oral conventional types of drug delivery systems are known to provide a prompt release of the drug. Therefore to achieve as well as to maintain the drug concentration within the therapeutically effective range needed for treatment .

4. DELAYED RELEASE DOSAGE FORMS Delayed release systems release a bolus of the drug after a predetermined time in a predetermined location, i.e. they do not release the drug immediately after ingestion, for example enteric-coated tablets .

5. Extended Release products : Extended Release dosage forms are the ones that allow a reduction in dosing frequency to that presented by a conventional dosage form e.g. solution or an immediate release dosage form. 2. Delayed Release products : These are designed to release the drug from dosage form at a time other than promptly after administration. The delay may be time based or based on the influence of environmental conditions as gastrointestinal pH.

6. DESCRIPTION Piroxicam is a non steroidal anti inflammatory drug it having a long plasma half-life. It is used in the treatment of various rheumatic disorders and dysmenorrhea, Arthritis like gout. Piroxicam is an NSAID and, as such, is a non-selective COX inhibitor possessing both analgesic and antipyretic properties. Inhibits cyclooxygenase (an enzyme needed for prostaglandin synthesis), stimulating anti-inflammatory response and blocking pain impulses. It Inhibits prostaglandin synthesis by interfering with cyclooxygenase needed for biosynthesis .

7. AIM OF THE STUDY The main aim of the present study was to develop robust formulation of Piroxicam multiple unit particulate system (pellets in tablets or MUPS) as a delayed release dosage form and study the in vitro release pattern of test product to compare with the marketed reference product. Non steroidal drug delivery system (Piroxicam) is a acid labile drugs. These drugs will degrade in acidic environment of stomach and will lead to therapeutic inefficacy.

8. PLAN OF WORK With the above aim and objective, the work was planned as follows: 1. Reference product characterization 2. Pre formulation study of Active pharmaceutical ingredient (API) • Omeprazole magnesium (API) powder characterization • Solubility studies of API at different pH media. • Compatibility studies of API with excipients. 3. Formulation, development and evaluation of delayed release multiple unit tablets using various buildups of polymers, binder concentrations etc.

9. DRUG PROFILE PIROXICAM Piroxicam occurs as a white crystalline solid, sparingly soluble in water, dilute acid and most organic solvents. It is slightly soluble in alcohol and in aqueous solutions. It exhibits a weakly acidic 4-hydroxy proton (pKa 5.1) and weakly basic pyridyl nitrogen (pKa 1.8). The molecular weight of piroxicam is 331.35. Its molecular formula is C15H13N3O4S

10. The chemical name for piroxicam is 4-hydroxyl-2-methyl-N-2-pyridinyl-2H-l,2,-benzothiazine-3-carboxamide 1,1-dioxide. STRUCTURAL FORMULA

11. PHARMACODYNAMICS Piroxicam is a non steroidal anti-inflammatory drug (NSAID) that exhibits anti-inflammatory, analgesic, and antipyretic activities in animal models. The mechanism of action of Piroxicam, like that of other NSAIDs, is not completely understood but may be related to prostaglandin synthetize inhibition.

12. PHARMACOKINETICS Absorption: Piroxicam is well absorbed following oral administration. Drug plasma concentrations are proportional for 10 and 20 mg doses and generally peak within three to five hours after medication. The prolonged half-life (50 hours) results in the maintenance of relatively stable plasma concentrations throughout the day on once daily doses and to significant accumulation upon multiple dosing. A single 20 mg dose generally produces peak piroxicam plasma levels of 1.5 to 2 mcg/ml, while maximum drug plasma concentrations, after repeated daily ingestion of 20 mg Piroxicam,

13. Distribution : The apparent volume of distribution of piroxicam is approximately 0.14 L/kg. Ninety-nine percent of plasma piroxicam is bound to plasma proteins. Piroxicam is excreted into human milk. The presence in breast milk has been determined during initial and long-term conditions (52 days) Metabolism: Metabolism of piroxicam occurs by hydroxylation at the 5 position of the pyridyl side chain and conjugation of this product; by cyclodehydration ; and by a sequence of reactions involving hydrolysis of the amide linkage, decarboxylation, ring contraction, and N- demethylation

14. EXCRETION FELDENE (piroxicam) and its biotransformation products are excreted in urine and faces, with about twice as much appearing in the urine as in the faces. Approximately 5% of a FELDENE (piroxicam) dose is excreted unchanged. The plasma half-life (Ty2) for piroxicam is approximately 50 hours .

15. MATERIALS AND EQUIPEMENTS LIST OF MATERIALS S.NO MATERIAL SOURCE 1. Piroxicam Ranbaxy Lab.pvt.ltd . 2. Lactose BP Bajaj Che . Pvt Ltd 3. Acrycoat 971 G Corel Pharma Pvt Ltd 4. Xanthan gum Rama chemicals 5. Colloidal silica Cobot sanmar 6. Purified talc Bajaj Chemicals Pvt Ltd 7. Magneium stearate Merck Pvt Ltd

16. LIST OF EQUIPMENTS PROCESS EQUIPMENT   Instruments for Formulation Development Weighing Electronic Single Pan Balance   Sieving process   Mechanical Sifter     Density study Tapped density tester USP   PSD by sieve Method Analytical Sieve Shaker   Blending Blender   Stirring Mechanical stirrer   Drug loading, Barriercoating, Enteric coating, film coating Fluidized Bed processor(Wurster coater)  

17. Disintegration Time Disintegration Test Apparatus USP Loss on drying Content Moisture analyzer Stability Stability chambers Coating Coater Friabilation Friabilator Hardness Hardnaess Tester

18. Analytical Instruments Ph pH meter   Water Content Water by KF method   Dissolution Dissolution Test Apparatus USP   Qualitative and Quantitative Analysis HPLC  

19. METHODOLOGY ANALYTICAL METHOD DEVELOPMENT Preparation of Piroxicam standard stock solution : 47.5mg of Piroxicam and is weighed into a clean 100ml volumetric flask, dissolved and made up to the mark with mobile phase, to attain a concentration of 475μg/ml . Sample preparation : 5ml of Piroxicam standard stock solution is mixed in a 25 ml volumetric flask and made up to the volume, to get the concentration of 95 μg /ml of Piroxicam respectively.

20. STANDARD CALIBRATION CURVE Calibration curve data for Piroxicam in pH 6.8 Phosphate buffer SI.N0. Conc. µg/ml) Absorbance at 240 nm Trail 1 Trail 2 Trail 3 Average ± SD 1 0 0 0 0 0 2 10 0.176 0.172 0.171 0.173 ± 0.003 3 20 0.322 0.327 0.331 0.327 ± 0.005 4 30 0.501 0.504 0.509 0.504 ± 0.004 5 40 0.65 0.665 0.651 0.655 ± 0.008 6 50 0.803 0.824 0.802 0.810 ± 0.012 7 60 0.958 0.989 0.989 0.978 ± 0.018 S.D = Standard deviation

21. Standard graphs for the calibration curve of Piroxicam In vitro dissolution profile in pH 6.8 Phosphate buffer15

22. Dissolution study parameters: Medium : pH 6.8 Phosphate buffer (Degassed) Apparatus : USP apparatus II (Paddle) Rpm : 50 Quantity : 500 ml Temperature : 37 ± 0.5ºC

23. Buffer preparation (1) Dissolve 6.9 g of sodium dihydrogen phosphate monohydrate (NaH2PO4.H2O ) in 1000 ml of distilled water. ( 2) Adjust the pH to 3.0 with Orthophospharic acid. (3) Filter the above solution through 0.45 um Nylon 66 membrane filt Mobile phase Mix the above pH 3.0 buffer solution and Acetonitrile in the ratio of 75:25 respectively (2) Degas in a sonicator for about 10 minutes. Standard stock solution Transfer about 47.5 mg of Piroxicam working standard, accurately weighed to a 100 ml volumetric flask, dissolve in and dilute to volume with mobile phase

24. Chromatographic System ( 1) A rapid and simple HPLC method using diode array detector has been described for analysis of Piroxicam. Chromatographic system is equipped with a range 79-2103 -nm UV detector. (2) Column: 4.6-mm x 150-mm column that contains 5 µm packing octyl silane chemically bonded to porous silica or ceramic micro-particles,  (4.6-mm x 150-mm, Xterra RP8, 5µm or equivalent). ( 3) Column temperature: Ambient ( 4) Flow rate: 1.0 ml per minute.

25. Calculations For 23.75 mg Tablets Quantity of Piroxicam dissolved in n the time interval as % of labelled amount. An x Ws x 5 x P x 500 x 100 Dn = --------------------------------------------- As x 100 x 100 x 100 x L Where, An = Peak area of Piroxicam for Test preparation, in n th time interval. AS = Peak area of Piroxicam for Standard preparation. Ws = Weight of Piroxicam standard taken, in mg, for Standard preparation. P = Potency of Piroxicam Standard calculated as Piroxicam. L = Labelled amount of Piroxicam in mg

26. Preparation of Delayed Release Tablets Procedure 1. Weigh all ingredients accurately. 2. Sifted Piroxicam, polymer, binder, diluent, lubricants through ≠ 40 sieve separately. 3. Blended Piroxicam, polymer, binder, diluents in a poly-bag. 4. Lubricant and glidant are added to the above blend. Compressed the blend of Step 4 materials into round concave shaped tablets with the help of 7 mm concave shaped punches on double punch tablet machine .

27. EVALUATION OF DELAY RELEASE FORMULATIONS The prepared Piroxicam Delayed Release Tablets were evaluated for general appearance, thickness, hardness, weight variation, friability and drug content. General appearance The tablets prepared were white, round, spherical shape. They were smooth, uniform and free from cracking and chipping . The degree of hardness varies with the different manufactures and with the different types of tablets. The permissible limit for hardness is 4-12 kg/cm2. The hardness was tested using Monsanto tester. “Hardness factor”, the average of the five determinations was determined and reported. Hardness test

28. Uniformity of weight (Weight variation test ) % Deviation = individual weight - average weight _____________________________ Average weight ×100 The limits are mentioned in the above table are as per U.S.P.   Average weight Percent difference 130 mg or less 10 More than 130 mg but less than 324 mg 7.5 More than 324 mg 5

29. Friability test Roche friabilator was used to measure the friability of the tablets. It was rotated at a rate of 25 rpm. Five tablets were weighed collectively and placed in the chamber of the friabilator. In the friabilator, the tablets were exposed to rolling, resulting from free fall of tablets within the chamber of the friabilator. After 100 rotations (i.e. in 4 minutes), the tablets were taken out from the friabilator and intact tablets were again weighed collectively. Permitted friability limit is 1.0%. The percent friability was determined using the following Formula (W1 – W2)/W1 × 100 Where, W1 = weight of the tablets before test W2 = weight of the tablets after test

30. Higuchi model Drug release from the Delay release devices by diffusion has been described by following higuchi classical diffusion equation. Q = [DE/ τ(2A- ECs) Cst ] Where, Q = Amount of drug release at time t D = Diffusion coefficient of the drug in the Delay release A = Total amount of drug in unit volume of Delay release Cs = The solubility of the drug in the Delay release E = Porosity of the Delay release T = Time in hrs at which q is the amount of drug is release

31. STABILITY STUDIES Stability is defined as the ability of particular drug or dosage form in a specific container to remain within its physical, chemical, therapeutic, and toxicological specification. Drug decomposition or degradation occurs during stability, because of chemical alteration of the active ingredients or due to product instability or due to lowered concentration of the drug in the dosage form . The optimized formulation of piroxicam tablets were selected for the stability studies. The accelerated stability studies were carried out according to ICH guidelines. These samples were analysed and checked for changes in physical appearance, hardness, drug content, and drug release after 1 month and compared it with the data obtained from soon after prepared tablets.

32. RESULTS AND DISCUSSION The Pre-formulation studies of drug were performed to characterize the Piroxicam. The powder flow properties of Piroxicam were studied to evaluate compressibility of the Piroxicam, since it has to be formulated as tablet. The results obtained are bulk density 0.334 mg/ml and tapped density was 0.356 mg/ml and Hausner’s ratio 1.06. The results showed that the compressibility of Piroxicam is 6.56, which indicates that the Piroxicam has excellent flow properties . The drug solution was prepared in 6.8 buffer and scanned using UV-Spectrophotometer in the stage of 400 – 200 to determine the λ max. The λ max of Piroxicam was found to be at 240 nm. But Piroxicam has placebo interaction so, I shifted to HPLC method development .

33. FTIR of Piroxicam

34. FTIR of Xantham gum

35. Fig. 11 FTIR of Acrycoat 971G

36. Flow properties of Piroxicam all formulations Sr no Parameters P1 P2 P3 P4 P5 P6 P7 1 Angle of repose 31.3 32.2 33.0 31.7 33.02 31.0 34.2 2 Bulk density( gm /ml) 0.296 0.307 0.313 0.301 0.320 0.301 0.301 3 Tapped density( gm /ml) 0.333 0.347 0.363 0.340 0.347 0.333 0.347 4 Hausner’s ratio 1.13 1.13 1.15 1.12 1.08 1.10 1.15 5 Compressibility index (%) 11.1 11.5 13.7 11.3 12.0 10.4

37. Evaluation parameters of all formulations of Piroxicam tablets S.no Parameters P1 P2 P3 P4 P5 P6 P7 1 Color Cream white Cream white Cream white Cream white Cream white Cream white Cream white 2 Surface Smooth Smooth Smooth Smooth Smooth Smooth Smooth 3 Thickness (mm) 3.3-3.4 3.3-3.4 3.3-3.4 3.3-3.4 3.3-3.4 3.3-3.4 3.3-3.4 4 Hardness (Kg/cm 2 ) 4.0±0.1 4.2±0.2 4.3±0.1 4.1±0.2 4.2±0.1 4.0±0.1 4.3±0.1 5 Weight (mg) 148.20±2.5 149.32±1.5 149.35±1.5 148.76±2.5 148.36±3.5 149.56±2.5 149.23±1.5 6 Friability 0.09±0.001% 0.05±0.001% 0.08±0.001% 0.09±0.002% 0.07±0.001% 0.09±0.001% 0.08±0.002% 7 Assay (%w/w) 99.96 100.2 98.65 99.23 100.6 99.3 99.52

38. Cumulative % of drug released versus time for innovator and formulation Time cumulative % of drug release innovator 0 0 5mints 26 ± 0.70 12 ± 1.2 10mints 48 ± 0.70 30 ± 0.1 15mints 77 ± 2.82 52 ± 0.9 20 mints 99 ± 0.70 86 ± 1.2

39. Dissolution samples of formulation HOURS sample 1 sample 2 sample 3 sample 4 sample 5 sample 6 Mean 5mints 11 13 12 11 9 10 11 10mints 30 32 31 30 31 32 31 15mints 54 53 55 54 53 55 54 20 mints 99 87 86 84 90 88 89

40. Cumulative % of drug released versus time for innovator and formulation Time cumulative % of drug release innovator 5mints 11 ± 0.70 12 ± 1.2 10mints 31 ± 1.41 30 ± 0.1 15mints 54 ± 0.70 52 ± 0.9

41. OBSERVATION Accelerated stability studies of the formulation 6 were done at 40o C, and at 75%RH for two months. It was seen that physically there was no change with respect to appearance hardness, thickness and drug content. The dissolution profiles of first month and second moth are similar. When compared to formulation 6.this indicates that the formulation was stable at 40oc and 75% RH for two months.

42. CONCLUSION: Pre compressional and Post compressional parameters were found to be within the satisfactory limits and hence suitable to formulate delayed release tablets. The results of in-vitro drug release profile of delayed release tablets depicts that increase in polymer concentration, increases the retardation of drug release from the Piroxicam tablet. The flow properties of Piroxicam formulations angle of repose of was found to be 31.0 ᶿ, Bulk density is 0.301 ( gm /ml) , tapped density F6 is 0.333, Hausner’s ratio was found to be 1.10, compressibility index was found to be 10.4%. The evaluation test of delayed release formulation perform the appearance is smooth surface & cream white in colour, thickness is 3.3-3.4 mm, weight variation was found to be 149.56±2.5, friability was found to be 0.009±0.001%, & Assay was found to be 99.3. drug content, invitro drug release studies by using basket method results was found to be 99 ± 7.77.

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