Formulation development and evalution of matrix tablet of
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  • 1. Presented By Guided By Mr. Gajanan S. Ingole Mr. K.B. Charhate ANURADHA COLLEGE OF PHARMACY, CHIKHLI.
  • 2. 1. Introduction 2. Literature review 3. Drug and excipients profile 4. Aim and objective 5. Rational and plan of work 6. Materials and equpiments 7. Experimental work 8. Results 9. Discussion 10. Conclusion 11. References 2
  • 3. Oral delivery of drugs is the most convenient route of Drug delivery systems due to  Ease of administration  Patient compliance  Flexibility in formulation Tablets ingested orally Tablets used in oral cavity Tablets administere d by other route Tablets administere d by other route Tablets used to prepare solution Matrix Tablets Type of controlled drug delivery systems, which release the drug in continuous manner. a matrix is defined as a well-mixed composite of one or more drugs with gelling agent i.e. hydrophilic. release the drug by both controlled and diffusion controlled mechanisms. 3
  • 4. Easy to manufacture,effective and low cost . avoids the high blood concentration. maintain therapeutic concentrations over prolonged periods. Reduce the toxicity. Minimize the local and systemic side effects. Increase the stability. 4 The remaining matrix must be removed after the drug has been released. The release rates are affected by various factors such as, food and the rate transit through the gut. Release rate continuously diminishes due to an increase in diffusional resistance
  • 5. A)On the Basis of Retardant Material Used • Hydrophobic Matrices • Lipid Matrices • Hydrophilic Matrices • Biodegradable Matrices • Mineral Matrices B)On the Basis of Porosity of Matrix • Macroporous Systems • Microporous System • Non-porous System 5
  • 6. POLYMERS EXAMPLE i) Hydrogels Polyhydroxyethyl methylacrylate. ii) Soluble polymers Polyethylene glycol (PEG) iii)Biodegradable polymers Polylaceticacid (PLA) iv)Non biodegradable polymers Polyethylene vinyl acetate.(PVA) v)Mucoadhesivepolymers Sodium carboxymethyl cellulose. 6
  • 7.  Specific polymers have been designed to release drugs into specific regions of the gastrointestinal tract. A)pH dependent polymer: EudragitE,EudragitL,EudragitS,Hydroxyproylmethylcellulose phthalate. B)pH independent polymer: Hydroxy propyl methyl cellulose, Kollidon. 7
  • 8.  Kumar et al; in their review “Oral Extended Release Drug Delivery System” providing the recent literature regarding development and design of extended release tablets.  Patel et al; in their Overview “Extended Release Matrix Technology” This article contains the basic information regarding extended-release formulation and also the different types of the same.  Patel et al; in their review “Matrix Type Drug Delivery System: A Review” Focused on to formulate tablets in order to avoid the first pass metabolism and increase the bioavailability. Hence in this work an attempt was made to formulate sustain release. system for in order to achieve even plasma concentration profile up to 24 hrs. it can be easily concluded that sustained- release formulation are helpful in increasing the efficiency of the dose as well as they are also improving the patient’s compatibility.  Mulani H et al, in their research work pH independent sustained release matrix tablet was formulated. It was found that Kollidon® SR is suitable for pH-independent extended release matrix tablets.  Pao-Chu Wu et al; their study was to develop and optimize the propranolol once-daily extended release formulations containing HPMC,Microcrystalline cellulose (MCC) and lactose. 8
  • 9. Drug Profile Name: NSL Assay:101. 4 %w/w (By HPLC, on dried base). Solubility: soluble in ethanol and insoluble in water. Half-life: Plasma half-life is 7-12 hrs Description: yellow crystalline powder Category: calcium channel blockers Loss on drying: 0.15% (By Karl Fisher) 9
  • 10. Clinical Pharmacology Mechanism of Action Distribution Metabolism Elimination Uses Contraindic ation 10
  • 11. Excipients Profile Lactose Monohydrate Sodium Lauryl Sulfate Cellulose Microcrystalline Magnesium Stearate Colloidal Silicon Dioxide Instacoat Universal Brown 11
  • 12. Polymer Profile Hydroxypropylmethylcellulose Polymethacrylates 12
  • 13. Aim:  The aim of present study is to develop & characterized matrix tablet of antihypertensive drug using pH dependent and independent polymer. Objectives:  To deliver the dosage form at the site of absorption their by enhancing the bioavailability.  To delay and control the release of drug through the formulation.  To match the invitro dissolution profile of marketed reference product.  To formulate Site specific drug delivery.  To formulate Stable formulation.  To formulate Cost effective dosages form with respect to marketed reference product. 13
  • 14.  RATIONAL  Antihypertensive therapy has a well established place to prevent the complications of high blood pressure.  Amongst the existing agents NSL is effective ones.  formulation of matrix tablet provides an increase in the bioavailability of calcium channel blocker.  Manufacturing of Antihypertensive drug is easy.  reduces the frequency of administration  improves patient compliance, better selectivity and longer duration of action. 14
  • 15. PLAN OF WORK Literature survey. Selection of material Preformulation studies. Drug excipients compatibility studies Preparation of various formulations Evaluation of tablet Stability Studies Result and Discussion Conclusion 15
  • 16. Sr. No. Parameters Observations 1 Dosage form Solid Oral 2 Brand name of the product Sular 3 Generic name of the product NSL tablet 4 Manufactured by Skye pharma production SAS 5 Label claim Each tablet contain 34 mg of NSL 6 Description Orange oval tablet with SC1503 marking one side &plain other side 7 Excipients Hypromellose,Lactose, Hypromellose phthalate, Glyceryl behenate, Silicon dioxide,SLS,Povidone, Magnesium sterate, Methacrylic acid copolymer. 8 Thickness(nm) 6.76-6.88 9 Hardness(N) 160 10 Container HDPE 11 Storage 20-250C Protect from light & moisture16
  • 17. Preformulation Study Formulation of matrix tablet Optimization Study Stability Studies 17
  • 18. A)Preformulation Study a)Characterstics of the Bulk Drug and Powder Blend Properties 1)Bulk density 2)Tapped density 3)Compressibility index 4)Hausner’s ratio 5) Loss on drying (LOD) b)Drug Excipient Compatibility Study 18
  • 19. Sr. No Ingredients Trial Batches in mg F1 F2 F3 F4 F5 F6 F7 F8 F9 F10 Intragranular 1 NSL 34 34 34 34 34 34 34 34 34 34 2 Hypromellose (Methocel prem K100LV) 50 50 - - - - - - - - 3 Lactose monohydrate (pharmatose 200M) 30 30 30 30 46.6 38.3 38.3 38.3 76.6 4 Methacrylic Acid Copolymer Eudragit L10055 - - 50 36 56 46 46 46 46 46 5 Microcrystalline cellulose (Avicel PH101) 140.4 136.8 136.8 136.8 231.8 184.2 214.9 168.9 253.2 176.6 6 Sodium lauryl sulphate(Texaponk12pPH) - 3.6 3.6 3.6 5.6 4.6 4.6 4.6 4.6 4.6 Binder 7 IPA q.s q.s q.s q.s q.s q.s q.s q.s q.s q.s 8 Purified water q.s q.s q.s q.s q.s q.s q.s q.s q.s q.s Extragranular 9 Hypromellose(Methocel K100CR) 100 100 100 114 177.3 145.7 115 161 115 115 10 Colloidal silicon dioxide(Aerosil200) 2 2 2 2 3.1 2.6 2.6 2.6 2.6 2.6 11 Magnesium stearate 3.6 3.6 3.6 3.6 5.6 4.6 4.6 4.6 4.6 4.6 Total wt of core tablet 360 360 360 360 560 460 460 460 460 460 Coating solution 12 Instacoat Universal brown A0G11058IHS 10.8 10.8 10.8 10.8 16.8 13.8 13.8 13.8 13.8 13.8 13 Purified water q.s q.s q.s q.s q.s q.s q.s q.s q.s q.s Total wt of coated tablet 370.8 370.8 370.8 370.8 576.8 473.8 473.8 473.8 473.8 473.819
  • 20. Sifting Dry Mixing Binder Preparation Granulation DryingSifting Pre- Lubrication Lubrication Compression Coating 20
  • 21. b) In-Process Evaluations of Tablet 1)Tablet appearance 2)Weight Variation 3)Hardness 4)Thickness5)Friability 6)Dissolution 7) Assay 21
  • 22. on the basis presence of pH dependent polymer Formulation were modified with subject to pH independent polymer concentration of polymer and surfactant were changed the capacity of a drug substance to maintain its identity, quality and purity Definition • quality of the drug substance • shelf life for drug substance Objective • 1st and 2nd month Stability testing • assay and% drug release of optimized batch was compared Method 22
  • 23.  Preformulation Sr.No . Tests Specification Results 1 Description Yellow crystalline powder Yellow crystalline powder 2 Solubility Soluble in ethanol and insoluble in water. Complies 3 Water content(%w/w) Not more than 0.50 0.15% 5 Assay (%w/w) Not less than 99.0 & Not more than101.0 96.9 6 Bulk Density (gm/ml) - 0.19 7 Tapped Density (gm/ml) - 0.334 8 Compressibility Index (%) - 42.42 9 Hausner ratio - 1.7 23
  • 24. Sr. No. Contents Physical Description Initial Condition – Dry 40C/75% RH 15days 1months 1 API Yellow crystalline powder No Change No Change 2 API+ Hypromellose (Methocel prem K100LV) Light yellow crystalline powder No Change No Change 3 API+ Lactose monohydrate(pharmatose 200M) Light yellow crystalline powder No Change No Change 4 API+ Methacrylic Acid Copolymer (Eudragit L10055) Light yellow crystalline powder No Change No Change 5 API+ Microcrystalline cellulose(Avicel PH101) Light yellow crystalline powder No Change No Change 6 API+ Sodium lauryl sulphate(Texaponk12pPH) Light yellow crystalline powder No Change No Change 7 API+ Hypromellose(Methocel K100CR) Light yellow crystalline powder No Change No Change 8 API+ Colloidal silicon dioxide(Aerosil 200) Light yellow crystalline powder No Change No Change 9 API+ Magnesium stearate Light yellow crystalline powder No Change No Change 10 API+ Instacoat Universal brown A0G11058IHS Dark yellow crystalline powder No Change No Change 11 API+ All Excipients Light yellow yellow crystalline powder No Change No Change Drug –Excipient Compatibility study 24
  • 25. Trial Evaluation Parameters LOD at105ºC (%) BD(gm/cm3) TD(gm/cm3) CI (%) HR F1 3.34 0.503 0.711 29.231 1.413 F 2 3.99 0.407 0.550 26.0 1.351 F 3 3.10 0.315 0.530 26.80 1.355 F4 2.55 0.350 0.533 25.23 1.315 F 5 3.75 0.295 0.404 26.923 1.368 F6 3.25 0.326 0.439 25.714 1.346 F 7 3.41 0.321 0.411 21.875 1.280 F 8 3.48 0.406 0.515 21.212 1.269 F9 3.45 0.340 0.451 24.59 1.326 F10 3.46 0.320 0.423 25.21 1.319 Characteristics of Lubricated Blend 25
  • 26. Formula optimization Trial without pH dependent polymer Trials with pH dependent polymer. Optimization of effective drug release surface area. Optimization of HPMC Optimization of MCC and Lactose ratio. Final optimized formula 26
  • 27. Trials Evaluation Parameters of Uncoated Matrix tablet (without pH dependant ) Av.w (Mg) Thick (mm.) Hardness (N) Friability (%) F1 360 5.45 138 0.04 F 2 361 5.28 142 0.06 Dissolution in (0.1 N HCL+0.5% SLS), paddle 50 rpm, 900ml Time (Hrs) % Drug Release Sular F1 F2 1 2 1 4 2 7 1 9 4 20 2 20 6 32 22 32 8 39 40 43 10 57 45 57 12 74 59 68 15 78 75 80 16 87 83 89 18 90 86 90 20 91 88 98 24 95 92 97 0 20 40 60 80 100 0 2 4 6 8 10 12 14 16 18 20 22 24 %DrugRelease Time(Hrs) % Drug Release inHCL+0.5%SLS Sular F1 F2 27
  • 28. Time (Hrs) % Drug Release Sular F2 1 4 4 2 12 10 4 30 21 6 47 29 8 62 42 10 80 53 12 90 62 15 92 73 16 94 80 18 93 85 20 93 90 24 95 94 0 20 40 60 80 100 0 2 4 6 8 10 12 14 16 18 20 22 24 %DrugRelease Time(Hrs) %Drug Release in pH6.8 +0.5 % SLS Sular F2 Dissolution in ph 6.8 +0.5 % SLS, paddle, 50 rpm, 900 ml 28
  • 29. Trials Evaluation Parameters of Uncoated Matrix tablet ( pH dependant ) Av.wt(Mg) Thickness (mm.) Hardness (N) Friability (%) F3 360 5.10 138 0.03 F4 361 5.07 145 0.04 % Drug Release in HCl+0.5%SLS. Time (Hrs) % Drug Release Sular F3 F4 1 2 4 1 2 7 12 3 4 20 23 13 6 32 38 22 8 39 46 32 10 57 62 49 12 74 80 64 15 78 89 72 16 87 95 79 18 90 97 84 20 91 98 88 24 95 98 92 0 20 40 60 80 100 0 2 4 6 8 10 12 14 16 18 20 22 24 %DrugRrelease Time(Hrs) % Drug Release inHCL+0.5%SLS Sular F3 F4 29
  • 30. % Drug Release in pH 6.8+0.5%SLS Time (Hrs) %Drug Relesase Sular F3 F4 1 4 5 5 2 12 21 12 4 30 40 28 6 47 52 45 8 62 73 60 10 80 94 74 12 90 94 83 15 92 96 91 16 94 98 93 18 93 100 96 20 93 100 96 24 95 100 97 0 20 40 60 80 100 0 2 4 6 8 10 12 14 16 18 20 22 24 %DrugRelease Time(Hrs) % Drug Release in pH 6.8+%0.5%SLS Sular F3 F4 30
  • 31. Trials Evaluation Parameters of Uncoated Matrix tablet (Optimization of effective drug release surface area.) Av.wt. (Mg) Thickness(m m.) Hardness (N) Friability (%) F4 361 5.07 145 0.04 F5 560 6.54 175 0.11 F6 460 5.50 178 0.20 Time (Hrs) % Drug Release Sular F4 F5 F6 1 2 1 3 3 2 7 3 8 9 4 20 13 18 22 6 32 22 29 35 8 39 32 38 43 10 57 49 47 53 12 74 64 56 71 15 78 72 68 82 16 87 79 74 91 18 90 84 79 95 20 91 88 84 97 24 95 92 92 100 0 20 40 60 80 100 0 2 4 6 8 10 12 14 16 18 20 22 24 %DrugRelease Time(Hrs) % Dug Release in HCL+0.5% SLS Sular F4 F5 F6 % Drug Release in HCl+0.5%SLS. 31
  • 32. Time (Hrs) % Drug Release Sular F4 F5 F6 1 4 5 7 6 2 12 12 14 15 4 30 28 31 35 6 47 45 52 53 8 62 60 59 68 10 80 74 73 82 12 90 83 79 93 15 92 91 88 95 16 94 93 92 95 18 93 96 93 96 20 93 96 95 97 24 95 97 95 98 32 0 20 40 60 80 100 0 2 4 6 8 10 12 14 16 18 20 22 24 %DrugRelease Time(Hrs) % Drug Release in pH 6.8+%0.5%SLS Sular F4 F5 F6 %Drug Release in pH 6.8 +0.5 %SLS
  • 33. Trials Evaluation Parameters of Uncoated Matrix tablet) (Optimization of HPMC) Av.wt. (Mg) Thickness(m m.) Hardness (N) Friability (%) F6 460 5.50 178 0.20 F7 460 5.45 179 Nil F8 460 5.51 175 0.22% Drug Release in 0.1N HCL+0.5% SLS. Time (Hrs) % Drug Release Sular F6 F7 F8 1 2 3 4 3 2 7 9 11 8 4 20 22 23 17 6 32 35 35 28 8 39 43 44 35 10 57 53 57 53 12 74 71 75 62 15 78 82 83 72 16 87 91 92 76 18 90 95 94 81 20 91 97 96 85 24 95 100 98 88 0 20 40 60 80 100 0 2 4 6 8 10 12 14 16 18 20 22 24 %DrugRelease Time(Hrs) %Drug Release in HCL+0.5% SLS Sular F6 F7 F8 33
  • 34. %Drug Release in pH 6.8 +0.5 % SLS Time (Hrs) % Drug Release Sular F6 F7 F8 1 4 6 6 2 2 12 15 15 8 4 30 35 32 26 6 47 53 50 39 8 62 68 66 57 10 80 82 85 72 12 90 93 93 80 15 92 95 96 83 16 94 95 96 85 18 93 96 95 82 20 93 97 94 82 24 95 98 97 86 0 20 40 60 80 100 0 2 4 6 8 10 12 14 16 18 20 22 24 %DrugRelease Time(Hrs) Dissolution in pH 6.8+0.5 % SLS Sular F6 F7 F8 34
  • 35. Trials Evaluation Parameters of Uncoated Matrix tablet (Optimization of MCC and Lactose ratio) Av.wt. (Mg) Thickness (mm.) Hardness (N) Friability (%) F7 460 5.45 179 Nil F9 460 5.49 175 0.04 F10 460 5.51 169 Nil% Drug Release in HCL+0.5% SLS Time (Hrs) % Drug Release Sular F7 F9 F10 1 2 4 8 2 2 7 11 15 8 4 20 23 29 21 6 32 35 42 33 8 39 44 52 40 10 57 57 64 55 12 74 75 83 74 15 78 83 90 80 16 87 92 95 88 18 90 94 99 90 20 91 96 100 93 24 95 98 100 99 0 20 40 60 80 100 0 2 4 6 8 10 12 14 16 18 20 22 24 %DrugRelease Time(Hrs) %Drug Release in(HCL+0.5% SLS) Sular F7 F9 F10 35
  • 36. % Drug Release in pH 6.8 +0.5 % SLS Time (Hrs) % Drug Release Sular F7 F9 F10 1 4 6 8 6 2 12 15 20 14 4 30 32 36 31 6 47 50 55 46 8 62 66 70 62 10 80 85 86 79 12 90 93 95 89 15 92 96 98 92 16 94 96 98 94 18 93 95 99 97 20 93 94 100 98 24 95 97 100 99 36
  • 37. Evaluation Parameters High Hardness Low Hardness Optimum Hardness Av.wt. (Mg) 461 460 460 Thickness (nm.) 5.40 5.61 5.59 Hardness (N) 181 120 169 Friability (%) 0.02 0.30 Nil Assay of Formulation % Labeled amount Drugs Innovat or F1 F2 F3 F4 F5 F6 F7 F8 F9 F10 NSL 99.8 98.0 99.2 98.3 98.2 97.3 99.1 99.1 98.0 99.23 99.5 Stability study results Parameter Initial 40°C / 75%RH After 1 month After2 month Description Orange colored round shape biconvex film coated tablet plain on both side. Complies Complies Average Weight (mg) 460.0 459.9 459.9 Assay (%) 99.50 99.55 99.51 Evaluation of finally optimized formula
  • 38. % Drug Release in 0.1 N HCL Time (Hrs) % drug release Initial 1month 2 months 1 2 2 2 2 8 7 8 4 21 21 21 6 33 34 34 8 40 41 41 10 55 56 56 12 74 75 75 15 80 81 81 16 88 88 89 18 90 90 90 20 93 94 93 24 99 98 99 38
  • 39. Time (Hrs) % drug release Initial 1month 2 months 1 6 6 6 2 14 14 14 4 31 32 31 6 46 47 46 8 62 63 63 10 79 79 79 12 89 89 90 15 92 93 92 16 94 94 94 18 97 97 97 20 98 98 98 24 99 98 99 % Drug Release in pH 6.8+0.5% SLS 39
  • 40. 1)Compatibility studies 2)Evaluation of Blend 3)In Process Evaluation Tests for Tablets 4)InVitro Release Study 5)Stability Study of Optimized Batch 40
  • 41. Relatively well absorbed into the systemic circulation with 87% of the radiolabeled drug recovered in urine and feces Suitable candidate for delayed/controlled release matrix tablet Market reference product explorted trilayer tablet approach with inactive layer sandwiching drug layer Similar profile was achieved in trial mention by using monolayer tableting approach Delayed release matrix tablet s best promising option for drug get metabolized in gut wall. The role of ph dependent and independent polymer enhance the flexibility and efficacy of dosage form. 41
  • 42.  Robinson, J.R., Lee, V.H.L., In, Controlled Drug Delivery: Fundamentals and Applications (Robinson, J.R., Lee, V.H.L, ed.), 2nd edition. Marcel Dekker, New York, 1987, pag16.  Lachman L, Lieberman H. A, Kanig J. L, The Theory and Practice of Industrial Pharmacy, 3rd ed., Varghese publishing house, Bombay. 1987: Pag294, 336, 413.  Kumar .S, Oral Extended Release Drug Delivery System Asian J. Pharm. Tech. 2012; Vol. 2: Issue 2, Pag 38-43.  Jain N K, Controlled and novel drug delivery system, in progress in controlled and novel drug delivery system, C B S publishers and distributors, New delhi, 2004, pag419-35.  Bramhankar DM, Jaiswal S B, “Biopharmaceutics and pharmacokinetics”, 1st ed, Vallabh Prakashan; 2008, Pag335-371.  Patel K, An Overview: Extended Release Matrix Technology international Journal Of Pharmaceutical And Chemical Sciences Apr – Jun 2012, vol. 1 (2).  Chien Y. W., Novel drug delivery systems, volume-50, Marcel Dekker, Inc. New York 2002, pag.1-43. 42
  • 43.  Alford N Martin, Patrick J. Sinko, Martin’s Physical pharmacy and pharmaceutical sciences, 2006.  Patel H.,Matrix Type Drug Delivery System: A Review JPSBR,Volume 1, Dec 2011,pag143-151.  Vyas S.P, Khar R.K,Controlled Drug Delivery: Concepts and Advances, Ist ed,vallabh prakashan, 2002, pag 156-189  Aulton ME,Pharmaceutics: The Science of Dosage Form Design  Wadher.J, Formulation and Evaluation of Sustained Release Matrix Tablets of Metformin Hydrochloride Using pH Dependent and pH Independent Methacrylate Polymer, British Journal of Pharmaceutical Research2011 1(2),pag29-45.  Mulani H, Development of pH-independent matrix type sustained release drug delivery system of propranolol hydrochloride Journal of Applied Pharmaceutical Science2011 01 (03), Pag83-92.  Mohd Azharuddin, Krishnananda Kamath, T. Panneerselvam, Subash S. Pillai, A.R. Shabaraya,Formulation and evaluation of controlled release matrix tablets Of antihypertensive drug using natural and synthetic Hydrophilic polymers research in Biotechnology, 2011 2(4),pag26-32 43
  • 44. Thank You 44