346 Full Text Available On

Transcription

1 International Journal of Universal Pharmacy and Bio Sciences 2(5): September-October 2013 INTERNATIONAL JOURNAL OF UNIVERSAL PHARMACY AND BIO SCIENCES IMPACT FACTOR 1.89*** Pharmaceutical Sciences ICV 3.00*** RESEARCH ARTICLE!!! Received: ; Accepted: EFFECT OF TYPE OF BINDER AND THEIR CONCENTRATION ON THE FORMULATION OF FIXED DOSE COMBINATION DRUGS: THE ROLE OF BRITTLE FRACTURE INDEX AS TOOL FOR FORMULATION OPTIMIZATION Udaya Bhanu Busi *, Lakshmana Rao Potti, Prasada Rao. M, Rama Kotaiah. Mogili, 1 sivasankar R. Beeravalli, 2 subhani Shaik Department of Pharmaceutics, M.A.M College of Pharmacy, Kesanupalli, Narasaraopet , Andhra Pradesh, India. 1 Fredericksburg, Virginia. 2 Alliance Institute of Advanced Pharmaceutical and Health Sciences, Hyderabad KEYWORDS: BFI, Dissolution Profile, PVP, Aceclofenac, Paracetmol. For Correspondence: UDAYA BHANU BUSI * Address: Department of Pharmaceutics, M.A.M College of Pharmacy, Kesanupalli, Narasaraopet , Andhra Pradesh, India. udayabanubusi@gmail.com ABSTRACT The effect of binder type and concentration on the formulation of Paracetamol and Aceclofenac tablets was evaluated. Three types of binders with different chemistries were evaluated at four distinctly different types of binders each at four concentrations from a low of 2% and high of 12.5% different use levels. The Brittle Fracture Index (BFI) for each formulation was determined by punching tablets with a hole in the centre. A correlation was attempted between the BFI value and the dissolution rate and extent of Paracetamol and Aceclofenac tablets from the formulations. Tablets with PVP as binder showed excellent BFI across all use levels and fast and complete release of the poorly soluble Aceclofenac. 346 Full Text Available On

2 INTRODUCTION: Fixed dose combination (FDC) of an analgesic like Paracetamol (1) and anti inflammatory drug like Aceclofenac (2) is very commonly formulated due to its synergistic effect in controlling pain and inflammation. These combinations are typically difficult to formulate due to the fact that the dose of both drugs is different and one of drugs is high dose poorly compressible. Also, the tablet has to release the drug quickly by disintegrating fast in order to provide quick relief to the patient. Hence, the selection of binder becomes extremely critical for successful development of such fixed dose combinations. The binder must not only be able to provide tablets of sufficient mechanical strengths but also should be able to make tablets which quickly disintegrate and probably help in dissolving the poorly water soluble drug like Aceclofenac. Laboratory scale experimentation on binder selections may not be adequate to provide significant information on how the product will behave when scaled up to production scale and run on high speed machines. However certain tools are developed which provide such insights even at small bench top scale. Brittle fracture index (BFI) is one such tool. BFI is a dimensionless quantity and hence is independent of the scale of operation. It measures the inherent strength of the granule when they are compressed into tablets. The effect of binders of three different chemistries on the physical properties of the tablets and in vitro dissolution (3,4) profiles was evaluated. The effect of binder on the hardness of the tablets was characterized by determining the BFI (5). In literature, Paracetamol tablets has been prepared to study the influence of some starch binders on the brittle fracture tendency (6), to investigate the potential of carnauba wax in ameliorating brittle fracture during Paracetamol tableting (7), to study the effects of pregelatinization of native sorghum and plantain starches on the mechanical properties of a paracetamol tablet formulation in comparison with corn starch BP (8), to study of the effects of natural and pregelatinized sorghum, plantain, and corn starch binders on the compressional characteristics of a paracetamol tablet formulation using density measurements and the Heckel and Kawakita plots for analysis (9), for classifying, grouping and ranking binders based on their abilities to ameliorate capping and lamination in paracetamol tablets using BFI as a tool (10), to prepare paracetamol tablets using PVP-K30 and K90 as binders (11). 347 Full Text Available On

3 The objective of the present work was to evaluate the role of BFI in selecting the binder which will be able to predict the behavior of the Paracetamol and Aceclofenac tablets when scaled up. MATERIALS AND METHODS Materials: Paracetamol (EMCO industries), Aceclofenac (EMCO industries), Povidone K30 (PVP K30, Ashland Specialty Chemicals), HPMC 5 cps (Dow Chemicals), Starch 1500 (Colorcon), Cros Carmellose sodium USP (Ac-di-sol, FMC), Microcrystalline cellulose (Avicel PH 101, FMC), Magnesium stearate (Peter Graven), Colloidal silicon dioxide (Aerosil 200 Pharma, Evonik). Purified water USP was used as granulation fluid. All other chemicals and reagents used were of A.R. Grade of Merck and were used as such without further processing. Methods Preparation of FDC Tablets by Wet Granulation Method: The tablets were formulated using the basic formula as given in Table 1. Wet granulation was carried out using water as granulating fluid. The granules were dried in a tray dryer set at 50 deg C till the loss on drying (LOD) below 2.5% w/w was achieved. The dried granules were sized thru # 20 sieves. To the granules Carmellose sodium and lubricants were added and mixed. Tablets were compressed on 12.5 mm circular flat bevelled edged die/punch set on a single stroke compression machine. Each batch was compressed to give tablets. The physical properties of the tablets are recorded in Table 2. For measuring the BFI, the granules were compressed on 12.5 mm circular punch with a 4 mm hole in the centre (Fig 1) The hardness of these tablets were measured and the BFI values were calculated using the formula (12-16) BFI = [0.5(T/To)]... (1) And T or To is computed using the equation T or To =2F/πDh (2) Where T or T₀ = tensile strength (MN/m 2 ) of tablet without or with centre hole respectively; F = diametric compression load (MN) needed to cause tensile failure of the tablet; D = tablet diameter (m); h = tablet thickness (m). Invitro Drug Release Study: The tablets compressed were subjected to in vitro dissolution profile testing. The dissolution profiles are shown in Fig 1.The in vitro dissolution studies were performed using USP type II dissolution apparatus at 50rpm. 348 Full Text Available On

4 Dissolution test was carried out for a total period of 1hr using water and other respectable dissolution liquids (900 ml) as dissolution medium at 37 ± 0.5 c. An aliquot (5ml) sample was withdrawn at specific time intervals and replaced with fresh medium to maintain a constant volume. The samples were filtered, and analysed by UV spectrophotometer at respective wavelengths. The concentration was calculated using standard calibration curve. RESULTS AND DISCUSSIONS All the formulations were within the acceptable range of average weight, friability values. A strong concentration dependency was observed for hardness achieved with different levels of PVP. The hardness was varying from 54 N for low concentration of PVP to 110N for high concentration. HPMC E5 and PGS did not show a significant concentration dependency for achieved hardness. HPC behaved in a similar manner as PVP with the highest hardness of N amongst all formulations. Both HPMC E5 and PGS show tablets of significantly lower hardness as compared to PVP and HPC at all use levels. DT for tablets formulated with both PVP and HPC show a strong concentration dependency with higher concentrations showing high DT values. However, all formulations pass the 15 minutes DT test criteria for uncoated tablets. HPMC and PGS based tablets show faster DT as compared to PVP and HPC based tablets. All formulations show friability < 0.5% irrespective of the type of binder used or concentration of binder used. BFI values range from 0 to 1. A high value (tending to 1) implies high fracture tendency, while a low value (tending to 0) implies low fracture tendency. The BFI values are given in Table 3. Tablets formulated with PVP have a uniform BFI values in the range of 0.44 to 0.55 showing that PVP based tablets do not show concentration dependency as far as the BFI value is concerned. Hence this binder can be used at as low a concentration as 2% in order to get tablets of excellent physical properties and trouble free machine ability at higher scale of operation. Tablets with HPMC E5 and PGS have very low BFI indicating that these formulations can potentially scale upon pose enormous problems during scale machine up and on high speed machines. HPC based tablets show a very high degree of concentration dependency as far as BFI is concerned. At low concentrations, the BFI values are significantly lower than those achieved by PVP at similar BFI concentration. However, at higher concentrations tablets of excellent BFI are achieved. 349 Full Text Available On

5 The rate of dissolution of Paracetamol and Aceclofenac significantly varies between the binders used in the study. When the dissolution rate and extent are compared for aceclofenac, PVP based formulations showed significantly faster and more complete dissolution of the Aceclofenac as compared to other binders. Fastest dissolution of the drug is achieved at 2% PVP level. In case of other binders, HPC at higher concentration is unable to achieve the 75% (Q) in 45 minutes criteria for dissolution of Aceclofenac. Paracetamol dissolution does not show dependency on the type and concentration of binder used. CONCLUSIONS Fixed dose combination of Aceclofenac and Paracetamol is difficult to formulate due to the poor compressibility of Paracetamol and insoluble nature of Aceclofenac. The selection of the type and concentration of binder may play a critical role in ensuring tablets of sufficient hardness, excellent machinability and acceptable dissolution characteristics. The aim of the present work was to evaluate the role of BFI in selecting the binder which will be able to predict the behavior of the tablets when scaled up. Tablets were formulated with four distinctly different types of binders each at four concentrations from a low of 2% and high of 12.5%. The wet granulation process was followed and tablets were all compressed at equivalent weight and thickness levels. BFI was calculated by compression tablets with a hole in the center for each batch. The tablets were evaluated for physical parameters and in vitro dissolution profile testing. Tablets with PVP as binder showed excellent BFI across all use levels and fast and complete release of the poorly soluble Aceclofenac. This study indicates that BFI is an excellent tools for selection of binder especially in case of high dose poorly compressible drugs, On basis of results of experiments on very small scale commercially scalability of the product can be evaluated. 350 Full Text Available On

6 Table.1. Formulations of Paracetamol and Aceclofenac Tablets S.No Ingredients F1 F2 F3 F4 F5 F6 F7 F8 F9 F10 F11 F12 F13 F14 F15 F16 1 Paracetamol Aceclofenac PVP K HPMC 5cPs HPC LF Starch MCC Ac-di-sol Magnesium stearate Aerosil Total tablet weight S.No Formulation Code Table.2.Physical Parameters of Tablets Avg. Weight mg Hardness (N) Thickness mm Friability (%) Disintegration Time(sec) 1 F F F F F F F F F F F F F F F F Full Text Available On

7 S.No Table.3.Comparitive Brittle Fracture Index Formulation Code Tensile Strength (T MN/m 2 ) Tensile Strength (To MN/m 2 ) BFI 1 F F F F F F F F F F F F F F F F Fig.1. Picture of Paracetamol and Aceclofenac Tablets with and without hole 352 Full Text Available On

8 %DRUG RELEASE %DRUG RELEASE Comparision of Aceclofenac Dissolution Profile for all Binders F1 F2 F3 F4 F5 F6 F7 F8 F9 F10 F11 F12 F13 F14 F15 F PVP K30 HPMC E 5 HPC-LF STARCH 1500 TIME(MIN) Fig.2. Dissolution Profile of Paracetamol and Aceclofenac Tablets Comparision of Paracetamol Dissolution Profile for All Binders F1 F2 F3 F4 F5 F6 F7 F8 F9 F10 F11 F12 F13 F14 F15 F PVP K30 HPMC E 5 HPC-LF STARCH 1500 TIME(MIN) Fig.3. Dissolution Profile of Paracetamol and Aceclofenac Tablets 353 Full Text Available On

9 Comparitive Brittle Fracture Indices across all Binders F1 F2 F3 F4 F5 F6 F7 F8 F9 F10 F11 F12 F13 F14 F15 F16 T T0 BFI Fig.4. Comparison of BFI of Paracetamol and Aceclofenac tablets REFERENCES: Bandelin FJ (1989). Compressed tablet by wet granulation. In: Herbert A. Lieberman, Leon Lachman and Joseph B. Schwartz (Eds.), Pharmaceutical Dosage Forms: Tablets. 2nd ed. Vol 1; Marcel Dekker Inc. New York pp Rubinstein MH (1990). Tablets. In: Michael E. Aulton (Ed.), the Science of Dosage Form Design; Longman Group, UK pp Ebere I. Okoye, Anthony O. Onyekweli, Olobayo O. Kunle and Matthew I. Arhewoh, Scientific Research and Essays Vol. 5 (5), pp , 4 March, Uhumwangho, M.U. Influence of some starch binders on the brittle fracture tendency of Paracetamol tablets, Afri. J. Biotech, 2006, 5(20), Uhumwangho, M.U potential of carnuba wax in ameliorating brittle fracture during tableting. Pak. J. Pharm. Sci. 2009, 22(1), Alebiowu G, Itiola OA. Compressional characteristics of native and pregelatinised forms of Sorghum, Plantain and Corn starches and the mechanical properties of their tablets. Drug Dev. Ind. Pharm. 2003; 28(6): Full Text Available On

10 9. Alebiowu G, Itiola OA. Effects of pregelatinised forms of Sorghum, Plantain and Corn starches on the compressional properties of paracetamol tablets. Phrm.tech, 2001, Ebere I. Okoye. BFI as a tool in the classification, grouping and ranking of binders used in tablet formulation: paracetamol tablets. Int. J. App. Bio. Pharm. Tech. 2012, 3(2), Roohullah ZI, JA Khan, SMA Daud and BA Obaidullah. Preparation of paracetamol tablets using PVP K30 and K90 as binders. Acta Pharm. Turcica. 2003, 45, Okor RS (2005). Brittle fracture during tableting a problem for the pharmaceutical industry. Trop. J. Pharm. Res. 4(2): Odeku OA, Itiola OA (1998). Evaluation of khaya gum as a binder in a paracetamol tablet formulation. Pharm. Pharmacol. Commun. 4: Olufunke DA, Oludele AI, Oluwatoyin AO (2005). Effects of Plantain and Corn Starches on the Mechanical and disintegration properties of Paracetamol tablets. AAPS Pharm. Sci. Tech. 6(3): E458-E E. N. Hiestand, Rationale for and the Measurement of Tableting Indices, Pharm. Powder Compaction Tech. Alderborn and Nystrom, ed. Marcel Dekker, Inc. p (1996). 16. G. E. Amidon, Physical and Mechanical Property Characterization of Powders, Physical Charact. of Pharm. Solids, H. G. Brittain, ed. Marcel Dekker, Inc., p (1995). 355 Full Text Available On