2 Iraqi J Pharm Sci, Vol.19 (1) 2010 Metoprolol bilayer tablets 21 Formulation of Metoprolol Bilayer Tablets as an Oral Modified Release Dosage Form Mohammed S. Jabbar* ,1 and Yehia I. Khalil** *Department of Pharmaceutics, College of Pharmacy, University of Basrah, Basrah ,Iraq. **Department of Pharmaceutics, College of Pharmacy, University of Baghdad, Baghdad, Iraq. Abstract Metoprolol is a β1 adrenergic blocker used in treatment of heart diseases. Metoprolol (100mg) tablets was formulated as a modified release oral system utilizing the concept of bilayer system, first layer contained (30mg) as immediate release and the other (70mg) in the sustained release matrix. The immediate release layer consisted of lactose or microcrystalline cellulose as diluents with sodium starch glycolate or sodium croscarmellose as disintegrants. The result showed that the layer contains microcrystalline cellulose and 2% sodium starch glycolate gave disintegration time similar to that of conventional metoprolol tartrate tablet. This result was subjected in the subsequent preparation of the bilayer tablet. The sustained release layer was prepared using three polymers: ethylcellulose (EC), Hydroxypropyl methylcellulose (HPMC) and hydroxyl ethylcellulose (HEC) as retardant materials. It was found that the combination of EC with HPMC in ratio of 2:1 in F11 was best formula because of it’s release profile and the tablet integrity and dimensions were conserved for the period of the test, but according to similarity factor (f 2), F15 (which contained EC:HPMC in ratio 2:1 with polyvinyl pyrrolidone (PVP) as a binder) was the best formula showed higher (f2) among all other formulas and equals to 72.3 comparing to reference product. Key words: Metoprolol, Bilayer tablet, Immediate release, Sustained release. الخالصة كُظبو يغ(111حجىة انًُزىثزونىل ) َسزخذو فٍ عالج أيزاض انقهت. رى رصُُغ 1ُزىثزونىل هى حبصز أدرَُبنٍُُ ةانً يغ( 01ال )ركىٌ يجبشزح انزحزر وو يغ(31رحىٌ ) دوائٍ فًىٌ يزغُز انزحزر ثإسزخذاو يجذأ َظبو ثُبئٍ انطجقخ، انطجقخ األونً يدهزٌ انزجهىر كًخففبد يع صىدَىو نسهُهىسانزحزر رزكىٌ يٍ كم يٍ انالكزىس أوا انطجقخ يجبشزح قبنت ثطُئ انزحزر. فٍ االخزي % يٍ 2يدهزٌ انزجهىر يع نسهُهىسَشأانكالَكىنذ أو صىدَىو انكزوسكبريهىس كًفككبد. رجٍُ انُزبئح ثإٌ انطجقخ انزٍ رحىٌ عهً ا ُذَخ ونذنك اٌسزخذيذ فٍ انزحضُزاد انالحقخ نهحجىة ثُبئُخ صىدَىو َشأانكالَكىنذ رعطٍ وقذ رفكك يشبثه نحجخ انًُزىثزونىل انزقه انطجقخ. ُحضزد انطجقخ ثطُئخ انزحزر ثإسزخذاو ثالثخ ثىنًُزاد هٍ االثُم سهُهىس ،انهبَذروكسٍ ثزوثُم يثُم سهُهىس و انهبَذروكسٍ هى 11فٍ انصُغخ 1:2ُم سهُهىس ثُسجخ وخذ إٌ خهُط يٍ االثُم سهُهىس و انهبَذروكسٍ ثزوثُم يث اثُم سهُهىس كًثجطبد رحزر. إعزًبدا" عهً عبيم خالل فززح اإلخزجبر، نكٍ ىيحبفع عهُه كبٌ أفضم صُغخ ثسجت انشكم اندُذ نهزحزر وهُكهُخ انحجخ وأثعبدهب بَزونُذوٌ كًبدح يع انجىنٍ فُُم ث 1:2)انزٍ رحىٌ االثُم سهُهىس و انهبَذروكسٍ ثزوثُم يثُم سهُهىس ثُسجخ 11انزشبثه، انصُغخ يقبرَخ ثبنًُزح انًزخعٍ. 02.3راثطخ( كبَذ أفضم صُغخ وأظهزد اعهً عبيم رشبثه وهى Introduction Tablets may be defined as solid pharmaceutical dosage forms containing drug substances with or without suitable diluents and have traditionally prepared by either compression, or molding methods. Recently, punching of laminated sheets, electronic deposition methods, and three-dimensional printing methods have been used to formulate tablets (1) . Modified-release tablets are coated or uncoated tablets that contain special excipients or they are prepared by special procedures, or both, designed to modify the rate, place or time of release of the active substance(s) (2) . Layered tablets, type of modified release, are prepared by compressing several different granulations fed into a die in succession, one on top of another, in layers. Each layer comes from a separate feed frame with individual weight control to form two- or three- layered tablets, depending on the number of separate fills. Each layer may contain a different medicinal agent, separated for reasons of chemical or physical incompatibility, staged drug release, or simply for unique appearance of the layered tablet (3) . Some layers may be formulated to exert certain functions. Rahmanz Z. et al, designed a bilayer floating tablet of captopril in which one layer responsible for floating of the tablet for prolongation the gastric residence time with a controlled release mechanism (4) . The bioavailability of propranolol was enhanced by formulating a bilayer and multilayer buccal mucoadhesive tablet in which one layer adhere to the buccal mucosa so localized the drug in the oral cavity and avoid hepatic first pass metabolism (5) . 1Corresponding author E- mail : mohamedsattar2@yahoo.com Received : 1 /8 /2009 Accepted : 28/12/2009 Iraqi J Pharm Sci, Vol.19 (1) 2010 Metoprolol bilayer tablets 22 The bioavailabilty of rosiglitazone was improved by developing a bilayer and floating- bioadhesive drug delivery system exhibiting a unique combination of floatation and bioadhesion to prolong residence of rosiglitazone in the stomach (It is highly soluble in 0.1 mol/l HCl) so improve its bioavailability (6) .Bilayer tablet is suitable for sequential release of two drugs in combination, with one layer of drug for immediate release while the second layer designed to release drug in an extended release manner. Bhavesh S. et al developed bilayer tablet for treatment of migraine consisting from Ibuprofen in the sustained release layer and metoclopramide (to enhance the absorption of non-steroidal anti- inflammatory drug) in the immediate release layer (7) .The most important application of the bilayer is a quick/slow release system provides an initial burst of drug release followed by a constant rate (ideally) of release over a defined period of time. This type of system is used primarily when a maximum response needs to be achieved quickly, and it is followed by a sustained release phase to avoid repeated administration. When a single constant rate for drug release does not entirely satisfy the therapeutic objective, the quick/slow delivery system may be an interesting alternative. This biphasic release system can be achieved by the application of an immediate release layer to the conventional layered matrix tablet (8) .Suitable candidate drugs for this type of administration include nonsteroidal anti-inflammatory drugs (NSAIDs) and antihypertensive, antihistaminic, and anti-allergic agents (9) . Metoprolol (MT) is a cardioselective β1blocker exert equilibrium-competitive antagonism of the actions of catecholamines and other adrenomimetics at β-receptors, used in treatment of hypertension, angina pectoris, myocardial infarction, cardiac arrhythmias and heart failure (10) . Peak plasma concentrations are achieved within 1.5 to 2 hours after a single oral dose, but because of the drug’s short half-life (3 to 4 hours), the therapeutic plasma concentration can be maintained only if the metoprolol is administered frequently (11) . These characteristics make metoprolol a suitable candidate for administration by a quick/slow delivery system. The purpose of this study is to design a quick/slow delivery dosage form as biphasic bilayer tablet in which one layer containing superdisintegrant like sodium starch glycolate or sodium croscarmellose responsible for immediate release of the drug and the other is matrix layer of retardant polymer like Ethylcellulose (EC), Hydroxypropyl methylcellulose (HPMC) and hydroxyethylcellulose (HEC) responsible for sustained action. Materials and Methods Materials Metoprolol tartrate, hydroxypropyl methylcellulose and colloidal silicon dioxide (CabOSil) from Sigma, Germany. Metoprolol tartrate 50mg tablet: UK limited, England. Metoprolol tartrate 100mg sustained release: Ratiopharm, Germany. Ethylcellulose from Acros organics, United States. Hydroxyethylcellulose from Merck, Germany. Lactose from Riedel-DeHaen, Germany. Microcrystalline cellulose (Avicel PH 102) and croscarmellose from Hekma Drug Industry, Jordan. Starch and talc from AFCO, India. Polyvinylpyrrolidone, sodium starch glycolate (Explotab) and magnesium stearate from BDH laboratory, England. Methods Preparation of Immediate Release (IR) Granules Different formulas (table 1) were prepared using wet granulation method to achieve most acceptable pharmacopial requirements and consider as comparable test with the reference one (Metoprolol tartrate UK limited 50 mg) tablet.After weighing the drug and the excipients enough to prepare 40 tablets in dried form, and then blend the ingredients using mortar and pestle, the powders were mixed with binding solution (10% alcoholic starch paste) gradually until proper ball test consistency was resulted.The wet mass was screened through sieve (10 mesh) and dried in pre warmed oven at 60 ºC for one hour. The dried granules then reduced in size by screening them through 12 mesh size sieve. A known weight of granules equivalent to the stated dose was mixed with calculated amount of magnesium stearate and talc powder for five minutes. Table 1: Different formulas of metoprolol granules as immediate release (IR) layer IInnggrreeddiieenntt ((mmgg)) IIRR11 IIRR22 IIRR33 IIRR44 IIRR55 IIRR66 MMeettoopprroollooll ttaarrttrraattee 30 30 30 30 30 30 MMiiccrrooccrryyssttaalllliinnee cceelllluulloossee ((MMCCCC)) 103 100 100 LLaaccttoossee 103 100 100 SSooddiiuumm ssttaarrcchh ggllyyccoollaattee 3 3 CCrroossccaarrmmeelllloossee 3 3 1100%% aallccoohhoolliicc ssttaarrcchh ppaassttee 15 15 15 15 15 15 MMgg sstteeaarraattee 1 1 1 1 1 1 TTaallcc 1 1 1 1 1 1 TToottaall wwtt 150 150 150 150 150 150 Iraqi J Pharm Sci, Vol.19 (1) 2010 Metoprolol bilayer tablets 23 Preparation of Sustained Release (SR) granules Different formulas (table 2) were prepared using wet granulation method like immediate release granule to achieve most acceptable pharmacopial requirements. After weighing the drug, polymer(s) and diluent enough to prepare 40 tablets in dried form, and then blend the ingredients using mortar and pestle, the powders were mixed with binding solution gradually until proper ball test consistency was resulted. The wet mass was screened through sieve (10 mesh) and dried in pre warmed oven at 60 ºC for one hour. The dried granules then reduced in size by screening them through 12 mesh size sieve. A known weight of granules equivalent to the stated dose was mixed with calculated amount of magnesium stearate, CabOSil and talc powder for five minutes. Table 2 : Different formulas of metoprolol granules as sustained release layer VV aa rr ii aa bb ll ee ff oo rr mm uu ll aa ss MM ee tt oo pp rr oo ll oo ll tt aa rr tt rr aa tt ee EE CC HH PP MM CC HH EE CC LL aa cc tt oo ss ee mm ii cc rr oo cc rr yy ss tt aa ll ll ii nn ee cc ee ll ll uu ll oo ss ee 11 00 %% aa ll cc oo hh oo ll ii cc ss tt aa rr cc hh pp aa ss tt ee PP oo ll yy vv ii nn yy ll pp yy rr rr oo ll ii dd oo nn ee MM gg SS tt ee aa rr aa tt ee CC aa bb OO SS ii ll TT aa ll cc TT oo tt aa ll LL aa yy ee rr WW tt mm gg EEffffeecctt ooff EECC FF11 70 70 172 35 1 1 1 350 FF22 70 140 102 35 1 1 1 350 FF33 70 210 32 35 1 1 1 350 EEffffeecctt ooff HHPPMMCC FF44 70 70 172 35 1 1 1 350 FF55 70 140 102 35 1 1 1 350 FF66 70 210 32 35 1 1 1 350 EEffffeecctt ooff HHEECC FF77 70 70 172 35 1 1 1 350 FF88 70 140 102 35 1 1 1 350 FF99 70 210 32 35 1 1 1 350 EEffffeecctt ooff EECC-- HHPPMMCC FF1100 70 70 70 102 35 1 1 1 350 FF1111 70 140 70 32 35 1 1 1 350 EEffffeecctt ooff EECC-- HHEECC FF1122 70 70 70 102 35 1 1 1 350 FF1133 70 140 70 32 35 1 1 1 350 DDiilluueenntt ttyyppee FF1144 70 140 70 32 35 1 1 1 350 BBiinnddeerr ttyyppee FF1155 70 140 70 32 35 1 1 1 350 Preparation of Metoprolol Bilayer Tablet The quantities of material required to produce the tablets were individually weighed. The SR layer was manually poured into the 10 mm die and was gently precompressed so that a flat surface was created. Then the other IR layer was poured into the die to create the second layer. The layered granules were then compressed to a specified maximum compression. Evaluation of Bilayer Tablet Disintegration Test The different formulas of IR layer were compressed alone at the same compression forced and their disintegration times were compared with the reference conventional tablet (Metoprolol 50 mg).The disintegration time was determined in 0.1N HCl (pH 1.2) (2) . Iraqi J Pharm Sci, Vol.19 (1) 2010 Metoprolol bilayer tablets 24 Friability Test This test was done for 20 tablets, starting by weighing them and then operating the friabilator at 25 rpm for 4 minutes, re- weighing the tablets to determine the loss in their weight (12) . Tensile Strength The tensile strength of five tablets of each prepared formula was determined from diametrical compression tests, which were performed using a universal hardness tester to measure the maximal diametrical crushing force (F) accurately. Together with the measured diameter (d) and thickness (t) of the tablets (by micrometer), the tensile strength (σ t) is then calculated according to the following equation (13) : dt F t   2  Uniformity of Dosage Units The content uniformity was performed for the prepared metoprolol bilayer tablet by taking five tablets and assayed individually. The requirement for this test is met if the amount of ingredient in each of the five tablets lies within the range of 90-110% of the label claim (14) . Dissolution behavior A suitable dissolution tests were carried out to demonstrate the appropriate release of metoprolol, the dissolution studies were carried out using the USP basket method at 37 ºC ± 0.5 ºC and rotation speed 100 rpm as follows (14) :- One tablet of each prepared formula was running out in a dissolution jar containing 900ml of 0.1 N HCl (pH 1.2) for two hours, then in 500ml of phosphate buffer (pH 6.8) for the rest of the experiment. Samples of 5ml were withdrawn at specific time intervals (first at 5, 10 and 15 min then at 1,2,3,4,5,6,7,8,9,10,11 and 12 hr), the volume of samples were replaced with the same buffer solution. Samples were filtered and diluted, analyzed using UV spectrophotometer at 223 nm, the procedure was triplicated for each run test. Some variables that affect the dissolution behavior had been studied like retardant polymer type, polymer concentration, polymer – polymer ratio, type of diluent, type of binder and pH of dissolution media (1.2, 4.6 and 6.8). Swelling and Erosion Study The swelling and erosion studies were performed for optimized formulation. Briefly, weighed tablets with watch glass [H1] and placed in dissolution vessel, containing 0.1 M hydrochloric acid for first 2 hr followed by 6.8 pH phosphate buffer for 4 hr using paddle method at stirring speed of 100 rpm. At selected time interval (1 to 6 hr) the tablets were withdrawn. The watch glass and tablets were blotted dry to remove water and weighed [H3]. The axial and radial swelling was measured using micrometer. The wetted tablets were dried in an oven at 110 °C for 24 hr, cooled and dried in a dessicator and finally weighed as dry weight [H2] (15) : The percent absorption was calculated as A%=100[H3-H2]/H2 The percent erosion was calculated as E%=100[H1-H2]/H1 Fourier Transform Infrared Studies (FT-IR) The FT-IR spectra of metoprolol tartrate, physical mixtures and granules of immediate release and sustained release layers were obtained after making potassium bromide discs in the range of 4000 cm -1 to 500 cm -1 to detect drug–excipients interaction, if any (16) . Statistical Analysis The results of the experiments are given as a mean of triplicate samples ± standard deviation and were analyzed according to the one way analysis of variance (ANOVA) at the level of (P < 0.05). Results and Discussion Evaluation of Bilayer Tablet Disintegration Test All the disintegration times of the prepared formulas are shown in table (3) are within the pharmacopial requirements but the IR3 is the closest one to the standard metoprolol tartrate 50 mg conventional tablet so it was used for the further bilayer formulation. Table (3) the disintegration time of the prepared immediate release (IR) layer Friability Test and Tensile Strength As shown in table (4), all the prepared formula had acceptable weight loss (not more than 1%) and high tensile strength this is mainly due to the composition of each layer. Microcrystalline cellulose used as diluent in the immediate release layer, is well known to FFoorrmmuullaass DDiissiinntteeggrraattiioonn ttiimmee ((mmiinn)) IIRR11 1166±±22 IIRR22 55±±22 IIRR33 ((1111±±11..55)) IIRR44 33±±11 IIRR55 33..55±±00..55 IIRR66 22..55±±00..55 SSttaannddaarrdd ttaabblleett ((MMeettoopprroollooll ttaarrttrraattee 5500mmgg ttaabblleett)) ((1100±±11)) Iraqi J Pharm Sci, Vol.19 (1) 2010 Metoprolol bilayer tablets 25 deform in a predominantly plastic manner which is a direct result of the presence of slip planes or dislocations and is thought to be an important factor affecting the compressibility of microcrystalline cellulose (17) and result in the consolidation of granules and increased intraparticulate bonding during compaction in addition to the homogenous distribution of bonds in the compact (18) . On the other hand, all the sustained release layers containing a considerable amount of the retarding polymer (20% to 60% of tablet weight) which improve the compressibility of the matrix and this elevated with increase the polymer concentration (19) . The formulas (F7, F8 and F9) have lower strength than that of other formulas this may be attributed to the better capability of the granulating solvent to dissolve the polymeric support of EC (and not to HEC), thus improving the strength properties of tablets (20) . Table (4) Physical properties of the prepared bilayered tablet Uniformity of Dosage Units Table (4) shows that, all the prepared formulas complied with the United State pharmacopial specification which is 90-110% of metporolol content in each individual tablet (14) . Variables Affecting the Dissolution Profile of Metoprolol Bilayer Tablets The Effect of Retarding Polymer Type The release of metoprolol from formulas F2, F5 and F8 which contain (1:2) drug: polymer ratio for EC, HPMC and HEC respectively is shown in figure (1). A significant difference (P < 0.05) was found among the cumulative amount of metoprolol released (after the first hour) with time depending on the nature of each polymer. EC is hydrophobic polymer and the drug release occurs by dissolution of the active ingredient through capillaries composed of interconnecting drug particle clusters and the pore network as drug release continues, the interconnecting clusters increase the pore network through which interior drug clusters can diffuse causing eventually rapture of the matrix system and rapid release (21) . HPMC and HEC are hydrophilic polymers on first contact of theirs matrix system with aqueous fluid rapid uptake of water occurs, chains gradually uncoil and extend but never form into linear coils, as the water content increases, the polymer becomes hydrated and the layer takes on the full characteristics of a gel. This is followed by retardation of water uptake by the rest of the tablet due to the formation of this gel layer. The major difference in the release profile of these two polymers due to the difference in the rate of hydration resulted from type of substitution on the cellulosic backbone (22) . 0 10 20 30 40 50 60 70 80 90 100 0 1 2 3 4 5 6 7 8 9 10 11 12 Time (hr) % M T R el ea se d F2 (EC) F5 (HPMC) F8 (HEC) pH 1.2 pH 6.8 Figure 1: The effect of polymer type at (1:2) drug: polymer ratio on the cumulative release of MT at 37 ºC. The Effect of Retarding Polymer Concentration The effect of polymer concentration on metoprolol release from the bilayer tablets was studied for each type of polymers and the result illustrated in the figure (2). Formulas F1, F2 and F3 were prepared utilizing EC at ratio FFoorrmmuullaass FFrriiaabbiilliittyy ((%%)) TTeennssiillee SSttrreennggtthh kkgg //ccmm 22 MMeettoopprroollooll ccoonntteenntt ((%%)) FF11 00..4455 1133..11 9999±±44..55 FF22 00..3388 1133..33 9933±±22..99 FF33 00..2255 1155..66 9977±±55..99 FF44 00..5511 1100..44 9999±±44..88 FF55 00..4444 1122..99 9988±±44..22 FF66 00..3355 1144..33 9955±±22..11 FF77 00..9900 55..99 9988±±44..99 FF88 00..7799 66..99 9955±±44..44 FF99 00..5511 77..66 9933±±22..22 FF1100 00..3377 1166..00 9955±±11..99 FF1111 00..2255 1166..44 9988±±44..22 FF1122 00..5577 1122..88 9922±±11..22 FF1133 00..5500 1133..55 9966±±55 FF1144 00..2200 1155..00 9933±±44..99 FF1155 00..1155 1177..44 9922±±33..55 Iraqi J Pharm Sci, Vol.19 (1) 2010 Metoprolol bilayer tablets 26 of 1, 2 and 3 (in respect to the metoprolol) respectively. The same ratios were used for HPMC in formulas F4, F5 and F6, and for HEC in formulas F7, F8 and F9 respectively. It appears that there is a significant difference (P < 0.05) in the release of metoprolol from matrices of EC (F 1-3), HPMC (F 4-6) and HEC (F 7-9) when the polymer concentration was increased. In case of EC the results can be attributed to the decrease in the porosity with a concomitant increase in the tortuosity of matrix (19) . The most important factor affecting the rate of release from hydrophilic matrices is the drug:polymer ratio. The increase in polymer concentration causes an increase in the viscosity of the gel and formation of a gel layer with a longer diffusional path leading to a decrease in the drug release (23) . EC polymer 0 10 20 30 40 50 60 70 80 90 100 0 1 2 3 4 5 6 7 8 Time (hr) % M T R e le a s e d F1 (1:1) F2 (1:2) F3 (1:3) pH 1.2 pH 6.8 HPMC polymer 0 10 20 30 40 50 60 70 80 90 100 0 1 2 3 4 5 6 7 8 9 10 11 12 Time (hr) % M T R e le a s e d F4 (1:1) F5 (1:2) F6 (1:3) pH 1.2 pH 6.8 HEC polymer 0 10 20 30 40 50 60 70 80 90 100 0 1 2 3 4 5 6 7 8 9 10 11 Time (hr) % M T R e le a s e F7 (1:1) F8 (1:2) F9 (1:3) pH 1.2 pH 6.8 Figure 2: The effect of varying drug:plymer ratio on the cumulative release of MT at 37ºC. The Effect of Polymer-Polymer Ratio Four formulas (F10, F11, F12 and F13) were prepared by mixing hydrophobic EC with HPMC and HEC (both hydrophilic polymer) in different ratios 1:1 and 2:1 and the result shown in figure (3).As shown in the figure (2) EC alone was not able to sustained the release of metoprolol beyond 6hr even with 60% of the polymer used (as in F3) in spite of excellent granular and tablet properties this is mainly due to high solubility of the metoprolol that lead to rapid ingress of water and loss the integrity of the matrix (24) . The use of hydrophilic matrix alone for extending drug release for highly water soluble drugs is restricted due to rapid diffusion of the dissolved drug through the hydrophilic gel network. For such drugs it becomes essential to include hydrophobic polymers in the matrix system (25) . So the mixing of hydrophobic with hydrophilic polymer to improve the retardant ability resulting in good release profile and the tablet integrity and dimensions were conserved for the period of the test. 0 10 20 30 40 50 60 70 80 90 100 0 1 2 3 4 5 6 7 8 9 10 11 12 Time (hr) % M T R e le a s e F10: EC:HPMC (1:1) F11: EC:HPMC (2:1) pH 6.8pH 1.2 0 10 20 30 40 50 60 70 80 90 100 0 1 2 3 4 5 6 7 8 9 10 11 12 Time (hr) % M T R e le a s e F12: EC:HEC (1:1) F13: EC:HEC (2:1) pH 6.8pH 1.2 Figure 3: The effect of EC: Hydrophilic polymer ratio on the on the cumulative release of MT at 37 ºC. Iraqi J Pharm Sci, Vol.19 (1) 2010 Metoprolol bilayer tablets 27                        100 0.5 n 1t 2 t T t R n 1 1log50 2 f The Effect of Diluent Type To study the effect of diluent, F11 which contain lactose as a diluent compared with the F14 which contain microcrystalline cellulose as in figure (4). Although both lactose and microcrystalline cellulose consider as hydrophilic filler, there was retardation in the release when changing from lactose to microcrystalline cellulose (from 84% to 75% at 8hr). This may be due to the high solubility of lactose so that it will act as channeling agent, permitting a rapid ingress of dissolution medium into the matrix tablets, thus facilitating drug release (26) . While the presence of a swelling, insoluble filler like microcrystalline cellulose changes the release profile due to a change in the rate of swelling at the tablet surface (27) . 0 10 20 30 40 50 60 70 80 90 100 0 1 2 3 4 5 6 7 8 9 10 11 12 Time (hr) % M T r e le a s e d F11 (Lactose) F14 (MCC) pH 1.2 pH 6.8 Figure 4: The effect of diluent type on the cumulative release of MT from formulas F11 (Lactose) and F14 (MCC) at 37 ºC. The Effect of Binder Type To study the effect of binder, F11 which contain starch as a binder compared with the F15 which contain polyvinylpyrrolidone (PVP) as in figure (5). It was seen that slight retardation in the release of metoprolol from matrix when the starch was replaced by PVP (from 84% to 77% at 8hr). It was hypothesized that this may have been resulted from a change in the properties of the ‘pseudo-gel layer’ surrounding the tablet, which controls the drug release rate through intimate mixing during hydration of the dosage form and through the formation of strong hydrogen bonds between PVP and HPMC (28) . The Effect of the pH of the Dissolution Media Three tablets of F11 were running out separately in dissolution jars containing 900ml of pH 1.2, 4.6 and 6.8 the procedure was triplicated for each run test and the result of the drug released compared with that obtained normally (2 hr at pH 1.2 then at 6.8) as in figure (6). There was no significance differences (P> 0.05) among the release of metoprolol at different pH media this mainly due to two reasons. First, the metoprolol is highly soluble drug and its solubility dose not affected by the pH (29) . Second, the mechanism of the drug release is by swelling the polymer to form barrier gel that resist the diffusion and the HPMC swelling property not affected by the pH of the media (22) . 0 10 20 30 40 50 60 70 80 90 100 0 1 2 3 4 5 6 7 8 9 10 11 12 Time (hr) % M T R e la s e d F11 (Starch) F15 (PVP) pH 1.2 pH 6.8 Figure 5: The effect of binder type on the cumulative release of MT from formulas F11 (Starch) and F15 (PVP) at 37 ºC. 0 10 20 30 40 50 60 70 80 90 0 1 2 3 4 5 6 Time (hr) % R e le a s e d F11 (2hr at pH 1.2 then 6.8) F11 (at pH 1.2) F11 (at pH 4.6) F11 (at pH 6.8) Figure 6: The effect of pH variation on the total amount of metoprolol release at 37 ºC. Selection of the Best Formula To select the most promised formula in this study, reference product equivalent to 100 mg of metoprolol as a sustained release tablet (Metoprolol Ratiopharm® 100 sustained release) was utilized as a standard one, this was carried out using similarity factor (f 2) introduced by Moore and Flanner as shown in equation (3). A difference not exceeding 10% at any sampling time point between reference and test products may be acceptable and f 2 value of 50-100 indicates similarity in the dissolution profiles (30) : …… (3) Iraqi J Pharm Sci, Vol.19 (1) 2010 Metoprolol bilayer tablets 28 Where n is the number of dissolution time points, Rt and Tt are the reference and test dissolution values at time t. F15 (which contain EC:HPMC in ratio of 2:1 and PVP as a binder) showed higher (f 2) among all other formulas and equals to 72.3 as shown in figure(7). 0 10 20 30 40 50 60 70 80 90 100 0 1 2 3 4 5 6 7 8 9 Time (hr) % M T R e le a s e d F15 ST pH 1.2 pH 6.8 Figure 7: The dissolution profile of selected formula F15 versus reference standard (ST) with (f ¬2¬) =72.3 at 37 ºC. Swelling and Erosion Swelling and erosion had been studied to the best formula F15 and the result shown in figure (8) revealed that the tablets were swollen and retained their physical integrity till the end. Although there is an increase in both percentage water absorbed and percentage erosion of the tablet, but the percentage water absorbed was more dominant than erosion indicating that the release was biphasic mechanism mainly by diffusion than erosion (31) . 0.00 0.50 1.00 1.50 2.00 2.50 3.00 3.50 4.00 1 2 3 4 5 6 Time hr % S w e ll in g 0.00 0.50 1.00 1.50 2.00 2.50 % E ro s io n Swelling Erosion pH 1.2 pH 6.8 Figure 8: Swelling-eroding behavior of optimized selected formula F15. FT-IR Studies The FT-IR spectra of metoprolol tartrate, physical mixtures and granules of immediate release and sustained release layers are shown in figures (9) and (10). The O-H stretching vibration peak of metoprolol is seen in 3458 cm -1 and the C-N peak is seen at 2872 cm -1, N-H bending vibration at 1590 cm -1, at 1112 cm -1 the C-O stretching bond, at 1458 cm -1 the C=C, and at 1244 cm -1 the C-O stretching bond are obvious (32). Similar peaks are observed in the corresponding physical mixture and granules. Furthermore, the broadening of O-H stretching vibration peak mainly due to hydrogen bonding of the drug with the polymers and other excipients, also the absence of significant shifts in the wave numbers of the IR peaks of the granules compared with physical mixture indicates lack the possibility of interaction between metoprolol tartrate and excipients used in this bilayer tablets (16) . Figure 9: FT-IR spectra of Metoprolol, physical mixture and granules of the IR layer. Iraqi J Pharm Sci, Vol.19 (1) 2010 Metoprolol bilayer tablets 29 Figure 10: FT-IR spectra of Metoprolol, physical mixture and granules of the SR layer. References 1. Remington: The science and practice of pharmacy, 21 st ed., Lippincot, Williams, & Wilkins; U.S.A, (2006), 889. 2. British Pharmacopoeia BP (CD). The stationary office, Crown copyright, London, (2009). 3. 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