ISSN: Original Article Compression and mechanical properties of paracetamol tablets formulated with co-processed goat fat as lubricant

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1 Available online at International Journal of Pharmacy and Pharmaceutical Science Research Universal Research Publications. All rights reserved ISSN: Original Article Compression and mechanical properties of paracetamol tablets formulated with co-processed goat fat as lubricant Stephen Olaribigbe Majekodunmi* and Emem Bokime Matthew Department of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmacy, University of Uyo, Uyo, Nigeria. * Received 22 July 2014; accepted 08 August 2014 Abstract AIM: The lubricant activity of goat fat coprocessed with magnesium stearate plus talc (GMT) was compared with magnesium stearate plus talc (MT) using compressional characteristics of paracetamol granules and mechanical properties of their tablets as assessment parameters. METHOD: Granules were lubricated with different concentrations of 0.5% w / w, 1.5% w / w, 2.0% w / w and 2.5% w / w of the co-processed lubricant of goat fat, magnesium stearate and talc (GMT) and combination of magnesium stearate and talc (MT) and without lubricant in a paracetamol tablet formulation. RESULTS: Compressional characteristics analyzed using density measurement and the Heckel and Kawakita plots revealed that GMT did not facilitate the increase in the densification of the granules during the filling and at low pressures, D b. Also, GMT reduced the plastic deformation of the granules measured by the Py-yield pressure of deformation under compression. The mechanical properties determined by the tensile strength, T, and brittle fracture index, BFI, of the tablets produced were affected by GMT. The T and BFI of tablets with GMT were lower than those of MT. The results suggest that though GMT lowered the plasticity of the granules, it improved their flow rate and assisted in producing tablets with fewer tendencies to cap or laminate. CONCLUSION: This work concluded that goat fat, an expensive and easily available lipid, is an effective and viable lubricant that can be co-processed with magnesium stearate/talc for an effective lubrication of granules and may be useful in reducing lamination and capping in formulations that are susceptible to these two defects of tablets Universal Research Publications. All rights reserved Keywords: Goat fat, magnesium stearate, Heckel plot, Kawakita plot, tensile strength, brittle. 1. INTRODUCTION A lubricant, an additive to reduce friction, is an essential component of a drug formula since lubrication is often required to ensure the success of pharmaceutical manufacturing. Historically, use of animal fats as lubricants to reduce friction in transportation can be traced back to Egyptian time. However, the development of modern tribology, which is the study of friction and lubrication, did not gain ground until Frank P. Bowden established a research laboratory on friction, lubrication, and bearings in Melbourne, Australia during World War II [1]. Since then, a systematic study on friction and lubrication, termed tribology, was initiated. In particular, in the pharmaceutical industry, the application of lubrication or tribology in drug development has become increasingly important for developing a successful manufacturing process [2]. For pharmaceutical operations such as blending, roller compaction, tablet manufacturing, and capsulefilling, lubrication is essential in order to reduce the friction between the surfaces of manufacturing equipment and that of organic solids as well as to ensure the continuation of an operation [3]. Pharmaceutical lubricants are the agents added to tablet and capsule formulations in a very small quantity (usually 0.25% 5.0%, w / w ) to improve the powder processing properties of formulations. Albeit a fairly small amount, lubricants also play important roles in manufacturing; they decrease friction at the interface between a tablet s surface and the die wall during ejection so that the wear on punches and dies are reduced; they prevent sticking of tablets to punch faces as well as sticking of capsules to dosators and tamping pins. In terms of powder flow, lubricants can improve the flowability of blends and aid unit operations. For instance, for the blending of active pharmaceutical ingredients (APIs) of small particles with other excipients, the adhesion force between particles can significantly reduce the powder flowability by increasing inter-particle friction; poor flow can cause insufficient mixing of the blends (content uniformity) and rat-holing in the hopper of a tablet press (segregation issue), impacting both product quality and operation. To overcome these issues, lubricants are added (glidants) to enhance powder flow by reducing the inter- 53

2 particle friction. Regarding lubrication agents, although magnesium stearate and stearic acid are the most frequently used lubricants in the pharmaceutical industry, there are other lubricants in use as well [4]. The flowability of blends in pharmaceutical operations is critical for the success of manufacturing. Since the addition of magnesium stearate in a formulation generally improves the flowability of the formulation, it is often used as a flow agent. The flowability of a blend is typically assessed by measuring the following parameters: static angle of repose, Carr index, Hausner ratio, and the flow-function obtained from a shear-cell measurement [5]. Of these parameters, the flow-function is the most useful parameter for assessing blend flowability, but other parameters are often used because of their simplicity. In general, the flowability of a blend is affected by many factors: the type of lubricant, the interaction of the lubricant with other materials, lubricant concentration, and mixing time. For example, relative to other lubricants including magnesium silicate, calcium stearate, and stearic acid, magnesium stearate is the most effective lubricant in improving the flowability of lactose even with a small amount [6]. This is because the particles of magnesium stearate preferentially interact with lactose particles and fill the surface cavities of these particles. The impact of magnesium stearate on the flowability of a blend also depends on the material nature of the blend. For instance, for a free-flow blend, the effect of the lubricant on the blend flowability is not significant. However, as the blend becomes more cohesive, the presence of lubricant greatly improves its flowability [7]. Goat fat, obtained from goats (Capra hircus), is a cheap and readily available semisolid fatty substance because hundreds of goats are on daily basis slaughtered in Nigeria, Goat fat contains lipid-oily and fatty substancesby their nature exert lubricity over surfaces encountered with. It is therefore that when applied in carefully regulated amount they will improve the lubrication efficiency in lubricants used in tableting. Majekodunmi and Matthew [5] discovered that the use of goat fat as co-processed lubricant with magnesium stearate and talc in the formulation of paracetamol tablets has shown that goat fat enhances the disintegrating, packaging and flow properties of the paracetamol granules. In this present work, Goat fat is co-processed with 50:50 mixture of magnesium stearate and talc. using the compression and mechanical properties of a paracetamol tablet formulation as assessment parameters. In analyzing the compression data, the compression equations of Heckel [8] `and Kawakita and Ludde [9] were used. Tensile strength and brittle fracture index (BFI), which are two measures of mechanical properties of tablets, were used for the evaluation of tablet mechanical properties. The Heckel equation is widely used for relating the relative density, D, of a powder bed during compression to the applied pressure, P. It is written as: Ln (I/I-D) KP + A (1) The slope of the straight line portion, K, is the reciprocal of the mean yield pressure, P, of the material. From the value of A the intercept, the relative density, D a, can be calculated using the following equation [10]. D a = I e -A (2) The relative density of the powder at the point when the applied pressure equals zero, D o is used to describe the initial rearrangement phase of densification as a result of die filling. The relative density, D b describe the phase of rearrangement at low pressures and it is difference between D a and D b. i.e. D b = D b - D o (3) The Kawakita equation is used to study powder compression and the degree of volume reduction, C. It is written as: C = V o V p /V o = abp/1 + bp (4) The equation in practice can be rearranged to give P/C = P/a + 1/ab, where Vo is the initial bulk volume for granular materials and Vp is the bulk volume after compression. The constant a is equal to the minimum porosity of the material before compression while the constant b is related to the plasticity of the material. The reciprocal of b gives a pressure term, P k, which is the pressure required to reduce the powder bed by 50% [11], [12]. Both the Heckel and Kawakita plots have their limitations and are believed to generally exhibit linearity at high and low pressures, respectively [13]. Bond strength and lamination tendency are two important mechanical properties of tablets, which are measurable by tensile strength and brittle fracture index (BFI) values, respectively [14]. The BFI was devised by [15]. It is obtained by comparing the tensile strength of tablets with a hole at their center, which acts as a built in stress concentration defect, with the tensile strength of tablets without a hole. The BFI is defined as: BFI = 0.5 (T/T o ) 1 (5) Where T is the tensile strength of the tablet without a hole and T o is the apparent tensile strength of the tablet when a hole is present both at same relative density. The BFI is a measure of localized stress relief within the tablet (at the edge of the hole) by plastic deformation. A low value of the BFI indicates the ability of the material to relieve localized stresses while a value approaching unity indicates a tendency of the material to laminate or cap. 2. MATERIALS AND METHODS 2.1 Materials The materials used were paracetamol powder BP, corn starch BP (BDH Chemicals Ltd, poole, UK), Lactose BP (AB Knight and Co., London, UK), Goat (Capra hircus), fat obtained from slaughtered in Uyo, Magnesium stearate and Talc; Acetone (BDH Chemicals Ltd; Poole, UK) and 95% Ethanol (Aldrich Laborchemickalien GMBH, Seelze, Germany. 2.2 METHODS Preparation of processed powdered lubricant mixture Equal amounts of magnesium stearate and talc were triturated together using a porcelain mortar and pestle for a period of 5 min to ensure a uniform mixing of the two powders (lubricants). The mixture was sieved using mesh 54

3 100 (150 μm) sieve and then stored in a screw-capped bottle until needed. Goat fat was co processed with MT as reported earlier [5], i.e. goat fat weighing 1.20 g, was placed inside a beaker containing 250 ml of 95% ethanol. This was then placed in a water bath set at 600C, to allow the melting and dissolving of goat fat in the ethanol. Magnesium stearate talc mixture (MT) weighing 38.8 g was added and mixed with the ethanolic solution of cocoa butter in the beaker. The mixture (GMT) was placed in the dessicator for 72 h to allow for the ethanol to evaporate off. The remaining mix contains 3.0% w / w of goat fat in the total mixture (this % w / w is the optimum concentration obtained in the preliminary studies). The processed powdered lubricant mixture was then stored in a screw capped bottle until ready for use Preparation of granules The wet granulation method of massing and screening was used. A 1500 g batch of formulation of paracetamol (85 % w / w ), corn starch (5 % w / w ) and lactose (10 % w / w ) was dry mixed in a Hobart planetary mixer (Hobart Canada Inc., Don Mill, ON, Canada). This was moistened with the appropriate amount of starch binder. Massing was continued for 5 min and the wet mass was granulated using a sieve size 16 (1000 μm) attached to an Erweka (Model AR 400) granulator (Erweka Apparatebau GmbH, GmbH Heusenstammkr. Offebach, Main, Germany). The resulting granulation was then dried in a hot air oven (P-Selecta , China). (Capra hircus), The dried granulation was screened through a mesh 16 (1000 μm) to produce the required uniform size of granules. The granules obtained were then divided into 13 equal parts before addition of lubricant into each part [13, [14] Addition of lubricants to the granules The lubricant was not added to the first part of the granulation which serves as control sample, while granulations in parts 2-7 were mixed with different concentrations (0.5 % w / w, 1.0 % w / w, 1.5 % w / w, 2.0 % w / w, 2. 5 % w / w and 3.0 % w / w ) of magnesium stearate talc (MT) lubricant mixture to produce the respective batches (2 7) [5]. The bottles containing the lubricated mixtures were then gently shaken for ten minutes to ensure proper mixing. The same method was used for adding goat fat treated magnesium stearate plus talc (GMT) to granulation parts 8-13 to produces batches Granular density of each batch was determined by the pycnometer method with acetone as displacement fluid Preparation of tablets Quantities (550mg) of granules from each batch were compressed into tablets with three predetermined loads (25, 50 and 75 Kpcm-2) using a manesty F3 single punch tableting machine (Model SSF-3, Cadmach Machine Co. PVI. Ltd., India) rotatory with a 10.5 mm die and flatfaced punch assembly. A set of tablets was produced from each pressure. After ejection, the tablets were stored in airtight containers to allow for elastic recovery and hardening, and prevent falsely low yield values before the tablets were subjected to analysis. Their weight (w) and dimension were then determined to be within ± 0.01 mg and 0.01mm respectively, and their relative density (RD) was calculated using the equation: RD = m/vtρs (6) where Vt is the volume (cm3) of the tablet and ρs is the particle density ( ) of solid material. The volume reduction, which increased with the successive increase in the compression pressure, led to variablerelative density. Heckel plots of ln (1/1-D) vs applied pressure (P) and Kawakita plots P/C vs P were constructed for all batches Determination of mechanical properties The tensile strength of the normal tablets (T) and of apparent tensile strength (T O ) fo those containing a hole, were determined at room temperature by diametral compression (Fell and Newton, 1970) using a Monsanto hardness tester (Monsanto Chemical Corp) and by applying the equation: T = 2F Πdt (7) Where T (or T o ) is the tensile strength of the tablet (MNm - 2 ), F is the load (MN) needed to cause fracture, d is the tablet diameter (m), and t is tablet thickness. Results were taken from tablets, which split cleanly in to 2 halves without any sign of lamination. All measurements were measured in triplicate or more and the results given are the means of several determinations. The BFI of the tablets were calculated using equation D = w/v 1 σ s STATISTICAL ANALYSIS Statistical analysis was done using one way ANOVA followed by Duncan s test. The other data were evaluated using Graph Pad Prism software. Data were expressed as mean ± SD. A p-value < 0.05 was considered significant 3.0 RESULTS AND DISCUSSION Figure 1 in this work shows representative Heckel plots for paracetamol granules containing 0% w / w and 2% w / w of each of the lubricants. Two phases of compression are discerning in the plots with the second phase commencing approximately at Mnm -2. Values of mean yield pressure, P y, were calculated from the region of the plots showing the highest correlation coefficient for linearity of > for all the batches (generally between and MNm-2). The intercept, A, was determined from extrapolation of the region for the calculation of Py; the values of Da and Db were calculated from equations 2 and 3, respectively. The values of Py, Do, Da and Db for all the starches are presented in Table 1. The values of D o for the various batches increased with increase in lubricant concentration, implying that the initial packing of the granules in the die as a result of the die filling increased with increase in lubricant concentration, which would facilitate more packing due to reduction in intragranular friction. It can be observed that the Do values for the granules containing GMT were higher than those for the granules with MT, showing that the GMT facilitated a higher initial packing of the granules in the die in the presence of goat fat. Db represents the phase of rearrangement of particles at low pressure. It can be observed that the Db values for the granules with GMT were relatively lower than those for the granules with MT. This suggests more 55

4 Table 1: Parameters obtained from density measurements and from Heckel and Kawakita plots for the paracetamol tablets formulation Concentr P Lubricant ation D y P o (% w MNm -2 D a D b D k i MNm -2 / w ) None ± ± ± ±0.16 Magnesium stearate + talc Goat fat + magnesium stearate + talc ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ±0.13 Fig. 1: Heckel plots for granulation containing 0.0% w / w and 2.0 w / w -MT and GM fragmentation of granules with MT at low pressure than for granules with GMT and subsequent filling of void spaces between the particles [16], [17]. These values are also found to be increasing with increase in lubricant for the granules. This implies that with increase in concentration, the lubricants would facilitate more packing of granules in the die and increase inter-granular contact at low pressures. The values of Da represent the total degree of packing achieved at zero pressure. The values at low pressures are higher for granules with MT than those with GMT. These values are seen to increase with increase in lubricant concentration. The mean yield pressure, Py, is inversely related to the ability of a material to deform plastically under pressure. The values of Py for the batches with GMT were higher than for those with MT. This implies that the onset of plastic deformation in the granules with GMT occurred at higher pressures. The values of Py for granules treated with MT generally increased in lubricant concentration, while for granules with GMT, a decrease was initially observed up to 2.0% w / w lubricant concentration before an increase was observed. This observation for GMT-treated granules could be due to the fact that goat fat, a semi-solid fat, will enhance the chances of the granules to undergo the 56

5 Fig. 2 Kawakita plots for granulations containing 0.0% w / w and 2.0% w / w lubricant of MT and GMT Table 2: Tensile strength and brittle fracture index values for paracetamol tablets at a relative density of 0.90 Lubricant Concentration (% w / w ) Tensile strength (MNm-2) Brittle fracture index None Magnesium stearate + talc Goat fat + magnesium stearate + talc Fig. 3: Log tensile strength versus relative density for paracetamol tablets containing 0.0 % w / w, ( ), 1.5% w / w and 2.5% w / w lubricant-mt ( ), GMT ( ); with hole, (.) and without a hole (---). 57

6 mechanism of powder consolidation relating to asperitic melting of the local surfaces of particles, particularly at higher compressional loads. This consolidation could be responsible for the increase in Py at higher lubricant concentration for GMT-treated granules. However, the Py value of the base granulation is comparable to what would be expected from an 85% w / w formulation of paracetamol. The Py of pure paracetamol was reported by [18], [19] to be 96.9 and 110 MNm -2 Figure 2 shows representative Kawakita plots for paracetamol granules containing 9% w / w and 2% w / w of each of the lubricants. A linear relationship was obtained at all compression pressures used with a correlation coefficient of for all the batches, thus, the Kawakita equation was used to predict the densification mechanism of the paracetamol granules. Values of a and ab were obtained from the slope and intercept of the plots, respectively. Values of Di give the initial relative density of the batches, while Pk values were obtained from the reciprocal of values of b. The values of Di and Pk are included in Table 2. The Di values increased with increase in lubricant concentration, with Di values for the batches treated with GMT being higher than those for the batches with MT. The Di values are also seen to be higher than the values of Do. Bearing in mind that the methods of determination of Do and D1 have their limitations [13], [16], the differences in the values of Do and Di are probably due to the fact that while Do describes the loose initial relative density of the batches due to die filling, Di provides a measure of the packed initial relative density of the batches with the application of small pressure or what may be referred to as tapping of the granules [20]. Low values of Pk indicate materials that are soft and that readily deform under pressure. Table 2 shows that the values of Pk for the batches initially decreased with increase in lubricant concentration up to 1.5% w / w, but increased from 2.0% w / w lubricant concentration. This suggests that there is a limit to which inclusion of lubricant in the granules could assist in increasing deformation under load. The values of Pk for the batches treated with GMT are higher than those treated with MT. This indicates that the inclusion of goat fat in the lubricant mix did not necessarily increase the softness of the granulation and its ability to deform plastically under pressure more than those containing MT. The influence of the type and concentration of lubricant does not appear to be clear-cut in these results. Alebiowu and Itiola [16] have shown that Py is different from Pk in that while the Py value relates essentially to the onset of plastic deformation during compression, the Pk value appears to relate to the total amount of plastic deformation occurring during the compression process. Thus, the present results suggest that the use of GMT would not necessarily facilitate the onset of plastic flow and improve the total amount of plastic flow in the paracetamol granules when compared with the use of MT. The results of the tensile strength tests on the paracetamol tablets were found to fit the general equation: Log T (or To) = AD + B (8) With a correlation coefficient of > A and B were constants, which depend on the nature and concentration of binder present in the formulation and on whether the tablet had a hole in it or not. Representative plots for tablets made from batches containing 0.0% w / w and 2.0 % w / w of lubricants are presented in Figure 3. It can be seen that at all relative densities the tensile strength of a tablet with a hole was less than that of the same without a hole, the hole acting as a stress concentrator [15], [21]. Values of T and BFI for all batches at D = 0.90, which is representative of commercial paracetamol tablets, are presented in Table 3. It can be seen that the values of T generally increased with increase in lubricant concentration for tablets containing GMT having the lowest BFI value. It could be due to the presence of goat fat, which, being a semisolid fat, would assist in melting of the asperities due to the heat produced during compression. On cooling, those asperities would solidify to form solid bonds between the particles [22]. With increase in lubricant concentration, these facilitated solid bonds would assist in increasing reduction in the lamination and capping tendency of the GMT tablets on ejection from the die. It can also be observed that at all lubricant concentration; tablets containing GMT generally have lower T values than tablets with MT. This could be due to the higher amount of plastic deformation occurring at both the onset of compression, Py, and during the compression process, Pk, for MT-treated granules. The tensile strength and BFI results suggest that paracetamol tablets containing GMT could be a more useful lubricant than MT when problems of lamination and capping are of more importance than bond strength, especially on high speed tableting machines with short dwell time for the plastic deformation of materials. 4.0 CONCLUSIONS The results of the present work conclude that goat fat co-processed with MT would: 1-Enhance the packing and flow properties of the paracetamol granules. 2-Increase both the loose relative density (i.e. Do) and packed relative density (i.e. D i ) of the granules in the die. 3-Not necessarily increase the plasticity of the granulation as shown in the values of P y onset of plastic deformation during compression, which were higher for the granules containing GMT than for those containing MT. 4-Not assist in increasing the bonding strength of the paracetamol tablets, but facilitate the reduction in the capping and lamination tendency of the tablets. 5-Goat fat, an inexpensive and easily available lipid, is an effective lubrication which can be useful in reducing lamination and capping in formulations that are susceptible to these two defects of tablets 5.0 REFERENCES 1. 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