Acta Poloniae Pharmaceutica ñ Drug Research, Vol. 64 No. 1 pp. 73ñ79, 2007 ISSN 0001-6837 Polish Pharmaceutical Society A COMPARATIVE STUDY OF THE DISSOLUTION CHARACTERISTICS OF CAPSULE AND TABLET DOSAGE FORMS OF MELT GRANULATIONS OF PARACETAMOL ñ DILUENT EFFECTS MICHAEL U. UHUMWANGHO* and ROLAND S. OKOR Department of Pharmaceutics, University of Benin, Benin City, Nigeria Abstract: The dissolution characteristics of melt granulations of paracetamol in capsule and tablet dosage form were compared to determine whether the dissolution characteristics of the granules can be actualized by formulating them as rapidly disintegrating tablets. The term melt granulation refers here to the wax-matrix granules that were formed by triturating the drug powder (paracetamol) with a melted carnauba wax. The matrix granules were admixed with diluents (lactose, α-cellulose or microcrystalline cellulose) also in granular form to prevent size separation during encapsulation or tableting. The granules were filled into hard gelatin capsules (mean content weight, 500 ± 6.2 mg) or tableted (mean weight 500 ± 5.1 mg, and tensile strength 1.36 ± 0.2 to 1.7 ± 0.3 MN/m 2 ). The capsules and tablets were subjected to disintegration and in vitro dissolution tests. The dissolution data were analyzed on the basis of zero, first order rate kinetics and Higuchi square root of time relationship. The results showed that the dissolution profiles were generally consistent with a first order rate kinetics (r = 0.95). The first order dissolution rate constants of capsules and tablets of the matrix granules only (without diluents) were 0.31 ± 0.02 min -1 and 0.20 ± 0.03 min -1, respectively, indicating faster dissolution from the capsules. Therefore, the dissolution characteristics of the matrix particles were not intact after tableting. Addition of diluents to the capsule formulations had no effect on dissolution rates, whereas in the tablets, dissolution rates increased. For instance, inclusion of a diluent up to 50% w/w in the tablets increased the dissolution rate constants to 0.34 ± 0.04 min -1 (lactose), 0.42 ± 0.02 min -1 (α-cellulose), and 0.46 ± 0.03 min -1 (microcrystalline cellulose). Thus, α-cellulose and microcrystalline cellulose produced greater enhancer effect on the tablet dissolution rates compared to lactose. Both the capsules and the tablets disintegrated rapidly within 2 to 3 minutes. The dissolution enhancer effect of the diluents in the tablets only, relates to the aqueous swelling of the disintegrated particles. Keywords: melt granulations, matrix granules, sustained release, dissolution rates, tablets, capsules. Sustained-release dosage forms either as capsules or tablets provide a constant therapeutic plasma level of the drug, with less frequent administration and hence, improve patient compliance during medication. Such prolonged action dosage forms are particularly useful in the management of chronic illnesses such as hypertension, diabetes and schizophrenia. In the preparation of sustained release dosage forms drug particles (usually pellets) are coated with polymer film which serve as a barrier to drug release. The acrylate/methacrylate copolymers (1-4) and ethyl cellulose (5-10) have been frequently employed for this purpose. However, the requirement for organic solvents in the microencapsulation makes the procedure expensive and also harmful to the environment. A simpler and less expensive procedure for retarding drug release from particles is by a process of melt granulation, whereby the drug powder is triturated with a melted wax followed by screening through sieves of mesh aperture size 710 µm (11-16). The resulting granules are non-disintegrating in aqueous fluids because of the hydrophobic nature of the wax, in which the drug particles are dispersed. Hence, the term wax-matrix granules have been applied here to the granules. Examples of waxes that have been employed in the melt granulation procedure include glycerol monooleate, glyceryl monostearate, carnauba wax (17) and more recently goat fat (16). Carnauba wax is superior to the other waxes in producing less sticky masses thus promoting free flow of resulting granules. These matrix granules may be encapsulated or tableted for sustained release application. In the latter case (i.e. the tablets) the problem to be envisaged is the deformation and cohesion of the particles during compression, such that the matrix particles are not liberated intact following disintegration of the tablet in aqueous fluids. The implication is that the individual dissolution characteristics of the matrix particles will be impaired. This problem may be ameliorated by inclusion of diluent excipients acting as interspersing agent to minimize * Corresponding author: e-mail: mike2003u@yahoo.com (M.U. Uhumwangho), telephone +234-8052057767 +234-8066446552 73
74 MICHAEL U. UHUMWANGHO direct contact between the matrix particles during compaction and thereby liberate the particles intact after disintegration of the tablet in an aqueous medium. To give an indication whether or not the wax-matrix particles were deformed during tableting (which will impair their individual release characteristic), we have in this study compared the dissolution characteristics of the matrix particles in capsules (where there will be no particle deformation) to tablets (where the particles will deform during compaction). The influence of various diluents (lactose, α-cellulose and microcrystalline cellulose) on the dissolution characteristics of the capsules and the tablets was investigated, as this will reflect their ability to prevent or minimize deformation to the matrix particles during tableting. EXPERIMENTAL Materials Carnauba wax (Halewood Chemicals Ltd, England) is a fine waxy solid with melting point of 82 ñ 88 O C, yellowish in color and was used as the matrix former. Maize starch (BDH Chemicals, Poole, UK) was used as binder (20% w/w) in the form of mucilage and as disintegrant (5% w/w) as dried powder, while magnesium stearate (Sakai Chem Co., Japan) was used as a lubricant at a concentration of 0.5% w/w in the tablet formulations. Paracetamol powder (BDH Chemicals, Poole, UK) was selected as the test drug, because of its ease of assay by spectrophotometric methods. Lactose powder (BDH Chemicals, Poole, UK), microcrystalline cellulose (FMC Corporation, Philadelphia, PA) and α- cellulose locally obtained by alkali digestion of maize cob (18, 19) were the test diluents. Melt granulation technique The wax material (20 g) was melted in a stainless steel container in a water bath at temperature higher than the melting point of the wax material (i.e. 90 O C). A sample of the paracetamol powder (80 g) was then added to the melted wax and mixed well with a glass rod, then allowed to cool to room temperature (30 O C). The mass was pressed through a sieve of mesh 10 (aperture size; 710 µm) to produce the matrix granules. The term matrix indicates that the granules will not disintegrate to smaller particles in aqueous fluids. Granules of the diluents were produced by a wet granulation technique using starch mucilage (20% w/v) as binder. The wet mass was screened and dried on a tray in a hot air oven (Kottermann, Germany) at 50 C for 2 h. The granules produced by melt granulation technique were then admixed with granules of the diluents in different proportions as shown in Table 1. The diluents were also granulated to prevent size separation during compression to tablets or filling into capsules. Encapsulation Samples of the matrix granules or their admixtures with the diluents (500 mg) were filled manually into plain hard gelatin capsules. The capsules were kept in air-tight containers before their use in disintegration and dissolution tests. Tableting The granules or their admixtures with the different diluents were compressed using a single punch Figure 1. Comparison of the dissolution profiles from the capsules ( ) and the tablets ( ),without diluent Table 1. Composition of matrix granule of paracetamol and their admixtures with the diluent granules. Matrix granules (g) Diluent (g) Proportion Drug content of diluent (%) (mg/500 mg sample) 100 0 0 400 80 20 20 320 60 40 40 240 50 50 50 200 40 60 60 160 20 80 80 80 Note: The matrix granules consisted of the drug and wax in the ratio 4 : 1.
A comparative study of the dissolution characteristics of capsule... 75 Figure 2. Effect of lactose on the dissolution profiles of the tablets, lactose content: 0% (o), 20% ( ), 40% ( ), 50% ( ) 60% ( ), 80% ( ). Note: The dissolution profiles of the capsules were independent of lactose content. Figure 3. Effect of α-cellulose on the dissolution profiles of the tablets, α-cellulose content: 0% (o), 20% ( ), 40% ( ), 50% ( ) 60% ( ), 80% ( ). Note: The dissolution profiles of the capsules were independent of α-cellulose content.
76 MICHAEL U. UHUMWANGHO Figure 4. Effect of microcrystalline cellulose on the dissolution profiles of the tablets, microcrystalline cellulose content: 0% (o), 20% ( ), 40% ( ), 50% ( ) 60% ( ), 80% ( ). Note: The dissolution profiles of the capsules were independent of microcrystalline cellulose content. Table 2. Influence of diluents on tablet hardness. Diluent Tensile strength (MN/m 2 ) of tablets with diluents content (%) Lactose α-cellulose Microcrystalline cellulose 0 1.74 ± 0.3 1.74 ± 0.3 1.74 ± 0.3 20 1.69 ± 0.2 1.70 ± 0.2 1.70 ± 0.4 40 1.68 ± 0.3 1.68 ± 0.4 1.72 ± 0.2 50 1.61 ± 0.4 1.64 ± 0.1 1.70 ± 0.1 60 1.46 ± 0.1 1.56 ± 0.2 1.69 ± 0.2 80 1.36 ± 0.2 1.50 ± 0.3 1.66 ± 0.2 Table 3. Influence of diluents on tablet dissolution rate constants (k 1 ) of the tablets. Diluent k 1 values (min -1 ) content (%) Lactose α-cellulose Microcrystalline cellulose 0 0.20 0.20 0.20 20 0.24 0.28 0.27 40 0.29 0.34 0.36 50 0.34 0.42 0.46 60 0.44 0.53 0.55 80 0.51 0.68 0.71
A comparative study of the dissolution characteristics of capsule... 77 tableting machine (Type F 3, manesty Poole, England) at constant load (30 arbitrary units on the load scale) to form flat faced tablets of 12.5 mm diameter, 3.36 mm thickness, and 500 mg weight. The tablets were compressed to a tensile strength value of between 1.36 ± 0.2 to 1.7 ± 0.3 MN/m 2 and packing fraction, 0.93 ± 0.06. Immediately prior to compression of the granules, magnesium stearate (0.5% w/w) and dried maize starch powder (5% w/w) were added. Tablet tensile strength (T) This is the stress needed to fracture a tablet by diametral compression. It is given by (20) as: T = 2P/πDt (1) where P is the fracture load that causes tensile failure of a tablet of diameter, D and thickness, t. The fracture loads (Kg) of ten tablets were determined individually with the Monsanto hardness tester, following Brook and Marshall (21). The mean values of the fracture loads were used to calculate T values for the various tablets. Disintegration test (DT) The method described in the British Pharmacopoeia BP (22) was followed using water maintained at 37 C as the disintegration fluid. Six tablets or capsules were used in each determination, which was carried out in triplicate and the mean results are reported. Dissolution test A filled capsule shell or tablet was placed in a cylindrical basket (aperture size 425 µm, diameter 20 mm; height 30 mm), which was immersed in 800 ml of leaching fluid (0.1 M hydrochloric acid maintained at 37 ± 2 O C). The fluid was stirred at 100 rpm with a single blade Gallenkamp stirrer (Model APP No 4B 5784A). Samples of the leaching fluid (5 ml) were withdrawn at selected time intervals with a pipette fitted with a cotton wool plug and replaced with an equal volume of drugfree dissolution fluid. The samples were suitably diluted with blank dissolution fluid and were analyzed spectrophotometrically at λ max, 245 nm (Model Spectronic 21D, Bausch and Lomb, USA) for content of paracetamol The samples were filtered before assay. The amounts released were expressed as a percentage of the initial amount of drug in the capsule or tablet (Table 1). The dissolution test was carried out in quadruplicate and the mean results are reported. Individual results were reproducible to ± 10% of the mean. Determination of rate order kinetics The dissolution data were analyzed on the basis of zero order (cumulative percentage of drug released vs. time) and first order rate (log cumulative percentage of drug remaining vs. time) as well as Higuchi model (cumulative percentage of drug released vs. square root of time) in order to determine the mechanism of drug release. Thus the mathematical models tested, being the most frequently reported kinetics of drug release from drug particles and their solid dosage forms (23), were (24, 25): Zero order equation: m = k 0 t (2) First order equation: log m 1 = log m 0 ñ 0.43 k 1 t (3) Higuchi equation: m = k 2 t 1/2 (4) where m is the percentage (%) amount of drug released in time t; m 1 is the residual amount (%) of drug in time t, m 0 is the initial amount of drug (100%) at the beginning of the first order release, k 0, k 1 and k 2 are the release rate constants for the zero, first order and the Higuchi models, respectively. The linear correlation coefficient (r) for each rate order was calculated. The dissolution profile was considered to follow a particular rate order if the r value was 0.90 (16, 23). RESULTS Disintegration times Both the capsules and the tablets disintegrated rapidly within 2-3 min due to the high content of starch disintegrant, 5% w/w in the tablet formulations. Tablet hardness As measured by the tensile strength it varied between 1.36 ± 0.2 to 1.74 ± 0.3 MN/m 2 depending on the type and content of diluent in the tablet (Table 2). However, addition of diluents decreased compressibility as reflected by the slight decrease in T values. Lactose was more effective than α-cellulose or microcrystalline cellulose in decreasing compressibility of these matrix granules. However, sufficiently hard tablets were formed when the admixtures were compressed (T 1.40 MN/m 2 ). This means that diluents can be incorporated without serious impairment to compressibility of the matrix granules. Dissolution profiles of the capsules and tablets Plots of amounts (%) dissolved versus time (min) are presented in Fig. 1 for capsules and tablets without diluents. The dissolution generally followed a first order rate profile (r 0.95). The r values for the zero order analysis were 0.90. The first order dissolution rate constants were 0.31 ± 0.02 min -1 (capsules) and 0.20 ± 0.03 min -1 (tablets). Thus, the capsules displayed a faster dissolution compared with the tablets. Also, a time-lag of about 30 min preceded the dissolution from the tablets which was not the case with the capsules. Maximal release (m about 96%) was obtained in 6 h
78 MICHAEL U. UHUMWANGHO (capsules) and in about 8 h (tablets). The matrix granules thus displayed a retarded release in both dosage forms compared with conventional granules of paracetamol, m = 97% achieved in one hour (16). The release was also consistent with Higuchi model (r 0.96) which shows that drug release was by diffusion mechanism through receding depleting zone (25). Influence of the diluents on the dissolution profiles of the tablets The diluents generally had no effect on the dissolution profiles of the capsules but increased the dissolution rates of the tablets and decreased the time lag preceding dissolution (Figs. 2 ñ 4). With the lactose excipient, for instance, the first order dissolution rate constant increased from 0.20 ± 0.03 min -1 to 0.51 ± 0.01 min -1, while the time lag decreased from 30 min to zero during increase in the diluent content from 0 to 80%. The extent of the change in dissolution rate constants can be seen in Table 3. The more hydrophilic diluents (α-cellulose and microcrystalline cellulose) were more effective than lactose in enhancing dissolution of the tablets. DISCUSSION Time lag in the dissolution profiles of tablets without diluents The observation is attributable to the possibility that the particles of the matrix granules resulting from disintegration of the tablets in the aqueous dissolution medium were more compact than the corresponding matrix particles from the capsules, due to the applied pressure during tableting. Hence, the less rapid aqueous leaching of the drug content from the tablets. Inclusion of diluents decreased the time lag by promoting hydrophilic swelling of the otherwise hydrophobic matrix granules. The diluents were able to influence the aqueous swelling of the matrix granules as a result of the interparticulate (i.e. matrix granules-diluent) deformation and cohesion during tableting. This means that the matrix and the diluent particles were not liberated separately into the dissolution fluid during tablet disintegration (as would be the case with the capsules) but rather remained cohesed to each other even after disintegration of the tablets. The faster dissolution of the capsules (without diluents) compared with tablets (also without diluent). This was not expected, considering that both the capsules and the tablets disintegrated rapidly. The observation can be attributed to the more compact particles resulting from tablet disintegration compared with the matrix particles in the capsule which were not subjected to compaction. Hence, the latter were more porous and hence displayed a higher capacity for aqueous leaching of their drug content. The dissolution enhancer effect of the diluents in the tablets As explained above, the presence of the hydrophilic diluent in the particles following tablet disintegration promoted aqueous swelling and dissolution of the otherwise hydrophobic matrix particles. The more hydrophilic diluents (α-cellulose and microcrystalline cellulose) thus displayed the greater enhancer effect compared with lactose (Table 3). A similar enhancer effect was not seen in the capsules because in this case the matrix and the diluent particles were liberated separately into the dissolution medium following the disintegration of the capsule shell, and hence without a mutual effect on each other. CONCLUSION The study has shown that drug release from waxmatrix granules of paracetamol can be further retarded by their compression to rapidly disintegrating tablets, the matrix particles having become more compact. Inclusion of hydrophilic diluents such as α-cellulose and microcrystalline cellulose were unable to prevent deformation of the matrix particles as expected, but instead enhanced their dissolution. Thus, the diluents enhanced the dissolution rate of the tablet, while the diluents had no effect on the dissolution rate of the capsule. This finding can be used to obtain controlled release of the system studied. REFERENCES 1. Jayaswa S. B., Gode K. D., Khanna S. K.: Aust. J. Pharm. Sci. 9, 22 (1980). 2. Plaizier-Vercammen J., Dauwe D., Brioen P.: STP Pharma. Sci. 7, 491 (1997). 3. Jovanovic M., Jovicic G., Djuric Z., Agbaba D., Karljikovic-Rajic K., Nikolic L., Radovanovic J.: Acta Pharm. Hung. 67, 229 (1997). 4. Uhumwangho M. U., Okor R. S.: Afr. J. Biotech. 5, 766 (2006). 5. Upadrashta S.M., Katikaneni P.R., Hileman G.A., Keshary P.R.: Drug Dev. Ind. Pharm. 199, 449 (1993). 6. Katikaneni P. R., Upadrashta S. M., Neau S. H., Mitra A. K.: Int. J. Pharm. 123, 119 (1995). 7. Shlieout G., Zessin G.: Drug Dev. Ind. Pharm. 22, 313 (1996). 8. Pollock D. K., Sheskey P. J.: Pharm. Tech. 20, 120 (1996).
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