A STUDY OF COMPRESSION PROCESS AND PROPERTIES OF TABLETS WITH MICROCRYSTALLINE CELLULOSE AND COLLOIDAL SILICON DIOXIDE

Acta Poloniae Pharmaceutica ñ Drug Research, Vol. 73 No. 5 pp. 1259ñ1265, 2016 ISSN 0001-6837 Polish Pharmaceutical Society PHARMACEUTICAL TECHNOLOGY A STUDY OF COMPRESSION PROCESS AND PROPERTIES OF TABLETS WITH MICROCRYSTALLINE CELLULOSE AND COLLOIDAL SILICON DIOXIDE JITKA MUéÕKOV 1*, MARK TA LOUéENSK 1 and TOM ä PEK REK 2 1 Department of Pharmaceutical Technology, Charles University in Prague, Faculty of Pharmacy in Hradec Kr lovè, HeyrovskÈho 1203, 500 05 Hradec Kr lovè, Czech Republic 2 Zentiva, k.s., Prague, Czech Republic Abstract: This paper compares the compressibility and properties of tablets from Prosolv SMCC 90 and a mixture of Avicel PH-102 and colloidal silicon dioxide with a different specific surface. The effect of an addition of the lubricant magnesium on these parameters under varying conditions of mixing and the homogeneity of the lubricant in the mixtures are also examined. Compressibility is evaluated by means of the energy balance of the compression process; the examined properties of tablets are tensile strength and disintegration time. The total energy of compression was increased with compression force, the highest being in Prosolv SMCC 90. Its values did not differ for differing conditions of mixing with the lubricant. Plasticity was slightly decreased with compression force and in the mixture with magnesium it was not influenced by the conditions of mixing. Tablets made from Prosolv SMCC 90 and Avicel PH-102 were stronger than those from the mixtures from Avicel PH-102 and both types of Aerosil. The addition of magnesium markedly decreased the strength of tablets from Avicel PH-102. An increase in the period and frequency of mixing with the lubricant resulted in a further decrease in strength. Disintegration time was longer in tablets from Avicel PH-102 and Prosolv SMCC 90, and it was further prolonged by an addition of magnesium. Keywords: Avicel PH-102, Prosolv SMCC 90, colloidal silicon dioxide, energy profile of compression, magnesium, tensile strength of tablets, disintegration time of tablets A combination of microcrystalline cellulose (MCC) Avicel PH-102 and colloidal silicon dioxide is a common combination of these excipients in a directly compressible tableting material. In this tableting material, Avicel PH-102 functions as a dry binder and colloidal silicon dioxide as a glidant (1, 2). Both substances are also components of the coprocessed dry binder Prosolv SMCC 90, composed of 2% of colloidal silicon dioxide and 98% of microcrystalline cellulose (3, 4). This co-processed dry binder exerts excellent compressibility and also lower sensitivity to additions of lubricants due to the presence of colloidal silicon dioxide, which on the surface of MCC blocks the binding sites for the lubricant and thus decreases the effect of the lubricant on the binding of MCC (5-7). The substance is prepared using the method of spray drying, in which silicon oxide simply adheres to the surface of microcrystalline cellulose, where it is deagglomerated and uniformly distributed. Deagglomeration does not take place in a physical mixture of both substances, it contains large agglomerates of silicon dioxide (8). Colloidal silicon dioxide is mostly known under the trademark Aerosil. It exists in several types, which differ in their specific surfaces, which vary in a range of 100-380 m 2 /g. The most common type employed as a glidant is Aerosil 200 of the specific surface of 200 m 2 /g (9). The paper aimed to compare the compressibility of tableting materials and properties of tablets with Avicel PH-102 and Aerosil with different specific surfaces versus Prosolv SMCC 90. It also examined the effect of the addition of the lubricant magnesium on the same parameters under varying conditions of mixing. Compressibility was evaluated by means of the energy balance of compression process, the examined properties of tablets were tensile strength and disintegration time. EXPERIMENTAL Materials The study employed microcrystalline cellulose Avicel Æ PH-102 (FMC Corporation, USA), silici- * Corresponding author: e-mail: muzikova@faf.cuni.cz 1259

1260 JITKA MUéÕKOV et al. fied microcrystalline cellulose Prosolv Æ SMCC 90 (JRS PHARMA, Germany), colloidal silicon oxide in two types, i.e., Aerosil Æ 200 and Aerosil Æ 255 (Evonic Industries AG, Germany). The lubricant employed was magnesium (Acros Organics, USA). Preparation of tableting materials The study employed the following tableting materials: Avicel PH-102 Prosolv SMCC 90 Avicel PH-102 + 2% Aerosil 200 Avicel PH-102 + 2% Aerosil 255 Avicel PH-102 + 1% magnesium Prosolv SMCC 90 + 1% magnesium Avicel PH-102 + 2% Aerosil 200 + 1% magnesium Avicel PH-102 + 2% Aerosil 255 + 1% magnesium For the first stage of the study, mixtures of Avicel PH-102 with 2% of Aerosil 200 and Aerosil 255 were prepared. Colloidal silicon dioxide was premixed with Avicel PH-102 in a melamine mortar for 1 min and subsequently the mixtures were mixed in a mixing cube KB 15S (Erweka GmbH, Germany) for 5 min. The rate of rotation of the cube was 17 rev/min, the amount of prepared mixtures was 30 g. For the second stage of the study, the lubricant magnesium in a concentration of 1% was added to the mixtures of Avicel PH-102 with colloidal silicon dioxide under three different conditions of mixing, i.e., 2.5 min 17 rev/min, 5 min 17 rev/min and 2.5 min 34 rev/min. The mixture with magnesium under the same conditions of mixing was prepared also with Avicel PH-102 and Prosolv SMCC 90. The amount of tableting materials prepared in the same manner was 20 g. Preparation of tablets and energy evaluation of compression process Tablets were compressed using the material testing equipment T1-FRO 50 TH.A1K Zwick/Roell (Zwick GmbH&Co., Germany) by means of a special die with a lower and an upper punch. The rate of compaction was 40 mm/min, pre-load was 2 N, and the rate of pre-load 2 mm/s. The tablets were of cylindrical shape without facets of a diameter of 13 mm and weight of 0.5 ± 0.0010 g. Compression forces for tableting materials without magnesium were 2.5, 3 and 3.5 kn. Tableting materials with magnesium were compacted using a compression force of 3.5 kn. At each compression force 16 tablets were compacted. In 10 tablets the computer program testxpert V 9.01 simultaneously recorded the energy process of compression by means of the ìforce-displacementî record and numerically evaluated the energy balance of compression, i.e., the energy consumed for friction E 1, energy accumulated by the tablet after compression E 2, and the energy released during decompression E 3, total energy E max, which is the sum total of all energies, and plasticity (10). Measurement of the tensile strength of tablets The tensile strength of tablets was measured in 10 tablets more than 24 h after compression. Measurements were performed using a Schleuniger apparatus ((Dr. Schleuniger Pharmatron AG, Switzerland), which measures the diameter and height of tablets with a precision of 0.01 mm and destruction force in N. The tensile strength of tablets was subsequently calculated according to the equation [1] (11) : P = 2 F/(π d h) [1] where P is tensile strength of tablets in MPa, F is destruction force in N, d is the diameter of tablets in mm, h is the height of tablets in mm. Measurement of the disintegration time of tablets Disintegration time was always measured in 6 tablets at each compression force at least 24 h after compaction. The measurements were made on a device for testing the disintegration time of tablets Erweka ZT 301 (Erweka GmbH, Hausenstamm, Germany) using the method described in the European Pharmacopoeia 8 th edition (12). The test was carried out without discs in the medium of purified water tempered for 37 ± 1 O C. The tablets were considered disintegrated at the moment when on the net of the tube there was no remainder. Testing of homogeneity of tableting materials Homogeneity of mixtures with 1% of magnesium obtained under different mixing conditions was tested on a FTIR spectrometer Nicolet in10 MX (Thermo, USA), by means of which maps of distribution of the lubricant in the tablet were obtained. In each mixture, two tablets were compressed using a compression force of 3.5 kn. Tablets were cut using a surgeon blade. No polishing was applied prior to measurement. The cut tablets were placed on a microscopic glass crosssection side up and analyzed. Each spectrum was accumulated by acquisition of 1 scan. The image was acquired from an area of 100 100 pts. with 30 micrometer steps.

A study of compression process and properties of tablets with... 1261 Statistical processing of results The results of tensile strengths and disintegration time of tablets were statistically processed by means of the computer program Excel. The values of energies and plasticity were statistically processed by the computer programme testxpert V 9.0 directly during compaction. In the case of similar significance of values, unpaired t-test at a level of significance of 0.05 was employed. RESULTS AND DISCUSSION The study aimed to compare the compressibility and properties of tablets from silicified microcrystalline cellulose Prosolv SMCC 90 with physical mixtures of microcrystalline cellulose with varying types of colloidal silicon dioxide in a concentration of 2%. The employed microcrystalline cellulose was Avicel PH Æ -102, colloidal silicon dioxide was used in two types of Aerosil Æ 200 and Aerosil Æ 255. Avicel PH-102 alone was also evaluated. Compressibility was tested by means of the energy profile of compression, i.e., by means of calculation of total energy E max, energy for friction E 1, energy accumulated by the tablet after compression E 2, energy of decompression E 3, and plasticity. Another parameter related to compressibility is also tensile strength, which was tested in completed tablets together with disintegration time. In the first stage of the study, these parameters were evaluated at three compression forces of 2.5, 3 and 3.5 kn. Compression forces were selected in such a way that the resultant strength may oscillate as close as possible to the optimal range of strength of 0.56ñ1.11 MPa (13). In the second stage of the study, the effect of an addition of 1% of magnesium was tested under three different conditions of mixing (2.5 min and 17 rev/min, 5 min and 17 rev/min, 2.5 min and 34 rev/min) for the above-mentioned parameters of tableting materials and tablets. In addition, in these mixtures an analysis of homogeneity of the distribution of the lubricant was performed by means of a FTIR spectrophotometer Nicolet in10 MX. Evaluation of tableting materials without magnesium Energy profile of compression The results of the energy profile of compression of tableting materials without a lubricant are shown in Table 1. The total energy of compression E max increases with compression force and is the highest in the case of Prosolv SMCC 90 excepting the compression force of 2.5 kn, where there is no marked difference in the values between the tableting materials. As the total energy is given by the sum total of the energy for friction E 1, energy accumulated by the tablet after compression E 2 and the energy for friction E 3, it is evident from these energies that the comparison of their values is determined primarily by the energy for friction E 1, in which the course of values is analogous. The values of the energy accumulated by the tablet after compression E 2 increase again with the compression Table 1. Values of energy profile of compression and plasticity: tableting materials without magnesium. Tableting CF E max ± SD E 1 ± SD E 2 ± SD E 3 ± SD PI ± SD material [kn] [J] [J] [J] [J] [%] 2.5 5.68 ± 0.12 2.030 ± 0.101 3.414 ± 0.034 0.239 ± 0.010 93.44 ± 0.31 Prosolv SMCC 90 3 11.26 ± 0.13 6.967 ± 0.158 3.998 ± 0.005 0.299 ± 0.005 93.04 ± 0.13 3.5 13.57 ± 0.12 8.593 ± 0.108 4.609 ± 0.032 0.363 ± 0.006 92.70 ± 0.10 2.5 5.52 ± 0.06 2.086 ± 0.066 3.190 ± 0.019 0.245 ± 0.003 92.87 ± 0.10 Av PH102 3 7.01 ± 0.07 2.880 ± 0.084 3.824 ± 0.025 0.304 ± 0.006 92.63 ± 0.12 3.5 9.04 ± 0.14 4.245 ± 0.146 4.423 ± 0.028 0.370 ± 0.005 92.28 ± 0.10 2.5 5.35 ± 0.09 2.075 ± 0.068 3.050 ± 0.028 0.221 ± 0.009 93.24 ± 0.24 Av PH102 + A 200 3 7.14 ± 0.16 2.732 ± 0.124 4.127 ± 0.062 0.276 ± 0.004 93.73 ± 0.15 3.5 8.76 ± 0.25 3.577 ± 0.205 4.850 ± 0.061 0.330 ± 0.003 93.64 ± 0.09 2.5 5.53 ± 0.08 1.867 ± 0.064 3.449 ± 0.020 0.212 ± 0.003 94.22 ± 0.10 Av PH102 + A 255 3 6.77 ± 0.11 2.326 ± 0.092 4.174 ± 0.045 0.268 ± 0.003 93.97 ± 0.10 3.5 8.58 ± 0.23 3.533 ± 0.166 4.716 ± 0.098 0.333 ± 0.008 93.40 ± 0.25 Explanations: Av PH102 - Avicel PH 102; A 200 - Aerosil 200; A 255 - Aerosil 255; CF - compression force; E max - total energy; E 1 - energy of friction; E 2 - energy accumulated by the tablet; E 3 - energy of decompression; Pl - plasticity; SD - standard deviation

1262 JITKA MUéÕKOV et al. force. Slightly higher values are shown by the mixtures of Avicel PH-102 with both types of Aerosil, the lowest values being shown by Avicel PH-102 alone. In the energy of decompression E 3, which also increases with compression force, the result is a contrary one, because the lowest values are shown by the mixtures of Avicel PH-102 with both types of Aerosil. The final parameter under evaluation is plasticity, which as a result of a decrease in the pores in the tablet is slightly decreased with compression force. The lowest values of plasticity are shown by Avicel PH-102 alone, followed by Prosolv SMCC 90, and the highest values are recorded for mixtures of Avicel PH-102 with both types of Aerosil. However, it is necessary to state that the differences in the values are in no way marked. Tensile strength and disintegration time of tablets The results of tablet strength are shown in Figure 1. Tensile strength increases with compression force in all tableting materials. Its higher values are shown by Avicel PH-102 and Prosolv SMCC 90, while at the compression force of 2.5 kn a higher value is found in Prosolv SMCC 90, in the compression force of 3 kn the value equals to that of Avicel PH-102 and in the compression force of 3.5 kn the value is higher for Avicel PH-102. It means that in Avicel PH-102 binding capacity is increased Figure 1. Tensile strength of tablets in function of compression force: tableting materials without magnesium Figure 2. Disintegration time of tablets in function of compression force: tableting materials without magnesium

A study of compression process and properties of tablets with... 1263 Table 2. Values of energy profile of compression and plasticity at the compression force of 3.5 kn: tableting materials with magnesium. Tableting Mixing E max ± SD E 1 ± SD E 2 ± SD E 3 ± SD PI ± SD material min; rev [J] [J] [J] [J] [%] 2.5; 17 8.73 ± 0.09 3.802 ± 0.087 4.549 ± 0.028 0.382 ± 0.007 92.26 ± 0.09 Prosolv SMCC 90 5; 17 8.79 ± 0.09 3.857 ± 0.093 4.550 ± 0.021 0.383 ± 0.004 92.23 ± 0.08 + 1% st 2.5; 34 9.19 ± 0.14 4.255 ± 0.130 4.552 ± 0.034 0.385 ± 0.004 92.20 ± 0.10 2.5; 17 8.27 ± 0.08 3.522 ± 0.106 4.371 ± 0.004 0.374 ± 0.004 92.11 ± 0.11 Av PH102 + 1% st 5; 17 7.86 ± 0.10 3.236 ± 0.104 4.251 ± 0.023 0.375 ± 0.006 91.88 ± 0.10 2.5; 34 7.84 ± 0.17 3.259 ± 0.151 4.214 ± 0.042 0.372 ± 0.004 91.89 ± 0.09 2.5; 17 9.56 ± 0.12 4.475 ± 0.126 4.703 ± 0.023 0.378 ± 0.004 92.57 ± 0.05 Av PH102 + A 200 + 1% st 5; 17 7.64 ± 0.09 3.021 ± 0.083 4.253 ± 0.015 0.370 ± 0.003 92.00 ± 0.06 2.5; 34 7.96 ± 0.07 3.319 ± 0.080 4.272 ± 0.013 0.372 ± 0.004 92.00 ± 0.09 2.5; 17 9.39 ± 0.09 4.334 ± 0.092 4.681 ± 0.017 0.376 ± 0.004 92.57 ± 0.06 Av PH102 + A 255 + 1% st 5; 17 9.52 ± 0.16 4.511 ± 0.155 4.638 ± 0.020 0.374 ± 0.004 92.54 ± 0.05 2.5; 34 9.50 ± 0.12 4.483 ± 0.115 4.645 ± 0.028 0.375 ± 0.003 92.53 ± 0.08 Explanations: Av PH102 - Avicel PH 102; A 200 - Aerosil 200; A 255 - Aerosil 255; CF - compression force; E max - total energy; E 1 - energy of friction; E 2 - energy accumulated by the tablet; E 3 - energy of decompression; Pl - plasticity; SD - standard deviation with increasing force, whereas in Prosolv SMCC 90 it is already high enough at the lowest compression force employed. Mixtures of Avicel PH-102 with both types of Aerosil show, under the employed compression forces, a markedly lower strength of tablets, and between their values there is no statistically significant difference except at the compression force 3.5 kn, where only at this compression force the strength of tablets vacillates slightly above the lower limit of the optimal strength of tablets (0.56 MPa) (13). The disintegration time of tablets against compression force is shown in Figure 2. The disintegration time of tablets from all tableting materials increases with compression force, this increase being more marked in Avicel PH-102 and Prosolv SMCC 90, in which the values of disintegration time are higher. The longest disintegration time is shown by Avicel PH-102, a somehow shorter one due to the slightly disintegrating effect of colloidal silicon dioxide Prosolv SMCC 90 (3), and the shortest disintegration time is shown by the tablets made from the mixtures of Avicel PH-102 and both types of Aerosil resulting from low strength of tablets. Evaluation of tableting materials with magnesium The lubricant magnesium in a concentration of 1% was added to the tableting materials tested in the first stage of the study under three conditions of mixing. A twofold mixing time and twofold mixing rate were tested. The employed conditions of mixing were as follows: 2.5 min 17 rev/min; 5 min 17 rev/min; 2.5 min 34 rev/ min. The employed compression force was 3.5 kn. Energy profile of compression The results of the energy profile of compression of tableting materials with a lubricant are shown in Table 2. The values of total energy of compression of individual tableting materials do not substantially differ for the mixing period of 5 min at a frequency of 17 rev/min and a period of 2.5 min at the double frequency of 34 rev/min. The values of this energy, under these conditions of mixing with a lubricant, are the highest in Prosolv SMCC 90 and the mixture of Avicel PH-102 and Aerosil 255. A mixing time of 2.5 min and a frequency of 17 rev/min increase the value of the total energy for the mixture of Avicel PH-102 and Aerosil 200. The given course of the dependence of total energy again corresponds to the component of the total energy the energy for friction E 1. In the values of the energy accumulated by the tablet after compression E 2 there are again no marked differences for the twofold time and frequency of mixing and the highest values are recorded in Prosolv SMCC 90 and a mixture of Avicel PH-102 and Aerosil 255. The highest values of the energy of decompression E 3 are recorded in Prosolv SMCC 90 for all mixing times. In general, nevertheless, at this energy there are no marked differences in the values from the standpoint of the

1264 JITKA MUéÕKOV et al. conditions of mixing. Plasticity is decreased with an increase in the time or intensity of mixing in Avicel PH-102 and in a mixture of Avicel PH-102 and Aerosil 200, in the two remaining mixtures it is even for all conditions of mixing. Tensile strength and disintegration time of tablets Figure 3 shows the strength of tablets for varying conditions of mixing with magnesium. The graph shows a slight decrease in strength due to doubling the time or frequency of mixing, where there are no statistically significant differences between the values. It indicates at a more perfect formation of the film of the lubricant on the carrier substance. The highest values of strength are shown by Prosolv SMCC 90, the values of other mixtures are similar, excepting the tablets from Avicel PH- 102 and Aerosil 200 which show slightly lower values of strength. If we compare the result of the strength of tablets with and without magnesium (Fig. 1), then it is clear that the addition of magnesium does not markedly decrease tablet strength in Prosolv SMCC 90 and the mixtures of Avicel PH-102 with both types of Aerosil, but it decreases it markedly in Avicel PH-102, which again demonstrates the existence of competi- Figure 3. Tensile strength of tablets at the compression force of 3.5 kn: tableting materials with magnesium (different conditions of mixing) Figure 4. Disintegration time of tablets at the compression force of 3.5 kn: tableting materials with magnesium (different conditions of mixing)

A study of compression process and properties of tablets with... 1265 tive inhibition of the binding sites for magnesium by colloidal silicon dioxide, both in the physical mixture and in the co-processed dry binder (7). Disintegration time of tablets presented in Figure 4 is prolonged by doubling the time and frequency of mixing with the lubricant only in Prosolv SMCC 90, which would indicate a more perfect formation of the film of the lubricant. Its values are in this substance the highest, which corresponds to the highest strength of tablets. In the case of other tableting materials, the disintegration time is either not markedly changed (Avicel PH-102) or it is rather decreased (Avicel PH-102 with both types of Aerosil) due to changes in the conditions of mixing. Testing the homogeneity of distribution of the lubricant in tablets In Avicel PH-102 and Prosolv SMCC 90, the best homogeneity was found under the mixing conditions of 2.5 min 34 rev/min. In the case of other conditions of mixing, larger agglomerations of magnesium were recorded. In the mixture of Avicel PH-102 and 2% Aerosil 200, the best homogeneity was for the condition of mixing 5 min and 17 rev/min, in the mixture of Avicel PH-102 and Aerosil 255, on the other hand, the best homogeneity was obtained under the conditions of mixing of 2.5 min 17 rev/min. CONCLUSION In conclusion, it can be stated that the total energy of compression increased with compression force in all tableting materials, the highest being in Prosolv SMCC 90. After addition of magnesium its values did not differ under the conditions of mixing of 5 min 17 rev/min and 2.5 min 34 rev/min. Plasticity slightly decreased with compression force and in mixtures with magnesium it was not influenced by the conditions of mixing. Tablets from Prosolv SMCC 90 and Avicel PH-102 showed a markedly higher strength than the tablets from the mixtures of Avicel PH-102 and both types of Aerosil. The addition of magnesium markedly decreased the strength of tablets from Avicel PH-102. Increased time and frequency of mixing resulted in a further decrease in strength. Disintegration time was longer in tablets from Avicel PH-102 and Prosolv SMCC 90, due to the effect of adding magnesium. In tablets from Prosolv SMCC 90, disintegration time was prolonged also by the influence of a longer time and higher frequency of mixing with the lubricant. Different conditions of mixing did not influence homogeneity of magnesium uniformly. Acknowledgment The study was supported by the firms FMC Corporation., JRS PHARMA and Evonic Industries AG, which supplied the samples of the excipients tested. REFERENCES 1. Bolhuis G.K., Waard H.: in Pharmaceutical powder compaction technology, Celik M. Ed., 2nd edn., p. 143, Informa Healthcare, London 2011. 2. Armstrong N.A.: in Pharmaceutical Dosage Forms ñ Tablets, Augsburger, L.L., Hoag, S.W., Eds., Vol. 2, 3rd edn., p. 176, Informa Healthcare USA Inc., New York 2008. 3. Moreton R.C.: in Handbook of Pharmaceutical Excipients, Rowe, R.C., Sheskey P.J., Cook W.G., Fenton M.E. Eds., 7th edn., p. 149, Pharmaceutical Press, London 2012. 4. Sherwood B.E., Becker J.W.: Pharm. Tech. 22, 78 (1998). 5. Tobyn M.J., Mc Carthy G. P., Staniforth J.N., Edge S.: Int. J. Pharm. 169, 183 (1998). 6. Van Veen B., Bolhuis G.K., Wu Y.S.: Eur. J. Pharm. Biopharm. 59, 133 (2005). 7. Bolhuis G.K., Hˆlzer A.W.: in Pharmaceutical powder compaction technology, Celik, M. Ed., 2nd edn., p. 205, Informa Healthcare, London 2011. 8. Edge S., Potter U.J., Steele F.D., Tobyn M.J., Chen A. et al.: Pharm. Pharmacol. Commun. 5, 371 (1999). 9. Hapgood K.P.: in Handbook of Pharmaceutical Excipients. Rowe, R.C., Sheskey P.J., Cook W.G., Fenton M.E. Eds., 7th edn., p. 198, Pharmaceutical Press, London 2012. 10. Ragnarsson G.: Force-Displacement and Network Measurements, in Pharmaceutical Powder Compaction Technology, Alderborn G., Nystrˆm Ch. Eds., p. 77, Marcel Dekker Inc., New York 1996. 11. Fell J.T., Newton J.M.: J. Pharm. Sci. 59, 688 (1970). 12. European Pharmacopoeia. 8 th edn, Vol. 1, p. 285, Council of Europe, Strasbourg 2013. 13. Belousov V.A.: Khim. Farm. Zh. 10, 105 (1976). Received: 28. 07. 2015