Pharmaceutical Chemistry Journal
Vol. 38, No. 1, 2004
DEVELOPMENT OF THE TECHNOLOGY OF ACTIVATED CHARCOAL TABLETS A. S. Gavrilov,1 E. V. Gusel’nikova,1 and A. Yu. Petrov1 Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 38, No. 1, pp. 41 – 44, January, 2004. Original article submitted July 10, 2003.
Commercial ready-to-use medicinal forms of activated charcoal can be subdivided into two types: (i) intended for emergency therapy and (ii) available in common drug stores. The latter type usually takes the form of tablets or capsules administered for the treatment of diarrhea ad meteorism [1]. The tablets of activated charcoal may contain various fillers, including surfactants, hydroxystarch, and saccharose [2], kaolin [1], albumin and lactose [3], aluminum oxide [4], aliphatic detergent [5], microcrystalline cellulose [6], pectin [7], and starch and sugar [8]. Russian pharmaceutical companies produce traditional tablets containing 83% of activated charcoal and 17% of starch [8]. The technology consists of several stages including wetting charcoal powder with a 10% starch jelly, granulation, drying to a water content of 30%, tablet pressing, and final drying to a water content below 1% [8]. Tablets produced using this method frequently possess insufficient mechanical strength and exhibit surface cracking and delamination. The aim of this study was to develop a technology for obtaining activated charcoal tablets corresponding to all requirements of the State Pharmacopoeia [9].
The tablets were analyzed as stipulated by the pharmacopoeial article [9]. The powder density of a granulated material was determined by a conventional method [10]. The particle size distribution (after drying the powder to constant weight) was studied in a granulometric device of the RKF-2U type equipped with 0.8 and 0.315-mesh sieves shaken for 5 min at a control voltage of 100 V. The powder friability characteristics were determined using a VP-12A device [11]. The disintegration of tablets was studied using a disk technique described in RSP-XI (Vol. 2, p. 158). The tablet strength under pressure was measured using an Erweka device in a regime of loading across the tablet diameter. RESULTS AND DISCUSSION As is known, unsatisfactory mechanical properties of tablets are mostly related to insufficient amount and/or inhomogeneous distribution of the binding agent. In order to check for the assumption concerning the importance of homogeneous distribution of the binder, we added various amounts of charcoal powder to the initial mixture (prepared from 10 g of charcoal and 12 g of a 10% starch jelly) dried to a residual water content of 30%. It was found that the presence of even 1% of ungranulated charcoal powder in the initial mixture leads to a 5 – 8% decrease in the mechanical strength of tablets. Tablets made of a mixture containing 1 – 5% of ungranulated charcoal exhibited surface cracking and edge delamination. The granulation process takes place within a narrow interval of the content of the liquid phase in the mixture. Depending on the ratio of liquid and solid phases, the mixture exhibits a transition from the state of capillary binding to ointment, whereby the granulate converts into a plastic mass [12]. We have performed a series of experiments in which 10 g of charcoal was wetted by various amounts of a 10% starch jelly. The quality of wetting was determined using a method described in [8]. These experiments showed that the optimum wetting is observed within an interval of the binding solution to charcoal ratios from 0.7 : 1 to 2.1 : 1.
MATERIALS AND METHODS The experiments were performed with activated charcoal of pharmacopoeial grade (RSP-X) (Sorbent Co., Perm) and potato starch (State Standard GOST 7699). For obtaining experimental and control batches of tablets, activated charcoal was wetted with a binder solution. The wet mass was stirred and granulated via a 2.0 ´ 15 mm slit sieve. The granulated material was dried at 75 – 105°C to a residual water content of 28 – 32% and tabletized using a 11-mm die press. The tablet weight before final drying was 0.39 – 0.41 g. The tablets were placed onto trays and dried in a shelf dryer to a residual water content below 1%. 1
Ural Institute of Medicinal Preparation Technology, Yekaterinburg, Russia.
41 0091-150X/04/3801-0041 © 2004 Plenum Publishing Corporation
42
A. S. Gavrilov et al.
TABLE 1. Effect of Agglomeration on the Properties of Activated Charcoal Granulates Friability, g/(cm2 · sec)
Particle size distribution*, %
Powder density, g/cm3
Control
3.43 ± 0.25
46.9/33.3/19.8
0.238 ± 0.02
Agglomerate
4.33 ± 0.26
64.5/22.5/13.0
0.281 ± 0.06
Sample
* Fractions retained on 0.8 and 0.315 mm mesh sieves and dust below 0.315 mm.
The effect of the starch jelly concentration on the quality of granulates and tablets was studied in another series of experiments, in which the same amount of charcoal (10 g) was wetted by mixing with 12 g of a starch jelly of various concentrations (3, 7, 10, 14%). Then, each the mixture was dried to a residual water content below 1% and the density of the resulting granulate was determined. It was established that, as the starch jelly concentration increases from 3 to 10%, the granulate density grows from 0.22 to 0.24 g/cm3, but further saturation leads to a decrease in the granulate density to 0.20 g/cm3. This behavior can be explained by a less effective distribution of the binder over the surface of charcoal particles as a result of a sharp increase in the density of the starch jelly. Thus, the results of our model experiments revealed the main factor responsible for the poor quality of charcoal tablets: inhomogeneous distribution of the starch binder in the bulk of charcoal. Effective wetting of the activated charcoal takes place only for the optimum ratio of components in the charcoal – binder mixture. A ratio below 0.7 : 1 leads to incomplete wetting, while a ratio above 1 : 2.1 corresponds to the formation of plastic gel not suited for commercial granulation. Increasing the starch jelly concentration above 10% is inexpedient because the resulting medium becomes highly viscous and cannot be effectively mixed with charcoal. The resulting mixture contains nonwetted charcoal particles and the density of granulate tends to decreases, rather than to increase. This behavior hinders the formation of a uniformly wetted granulate with homogeneously distributed binder, which leads to unstable pressing and unsatisfactory product quality. It was suggested that more effective distribution of the binder can be provided by increasing the duration of mixing, decreasing the viscosity at elevated temperatures, and using additional equipment (high-intensity mixers or extruders). This assumption was confirmed by experiments showing the
TABLE 2. Effect of Agglomeration on the Properties of Activated Charcoal Tablets Sample
Sorption capacity, mg/g
Strength, kgf
Wear resis- Disintegration tance, % time, min
Control
191.4 ± 3.5
< 1.0
97.76
14 ± 3
Agglomerate
184.6 ± 4.7
3.25 ± 0.25
99.97
15 ± 4
TABLE 3. Effect of Binder Type on the Sorption Capacity of Activated Charcoal Binder
Control (no binder) Sugar Lactose Sorbitol Al(OH)3 Pectin Na-CMC Starch
Binder concentra- Sorption capacity, Powder density, tion, % mg/g g/cm3
0
355
0.12
16.6 16.6 16.6 16.6 16.6 16.6 16.6
148 237 194 332 228 348 220
0.69 0.58 0.54 0.22 0.24 0.18 0.26
influence of the quality of granulation on the stability of pressing. In these experiments, 83 g of charcoal was wetted with 150 g of a 10% starch jelly and the mixture was divided into two parts. One part was additionally agglomerated using a cutter with 5.0-mm mesh grid. Then, both parts of the material were dried to a residual water content of 32 – 34%, granulated, and pressed into tablets. It was established that agglomeration leads to a reliable increase in the granulate density (to 0.281 g/cm3), provides for stable pressing, and improves the quality of tablets (Tables 1 and 2). In order to elucidate the effect of binders on the quality of tablets, a certain amount of activated charcoal (10 g) was wetted by solutions of various binding agents (1 g) in 11 g of water. The results of these experiments (Table 3) showed that the introduction of binders significantly decreases the sorption capacity of activated charcoal. The maximum decrease was observed in the experiments with saccharose, lactose, and sorbitol. Inorganic binders did not reduce the sorption capacity of charcoal so significantly, although aluminum hydroxide also led to a reliable decrease. Among the series of binders studied, only sodium carboxymethyl cellulose (Na-CMC) did not reduce the sorption capacity of charcoal. However, we failed to obtain high-quality tablets by wetting charcoal with a solution of this binder. This was related to the impossibility of introducing a sufficiently large amount of the binder from a 2% Na-CMC solution, whereas the use of more concentrated solutions was inexpedient because of significant viscosity. The experiments on pressing the obtained materials showed that the higher the granulate density, the more stable is the pressing process. Charcoal granulated with a 60% sugar syrup gave bright tablets with a sorption capacity of 148 mg/g with respect to Methylene Blue, a strength of 50 kgf, and a disintegration time of 3 min. Thus, it was established that, in order to obtain highquality tablets of activated charcoal, it is necessary to ensure homogeneous distribution of the binder. There are published data that this problem can be solved by introducing a dry binder agent into the initial mixture, followed by wetting this mixture with water. Our experiments showed that this ap-
Development of the Technology of Activated Charcoal Tablets
TABLE 4. Properties of Activated Charcoal Granulates Obtained by Wet Granulation and Dry Mixing Sample
Wet granulation Dry mixing
Friability, g/(cm2 · sec)
Particle size distribution*, %
Powder density, g/cm3
3.43 ± 0.25
46.9/33.3/39.8
0.228 ± 0.02
3.91 ± 0.12
64.7/20.5/14.8
0.269 ± 0.06
43
TABLE 5. Properties of Activated Charcoal Tablets Made of Granulates Obtained by Wet Granulation and Dry Mixing Sample
Sorption capacity, mg/g
Strength, kgf
191.4 ± 3.5
< 1.0
97.76
12 ± 3
188.6 ± 8.8
3.25 ± 0.25
99.81
13 ± 2
Wet granulation Dry mixing
Wear resis- Disintegration tance, % time, min
* Fractions retained on 0.8 and 0.315 mm mesh sieves and dust below 0.315 mm.
proach provides for the optimum particle size distribution in the granulate, in contrast to the traditional wet granulation process [13] posing contradictory requirements of sufficiently high binder concentration and sufficiently low solution viscosity [14]. Use of the new approach excludes inhomogeneous distribution of the binder (a factor leading to the formation of small loose granules [15]). An additional advantage is the possibility of controlling the granulation process without changing the composition of active and inert components [16]. It was decided to modify the order and parameters of technological operations so as to introduce a binder in the form of a dry powder into the mixture with activated charcoal and then produce wetting of the mixture with water so as to obtain a binder gel of the necessary concentration immediately in the bulk of the mixture. In other words, it is recommended to perform preliminary dry mixing of starch and activated charcoal and then wet the mixture with boiling water. In this case, the formation of a binder gel takes place directly in the bulk of the mixture. This ensures effective mixing and granulation of activated charcoal and allows any amount of the binder to be introduced in order to ensure the formation of sufficiently strong granules and tablets. In order to confirm the advantages of the proposed method, we prepared a mixture of activated charcoal (83 g) and starch (17 g), wetted this mixture with 153 g of boiling water, and stirred the mass for 10 min. The control batch was prepared using the well-known method, whereby 83 g of charcoal was wetted with 170 g of a 10% starch jelly (prepared from 17 g of starch and 153 g of water). Then the test and control mixtures were discharged onto trays, dried at 80 – 95°C to a residual water content of 31.4 and 30.7%, respectively, and pressed into tablets using a 11-mm die press. Finally, the tablets were dried to a residual water content of 1%. The quantitative characteristics of granulates and tablets are presented in Tables 4 and 5. As can be seen from Table 4, the proposed method reliably improves friability of the granulate, increases its density, and decreases the dusty fraction (below 0.315 mm) in the test granulate as compared to the control. Charcoal tablets made of this improved granulate exhibited increased strength and a homogeneous surface.
In order to determine the optimum amount of binder necessary for obtaining high-quality granulates and tablets, 83 g of charcoal was mixed with various amounts of starch, wetted with 153 g of boiling water, and stirred for 10 min. The mixtures were agglomerated using a cutter with 5.0-mm mesh grid, the agglomerates were dried on trays to a residual water content of about 30%, and the obtained granulate was pressed into tablets using a 11-mm die press. The quality of granulates was characterized by mechanical strength and particle size distribution (Table 6). The tablets were tested for sorption capacity with respect to Methylene Blue, strength, wear, and disintegration time (Table 7). As can be seen from data in Tables 6 and 7, the optimum binder content falls within the interval 8 – 17%. Outside this interval, either the tablet strength is lost or the sorption capacity decreased. Using the proposed method, it is also possible to obtain high-quality tablets with other binders, in particular, with Na-CMC. For this purpose, 83 g of charcoal was mixed with 17 g Na-CMC, wetted with 130 g of water at 40 – 60°C, and stirred for 2 h to provide for Na-CMC swelling. The mixtures were agglomerated, the agglomerates were dried to a residual water content of about 25 – 28%, and the obtained granulate was pressed into tablets. Finally, the tablets were dried at 100 – 105°C to a residual water content of 1%. The granulate had a density of 0.285 g/cm3 and a friability of 5.1 g/(cm2 · sec). We obtained 95 g of tablets meeting all pharmacopoeial requirements, possessing increased sorption capacity (410 mg/g) and a disintegration time below 15 min. The method of dry mixing allows the mixture of activated charcoal and binder to be granulated using a nonviscous solution of another binder such as sorbitol. The introduction of sorbitol into the tablet composition is expedi-
TABLE 6. Effect of Binder Concentration on the Properties of Activated Charcoal Granulates Obtained by Dry Mixing Binder concentration, %
Friability, g/(cm2 sec)
Particle size distribution*, %
Powder density, g/cm3
5
4.35 ± 0.25
46.9/33.3/19.8
0.241 ± 0.02
8
4.43 ± 0.26
64.5/22.5/13.0
0.291 ± 0.06
17
4.58 ± 0.33
69.5/20.5/10.0
0.274 ± 0.04
22
4.75 ± 0.32
64.4/22.5/13.1
0.261 ± 0.05
* Fractions retained on 0.8 and 0.315 mm mesh sieves and dust below 0.315 mm.
44
A. S. Gavrilov et al.
TABLE 7. Effect of Binder Concentration on the Properties of Activated Charcoal Tablets Made of Granulates Obtained by Dry Mixing Binder concentration, %
Sorption capacity, mg/g
Strength, kgf
Wear resistance, %
Disintegration time, min
5
267.4 + 3.5
< 1.0
97.76
1 ± 0.3
8
224.6 ± 4.7
3.25 ± 0.25
99.97
2 ± 0.1
17
210.2 ± 0.6
3.80 ± 0.25
99.98
11 ± 1.0
22
185.5 ± 2.2
3.60 ± 0.25
99.95
15 ± 1.0
ent from the standpoint of reduction of the side effect of charcoal manifested by a decrease in the motor-evacuation function of the intestine [3]. In this experiment, 250 g of charcoal was mixed with 50 g Na-CMC and wetted with a boiling solution of 70 g sorbitol in 350 g of water. The mass was stirred and allowed to stand for 4 h until Na-CMC swelling. Then, the mixture was agglomerated, the agglomerates were dried to a residual water content of about 30%, and the obtained granulate was pressed into 0.48 g tablets. Finally, the tablets were dried to a residual water content of 1%. This experiment showed that the proposed method ensures stable pressing of high-quality tablets of activated charcoal with sorbitol, possessing a sorption capacity of 354 mg/g (for Methylene Blue).
REFERENCES 1. M. D. Mashkovskii, Drugs [in Russian], Meditsina, Moscow (1984), Vol. 1, p. 296. 2. US Patent No. 3934007; Off. Gazette, 213(11), 200 (1974). 3. US Patent No. 4162306; Off. Gazette, 306(2), 188 (1984). 4. US Patent No. 5730918; Off. Gazette, 411(12), 47 (1990). 5. US Patent No. 3454502; Off. Gazette, 143(9), 390 (1966). 6. RF Patent No. 2180231; Byull. Izobret., No. 283(1), (2002). 7. RF Patent Application No. 96,101,340; Byull. Izobret., No. 280(3), (2001). 8. I. A. Murav’ev, Drug Technology [in Russian], Meditsina, Moscow (1971), p. 610. 9. Pharmacopoeial Article FS 42–324695, Suppl. Nos. 1 – 3, Activated Charcoal Tablets. 10. V. A. Belousov and M. B. Val’ter, Principles of Dosing and Tabletization of Powdered Drugs [in Russian], Nauka, Moscow (1980). 11. M. B. Val’ter, O. L. Tyutenkov, and N. A. Filipin, Stage Control in Tablet Production [in Russian], Meditsina, Moscow (1982). 12. C. E. Capes, Particle Size Enlargement, Vol. 1, Williams J. C. and Allen T.(eds)., Handbook Of Powder Technology, Elsevier, Amsterdam (1980). 13. G. D. Alonzo, R. E. O’Connor, and J. B. Schwartz, Drug Dev. Ind. Pharm., 16(12), 1931 – 1944 (1990). 14. N. O. Lindberg and C. Jonsson, Drug Dev. Ind. Pharm., 11(2 – 3), 387 – 403 (1985). 15. S. J. Reading and M. S. Spring, J. Pharm. Pharmacol., 36, 421 – 426 (1984). 16. H. G. Kristensen and T. Schaefer, Drug Dev. Ind. Pharm., 13(4 – 5), 803 – 872 (1987).
