Physicochemical Properties of Calcium Polycarbophil, a
TAKEHISA YAMADA, MASAKAZU KITAYAMA, MASAHIRO YAMAZAKI, OSAMU NAGATA, IKUMI TAMAI* AND
Research and Development Division, Hokuriku Seiyaku Co., Ltd, Katsuyama 911, and ^Department of
Pharmaceutics, Faculty of Pharmaceutical Sciences, Kanazawa University, Kanazawa 920, Japan
Results and Discussion
Decalcification of calcium polycarbophil
Calcium polycarbophil releases calcium ions under acidic conditions and polycarbophil thus obtained is efficacious in the treatment of constipation or diarrhoea associated with conditions such as irritable bowel syndrome (Danhof 1982). However, some patients may have low stomach acidity, so the decalcification ratio of calcium polycarbophil should be evaluated at various pHs. Our present results (Fig. 1) indicate that decalcification of calcium polycarbophil is complete at below pH 4 0, but decreases markedly above pH 4-0. This reflects the finding that the pKa value of polyacrylic acid is around 4-75 (Greenwald & Luskin 1980). As calcium ions are absorbed from the gastrointestinal tract (Bronner 1987), decalcification in vivo should be more efficient than would be predicted from the present in vitro study. When the time-course of decalcification ratios of calcium polycarbophil in artificial gastric
Fig. 1. Effect of pH on decalcification of calcium polycarbophil. Calcium concentration in the sample solution was measured by atomic absorption spectrochemical analysis. Each point represents the mean ± s.d. (n = 3). Standard deviations are smaller than the symbols.
juice was studied, decalcification was very fast and the decalcification ratio reached almost 100% after shaking for 2-5 min (data not shown). This implies that calcium polycarbophil would release calcium ions rapidly in the stomach to affbrd polycarbophil.
Equilibrium swelling of polycarbophil
The equilibrium swelling of polycarbophil in buffers of various pH values is shown in Fig. 2. Values of the equilibrium swelling under acidic conditions were small, corresponding to only about 10 times the initial weight, but, the equilibrium swelling increased markedly above pH 4 0, and the value was about 70 mL (g polycarbophil)-1 at pH 7 0. Thus, the equilibrium swelling of polycarbophil was dependent on pH, and was 7 times larger at pH 7-0 than at pH 4 0. It is considered that the lower hydration of polycarbophil under acidic conditions is advantageous to minimize side effects such as distention of the upper gastrointestinal tract. The value of the equilibrium swelling of polycarbophil at pH 7 0 was about one half of the value reported by Ch'ng et al (1985). Generally, factors which influence the equilibrium swelling of a macromolecular water-absorbing polymer include the cross-linking ratio of the polymer and the osmotic difference between inside and outside the polymer gel (Flory 1953). To clarify the above discrepancy, polycarbophils containing various contents of the cross-linking agent, divinylglycol, were synthesized according to the method reported by Miskel et al (1967). The equilibrium swelling ratios of the synthesized polycarbophils changed drastically with change of the cross-linking ratio (data not shown). From these results, it is suggested that the difference of swelling ratios found by Ch'ng et al (1985) and us may have been due to a difference in the cross-linking ratio of the polycarbophils used.
When polycarbophil gel was allowed to swell in 1-5% sodium bicarbonate solution, sodium ion concentration (349-5 ± 8-6 mM, mean ± s.d., n = 3) inside the hydrated gel was found to be twice that (166-8 ±0-6 mM) of the supernatant. Such a difference implies that the equilibrium swelling would be influenced by ionic osmolarity. The equilibrium swellings of polycarbophil in solutions of various ionic
FIG. 3. Effect of ionic strength on equilibrium swelling of polycarbo- phil. Each point represents the mean 土 s.d. (n = 3). Standard deviations are smaller than the symbols, except in one case.
strengths are shown in Fig. 3. The ratios of swelling at ionic strength 0 08 and 3-0 to that at 0-15 were 130 and 54%, respectively. Thus, the equilibrium swelling of polycarbophil decreased with increase of ionic strength. The effect of nonionic osmolarity on the equilibrium swelling of polycarbophil was also examined by using various glucose concentrations. We found that the equilibrium swelling ratio (versus control) was 102 4 土 10 or 104-6 ±21 when the osmolarity of the test solution was increased by 2 or 3 times with glucose, respectively, indicating that the equilibrium swelling ratio of polycarbophil was unaffected by non-ionic osmolarity.
Consequently, it is considered that the equilibrium swelling of polycarbophil is mainly affected by the ionic strength. Since there are many metal ions, such as sodium, potassium, calcium and magnesium ions, in the gastrointestinal fluid, the effects of these ions on the equilibrium swelling of polycarbophil were studied. As shown in Table 1, the equilibrium swelling of polycarbophil was markedly reduced by addition of calcium or magnesium ions, whereas it was increased in the cases of sodium and potassium ions. Thus, it is considered that hydrated gel shrinks owing to release of retained water upon ionic binding of calcium or magnesium ions to the acrylic acid resin component of polycarbophil.
To determine the effects of calcium ion on the equilibrium swelling of polycarbophil in the presence of sodium ion, various calcium salts were used as additives. When the counter ions of the calcium ion differed, the equilibrium swelling of polycarbophil was also changed (Table 2). Calcium carbonate
Table 2. Effects of various calcium salts on the equilibrium swelling
Applied source of calcium
Swelling ratio (%)
640 ±1 3
Calcium monohydrogen phosphate
Each value represents the mean 土 s.d. (n = 3). The amount of calcium applied (20%) was the same fbr all sources of calcium and corresponds to the amount in calcium polycarbophil.
and calcium hydroxide did not affect the equilibrium swelling of polycarbophil, but other calcium salts reduced it. We consider that this is related to the solubility of the calcium salts (calcium carbonate and hydroxide remained at the bottom of the tube). Even in the presence of both calcium ion (1-25 mmol) and sodium ion (6-3 mmol), the equilibrium swelling of polycarbophil was more than 42%, Calcium ion concentrations in gastrointestinal fluid are known to be below 10 mM (Thurebom 1961; Hunt & Wan 1967; Nakayaina & Van der Linden 1971) and the concentration was about 35 mM in the present study. We consider that the percentage reduction of the equilibrium swelling of polycarbophil would be less in the body. Since it is considered that calcium ion is present as the carbonate salt or monohydrogen phosphate salt in the intestine, the equilibrium swelling of polycarbophil in the presence of calcium salts in the intestine should be virtually the same as that in the absence of calcium salt. Thus, the equilibrium swelling should be sufficient to show the desired pharmacological effects.
In the diarrhoeal state, the water transport rate in the gastrointestinal tract is so fast that water can not be adequately absorbed (Sadik 1989). We therefore examined the viscosity,
Fig. 4. Effect of polymer content on viscosity of polycarbophil (•) or CMC-Na (O). Viscosities were measured using a rotational viscometer at a shear rate of 10 s_\ Each point represents the mean 士 s.d. (n = 3). Standard deviations are smaller than the symbols.
as an indicator of fluidity, of polycarbophil in comparison with that of CMC-Na. The viscosity of polycarbophil increased with increasing concentration, and was larger than that of CMC-Na at all concentrations examined (Fig. 4). A similar tendency was observed at all rates of shear examined (data not shown). As polycarbophil forms a gel, this gel could reduce the fluidity of the gastrointestinal contents and improve the looseness of stools in diarrhoea. Additionally, the reduction of fluidity would reduce the transport velocity of intestinal fluid, and so water would be better absorbed. That is, the anti-diarrhoeal action of polycarbophil is due to the gel formation and the reduction of fluidity arising from the increase of viscosity.
In conclusion, calcium polycarbophil is decalcified under gastric acidic conditions, and the produced polycarbophil absorbs water to form a gel under intestinal neutral conditions. This gel retains water and endows the intestinal contents with high viscosity. These physicochemical properties of calcium polycarbophil account for its efficacy in the treatment of constipation and diarrhoea associated with conditions such as irritable bowel syndrome.