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
The physicochemical properties of calcium polycarbophil were examined.
Calcium polycarbophil was decalcified rapidly under acidic conditions, affording polycarbophil. Polycarbophil absorbed about 10 times its own weight of water under acidic conditions, but the swelling ratio markedly increased at above pH 4 0 and reached 70 times the initial weight under neutral conditions. The swelling of polycarbophil was not affected by non-ionic osmolarity, but was affected by ionic strength, showing a decrease with increase of ionic strength. Monovalent metal ions such as sodium and potassium ions in gastrointestinal fluid did not reduce the equilibrium swelling of polycarbophil, but divalent ions such as calcium and magnesium ions did. However, calcium ion only slightly reduced the equilibrium swelling under sodium- rich conditions. The viscosity (as an indicator of fluidity) of polycarbophil was larger than that of CMC-Na at every shear rate and polymer content examined.
Calcium polycarbophil, a water-absorbing polymer, is the calcium salt of polyacrylic acid cross-linked with divinylgly- col. It has been developed as a treatment for constipation or diarrhoea associated with conditions such as irritable bowel syndrome. It releases calcium ions under acidic conditions and its pharmacological actions are due to the polycarbophil thus produced (Danhof 1982). The pharmacological efficacy of calcium polycarbophil has been proven in clinical trials (Winkelstein 1964; LaCorte et al 1982), although the mechanisms of the anti-constipation or anti-diarrhoeal action of calcium polycarbophil have not been clarified. Calcium polycarbophil and polycarbophil are chemically (Child et al 1955) and physiologically inert (Grossman et al 1957; Roth I960), and are not absorbed from the gastrointestinal tract into the systemic circulation (Child et al 1955). Therefore, the physicochemical properties of these compounds must be important in generating the pharmacological effects in the gastrointestinal lumen. However, little investigation of the physicochemical properties of calcium polycarbophil have been reported, except for studies of the swelling ratios of polycarbophil at various pHs and at various ionic strengths (Ch'ng et al 1985; Park & Robinson 1985).
The purpose of this study was to investigate the physicochemical properties of calcium polycarbophil in order to throw light on the mechanisms of the anti-constipation and anti- diarrhoeal action of this polymer. In this study, we evaluated the decalcification of calcium polycarbophil, and the effects of various factors such as pH, ionic strength, osmolarity and metal ions in the gastrointestinal fluid on the equilibrium swelling and viscosity (as an indicator of fluidity) of polycarbophil.
Correspondence: T. Yamada, Research and Development Division, Hokuriku Seiyaku Co., Ltd, Inokuchi 37, Katsuyama 911, Japan.
Materials and Methods
Calcium polycarbophil was purchased from Lee Laboratories (USA) and polycarbophil was prepared in our laboratory from calcium polycarbophil according to the following procedure. Calcium polycarbophil was decalcified with 01 M HCI five times and washed with purified water five times, then the polycarbophil thus obtained was freeze-dried in-vacuo (0-4 torr) using a DF-05G freeze dryer (Nihon Shinkugijutsu Co., Ltd, Japan) at —20°C. The product was ground in an R-8 analytical grinder (Nihon Rikagakukikai Co., Ltd, Japan). Sodium carboxymethylcellulose (CMC-Na) was purchased from Maruishi Seiyaku Co., Ltd (Japan). Lanthanum chloride solution was of atomic absorption spectrochemical analytical grade. All other reagents were of analytical grade.
Measurement of calcium concentration
Calcium concentrations were measured by atomic absorption spectrochemical analysis, using a model AA-860 atomic absorption spectrochemical analyser (Nippon Jarrel-Ash, Japan) equipped with an air-acetylene burner, at 423 nm.
Release of calcium ions from calcium polycarbophil
Fifty milligrams of calcium polycarbophil was placed in 50 niL buffer at various pHs, shaken fbr 20 min and centrifuged. To 1 mL supernatant, 01 M HCI containing 0-5% lanthanum chloride was added up to 25 mL. Calcium concentration in the sample solution was measured by atomic absorption spectrochemical analysis. The calcium concentration which was achieved by using 01 M HCI instead of each buffer, in the same manner, was considered to represent complete decalcification (control). The buffer systems used were diluted hydrochloric acid (pH 1-2), 01 M phosphate buffer (pH 2 0, 3 0), 01 M acetate buffer (pH 4-0, 5 0) and 01 M imidazole-hydrochloric acid buffer (pH 6 0, 7 0, 8-0).
Ionic strength was adjusted to 012 with sodium chloride and osmolarity was maintained at 290 mOsm kg -1 using mannitol.
Measurement of equilibrium swelling
Equilibrium swelling of polycarbophil and CMC-Na were measured by weighing the gel after centrifugation or by reading the meniscus at the interface between the fully hydrated polymer and the test solution. The equilibrium swelling of polycarbophil was calculated by dividing the gel volume or the gel weight by the weight of polycarbophil or calcium polycarbophil.
Effect of pH on apparent volume of equilibrium swelling Water sorption of polycarbophil as a function of pH was determined as the apparent volume expansion of polycarbophil. Fifty milligrams of polycarbophil was placed in a beaker, 100 mL buffer solution was added, and the mixture was incubated at 37°C for 24 h. The polymer solution was periodically stirred to remove trapped air bubbles. After 24 h, the fully hydrated polymer was transferred to a 10-mL graduated cylinder after removal of the supernatant by decantation, and was allowed to stand for 24 h. The meniscus of the interface between the fully hydrated polymer and the test solution was read. The buffer systems were as described above. The pH of the supernatant was measured with a pH meter (Horiba, Japan).
Osmotic difference between inside and outside of the hydrated gel
Polycarbophil (50 mg) was shaken in 50 mL 15% sodium bicarbonate solution for 1 h, then the mixture was centrifuged. Sodium ion concentrations of the supernatant and 1-5% sodium bicarbonate solution were measured with a model 710 automatic electrolytes analyser (Hitachi, Japan). Sodium ion concentration of 1.5% sodium bicarbonate solution was 177-7 ±0 3 mM. Sodium ion concentration in the gel was calculated as: Na+ in 1-5% NaHCO3 solution 一 Na+ in super- natant/volume of gel
Effect of ionic strength on equilibrium swelling
Calcium polycarbophil (250 mg) was placed in a 50 mL glass tube, to which was added 35 mL 0-1 M HC1. The mixture was shaken to release calcium and centrifuged. The pellet was washed with purified water, then 35 mL Britton-Robinson buffer (pH 7-0) containing various concentrations of potassium chloride was added and the mixture was shaken five times. After standing overnight, the sample was centrifuged and the weight of the pellet was measured. The ionic strengths of the test solutions were 0 08, 0 10, 0 15, 0-20, 0-50, 1 0, 2 0 and 30.
Effect of osmolarity on equilibrium swelling
After decalcification of 250 mg calcium polycarbophil, 35 mL 1-5% sodium bicarbonate solution containing 0, 5 0 or 10 0% glucose was added and the mixture was allowed to stand overnight. After centrifugation, the weight of the pellet was measured.
Effect of metal ions in gastrointestinal fluids on equilibrium swelling
After decalcification of 250 mg calcium polycarbophil, the obtained polycarbophil was hydrated with 35 mL 1-5% sodium bicarbonate solution. Calcium chloride (1.25 mmol), magnesium chloride (1-25 mmol), sodium chloride (2-5 mmol) or potassium chloride (2-5 mmol) was added to the swelling gel with 35 mL purified water. After centrifugation, the pellet was weighed.
Interaction between sodium ion and various calcium salts
Two hundred milligrams of polycarbophil was placed in the glass tube, then 35 mL 1-5% sodium bicarbonate solution was added and the mixture was shaken for 1 h. After centrifugation, various calcium salts (equivalent to 50 mg calcium) as powder and 35 mL 1-5% sodium bicarbonate solution were added to the gel. The mixture was shaken fbr 1 h and allowed to stand overnight. After centrifugation, the weight of the obtained gel was measured.
Polycarbophil was emulsified with 1-5% sodium bicarbonate solution at various concentrations and allowed to stand overnight. Polycarbophil concentrations were 0-8, 10, 1-2, 1-4, 1-6 and 2 0%. Viscosity of the test solutions was measured with a rotational viscometer (Rotobisco RV12, Haake), using a shear rate of 1-5-30 s_l, at 37°C. The viscosities of CMC-Na solutions of various concentrations were similarly measured, and the results were compared with those fbr polycarbophil.