Adsorptive property of kaolin in some drug formulations

Purpose: Kaolin is a known adsorbent, has lubricant property in powders and is therefore proposed as a lubricant in tablet formulations. This study was carried out to evaluate whether kaolin can adsorb some active drugs when mixed with them in tablet formulations even at very low concentrations. Method: Chloroquine and chlorpheniramine tablets were formulated with powder mixtures containing various concentrations of kaolin. The effect of kaolin on the physical properties of the tablets were examined and compared with those of standard lubricants like magnesium stearate and talc. Chloroquine and chlorpheniramine tablets and powders of amoxicillin/clavulanic acid oral powder and ampicillin/cloxacillin injection were also mixed with and without various concentrations of kaolin in water. Chemical assay of the drugs in the solutions were determined over time. Results: Kaolin significantly reduced the amount of each of the drugs in the solutions containing kaolin. Conclusion: Kaolin reduces the amount of some drugs when incorporated in drug formulations. Therefore, its inclusion in such drug formulations should not be encouraged.


Introduction
Many studies [1][2][3][4][5][6][7] in Nigeria have demonstrated the usefulness of many local raw materials in the formulation of pharmaceutical products.For example, kaolin has been shown to have superior lubricant property to talc and stearic acid at the concentration range of 0.2%-1.0%.Edible-clay also demonstrated such similar property 8 .Oladimeji et al's 9 assumption that kaolin, at such low concentrations, would not exert any appreciable adsorptive properties on drugs was not proven scientifically.However, it has been pointed out 10, 11 that the pressing need for local raw materials does not imply that their undesirable properties should be ignored.
Kaolin has long been employed to adsorb toxic substances from the alimentary canal and in the treatment of diarrhoea associated with food poisoning 12 .Although it has excellent lubricant properties in tableting, at low concentrations, its adsorptive nature may militate against its use even at such low concentrations.This work, therefore, aims at examining this assumption.

Materials and Methods
Pharmaceutical grade powders of kaolin, talc, lactose and maize starch (BDH, England), magnesium stearate (Hopkins & Williams, England), chloroquine sulfate (May & Baker, Nigeria), and chlorpheniramine maleate (Glaxo, Nigeria) were used.Also amoxycillin/clavulanic acid oral powder and ampicillin/cloxacillin injection powder, chloroquine and chlorpheniramine tablets were purchased from a local pharmacy.

Tablet Preparation
Granules containing either chloroquine sulfate or chlorpheniramine maleate, as active ingredients, were prepared using the wet granulation method 11 .Kaolin, talc, or magnesium stearate (0 -2% w/w) were separately added extra-granularly as lubricant/glidant to dried 50 g batches of free flowing granules of each drug formulation and mixed intimately for 10 min.The mixed granules were compressed using a singlepunch tableting machine, type KS (The Kilian and Co. GMBH, KOLN-NIEHL) into flat faced tablets (12.5 mm diameter and 300 mg in weight for chloroquine and 7.0 mm diameter and 80 mg in weight for chlorpheniramine formulations).

Dissolution studies
The chloroquine and chlorpheniramine tablets with or without kaolin were stored at ambient temperature for 1 month.Dissolution studies were then carried out on the tablets prepared in our laboratory and on those purchased locally, amoxycillin/ clavulanic acid, and ampicillin/cloxacillin powder combinations (also purchased locally) using Erweka Dissolution Apparatus 13 .For the drug samples purchased locally, the dissolution media were 500 ml of 0.5% w/w and 1% w/w kaolin in distilled water at 37±0.5 o C.

Assay of active ingredients in solution
Chloroquine and chlorpheniramine were assayed using the British Pharmacopoea (B.P.) titrimetric method for chloroquine sulfate tablet and B.P. spectrophotometric method for chlorpheniramine maleate tablet 14 .For the formed tablets, dissolution test was conducted after one month's storage.
For the study on amoxycillin/clavulanic acid oral powder, an amount of the powder equivalent to 0.1 g of the drug in the mixture was dissolved in sufficient distilled water to produce 100 ml.The solution (2 ml) was diluted to 100 ml with buffered copper sulfate solution, pH 5.2, and 10 ml was transferred to a test tube (covered with a stopper).The tube was heated on a water bath at 75 o C for 30 min, cooled rapidly to room temperature, and the volume was adjusted to 10 ml with distilled water.The extinction of a 1cm layer of solution at a maximum of about 320 nm was measured using the unheated buffered solution of the drug as blank (Smart A., 1991; unpublished article).
Each assay was carried out in five replicates and the mean drug content was recorded for each drug.

Results and Discussion
Kaolin enhanced the production of good quality tablets but it adversely affected the dissolution and release of the active drug in contact with it even at low concentrations.Table 1 shows that the presence of kaolin in the tablets caused a reduction in the amount of chloroquine and chlorpheniramine available in solution.The amount found in the solution decreased as the concentration of kaolin in the tablets increased.There was approximately 42% decrease in chloroquine concentration (from 82.4% to 41.1%) and 64% decrease in chlorpheniramine concentration (from 79.7% to 16.0%) when kaolin concentration in the tablets was 1%.The pure drug substances that were briefly exposed to kaolin were also affected.Table 2 shows that chloroquine and chlorpheniramine samples progressively lost their drug content in 1% kaolin suspension over a period of 40 min.Chloroquine lost about 50% in less than 8 min while chlorpheniramine lost the same amount in about 10 min.Probably, this is due to adsorption of the drugs by kaolin.Saturation of the adsorptive sites by chloroquine was within 20 min while chlorpheniramine achieved that in about 25 min.Also, the drugs purchased locally namely, chloroquine and chlorpheniramine tablets, amoxycillin/clavulanic acid and ampicillin/cloxacillin powder combinations were similarly affected.Within 60 min the amount of amoxycillin/clavulanic acid and ampicillin/cloxacillin powder combinations reduced from 100% to 89.5±0.8% and  3).These can be attributed to the adsorption of the drugs by the kaolin in the dissolution medium.
Kaolin is essentially a hydrated aluminium silicate 16 , the silica moiety being responsible for the absorptive activity of kaolin 17 .

Interaction studies
17, 18 between silica and some hydrophobic molecules showed that the positive charges on the molecules promote adsorption of the molecules on the silica.All the drugs studied here (chloroquine, chlorpheniramine, amoxycillin, clavulanic acid, ampicillin and cloxacillin) have nitrogen (N 2 ) atoms in their structure and these provide the binding sites for the silica in kaolin.The degree of the adsorption depends on the number of binding sites and how free these binding sites are Statistical comparison of the amount of drugs in solution in the presence or absence of kaolin, using a Student T-test at 95% confidence interval showed a 2-tailed pvalue of less than or equal to 0.01 indicating a significant adsorption of the drugs by kaolin.

Conclusion
The incorporation of kaolin in the formulation of chloroquine and chlorpheniramine tablets, and in amoxycillin/clavulanic acid and ampicillin/cloxacillin powder combinations significantly reduces the amount of the active drugs released into the dissolution medium from the formulations.Therefore, its inclusion in such drug formulations should not be encouraged.Kaolin, no doubt, has glidant properties.
Although the adsorptive ability of kaolin has been demonstrated for four drugs in this study, it is possible that kaolin may also adsorb other drugs.It is therefore not advisable to use kaolin as a lubricant in a tablet formulation.

Table 1 :
Content of chloroquine and chlorpheniramine in the tablets formulated with kaolin after 1 month storage