Effects of Weak and Strong Cation Exchange Resins on Moisture Uptake Behavior of Ranitidine Hydrochloride

1. Introduction

     Hygroscopicity and deliquescence in phar-maceuticals is a cause of concern for many reasons including chemical instability, poor flow, change in dissolution characteristics, and change in appearance [1]. Some drugs are sensitive to moisture in the environment to such an extent that if left in contact with moist air for even short periods of time, crystalline materials turn into problematic paste or even liquid. Typically, the pharmaceutical industry has sought to control this effect by using very tight environmental controls in their manufacturing and formulation areas. Loading a drug onto a functional polymer-resin imparts some of the characteristics of the polymer-resin to the resulting resinate, in particular, the physical properties of a fine free flowing powder.

     It is known that ranitidine hydrochloride, an H₂ receptor antagonist is subject to degradation upon aging and that such degradation is accelerated by moisture and light [2]. The most popular method for dealing with such stability problem of ranitidine is film coating of tablets with suitable polymers. A report states that polymorphic form II of this drug is less hygroscopic than form I and has better drying characteristics [3]. Complexation of ranitidine HCl with cyclodextrin has proved to have improved drying characteristics and decreased hygroscopicity [4].

     In the present work, effects of weak cation and strong cation exchange resins on the moisture uptake behavior of ranitidine HCl in the presence and absence of light was studied to assess their ability in protecting ranitidine HCl from moisture.

2. Materials and methods

2.1. Materials

     Ranitidine hydrochloride was a gift sample from Neon Laboratories Ltd., Palghar, India (Batch no. RH 8681204). The resins used were gifts from Ion Exchange India Ltd., Mumbai, India. Weak cation resins were Polacrilex resin with exchangeable H⁺ (Indion 264) and Polacrillin potassium (Indion 234). Strong cation exchange resin was sodium polystyrene sulfonate (Indion 254). Resins were purified prior to use by successive washing in deionised water, 95% and 50% ethanol, and finally deionised water, and dried at the room temperature.

2.2. Preparation of drug resin complexes (DRC)

     Complexes containing ranitidine HCl and different resins were prepared using the batch method under varying conditions like drug-resin ratio (1:1, 1:2, 1:3, 2:3 and 2:1), temperature (10, 30, 40 and 50 °C), pH (1.0, 1.5, 2.0, 6.5, 7.0, 8.0 and 10.0) and drug concentration (3, 6 and 12 mg/ml) to get the optimum condition for maximum drug loading. During preparation, the drug and resin were stirred at 400-500 rpm. Resinates for further study were prepared under optimized condition.

Figure 1. Equilibrium moisture content of ranitidine HCl, resins, and DRCs under different RH conditions at 25±1°C. Results are the mean of three determinations ±SD. Symboles (tRanitidine HCl; (p) Indion 234; (×) Indion 264; (*) Indion 254; (J)DRC 234; (W) DRC 264; (r) DRC 254.  

2.3. Drug content in resinates

     Accurately, 100 mg of resinate was stirred with 200 ml 2 N NaCl at 500-600 rpm on a magnetic stirrer. After every 2 h, the solution was replaced with fresh 2 N NaCl solution until no further drug was detected in solution. Total drug eluted was determined spectropho-tometrically at 313 nm [5]. The drug content per 100 mg resinate is shown in Table1.

2.4. Storage stability of drug, resins and resinates

     One gram of the dry resins and ranitidine HCl and resinates equivalent to 1 g of ranitidine HCl were weighed accurately in aluminium dish and dried for two h at 60 °C before study. They were then placed in the humidity chamber at 40E2 °C and 75E5% RH for 17 h. Physical changes were noted and the percentage of increase in weight was calculated thereafter [6].The results are summarized in Table 2.

2.5. Determination of equilibrium moisture content

     Initial moisture content of ranitidine HCl, resin and resinate was determined using a moisture balance (Model no. EB 340 MOC, Shimadzu Corporation, Singapore). EMC determinations were made by placing 0.1 g of ranitidine HCl and resins while resinates equivalent to 0.1 g of ranitidine HCl in aluminum dish, which were then kept in desiccators for a period of 7 days. A liberal amount of the saturated salt solution (with excess crystal) was placed in the desiccators to maintain constant humidity condition.  

     Studies were done in triplicate and accordingly three desiccators were employed for each humidity condition. The desiccators were maintained at the constant temperature of 25±1 °C in a stability chamber. After 7 days, samples were removed and an increase in weight of samples was determined.

EMC was calculated with the following formula:

where P is the percent of moisture on dry basis, A is the initial moisture content, W is the initial weight of sample and B the change in weight in g after equilibrium has been attained (After storage for 7 days at 25 °C). EMC values were calculated from P with the

aid of equation given below:

2.6. Evaluation of hygroscopicity

     The study was carried out according to method described by Kaur et al. [7]. One g of ranitidine HCl, resins and 1.83 g of resinates (equivalent to 1 g of ranitidine HCl) were exposed to high humidity (75E5% RH) and temperature (40E2 °C) in a humidity chamber. Increase in weight was recorded after 2, 4, 6, 8, 10, 12, 14 and 16 h in the absence and presence of light (15 watt florescence light × 2). The moisture isotherms are depicted in Figures 2 and 3.

Table 1. Drug content in different resinates.

3. Results and discussion

3.1. Drug-resin complexation studies

     All of the parameters, viz. drug-resin ratio, temperature, pH and drug concentration, affected either the rate or the extent of loading of ranitidine HCl on weak and strong cation exchange resins. Study on the effect of drug-resin ratio suggests a higher drug loading for all of the resins in drug-resin ratio of 1:3 than 1:2, but the difference was little, therefore, drug-resin ratio of 1:2 was selected as the optimized ratio. Increase in the temperature during complexation increases the ionization of drug and resin. However, this effect is more pronounced in poorly water soluble and unionizable drug. High temperature tends to increase the diffusion rates of ion by decreasing the thickness of the stationary layer. However, Frank and Koebel [8] reported that cationic exchange resins are not affected as significantly by temperature changes as anionic exchange resins. In the case of drug-resin complex formation, water-soluble drugs completely ionize at the room temperature, and continuous stirring in batch process does not allow development of thick executive zone. As ranitidine HCl is water-soluble and all of the resins are cationic, therefore, in all of the cases loading was good at 30 °C. Decrease in the loading at higher temperature was found which may be due to pronounced disruptive effect.

Figure 2. Moisture uptake of ranitidine HCl, resins and resonates under 40±2 °C and 75±5 % RH in the absence of light.

Symboles:(t)Ranitidine HCl; (p) Indion 234; (×) Indion 264; (*) Indion 254; (J)DRC 234; (W) DRC 264; (r) DRC 254. 

     Ranitidine HCl possess two Pka values 2.7 and 8.2 while the weak cationic exchange resins (Indion, 234 and 264) have Pka in the range of 4-6, and the strong cationic resin (Indion 254) has Pka between 1-2. Therefore, when drug was complexed with weak cation exchange resins, maximum drug loading was observed at pH 6.5 as at this pH the weak cation exchange resins and dimethyl amino group of ranitidine HCl, which is responsible for Pka of 8.2, remained in the ionized form to the maximum extent. While strong cation exchange resin with Pka 1-2 can't remain ionized to a greater extent at pH 6.5, therefore, the maximum loading was observed at the pH 1.5 where both the strong resin and drug remain ionized to a greater extent. High ionization of the drug at pH 1.5 may be attributed to the ionization of the side chain of ranitidine responsible for Pka of 2.3. Higher loading was observed for the concentration of 6 mg/ml than 3 mg/ml because of more availability of drug for binding. However, further increase in concentration to 12 mg/ml showed decreased loading owing to saturation and more competition between drug-drug ions for the active binding site on resins.

3.2. Storage stability of drug, resins and resinates

     Storage stability under 40 ± 2 °C and 75 ± 5% RH for 17 h showed ranitidine HCl to be deliquescent as it converted into liquid upon moisture gain, while all resins were hygroscopic but not deliquescent (Table 2). Among the resonates, the percentage of weight gain was minimum in DRC 264 (10.22%), and it retained its free flowing characteristics; however, other resinates showed reduced flow and formation of sticky mass. More interestingly, the percentage of moisture gain by resinates was slightly less than that of the resins. Minimum weight gain by DRC264 may be due to the properties of resin itself which gained only 11.03% moisture under 40±2 °C and 75±5% RH after17 h. Another reason for less moisture gain by DRC264 may be because it consists of H⁺ form of resin having more resistance to the moisture than K⁺ form (Indion 234) and Na⁺ form (Indion 254). K⁺ and Na⁺ forms of resin swell to a greater extent in the presence of water.

Figure 3. Moisture uptake of ranitidine HCl, resins and resinates under 40 ± 2°C and 75 ± 5 % RH in the presence of light.

Symboles: (t)Ranitidine HCl; (p) Indion 234; (*) Indion 264; (*) Indion 254; (J)DRC 234; (W) DRC 264; (r) DRC 254.

Table 2. Physical changes and % of weight gain by ranitidine HCl, resins and resinates after storage under 40±2 °C and 75±5% RH for 17 h.

Results are the mean of three determinations ±SD.