Friday, May 29, 2009


Stretch Drug Release Times

Guar gum is a potential matrix former for creating improved controlled-release tablets

Oral ingestion has long been the most convenient and commonly employed drug delivery route due to ease of administration, high patient compliance, few sterility constraints, and dosage form design flexibility. Hydrophilic polymers are becoming very popular for formulating oral controlled-release tablets. The hydrophilic gel-forming matrix tablets are frequently used for oral extended-release dosage forms due to their simplicity, cost effectiveness, and reduced risk of systemic toxicity from dose dumping.1 Furthermore, pH-independent drug release is preferable for oral extended-release formulations because it is not affected by intra- and inter-subject variations in either gastric pH or gastrointestinal transit time.

Propranolol hydrochloride, a non-selective beta-adrenergic blocking agent, is widely used in the treatment of hypertension, angina pectoris, and many other cardiovascular disorders.2 It is highly lipophilic and is almost completely absorbed after oral administration. Its bioavailability is very limited (30%) due to the hepatic first-pass effect, however.3 Its elimination half-life is also relatively short (about six hours).4 Therefore, it was chosen as a model drug for preparation of the once-daily extended-release dosage form.

Guar gum is a branched polygalactomannan isolated from the seeds of leguminous herbs.5 It is a linear (1?4) mannose to which (1?6) galactopyranoside single subunits are attached as the side chains.6 Guar gum is commonly used as a thickening agent in food industries and as a binder and disinte-grating agent in solid dosage forms.7 It has also been used as a carrier for colon targeted drug delivery in pure as well as treated forms.8 Guar gum is an inexpensive, biodegradable adjuvant and is official in the Indian Pharmacopoeia, the United States Pharmacopeia (USP), and the National Formulary. Researchers have recently demonstrated optimization techniques for developing functional solid dosage forms.

In this investigation, guar gum was used to form a controlled-release matrix. Various controlled-release formulations were prepared by wet granulation technique and evaluated for weight uniformity, friability, hardness, drug content uniformity, and in vitro drug release.

Materials and Methods

Propranolol hydrochloride was supplied by Maan Pharmaceuticals, Mehsana, Gujarat, India. Guar gum (viscosity of 1% aqueous dispersion is 4,000 cps) was obtained from H.B. Gum Industries, Kalol, Gujarat, India. Dicalcium phosphate and polyvinyl pyrrolidone (PVP) K30 were obtained from S.D. Fine Chemicals. All other materials used were of pharmaceutical grade.

Treatment of guar gum with acid: Guar gum (4 g) was mixed with a blend of 20 ml of alcohol and 1 ml of lactic acid. The alcohol was allowed to evaporate at room temperature, and the mass was dried in a microwave oven for one minute. Similarly, guar gum was treated with blends of alcohol and tartaric acid and alcohol and citric acid, then evaluated for swelling capacity.

Swelling capacity:9 The study was carried out in a 100 ml capacity graduated cylinder. The initial bulk volume of 1 g of treated adjuvant (guar gum) was noted and water was then added in sufficient quantity to yield 100 ml of uniform dispersion. The sediment volume of the swollen adjuvant was noted after 24 hours of storage at room temperature. The swelling capacity was calculated by taking the ratio of the swollen volume to the initial bulk volume. The swelling capacity study was also carried out in simulated gastric fluid (pH 1.2).

A mixture of natural and treated guar gum could be used as matrix-forming materials in tablet formulation.

Preliminary trials: Propranolol hydrochloride; untreated guar gum and guar gum treated with citric acid, tartaric acid, and lactic acid; and dicalcium phosphate dihydrate were physically mixed properly and bound with 3% weight/volume alcoholic PVP K30 solution. Prepared granules were then compressed into a tablet weighing 265 mg using 9.0 mm shallow biconcave punches in a Rotary Tablet Press (Rimek) and evaluated for weight uniformity, fri-ability, hardness, drug content uniformity, and in vitro drug release. The composition of various batches is shown in Table 1 (see left, top).

Propranolol hydrochloride tablet preparation: The same method was used to prepare tablets with an optimized concentration of guar gum and treated guar gum. The composition of study batches is shown in Table 2 (see left, center).

In vitro drug release:10Drug release studies were carried out using USP 23-NF 18 dissolution apparatus (Apparatus 1, 100 rpm, 37�0.5oC) in 900 ml 0.1 N HCl for two hours, because the average gastric emptying time is about two hours. The dissolution medium was replaced with 900 ml 6.8 pH phosphate buffer, and the dissolution was continued for eight hours. Ten ml of the sample were taken at the end of the specified time interval (hours two, three, four, five, six, seven, and eight) and analyzed by UV spectrophotometer at 290 nm.

Drug content of the tablets: The propranolol hydrochloride content in tablets was analyzed using the method specified in USP 23-NF 18.

Results and Discussion

The results of swelling capacity indicate that the swelling property was improved by treatment with different acids as compared to pure guar gum (see Table 3, left, bottom). Guar gum-containing tablets treated with both lactic and citric acids showed similar dissolution profiles, but the tablets containing tartaric acid-treated gum showed relatively faster drug release, because tartaric acid is less soluble in alcohol. Citric acid is more hygroscopic in nature than either tartaric or lactic acid; therefore, lactic acid-treated guar gum was selected for further study.

The physical parameters of the tablets show that all batches had the desired physical characteristics. The hardness, friability, and weight variation studies comply with USP standards.

Figure 1. Comparative drug release profile of study batches.

The results of swelling capacity indicate that the swelling property was improved by treatment with different acids as compared to pure guar gum.

The dissolution study from the preliminary trial shows that the drug was released at a very slow rate from the tablets prepared using untreated guar gum because of increased drug diffusion residence. The tablets containing treated gum showed a burst effect; about 90% of the drug was released within eight hours. Therefore, we decided to use a blend of treated and untreated guar gum to increase the sustaining effect.

As shown in Figure 1 (above), all study batches had satisfactory dissolution data for all formulations. The cumulative percent drug release for all formulations was in the range of 50% to 70% within seven hours. The regression coefficient was near 0.999, showing that the drug release follows the Higuchi model. The diffusion exponent value (n) of the Korsmeyer-Peppas model was found to be below 0.43, showing that diffusion is the mechanism of drug release from the dosage form.11

We concluded that a mixture of natural and treated guar gum could be used as matrix-forming materials in tablet formulation. �

Prajapati is assistant professor at Shri Sarvajanik Pharmacy College, Mehsana, North Gujarat, India. Contact him atM.N.Patel is a lecturer at B.S. Patel Pharmacy College, Mehsana, Gujarat. Shah is a student at Shri Sarvajanik Pharmacy College. L.D. Patel is dean and professor at DDIT Pharmacy College, Nadiad, Gujarat. C.N.Patel is a professor at Shri Sarvajanik Pharmacy College.


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