Polymer Particle Size Influence on Indomethacin Release from Tamarind Seed Polyose: A Potential Sustained-Release Excipient

October 2, 2006
Pharmaceutical Technology, Pharmaceutical Technology-10-02-2006, Volume 30, Issue 10

The authors investigated the influence of various particle size fractions of Tamarind seed polyose (TSP) on indomethacin (IND) release from matrix tablets. They assessed the TSP fractions for swelling, density, and flow properties and the IND matrix tablets for tensile strength, friability, and release profile. Release kinetics was evaluated using Higuchi and Peppas equations. The density and flow properties showed that the size fraction affects the suitability of TSP as an entrapment polymer. The release profile showed that the release of IND from TSP matrix is swelling dependent, thereby affecting the kinetics of release.

Hydrophilic polymers are used to prepare sustained-release formulations because of their safety and stability (1). These polymers also aid the controlled release of water-soluble and water-insoluble drugs. The release behavior of drugs is the complex interaction of swelling, diffusion, and erosion (2). Synthetic hydrophilic polymers are used more often than natural polymers, but because of the costs associated with synthetic polymers, researchers are now showing interest in the nonsynthetic polymers such as gums.

Tamarind seed polyose (TSP) is a polysaccharide gum extracted from the seeds of Tamarindus indica (lmli). TSP is a polymer with an average molecular weight of 52,350 and a monomer of mainly three sugars—glucose, galactose, and xylose—in a molar ratio of 3:1:2 (3). It is insoluble in organic solvents and dispersible in hot water to form a highly viscous gel such as a mucilaginous solution with a broad pH tolerance and adhesivety (4, 5). In addition, it is nontoxic and nonirritant with haemostatic activity (4). It had been previously used in some drug formulations (5, 6).

For this study, TSP was used to prepare sustained-release formulations of indomethacin (IND), an anti-inflammatory drug substance with a short half-life of 2.4 ± 0.4 h (7). Its dosage regimen is 25 mg thrice daily, with peptic ulceration as its major side effect. IND is a suitable candidate for a sustained-release formulation. Tablets were prepared using direct compression because a wet granulation method would cause an initial swelling of the polymer, thereby affecting the swelling profile of the various fractions during release testing of the matrix tablets.

Materials and methods

Materials. TSP was extracted according to the method described by Nandi et al. (8). After extraction, the dried material was milled into powder form with a pestle and mortar. Six particle-size fractions were obtained by sieving with various mesh-number test sieves. Indomethacin was supplied by Unicure India Pvt. Ltd. (Noida, India) and magnesium stearate was obtained from Amrut Industrial Products (Lucknow, India). Indomethacin and magnesium stearate were used as supplied.

Micromeritic property study. The bulk and tapped densities of the powder were determined with a measuring cylinder, and true density was determined using a liquid pycnometer with benzene as the displacement fluid. The porosity was determined using the equation

in which E, ρbulk, and ρtrue are the porosity, bulk density, and true density, respectively. The flowability (indicated by the angle of repose, Hausner ratio, and Carr's index) of the powder also was studied. The angle of repose was measured using the fixed-height method. Carr's index was calculated using the equation

and

is the Hausner ratio.

Swelling profile study. The swelling profile was determined by transferring accurately weighed 1 g of each fraction into separate 100-mL stoppered measuring cylinders. These were made up to volume with distilled water and observations made for increases in volume of the TSP. Readings were taken at specified times until a constant volume was observed in each of the cylinders.

Preparation of tablets. TSP was the matrix material in this investigation. To mix the materials thoroughly, appropriate quantities of IND and TSP for each formulation were blended geometrically using a pestle and mortar. Magnesium stearate was then added by sieving it through a 120-μm-size sieve (mesh number 120). Tablets weighing 300 mg each with drug-to-TSP ratios of 1:3 were compressed on a single-punch tablet machine (Korsch AG, Berlin, Germany) for 30 s. Tablets were analyzed after 24 h to allow for elastic recovery and hardening and to prevent false low-yield values. The radial breaking strength and thickness of the tablets were then measured for each formulation with a Monsanto-type hardness tester and micrometer screw gauge, respectively. Friability tests were carried out with a Roche friabilator (Indian Equipment Corporation, Bombay, India). The average of five determinations per formulation was calculated for each test, and the mean value was used. Tensile strength of the tablets was obtained by applying the tensile strength equation (9, 10)

in which T is the tensile strength (MNm–2 ), P is the hardness (N); D is the diameter (m), and t is the thickness (m) of the tablets.

In vitro drug release study. Dissolution profiles of IND from matrix tablets were determined using the British Pharmacopoeia 2004 method I (basket method) (11). Dissolution tests were conducted with a USP XXI dissolution tester (Indian Equipment Corporation, Bombay, India) at a rotation speed of 50 rpm. This was done first for 2 h in simulated gastric fluid (0.1 N HCL, pH.1.2) and then for 6 h in simulated intestinal fluid (phosphate buffer, pH 7.0). A volume of 1000 mL of the respective dissolution fluids was used. At predetermined timed intervals, a fixed-volume sample was withdrawn and immediately replaced with an equal volume of the dissolution fluid maintained at 37 ± 0.5 °C. The samples were filtered (0.45-μm filter) and analyzed for IND content at 319 nm using a visible-light spectrophotometer (Shimadzu UV-260, Shimadzu Corporation, Japan). The cumulative percentage of IND released was calculated using the standard calibration curve for IND. All experiments were performed in triplicate.

The drug-release kinetics was analyzed according to Higuchi's diffusion equation (12)

in which Mt/M is the fractional drug release into the dissolution medium, K is a constant related to the properties of the drug delivery system, and n is the diffusional exponent, which characterized the drug transport mechanism. The value of n is 0.5 for Fickian transport (diffusion) and 0.5 < n < 1.0 for nonFickian transport and 1.0 for zero-order (case-11 transport). The release approaches zero-order kinetics when the value of n approaches 1.0

Table I: Swelling profile (mL) to test swellability of the various Tamarind seed polyose sizes.

Results and discussion

General. Swelling was observed during the dissolution test. On contact between TSP matrix and the dissolution medium, the macromolecular chains of TSP swelled at the tablet surface because of hydration and formed a gel-like layer around a dry core. The degree of tablet swelling was dependent on the particle size of the TSP powder and may be related to the swelling profile of the powder's particle size (see Table I). The table shows the powder's fraction size influenced the swelling profile. This may be related to the porosity of the fractions (see Table II). Bigger particle sizes (i.e., 40–60, 60–80, and 80–120 mesh sizes) with higher porosities had a faster initial rate of swelling than lower particle sizes because of quicker water penetration into the powder's mass. At 42 h, however, equal swelling was observed in all particle sizes, which was likely a result of the larger surface area of the smaller particle sizes. This larger surface area would override the porosity effect over time, resulting in the various powder fractions having equal swelling at time 42 h, except the 40–120-mesh particle-size fraction. This swelling profile influenced the release of IND from the matrix tablets prepared with higher particle-size fraction of TSP, which had a high higher initial release of IND than tablets prepared from lower particle sizes (see Figure 1 and Table III).

Table II: Micromeritic properties of Tamarind seed polyose powder and the mechanical properties of the indomethacin tablets.

Drug release occurred by diffusion through the swollen gel-like layer. At the same time, slow but gradual erosion and dissolution of the swollen layer was observed, which was much faster for larger particle sizes fractions (i.e., 40–60 and 60–80 mesh sizes). The erosion and dissolution was not to the extent of disrupting the dissolution kinetics. Furthermore, the hydration of the deeper parts (core) of the matrix continued until the end of the experiment. At the end of the experiments, the tablets reduced in size.

Table III: Calculated diffusional constant (k), exponent (n) and linear regression coefficient (r).

A biphasic release incorporating two phases was observed for all matrix tablets (see Figure 1). The lag phase occurred during the initial hydration and the second phase occurred after hydration, which lasted until the end of the experiment. The period for each phase differs, depending on the particle size fraction of the TSP used in the formulation.

Figure 1: Higuchi linearization plot of in vitro release profiles according to various particle-size fractions (mesh sizes indicated) for the Tamarind seed polyose matrix tablets.

Micromeritic property. The micromeritic properties of the various size fractions are shown in Table II. Results show that particle size affects the micromeritics of the TSP powder. The true density increased with a decrease in particle size while the porosity decreased. The Hausner's ratios, Carr's indices, and angles of repose generally show that the smaller size fractions (i.e., 80–120, <80, and <120 mesh size) have poor flow. This could be a result of cohesive forces within the particles, which would prevent flow (14). Therefore, in using TSP as a directly compressible polymer in a matrix-sustained release tablet, the particle size used should be taken into consideration to avoid poor flow from the hopper and prevent nonuniformity of tablet constituents.

Tablet characteristics. The tablets' tensile strength increased, and the friability values reduced with smaller particle-size fractions (see Table II). These results could be attributed to greater particle–particle contact as a result of a reduction in particle size, creating more interparticulate bonding and, thus, increasing the tablet strength (10). The friability values generally did not fall within the adequate range (i.e., 0.8–1.0%) (14).

Influence of particle-size fraction on dissolution kinetics. The dissolution data, when treated according to Higuchi's equation indicated that the formulations released the embedded IND by diffusion, with linear regression values for the two phases observed (i.e., a biphasic release profile)—the first phase (lag phase) at the beginning of the experiment and the second phase until the end of the experiment (Figure 1). The lag phase has a slower slope with a lower linear regression coefficient value r, and the second phase has a higher slope and greater value of r (see Table III). The lag phase was a result of slow swelling of the macromolecular chains' swelling at the tablet's surface. The Higuchi equation application shows that the particle size of TSP had an influence on the release.

When the result was subjected to the Peppas equation, a Fickian transport mechanism was generally observed—except for the tablets prepared from the 40–60 particle-size fraction, which released by a nonFickian transport pattern. The diffusional constant n varied with the size fraction. Size fraction 40–120 had the lowest n value, implying that it releases more by Fickian diffusion than did the other size fractions.

Generally, the kinetics of IND release from TSP polymer tablet matrix is controlled mainly by the swelling characteristics of the particular-size fraction (see Tables I and III). This result is in agreement with the work of Levina and Rajabi-Siahboomi (15), who stated in their study with HPMC matrices that decreased availability of free water within the tablet matrix may lead to decreased drug diffusion across the gel layer formed during dissolution.

Conclusion

The results obtained from this work indicate that the release of indomethacin (IND) from IND–Tamarind seed polyose (TSP) matrix was swelling dependent. The swelling was particle-size fraction dependent (see Table I). Results showed that the flow properties of the TSP powders was generally not encouraging. Therefore, a formulator must be careful in choosing the size fraction in preparing IND–TSP matrix tablets when using a directly comprehensible polymer. If a granulation method is used, however, the need to choose the size fraction may not be applicable.

The release kinetics of this work suggests that in using TSP as a polymer to prepare IND matrix tablets, a wide particle- size fraction would be more suitable in producing a more sustained release (see Table III). The particle-size fraction of 40–120 mesh size had the lowest K value at both phases of the Higuchi equation plot.

Acknowledgment

G. Alebiowu is grateful to the Academy of Sciences for the Developing World (Trieste, Italy) and the Council for Scientific and Industrial Research (Delhi, India) for the award of a research fellowship at the Central Drug Research Institute, Lucknow, India, and to Obafemi Awolowo University, Ile-Ife, Nigeria for releasing him.

Gbenga Alebiowu, PhD,* is a senior lecturer at the department of pharmaceutics, Obafemi Awolowo University, Ile-Ife, Nigeria. Mahdu Khanna and Satyawan Singh are scientists E and F, respectively, at the Central Drug Research Institute, Chattar Manzil Palace, PO Box 173, Lucknow 226001, India, galebiowu@yahoo.co.uk

*To whom all correspondence should be addressed.

Submitted: Dec. 21, 2005. Accepted: April 24, 2006

Keywords: excipients, formulation, solid dosage forms, tableting

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