Modification and Characterization of Gellan Gum - Pharmaceutical Technology

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Modification and Characterization of Gellan Gum
The authors modified gellan gum using microwave technology and showed it can be used as an excipient in tablet formulations.


Pharmaceutical Technology
Volume 33, Issue 7, pp. 48-58

Carbohydrate polymers have been widely used in the formulations of pharmaceutical solid dosage forms becasuse of their biodegradability and lack of oral toxicity. Gellan gum (commercially available as Gelrite or Kelcogel) is a gel-forming polysaccharide produced by the microbe Sphingomonas elodea (formerly Pseudomonas elodea) and approved for food use by the US Food and Drug Administration in 1992 (1, 2). The gellan polymer consists of monosaccharide α-L-rhamnose, β-D-glucuronic acid, and β-D-glucose in a molar ratio of 1:1:2 linked to form a linear primary structure (3).

The native polymer is a high acyl gellan containing O-5-acetyl and O-2-glyceryl groups on the (1-3)-linked glucose residue. When exposed to alkali at high temperatures, both acyl groups are hydrolyzed, and the deacylated form of low acyl gellan is obtained. Low acyl gellan dissolves in water at temperatures >90 C. The low acyl solution forms gels in the presence of cations when cooled to gelling temperature (4). High acyl gellan solutions gel at much higher temperatures than do low acyl gellan solutions. High acyl gellan gels are very weak because the bulky acetyl and glyceryl groups prevent close association between gellan polymer chains in a double-helix formation and hinder compact packing of the cross-linked double helix. Aqueous solutions of gellan gum form gels on warming to body temperature and in the presence of cations (5). The mechanism of gelation involves the formation of double helical junction zones followed by aggregation of the double helical segments to form a three-dimensional network by complexation with cations and hydrogen bonding with water (6–8).

Gellan gum has been widely accepted for various pharmaceutical applications, although it has not been explored as a disintegrant in a tablet formulation. Gellan gels have been studied for application in ophthalmic drug delivery (9–11), oral sustained delivery (12, 13), beads (14), sustained delivery beads (15), controlled-release hydrogel with scleroglucan (16), and floating in situ gelling (17).

Since the implementation of polymeric materials in the field of pharmaceutical technology, numerous attempts have been undertaken to modify their physical and chemical properties and apply them in drug formulations. These approaches include cross-link polymers through covalent bonds using chemical and physical means. Formaldehyde, gluteraldehyde, and epichlorohydrin are among the most commonly used chemical means of cross-linking. Ultraviolet (18, 19) and gamma radiations (20) and temperature variations represent physical methods of cross-linking. Modifying temperature is one of the most favorable approaches because it avoids both the application of harsh chemical materials suitable for large-scale production and does not require a diversity of equipment and methods in the application (21).

Microwave technology is a growing interest in the pharmaceutical industry. Various applications include drying pharmaceutical excipients (22), granules (23-26), film coats (27), sterilization of ampules (28), and formulation of controlled-release beads (29).



Microwaves consist of thermal and nonthermal components. Microwave is a high-frequency radiation (300 MHz to 30 GHz) that possesses both electrical and magnetic properties. Transmitting microwave radiation results in the vibration of molecules by induced or permanent dipoles, thereby rapidly creating heat within the molecule. The intensity of vibration is a function of the quantity of microwave energy absorbed by the molecule. This value depends on the size, shape, and polarizability of the molecule as well as the extent of intermolecular bonding. Practically, the amount of energy absorbed by a molecule, P, is defined as:

in which f is the frequency of microwave, E is the electric field, E 0 is the dielectric constant of free space, Er is the dielectric constant of molecule, and tanδ is the loss tangent. The dielectric constant of a molecule is related to the polarizability of its constituent material, and the loss tangent is regarded as a measure of molecular interaction. Polar materials with a high level of molecular interaction are expected to absorb more energy, giving rise to a more intense molecular vibration and heat. The state of molecular interaction of an object may change its physicochemical properties over time (30, 31). Microwave heating offers rapid heat transfer, high speed, energy penetration, selective energy absorption, and instantaneous electronic control. It also requires compact equipment, fewer British thermal units (BTUs) and is environmentally clean.

Cross-linking natural macromolecules with microwave energy might solve toxicity problems resulting from remaining traces of chemical cross-linking agents and in vivo biodegradation products of chemically cross-linked macromolecules. This approach may help identify new uses for an existing excipient, which is relatively inexpensive and simpler than developing a new excipient.

The authors modified gellan gum by microwave technology and compared its various physicochemical properties with those of pure gellan gum. Confirmation of physical modification was carried out with differential scanning calorimetry (DSC) and X-ray diffractomy. Chemical changes in the modified material were analyzed with Fourier transfer infrared (FT-IR) spectroscopy. Optimization of the amount of distilled water and time of exposure in microwave was carried out using a 32 full-factorial design. Tablets of lactose and dibasic calcium phosphate that also contained modified gellan gum were prepared, and the effect on tablet disintegration time, hardness, and friability were measured.

Materials and methods

Materials. Gellan gum was received as a generous gift sample from CP Kelco (Mumbai, India). Dibasic calcium phosphate (DCP) IP, lactose IP, polyvinyl pyrollidone (PVP), and talc IP were used as received. All other solvents and chemicals were of AR grade. Deionized double distilled water was used throughout the study.


Table I: Factorial design for modification of gellan gum by microwave treatment.(ALL FIGURES ARE COURTESY OF THE AUTHORS)
Modification of gellan gum by microwave. Accurately weighed pure gellan gum (PGG) and deionized water were heated until the gum was completely hydrated. Aqueous hot solutions were poured in a lidless glass petri dish and cooled to room temperature. The entire mass was dried using a microwave unit (model MS-1921HE, LG Electronics, India) at 700 W for various time intervals. Dried material (modified gellan gum, MGG) was collected, passed through a #85 sieve, and preserved in a dessicator for further study. The experimental design was a 32 full-factorial design, and nine batches were prepared. The two independent variables were the amount of distilled water (X 1) and the time of exposure in microwave (X 2). The low (–1), medium (0), and high (+1) values of X 1 were 60, 70, and 80 mL; the low (–1), medium (0), and high (+1) values of X 2 were 8, 10, and 12 min, respectively. The swelling ratio in distilled water, HCl buffer (pH 1.2) and phosphate buffer (pH 6.8) were selected as dependent variables. The experimental design is shown in Table I.

Swelling ratio. The experiment was carried out in a 100-mL stopper graduated cylinder. The initial bulk volume of 1 g of MGG was noted and water was added in sufficient quantity to yield a 100-mL uniform dispersion. The sediment volume of the swollen mass was noted after 24 h at room temp. The swelling ratio was calculated by taking the ratio of the swollen volume to the initial bulk volume (32).

DSC. DSC thermograms were obtained (Model TA-60, Shimadzu, Japan). About 2 mg of sample were scanned in a hermetically sealed standard aluminum pan and heated over a 50–300 C temperature range at a rate of 10 C/min under constant purging of nitrogen at 40 mL/min. An empty sealed aluminum pan was used as a reference. The characteristic peaks and specific heat of the melting endotherm were recorded.

FT-IR spectroscopy. About 2% (w/w) of PGG and MGG samples, with respect to the potassium bromide (KBr) disk, was mixed with dry KBr (FT-IR grade). The mixture was ground into a fine powder before compressing into a disk. Each disk was scanned at a resolution of 4 cm–1 over a wave number region of 400–4000cm–1 using an FT-IR spectrometer (Spectrum GX FTIR system, Perkin Elmer, Waltham, MA). The characteristic peaks of IR transmission spectra were recorded.

X-ray powder diffractometry. These studies were performed with samples of PGG and MGG. The samples were filled into an aluminum sample holder and exposed to Cu K-α radiation (40 kV x 40 mA) in a wide-angle X-ray powder diffractometer (model X'Pert MPD, Philips Analytical, The Netherlands). Each sample was scanned in a continuous mode with the diffraction angle, 2θ, increasing from 5 < 2θ <100.

Particle size. Average particle size of PGG and MGG was measured with optical microscopy.

Angle of repose. The authors used the fixed-funnel and free-standing method to measure the angle of repose. The measurement was made in triplicate and the mean angle of repose was calculated.

Bulk and tapped density. Bulk and tapped densities of PGG and MGG were determined. The powder was placed inside the measuring cylinder of a tapped density apparatus, and the bulk volume was recorded. The samples were subjected to 200 taps, and the tapped volume was recorded. The bulk and tapped densities were computed.

Carr's index and Hausner ratio. The Carr's index and Hausner ratio of PGG and MGG were calculated by the equations provided in Aulton 2002 (33).


Table II: Formulation of lactose and DCP tablets.
Preparation of lactose and DCP tablet. Lactose was passed through a 60-mesh sieve and granulated using 10% w/v solution of PVP in alcohol. MGG was added intra-granularly. The wet coherent mass was passed through a 20-mesh sieve. The wet granules were dried at 60 C in a tray dryer. Fines were removed by sifting the granules on a 60-mesh sieve. The powder blend was then lubricated with talc. Lubrication was performed in a glass jar for 2 min (34). Granules of DCP were prepared similarly. Lactose (Batches A1 and A2) and DCP (Batches B1 and B2) tablets were prepared with and without disintegrant, respectively. Tablets were prepared on a rotary tablet press using flat-faced punches and dies (model Rimek-II, Karnavati Engg., Ahmedabad, India). The turret was rotated at a fixed speed of 30 rpm. Target weight of each tablet was 100 mg. The tablets were evaluated for disintegration time (DT), hardness and friability. Formulations are shown in Table II.

Disintegration time. The time required for disintegration of six tablets per batch was carried out in a USP disintegration test apparatus (model ED2L, Electrolab, Mumbai, India) containing 900 mL distilled water at 37 0.50 C.

Hardness and friability test. A hardness tester (Monsanto type) was used to measure tablet hardness (n = 5). Friability was evaluated as the percentage weight loss of 20 tablets tumbled in a friabilator (USP XXIII, model EF2, Electrolab, Mumbai) for 4 min at 25 rpm. The tablets were dedusted, and the loss in weight caused by fracture or abrasion was recorded as percentage friability.

Results and discussion

A gelation of PGG is a function of polymer concentration, temperature, and the presence of monovalent and divalent cations in solution. At low temperature, gellan forms an ordered helix of double strands. At high temperatures, single-stranded polysaccharides occur, which significantly reduce the viscosity of solution. PGG possesses high viscosity and gelling ability, which can be useful as release retardants in the preparation of a controlled-release formulation.

In our preliminary studies, we observed that the viscosity of PGG was reduced when it was exposed to high temperature. Hence, a modified form was prepared by exposing PGG in a microwave oven at higher temperature for different time periods. The results of physical changes attributed to PGG upon modification shows a marked decrease in viscosity as well as gelling ability. The MGG possesses excellent swelling property but lesser viscosity; this may be a result of the formation of single-stranded polysaccharides at higher temperature (35–37).




A 32 full-factorial design was constructed. The amount of distilled water (X 1) and time of exposure in microwave (X 2) were selected as independent variables. The swelling ratio in distilled water, HCl buffer (pH 1.2) and phosphate buffer (pH 6.8) were selected as dependent variables. A statistical model incorporating interactive and polynomial terms was used to evaluate the response.

in which Y is the dependent variable, b 0 is the arithmetic mean response of the nine runs, and b1 is the estimated coefficient for the factor X 1. The main effects (X 1 and X 2) represent the average result of changing one factor at a time from its low to high value. The interaction terms (X 1 X 2) show how the response changes when two factors are simultaneously changed (38). Factorial design was calculated with the help of Microsoft Excel 2007.




Swelling ratio in distilled water, HCl buffer, and phosphate buffer value for the nine batches (Batches A to I) showed a wide variation: 12.5–22, 9–18, and 7.5–16, respectively (see Table I). The data clearly indicate the values are strongly dependent on the selected variables. The value of correlation coefficient was found to be 0.9859, 0.9729, and 0.9571, respectively, indicating a good fit. It may be used to obtain a reasonable estimate of the response because a small error of variance was noticed in the replicates. The polynomial equation can be used to draw conclusions after considering the magnitude of the coefficient and the mathematical sign it carries, i.e., positive or negative. The data demonstrate that both the factors (X 1 and X 2) affect the swelling characteristics of MGG. The low value of the interaction between X 1 and X 2 indicates that it is not significant. A summary of regression output for dependent variables is shown in the following equations. The following equations for Y represent the regression output of dependent variables swelling ratio in distilled water, HCl buffer (pH 1.2), and phosphate buffer (pH 6.8), respectively.

in which DF is degree of freedom and F is Fischer's ratio.

A higher value of X 2 (time of exposure in microwave) was observed as compared with X 1 (amount of distilled water) in all three equations. It can be concluded that time of exposure in microwave (X 2) had more effect on swelling ratio than the amount of distilled water (X 1) in the modification of PGG. In all three media, X 1 and X 2 carried positive signs, meaning there was a positive effect of both factors on the swelling ratio. Batch I showed maximum swelling in all three media as compared with other batches. Therefore, Batch I was selected as the optimized batch and was used for further study. Higher values of X 1 (amount of distilled water) and X 2 (time of exposure in microwave) favors swelling ratio of MGG in distilled water, HCl, and phosphate buffer.


Figure 1: Differential scanning calorimetry (DSC) thermogram of (a) pure gellan gum and (b) modified gellan gum.
The purpose of treating PGG in microwave was to modify it. There was a no usage of any other material or chemical for microwave treatment except distilled water. MGG (optimized Batch I) was subjected to DSC, X-ray diffractomy, and FT-IR for confirmation of modification as well as any chemical changes afterward. Figures 1a and 1b depict the physical-state characteristic of PGG and MGG. The DSC thermogram of PGG exhibited an endothermic peak at 88.16 C and 270.5 C; however, it was slightly shifted to temperatures of 94.35 C and 284.29 C in MGG. In addition, a single exothermic peak was observed at 262.8 C in PGG and was slightly shifted to a lower temperature of 259.73 C in MGG. DSC analysis showed that the energy requirement was different for PGG and MGG, thereby indicating that the modification or change is only in the physical state. There were no major changes in peaks observed in PGG (see Figure 1a) and MGG (see Figure 1b), which indicated there were no chemical changes after microwave treatment. Moreover, the energy requirement of the treated sample was different, which indicates that the exposure time in microwave and the amount of distilled water exhibit significant influence on the modification of the physical properties of PGG.


Figure 2: X-ray powder diffractogram of pure gellan gum.
Figures 2 and 3 show the XRD patterns of PGG and MGG. The PGG pattern shows no peaks, which indicates its amorphous nature (see Figure 2). On the other hand, four different peaks were observed at different angles in MGG diffractogram (see Figure 3). These peaks suggest that PGG was converted from an amorphous to a crystalline structure. An X-ray diffractogram showed there was only a change in the physical state of PGG after microwave treatment.


Figure 3: X-ray powder diffractogram of modified gellan gum.
Microwave high energy is used for any treatment. There may be a chance of chemical degradation or changes of PGG during microwave treatment. FT-IR studies were performed to determine whether the samples had undergone any chemical degradation or modification. The FT-IR spectra of PGG (see Figure 4a) show characteristics peaks at ~1736 cm–1 for the carbonyl group, indicating C=O stretching; a strong band at ~3400 cm–1 for the OH group; a band at 2800–3000 cm–1 for C–H stretching; a band at ~1380 cm–1 for methyl C–H; and a band at ~1060 –1150 cm–1 for C–O stretching for alky ether. Figure 4b shows the FT-IR spectra of MGG, which has similar characteristics peaks. The authors observed the same functional group present before and after microwave treatment. Hence, the gellan gum had not degraded during the microwave treatment, or there was no chemical degradation, change, or modification observed in MGG.


Figure 4: FT-IR spectra of (a) pure gellan gum and (b) modified gellan gum.
On the basis of these results, treatment given in microwave did not change the chemical structure, modify, or degrade MGG. That is, the chemical nature and safety of the material was retained throughout and after microwave treatment. High energy (such as that used in microwave) did not affect the chemical characteristics of gellan gum. There was only a change in its physical state.


Table III: Results of physicochemical properties of pure and modified gellan gum.
Results of various physicochemical properties of PGG and MGG are shown in Table III. Flow properties of the powder are determined from the value of the angle of repose. Powder flowability depends on three general areas: the physical properties of the particle (e.g., shape, size, compressibility), the bulk powder properties (e.g., size distribution, compaction), and the processing environment (e.g., storage, humidity) (39). Angle of repose, Hausner ratio, flow rate through an orifice, and shear-cell methods are described in the US Pharmacopeia (40). The average particle size of PGG and MGG was 240 and 160 m. Bulk and tapped densities are listed in Table III. The angle of repose of PGG and MGG was 43 and 37, respectively. Results reveal that PGG and MGG exhibited passable and fair flow, respectively. Results of flow property and compressibility conclude that MGG is not suitable for direct compression. Therefore, granulation is recommended to improve flow. Compressibility data of MGG are superior to those of PGG.


Table IV: Results of lactose and DCP tablets containing modified gellan gum.
To investigate the disintegrant properties and the versatilities of the MGG, lactose, and DCP, tablets were prepared and evaluated for DT, hardness, and friability (see Table IV). There was an acceptable hardness and friability for lactose and DCP tablets. The incorporation of MGG in lactose tablets resulted in a marginal increase in hardness and a decrease in friability. DCP tablets remain unchanged , most likely because of the presence of facilitated flow and densification of the granule in the die. DCP shows higher fragmentation propensity as compared with lactose, which could be one of the reasons for higher hardness values of DCP tablets compared with lactose tablets.

Lactose tablets showed relatively faster disintegration (Batch A1) than DCP tablets (Batch B1), which may be attributed to an increased water uptake by lactose tablets. The slightly higher DT of DCP tablets compared with lactose tablets may be attributed to higher crushing strength and poor aqueous solubility (41). Results reveal that tablets containing an insoluble excipient (DCP) and MGG (Batch B2) showed substantial decrease in DT as compared with Batch B1, which contained no disintegrant. For lactose tablets with and without MGG, there was a decrease in DT. Lactose is a water-soluble excipient, and hence it works as an auxiliary disintegrant. A comparison of batches A2 and B2 shows that there was more decrease in DT in batch B2. Therefore, MGG led to excellent results in the presence of a hydrophobic excipient (DCP).

The following results were concluded when PGG was treated in microwave:
• There was remarkable reduction in viscosity but swelling remain intact
• Flow property and compressibility of MGG was changed as compared with PGG
• DSC thermograms proved that there was a change in energy requirements of MGG but not removal or addition of any peaks
• X-ray diffraction revealed that there was a change of nature from amorphous to crystalline, which indicates only a physical modification
• There were no chemical degradation, changes, or modification in functional groups of MGG, indicating no chemical changes in the structure, which was proved with FT-IR analysis.

MGG was explored as a disintegrant in lactose and DCP tablets. MGG functions as a disintegrant in tablet formulation and shows excellent DT with DCP (hydrophobic excipient) as compared with lactose (hydrophilic excipient).

The areas in which further work can be conducted include using a fluid-bed dryer or spray dryer for preparing a modified excipient. MGG can be used in combinations and ratios of presently accepted super disintegrating agent such as crospovidone, sodium starch glycolate, and croscarmellose.

Conclusion

Results of this study show that modified gellan gum can be used as a disintegrant in tablet formulation. Only physical modification was carried out in the microwave oven. Modified gellan gum shows excellent swelling capacity, flow property, and compressibility.

Dhiren P. Shah* is an assistant professor in the department of pharmaceutics at CK Pithawala Institute of Pharmaceutical Science and Research, Via Magdalla Port, Nr. Malvan Mandir, Dumas Road, Surat, Gujrat, India 395 007, tel. +91 261 6587286, fax: +91 261 272399. Girish K. Jani is a principal at SSR College of Pharmacy (UT of Dadra and Haveli, India).

*To whom all correspondence should be addressed.

Submitted: Sept. 10, 2008. Accepted: Oct. 1, 2008.




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