Table 2: Comparison of major IR peaks of drug polymer mixture with pure Cefixime

Major peaks cm^-1 wave number of
Cefixime	Cefixime : HPMC K4M (2:1)	CF7
3290.67	3294.53	3294.53
2947.33	2947.33	2939.61
1340.57	1338.64	1336.71
1091.75	1093.67	1095.60
1028.09	1028.09	1030.02

The gastro-retentive drug delivery system can be retained in the stomach and assists in improving the oral sustained delivery of drugs that have an absorption window in a particular region of the GIT. These systems help in continuously releasing the drug before it reaches the absorption window, thus ensuring optimal bioavailability. Several approaches are currently used to prolong gastric retention time. These include floating drug delivery systems, swelling and expanding systems, and other delayed gastric emptying devices.⁷ Floating drug delivery systems can be differentiated as polymer mediated non-effervescent and effervescent drug delivery systems, designed on the basis of delayed gastric emptying and buoyancy principles, appear to be an effective and rational approach to the modulation of controlled oral drug delivery.⁸ The principal of buoyant preparations offers a simple and practical approach to achieve increased gastric residence time for dosage form and sustained drug release.⁹ The present investigation describes the formulation development of an floating drug delivery system for cefixime trihydrate.

The present research work was to study systematically the effect of formulation variables on the release and floating properties of Cefixime Trihydrate floating tablet.

MATERIALS AND METHODS:

Cefixime trihydrate was received as a gift sample from Okasa Pharmaceutical Pvt Ltd Satara, Maharashtra, India. Hydroxypropyl methyl cellulose (HPMC K4M) 4000 mPa.s was received as a gift sample from Colorcon Asia Pvt Ltd. Carbopol 934P was purchased from Central Drug House and Sodium CMC, Sodium Bicarbonate and Magnesium Stearate were purchased from S.D. Fine Chemicals (Mumbai, India).All other ingredients were of analytical grade.

Preformulation study:

Prior to development of dosage forms with a new drug candidate, it is essential that certain fundamental physical and chemical properties of the drug molecule and other derived properties of the drug powder as well as excipients are determined.¹⁰

Table 3: Floating ability of various cefixime tablet formulation

Batch Code	Floating Lag time (min)	Floating duration (min)	Integrity
CF1	Not float	Not float	Intact
CF2	Not float	Not float	Intact
CF3	32	20	Intact
CF4	28	40	Broken after 6-8hr
CF5	20	60	Intact
CF6	40	>720	Intact
CF7	49 sec	>720	Intact

All values are expressed as mean ± SD, n=3, CF= Formulation codes

Excipients Compatibility study:

The successful formulation of a suitable and effective solid dosage form depends upon the careful selection of the excipients. Excipients are added to facilitate administration, promote the consistent release and bioavailability of drug. It’s necessary to study the compatibility of excipients with drug. Here IR spectroscopy was used to investigate and predict any physicochemical interaction between components in a formulation and to the selection of suitable compatible excipients.11 Infra red spectrophotometer (IR): Infrared (IR) spectroscopy was conducted and the spectrum was recorded in the wavelength region of 4000 to 400 cm⁻¹. The procedure consisted of, dispersing a sample (drug alone, polymers alone and mixture of drug and polymers in KBr) and compressing into discs by applying a pressure of 7 tons for 5 min in a KBr press. The pellet was placed in the light path and the spectrum was obtained.

Preparation of Floating Tablet of Cefixme :

Each floating tablet containing 200 mg Cefixime were prepared by direct compression method using different formula as shown in Table 1. Cefixime pure drug was mixed with required quantity of HPMC K4M, sodium CMC, carbopol 934P, sodium bicarbonate and lactose by geometric mixing in mortar and pestle for 10 min. Lactose being a water soluble filler was used to maintain constant tablet weight as well as to counter balance poor water solubility of drug. The above powder was lubricated with magnesium stearate in mortar and pestle for 2 min. The tablet constant weight was 550 mg per tablet. The lubricated blend was compressed into tablets using 12 mm flat-face round tooling on CLIT Pilot Press rotary tablet machine. Compression force was adjusted to obtain tablets of hardness 6-9 kg/cm²with 4.0± 0.2 mm tablet thickness.^12-16

Table 4: Interpretation of diffusional release mechanisms

Sr. No.	Release exponent	Drug transport mechanism
1	0.5	Fickian diffusion
2	0.5 < n < 1	Anomalous transport
3	1.0	Case II Transport
4	Higher than 1.0	Super case II transport

Table 5: Release kinetics for different Models

Formulations	n	k	r	Best fit model
CF1	0.7244	0.4071	0.9949	Zero Order
CF2	0.5680	1.2128	0.9885	First order
CF3	0.4873	2.1935	0.9828	Matrix
CF5	0.4693	3.0234	0.9952	Matrix
CF6	0.3951	5.3375	0.9960	Peppas
CF7	0.5762	1.5843	0.9910	Matrix

Evaluation of Floating Tablets:

In-Vitro Buoyancy Study ¹⁷

The in-vitro buoyancy was characterized by floating lag time and total floating time. The buoyancy test of tablet was performed by placing them in dissolution test apparatus containing 900 ml 0.1N HCl, maintained at 37±0.5^◦C and agitated at 50 rpm. The floating onset time (time period between placing tablet in the medium and buoyancy beginning) and floating duration of tablet was determined by visual observation. The results of floating are summarized in Table 3.

Estimation of cefixime trihydrate¹⁸

Initially Palladium Chloride (PdCl₂) solution was prepared as a 2×10^-3 M solution, followed by 0.2 % w/v solution of sodium lauryl sulphate (SLS) in water and than the Walpole’s acetate buffer of P^H 4.8. Tablets were powdered and a quantity of powder equivalent to 20 mg of the free base was extracted by shaking with 60 ml methanol for 15 min with stirrer. The mixtures were filtered through whatman filter-paper into 100ml volumetric flask and then diluted to volume with same solvent. From the above solution 0.25 – 0.6 ml is mixed with 2ml of PdCl₂, 4ml of buffer of P^H4.8 and 1ml of SLS was taken in 10 ml of volumetric flask. The flask was kept in thermostated water bath for 45 min at 80^oC and was diluted to volume with water. The solution was then cooled to room temperature and the intensity of developed yellow color was measured at 347 nm. The concentration was calculated from the equation obtained from standard calibration curve.

In vitro Drug Release Study

The in vitro drug release study was performed using USP 24 type-2 paddle dissolution test apparatus. The drug release study was carried out in 0.1 N HCl for 12 h in 900 ml of dissolution media, maintained at 37±0.5^◦C and paddle agitated at 100 rpm. Periodically 5 ml samples were withdrawn and filtered through whatman filter paper and samples were replaced by its equivalent volume of dissolution media. The concentration of Cefixime was measured spectrophotometrically at 285.10 nm using double beam UV/visible spectrophotometer (UV-1800, Shimadzu, Kyoto, Japan).Cumulative percentage drug release was calculated using an equation obtained from a standard calibration curve. Analysis of data was done by using ‘PCP Disso V-3’ software; India. The graph of times vs. % cumulative release is shown in Figure 1.

Table 6: Kinetic drug release data of cefixime floating tablet

Formulations	Zero order (R)	First order (R)	Matrix model (R)	Hix-Crowel Model (R)
CF1	0.9949	0.9904	0.9465	0.9943
CF2	0.9752	0.9885	0.9684	0.9884
CF3	0.9406	0.9815	0.9823	0.9748
CF5	0.8845	0.9765	0.9952	0.9579
CF6	0.7551	0.9448	0.9991	0.9014
CF7	0.9755	0.9824	0.9910	0.9710

Treatment of dissolution data with different kinetic equations:

To analyze the mechanism of release and release rate kinetics of the dosage form, the data obtained were fitted into Zero order, First order, Higuchi matrix, Peppas and Hixson Crowell model using ‘PCP-DISSO – V-3’ software. Based on the r-value, the best-fit model was selected.

Swelling index (Water uptake) study: ^13,
19

The swelling properties of HPMC matrices containing drug were determined by placing the tablet matrices in the dissolution test apparatus, in 900 ml of distilled water at 37 ± 0.5 ⁰C paddle rotated at 50 rpm. The tablets were removed periodically from dissolution medium. After draining free from water by blotting paper, these were measured for weight gain. Swelling characteristics were expressed in terms of percentage water uptake (WU %) according to the equation. The swelling index is given in Figure 2.

Weight of swollen tablet – Initial weight of the tablet

WU % = ---------------------------------------------------- x 100

Initial weight of the tablet

Stability Study:^20,
21

The formulated floating tablets were subjected for stability study at 40⁰C and relative humidity at 75 % for three months. The product was evaluated for, buoyancy, drug content and in vitro drug release and excipients interactions by FTIR.

RESULT AND DISCUSSION:

Preformulation study:

Initially, procured raw materials were characterized for given specifications and comply with provided literature value. Physical mixture of cefixime and polymers were prepared and evaluated for compatibility.

Excipient Compatibility study: The possible interaction between the drug and the polymers was studied by IR spectroscopy. The possible interaction between the drug and the polymers was studied by IR spectroscopy. The IR spectra’s of pure Cefixime, HPMC K4M, Sodium CMC, Carbopol 934P and physical mixture of Cefixime with HPMC K4M, Sodium CMC, Carbopol 934P in CF7 are shown in Table 2. Pure Cefixime showed 3290.67, 2947.33, 1340.57, 1091.75, 1028.09 cm^-1wave number as major peaks. The results revealed no considerable changes in the IR peaks of cefixime when mixed with polymers compared to pure Cefixime,

Table 7: Cumulative % drug release for stability study of batch CF7

Time (min)	Cumulative % Drug Release (Initial)	Cumulative % Drug Release (After storage at 40°C after 3 month)
0	0.000	0.00
30	13.543	13.90
60	17.999	18.60
120	21.657	20.86
180	25.883	27.02
240	32.322	31.56
300	38.477	37.88
360	44.072	42.09
420	51.704	49.23
480	56.776	54.25
540	62.332	63.56
600	68.738	67.07
660	74.219	68.21
720	79.409	78.145

Formulation of floating tablet:

For floating drug delivery system, the polymers used must be highly swellable in shortest time. Hence HPMC (HPMC K4M) was preferred because it is widely used as low-density hydrocolloid system; upon contact with water, a hydrogel layer would be formed to act as a gel boundary for the release of drug, but it would fail to retard the release of drug through the matrix because of its solubility in stomach pH. Various grades of HPMC were reported to have duration of buoyancy of more than 8 hours in the simulated meal medium, as well as in distilled water. Polymer with lower viscosity was shown to be beneficial than higher viscosity polymer in retarding drug release. In order to retain the dosage form in the stomach for a long period of time and to avoid erosion and dissolution Sodium CMC was used as a gelling agent in combination with HPMC to retard the drug release. Carbopol 934P was used as a swelling agent which also helped in gastric retention due to its adhesive properties. But carbopol 934P affected floating properties. Sodium bicarbonate (NaHCO₃) was incorporated in the formulation in such a way that when in contact with the acidic gastric contents, CO₂ is liberated and gets entrapped in swollen hydrocolloids, which provides buoyancy to the dosage form. Lactose was included in formulation as hydrophilic agent, with assumption that capillary action of lactose may facilitate higher drug release without affecting the matrix (floating ability), the incorporation of lactose showed appropriate release and floating time.

In all the formulations designed weight of a single tablet was kept constant. The weight of a single tablet was 550 mg.

Evaluation of Floating Tablet:

In-vitro Buoyancy study : Formulations from CF1 and CF2 did not float; this was due to the lower percentage of gas generating agent and high concentrations of carbopol 934P polymer. The formulation CF3, CF4, CF5 and CF6 floated but the lag time was more. CF6 the duration was more than 12 h. It was seen that as carbopol 934P concentration decreased, the floating capacity increased. CF7 floating lag time was less due to high gas generating agent which were formulated later considering the above results. It was observed that paddle speed affected the floating properties of tablet as shown in Table 3. It was also observed that paddle speed affected the floating properties of tablet. In the study with 400 ml 0.1N HCL without paddle it was found that the floating lag time decreased and the duration increased for the same formulations.

In-vitro Drug release Study:

From the dissolution study it was concluded that release from the matrix is largely dependent on the polymer swelling, drug diffusion and matrix erosion. The drug release study is carried out up to 12 hrs. The percentage drug release from batch CF1 to CF7 vary from 54.17% to 79.41%. Large concentration of high viscosity polymer induces the formation of strong viscous gel layer that slowed down the rate of water diffusion into the tablet matrix, which may result in the retardation or decreases the drug release. Being water soluble polymers, they dissolve and form pores filled liquid in which drug can there after diffuse in dissolution medium. Drug release of all batches is shown in Fig. 1. From the results of in vitro release study it was observed that, the order of release was found to be dependent on carbopol 934P concentration. Being a matrix forming agent HPMC directly affected the drug release.

Treatment of dissolution data with different kinetic equations:

The dissolution data was treated with different kinetic equations. The three parameters were used to study the release mechanism, n- Release exponent, k- Release rate constant and r-Correlation coefficient. Linear regression analysis and model fitting showed that as these formulation followed Matrix model, which has higher values of correlation coefficient. Thus the release of cefixime is controlled by matrix dissolution model.

Log % R = log K + n log t

Where,

% R = percentage drug release

K = release ratio constant

n = is the diffusional release exponent that could be used to

characterize the different release mechanism.

The value of exponent can be used to characterize the release mechanism of controlled release matrix tablet. The mean diffusional exponent values (n) ranged from 0.3951 to 0.8279 indicating that all these formulations presented a dissolution behavior controlled by anomalous transport, (When n tends towards< 0.5 (Table. 4).

While the kinetic constant (k) ranged from 0.2786 to 5.3375 indicating that cefixime release from hydrophilic binder matrices followed Fickian diffusion (Table. 5). The correlation coefficient revealed that Matrix model was better applicable to release data for CF7 model having good floating properties.

Figure 1: Drug release Profile of all formulations

The curve fitting results of the release rate profile of the designed formulations gave an idea on the mechanism of drug release.Data of in vitro release was fitted to various models like Krosmeyers-peppas, Zero order, First order, Higuchi matrix and Hixson crowel. The R² value indicated that Higuchi model is the best fitted model to the release profile of CF7 formulation. These results indicate that the release mechanism for Cefixime may be diffusion mechanism followed by Non-Fickian transport.

Swelling index (water uptake) study:

The swelling index of batches CF1 to CF7 is shown in Fig. 2. Polymer matrices representing swellable matrix drug delivery systems are porous in nature. When these matrices come in contact with water or aqueous gastrointestinal fluid, the polymer absorbs the water and undergoes swelling or hydration. The rapid formation of a viscous gel layer upon hydration suggests that swelling is associated with polymer chain relaxation with volume expansion. The liquid diffuses through the polymer matrix at a constant velocity, and the rate of diffusion of the liquid and that of macromolecular relaxation of the polymer are almost of the same magnitude or, possibly, the rate of diffusion of the liquid is relatively higher than that of relaxation of the polymer segment.

This mechanism gives the idea regarding the water uptake study of various grades of polymer. This phenomenon is attributes to that the swelling is maximum due to water uptake and then gradually decreased due to erosion. Swelling measurement was performed separately in order to collect on the basis of weight increase over time. The swelling is due to presence of hydrophilic polymer, which gets wetted and allows water uptake leads to increase in its weight.

The swelling index was calculated with respect to time. As time increase, the swelling index was increased, because weight gain by tablet was increased proportionally with rate of hydration. Later on, it decreased gradually due to dissolution of outermost gelled layer of tablet into dissolution medium. The direct relationship was observed between swelling index and polymer concentration. The increase in concentrations of sodium CMC increases swelling indices and faster rate of swelling. Results of Water uptake study showed that the order of swelling in these polymers could indicate the rates at which the preparations are able to absorb water and swell. Maximum liquid uptake and swelling of polymer was achieved up to 10 hrs and then gradually decreased due to erosion.

Fig. 2 Relationship between swelling index and time for all formulations

It was found that the formulation with high sodium CMC content had higher swelling index. In all the formulations not having sodium CMC undergone fast erosion so less swelling index (CF4).Shown in Fig. 2

Criteria for selection of optimized formulation:

Review study was carried out to fix the concentration of HPMC K4M, Carbopol 934P and SCMC to optimize formulations. The optimum drug release, floating lag time and total floating time were the main criteria for the selection of optimized formulation. The formulation CF7 was selected as the optimized formula

Stability study of batch CF7

Stability is the essential factor for quality, efficacy and safety of drug product. The drug product with insufficient stability can result in change of there physical (hardness, dissolution rate, phase separation) as well as chemical characteristics (formation of high risk decomposition substances). Present study was carried out to check the dissolution behavior and physical appearance of optimized batch CF7. The batch CF7 was selected as an optimum batch depending upon release rate and floating properties and the stability study was carried out at accelerated conditions of 40 °C / 75%RH Condition for period of three months.

There was no any change in physical appearance in the dosage form of batch CF7 over a period of three months in accelerated conditions (40°C / 75 %RH). The results of stability study after three month are given in table. 8 and cumulative % drug release of batch CF7 shows results of percentage release 78.15 % in 3 months.

The drug content was found to be 101.55 % and floating lag time of 50 seconds with duration of more than 12 hrs.

The IR of the sample showed no interaction with excipients. The spectrum showed all the major peaks.

CONCLUSION:

From the above experimental results it can be concluded that, Formulated tablets gave satisfactory results for various physicochemical parameters like hardness, friability, thickness, weight variation and content uniformity. Sodium bicarbonate has predominant effect on the buoyancy lag time, while HPMC K4M has predominant effect on total floating time and drug release. Carbopol also shows significant effect on drug release. Sodium CMC has given extra adhesion property and helped to maintain the integrity of the tablet. Floating matrix tablets showed good floating and a controlled release pattern. Swelling index has a significant effect on the drug release. The formulations CF7 showed higher swelling index compared to others. In-vitro release rate studies showed that the maximum drug release was observed in CF7 (HPMC K4M-14.5%, sodium CMC-5.5%, carbopol 934P-1.8%, sodium bicarbonate-14.5%, magnesium stearate-1%) formulations up to 12 hrs. Formulations CF7 found to be stable at 45^oC and 75% RH for a period of 3 months. FT-IR studies revealed that there was no interaction between cefixime and the polymers used.

From the study it is evident that a promising controlled release floating tablets of Cefixime can be developed to increase gastric residence time and there by increasing its bioavailability. Further detailed investigations are required to establish efficacy of these formulations.

REFERENCES

1. Gennaro AR. Remington, The Science and Practice of Pharmacy, 21^st Edition, 1682, 2005.

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5. Bretschneider B, Brandsch M, Neubert R. Intestinal transport of beta-lactam antibiotics: analysis of the affinity at the H⁺/peptide symporter(PEPT1), the uptake into caco-2 cell monolayers and the transepithelial flux. Phar Res. 1999; 16(1):55-61

6. Fera TM, Carbone M, Foca A. Activity of cefixime against Helicobacter pylori. Int J of Antimicrobial Agents. 1993;3:105-108.

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8. Singh BN, Kim KH. Floating drug delivery system: An approach to oral controlled drug delivery via gastric retention. J Cont Rel. 2000; 63:235 – 259.

9. Arora S. et al. Floating Drug Delivery Systems: A Review. AAPS Pharm Sci Tec 2005: E372-E390.

10. Wells J. Pharmaceutical preformulation. Pharmaceutics: The Science of Dosage Form Design. Aulton ME. Edinburgh London: Melbourne and New York, 1988; 3^rd ed: pp. 224.

11. Wells J. Pharmaceutical preformulation. Pharmaceutics: The Science of Dosage Form Design. Aulton ME. Edinburgh London: Melbourne and New York, 1988; 3^rd ed: pp 249-250.

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Received on 05.03.2009 Modified on 24.04.2009

Research J. Pharm. and Tech.2 (3): July-Sept. 2009,;Page 507-512

Ingredient (mg)	CF1	CF2	CF3	CF4	CF5	CF6	CF 7
Cefixime	200	200	200	200	200	200	200
HPMC K4M	100	100	100	100	100	100	80
Sodium CMC	15	35	50	-	65	65	30
Carbopol 934P	60	45	30	30	15	-	10
Lactose	114	109	109	159	109	124	142
Sodium bicarbonate	55	55	55	55	55	55	82
Magnesium stearate	6	6	6	6	6	6	6
Total weight of tablets	550	550	550	550	550	550	550

Cefixime

Preformulation study:

Table 4: Interpretation of diffusional release mechanisms

CF1

In vitro Drug Release Study

CF1

Treatment of dissolution data with different kinetic equations:

Stability Study: 20, 21

RESULT AND DISCUSSION:

Preformulation study:

Table 7: Cumulative % drug release for stability study of batch CF7

In-vitro Drug release Study:

Treatment of dissolution data with different kinetic equations:

Stability Study:^20,
21