Formulation development and in vitro Evaluation of sustained release matrix tablets of Cefpodoxime proxetil

 

A. Bhavani¹, B. Hemalatha¹*, K. Padmalatha²

¹Department of Pharmaceutics, Vijaya Institute of Pharmaceutical Sciences for Women, Vijayawada.

²Department of Pharmacology, Vijaya Institute of Pharmaceutical Sciences for Women, Vijayawada.

 

ABSTRACT:

The present focus is on the development of sustained release formulations due to its inherent boons. There are several advantages of sustained release drug delivery over conventional dosage forms like improved patient compliance, reduction in fluctuation and increased safety margin of potent drug. The present study was aimed to prepare a sustained drug delivery system to design a controlled release oral dosage form of Cefpodoxime proxetil. The sustained release matrix tablets of Cefpodoxime proxetil were prepared by wet granulation and evaluated for different parameters such as weight variation, drug content, thickness, hardness, friability and In vitro release studies. The in vitro dissolution study was carried out for 12 hours using USP (Type- II) paddle apparatus in hydrochloride (0.1N) as dissolution media for first 2 hours and phosphate buffer (pH 6.8) for next 10 hours. Based on the in vitro dissolution data, formulation F8 was selected as the best formulation from Cefpodoxime proxetil formulations (F1 – F9) as the drug release was retarded up to 12 hours with 96.29 % and followed zero order release kinetics & drug release mechanism was diffusion.

 

 

 

1. INTRODUCTION:

Sustained release drug delivery system was meant to discharge the medication in a delayed rate to keep up plasma drug levels. The medications having shorter half life are appropriate for the sustained release drug delivery system. Matrix tablets is a promising approach for the establishment of extended-release drug therapy as tablets offer the lowest cost approach to sustained and controlled release solid dosage forms (Jaimini Manish et al., 2012). Matrix tablets can be defined as the oral solid dosage forms in which the drug is homogeneously dispersed or dissolved within the hydrophilic or hydrophobic polymeric matrices (Mayur Karvekar et al., 2017). Hypothetically, sustained release dosage form should release the drug by a zero-order mechanism which maintains drug plasma level time similar to intravenous infusion (Prakhar Agarwal et al., 2019).

 

Cefpodoxime Proxetil, a BCS class-IV drug, has taken as the model drug for the present study. Cefpodoxime is an oral third generation cephalosporin antibiotic with effectiveness against most gram positive and gram negative bacteria. It is commonly used to treat acute otitis media, pharyngitis, and sinusitis. It has been reported that the absolute bioavailability of cefpodoxime proxetil when given orally is 50% and biological half-life is 1.9 to 2.8 hours.

 

Designing a sustained release formulation for the drug cefpodoxime proxetil may prolong therapeutic concentration of drug in the blood and decrease the frequency of dosing and also improve the efficacy of drug and patient compliance. Therefore in the present study, attempts were made to formulate a sustained release matrix tablet for the antibiotic cefpodoxime proxetil.

 

2. MATERIAL AND METHODS:

Cefpodoxime proxetil was received as a gift sample from Remedy Labs, Ahmedabad. All other chemicals like hydroxyl propyl methyl cellulose (HPMC K100 M), sodium alginate, chitosan, microcrystalline cellulose, magnesium stearate, talc, PVP K30 and isopropyl alcohol purchased were of analytical grade.

 

3. PREPARATION OF SUSTAINED RELEASE MATRIX TABLET OF CEFPODOXIME PROXETIL:

Sustained release matrix tablets of Cefpodoxime proxetil were prepared by wet granulation method. The formula for various batches of sustained release matrix tablets of Cefpodoxime proxetil was mentioned in table 1.

 

3.1 Preparation of wet granules: Accurately weighed quantities of polymer and Micro crystalline cellulose were taken in a polybag and mixed geometrically, to this mixture required quantity of Cefpodoxime proxetil was added and mixed for 3 minutes. Granulation was performed by using PVP K30 as a binder and isopropyl alcohol as a solvent and the prepared granules were dried at 25-27°C for 2 hrs. Afterwards granules were sized through sieve-18. Finally magnesium stearate and talc were added separately and mixed for further 2-3 minutes (Sarika S. Lokhande et al., 2019). These dried granules are then subjected to the pre-compression studies such as

 

Angle of repose

Bulk density and Tapped density

Compressibility Index and Hausner Ratio.

 

After that the mixed granules were compressed in to tablets. The same procedure was followed to prepare all other formulations (F1 to F9) (Prathiba V and Bharath A et al., 2008).

 

3.2 Compression of Cefpodoxime proxetil Sustain Release Tablets:

The required quantities of the granules were compressed on the flat beveled edged punch set on Rotary punch tablet Compression Machine (Karnavathi Minipress-I) to constant weight and at approximately of equal hardness with equal compression force and were subjected to evaluation (Kamboj S et al., 2013). The tablets formed did not show any defects like capping or chipping.

 

4. EVALUATION OF SUSTAINED RELEASE MATRIX TABLET OF CEFPODOXIME PROXETIL:

4.1 Pre-compression Studies:

a) Angle of Repose:

This is the maximum angle possible between the surface of pile of powder or granules and the horizontal plane. The granules were allowed to flow through the funnel fixed to a stand at definite height (h) (Sivaramu Kambampati et al., 2013). The angle of repose was then calculated by measuring the height and radius of the heap of granules formed (Harnish Patel et al., 2011).

θ = tan^-1 (h/r)

Where, θ is the angle of repose

h is the height of the heap of powder and

r is the radius of the heap of the powder

 

b) Bulk Density:

Apparent bulk density was determined by placing pre-sieved drug excipient blend in to a graduated cylinder and measuring the volume and weight as it is (Kumar Sunil et al., 2018).

Bulk density = Weight of sample in gram / Volume occupied by the sample

 

c) Tapped Density:

It is a ratio of weight mass and tapped volume (Rakesh Roshan Mali et al., 2015). The tapped density is obtained by mechanically tapping a graduated cylinder containing the sample until little further volume change is observed.

Tapped density = Weight of Powder/ tapped volume of Powder.

 

Table No - 1: Formula for different batches of Cefpodoxime proxetil tablet

INGREDIENTS	F1	F2	F3	F4	F5	F6	F7	F8	F9
Cefpodoxime proxetil	200	200	200	200	200	200	200	200	200
Chitosan	50	100	--	--	--	--	50	50	--
HPMC K 100M	--	--	50	100	--	--	50	--	50
Sodium alginate	--	--	--	--	50	100	--	50	50
Microcrystalline cellulose	140	90	140	90	140	90	90	90	90
PVP K-30	5	5	5	5	5	5	5	5	5
Magnesium stearate	3	3	3	3	3	3	3	3	3
Talc	2	2	2	2	2	2	2	2	2
Iso propyl alcohol	Q.S	Q.S	Q.S	Q.S	Q.S	Q.S	Q.S	Q.S	Q.S
Total weight(mg)	400	400	400	400	400	400	400	400	400

 

d) Compressibility Index or Carr’s Index:

The Carr index is frequently used in pharmaceutics as an indication of the flowability of a powder. The calculation of compressibility index is based on the tapped density and bulk density (Pogula M et al., 2010).

 

             Tapped density - Bulk density

CI= ----------------------------------------------- X 100

                         Tapped density

 

e) Hausner Ratio:

It indicates that the flow properties of the powder and measured by the ratio of tapped density to bulk density. A Hausner’s ratio of <1.25 indicates a powder that is free flowing whereas >1.25 indicates poor flow ability (Misa R et al., 2013).

 

                                  Tapped density

Hausner’s ratio = -------------------------------

                                      Bulk density

 

4.2 Post-compression Parameters:

a) Thickness: The thickness of the tablets was measured by screw gauge. It is expressed in mm.

 

b) Hardness:

The resistance of tablets to shipping or breakage under conditions of storage, transportation and handling before usage depends on its hardness. The hardness of the tablet was determined using a Monsanto hardness tester. It is expressed in kg/cm². (Harris Shoaib M et al., 2006).

 

c) Friability:

Friability is defined as the percentage of weight loss of powder from the surface of the tablets due to mechanical action. Friability generally reflects poor cohesion of tablet ingredients. 10 tablets were weighed and the initial weight of these tablets was recorded and placed in Roche friabilator and rotated at the speed of 25 rpm for 100 revolutions.  Then tablets were removed from the friabilator, dusted off the fines and again weighed and the weight was recorded (S. S Miyan et al., 2011).

 

                               W₁- W₂

Friability= ------------------------ X 100

                              W₁

 

Where w₁= weight of the tablet before test.                                                                      

            w₂ = weight of the tablet after test

 

d) Weight variation:

To find out weight variation, 20 tablets of each type of formulation were weighed individually using an electronic balance, average weight was calculated and individual tablet weight was then compared with average value to find the deviation in weight.

e) Drug content:

The tablets were tested for their drug content uniformity. At random 20 tablets were weighed and powdered. The powder equivalent to 100 mg of drug was weighed accurately and dissolved in 100 ml of 0.1N HCl. The solution was shaken thoroughly. The undissolved matter was removed by filtration through whatman No.1 filter paper. Then transfer 1 ml of above solution into 100 ml volumetric flask and make up the volume with 0.1N HCl. The absorbance of the diluted solutions was measured at 260 nm. The concentration of the drug was computed from the standard curve of the Cefpodoxime proxetil in 0.1N HCl (Krishna Murari et al., 2019).

 

f) In-vitro dissolution study:

In-vitro dissolution studies of the sustained release matrix tablets of Cefpodoxime proxetil were performed according to USP Type-II dissolution apparatus employing a paddle stirrer at 50 rpm using 900 ml of dissolution medium at 37 ± 0.5°C. Dissolution test was performed by employing 0.1 N HCl as dissolution medium for first two hours and by employing pH 6.8 phosphate buffer for next 10 hours. Samples of the dissolution medium (10 ml) were withdrawn at specific time intervals and replaced immediately with equal volume of fresh medium. The samples were filtered through whatmann’s filter paper and diluted if necessary and then analyzed by UV-Visible spectrophotometer at 260 nm. Drug concentration was calculated from the standard curve and expressed as cumulative percent drug release (Shaikh Siraj N et al., 2020).

 

5. RESULTS AND DISCUSSION:

5.1 Construction of Calibration Curve of Cefpodoxime proxetil:

The standard curve of Cefpodoxime proxetil in 0.1N HCl and phosphate buffer pH 6.8 showed a good linearity with R² of 0.1 N HCl is 0.999 and buffer is 0.999 in the concentration range of 0-10 µg/ml at 260 nm. The standard graph was constructed by taking the absorbance on Y-axis and concentrations on X-axis. Drug Concentration and absorbance followed linear relationship. The curve obeyed Beer-Lambert’s law.

 

Table No - 2: Standard calibration curve of Cefpodoxime proxetil

S. No	Concentration (µg/ml)	Absorbance in 0.1N HCl	Absorbance in phosphate buffer (pH 6.8)
1	2	0.130	0.185
2	4	0.250	0.345
3	6	0.380	0.526
4	8	0.510	0.722
5	10	0.640	0.907

 

 

Figure No - 1: Calibration curve of Cefpodoxime proxetil in 0.1N HCl

 

Figure No - 2: Calibration curve of Cefpodoxime proxetil in pH 6.8 phosphate buffer

 

5.2 Precompression parameters:

Table No - 3: Evaluation of precompression parameters

S. No	Formulation	Angle of repose (degrees)	Bulk density (g/cc)	Tapped density (g/cc)	Carr’s index (%)	Hausner’s ratio
1.	F1	25.43±0.35	1.041±0.3	1.16±0.1	11.41±0.28	1.114±0.12
2.	F2	26.46±0.32	1.021±0.4	1.12±0.2	9.21±0.23	1.09±0.23
3.	F3	23.31±0.32	1.01±0.2	1.11±0.1	9.22±0.25	1.09±0.21
4.	F4	26.89±0.18	1.02±0.28	1.11±0.21	8.13±0.30	1.08±0.15
5.	F5	29.14±0.42	0.96±0.24	1.03±0.27	7.15±0.25	1.07±0.21
6.	F6	28.14±0.25	0.95±0.24	1.03±0.27	9.52±0.18	1.095±0.22
7.	F7	29.12±0.19	0.94±0.2	1.03±0.2	9.32±0.27	1.095±0.25
8.	F8	24.21±0.21	0.96±0.2	1.04±0.2	8.24±0.26	1.08±0.16
9.	F9	27.14±0.23	1.041±0.3	1.16±0.1	11.42±0.23	1.10±0.17

 

The prepared granules for the compression of sustained release tablets were evaluated for various precompression parameters like bulk density, tapped density, carrs index, hausner ratio and angle of repose.

 

The angle of repose of all formulations was within the range of 23.31±0.32° to 29.14±0.42°. The bulk density was found to be in the range of 0.94±0.2 to 1.041±0.3 gm/cm³. The tapped density ranged between 1.03±0.2 to 1.16±0.1 gm/cm³. The compressibility index of all formulations exists in the range between 7.15±0.25 to 11.42±0.23. The result of the hausner’s ratio of all formulations is between 1.07±0.21 to 1.114±0.12. These values indicate that the prepared blend exhibited good flow properties.

 

5.3 Post compression parameters:

Table No - 4: Evaluation of postcompression parameters

S. No	Formulation	Weight Variation (mg)	Thickness (mm)	Hardness (kg/cm2)	Friability (%)	Content Uniformity  (%)
1.	F1	400.2±0.16	2.01±0.01	6.16±0.49	0.26±0.19	96.13±0.51
2.	F2	399.4±0.98	2.04±0.02	6.12±0.21	0.39±0.15	96.58±0.32
3.	F3	399.8±0.42	2.06±0.04	6.10±0.16	0.27±0.20	97.24±0.24
4.	F4	400.1±0.31	2.03±0.02	6.08±0.23	0.34±0.15	98.12±0.26
5.	F5	399.7±0.26	2.01±0.03	6.00±0.51	0.22±0.18	97.25±0.18
6.	F6	400.7±0.31	2.05±0.06	6.20±0.62	0.38±0.07	96.95±0.25
7.	F7	399.5±0.23	2.01±0.03	6.25±0.31	0.32±0.21	98.75±0.26
8.	F8	400.3±0.31	2.05±0.04	6.30±0.34	0.26±0.23	99.62±0.25
9.	F9	400.5±0.24	2.05±0.02	6.15±0.43	0.28±0.30	98.89±0.31

 

The hardness for the tablets of all formulations was within the range of 6.0 – 6.3 Kg/cm². The friability of all the formulated tablets was within 1%, which is an indication of good mechanical resistance of tablet. The drug content varied between 96.13% ± 0.51 to 99.62% ± 0.25for all the formulations. The thickness was measured for the tablets of all formulations and was found to be within the acceptable range. The weight of the tablet varied between 399.4 ± 0.98 mg to 400.7 ±0.31 mg for all the formulations. The variation in weight was within the range of ±5% complying with pharmacopoeial specification.   

 

5.4 In vitro Drug Release Study:

Table No – 5: Cumulative percent drug release from matrix tablets of cefpodoxime proxetil

 

Time	% Cumulative amount of drug dissolved
	F1	F2	F3	F4	F5	F6	F7	F8	F9
0	0	0	0	0	0	0	0	0	0
1	38.91	34.92	58.91	55.83	58.44	56.29	32.37	26.94	53.83
2	56.24	48.92	67.24	64.26	66.83	63.21	42.47	32.59	61.26
4	62.84	59.21	78.84	73.87	76.47	75.38	59.28	46.86	70.87
6	80.78	74.93	89.78	86.38	88.74	87.78	74.41	58.48	84.38
8	92.72	89.72	97.72	93.71	96.82	95.36	88.26	69.83	92.71
10	98.38	97.92	100	100	100	100	92.49	87.57	100
12	100	100					98.85	96.29

 

Figure No – 3: Comparison of Dissolution Profiles of Formulations F1 – F9

 

The in vitro drug release studies were performed to evaluate the release of Cefpodoxime proxetil from sustained release matrix tablets. The study indicated that as the amount of polymer in the tablet formulation increases, the drug release rate decreases. From all the formulations F8 formulation shows slow drug release when compared to other eight formulations.

5.4.1 Kinetic Modeling of Drug Release

In order to describe the release kinetics of optimized formulation (F8), the corresponding dissolution data was fitted in various kinetic models like zero order, first order, higuchi and Hixson crowell erosion.

 

Table No – 6: Kinetics Data

S. No	Time (hours)	Square root of Time	Log Time	Cumulative % Drug Release	Log % Cumulative Drug Release	Square root of % Drug Remaining	Log % Drug Remaining
1	0	0	0	0	0	10	2.000
2	1	1.000	0	26.94	1.430	8.548	1.864
3	2	1.414	0.301	32.59	1.513	8.210	1.829
4	4	2.000	0.602	46.86	1.671	7.290	1.725
5	6	2.449	0.778	58.48	1.767	6.444	1.618
6	8	2.828	0.903	69.83	1.844	5.493	1.480
7	10	3.162	1	87.57	1.942	3.526	1.094
8	12	3.464	1.079	96.29	1.984	1.926	0.569

 

Table No – 7: Regression Co-efficient (R²) of different kinetic models

Batch No	Zero order R2	First order R2	Higuchi R2	Peppas R2	Hixson Crowell R2
F8	0.961	0.888	0.982	0.588	0.975

 

From the above plots it was concluded that optimized formula showed zero order release and drug release described by diffusion mechanism because the R² value of Higuchi plot is more than Hixson Crowell R² value.

 

6. CONCLUSION:

Sustained release matrix tablets of Cefpodoxime proxetil were prepared by wet granulation method using PVP K30 in isopropyl alcohol as granulating agent. The polymers like Chitosan, HPMC K 100 M and Sodium alginate were selected as the release retarding polymers which retard the drug release over a period of time. The prepared granules for the compression of sustained release tablets were evaluated for various precompression parameters like bulk density, tapped density, carrs index, hausner ratio and angle of repose which indicate that the prepared blend exhibited good flow properties.

 

In vitro drug release of cefpodoxime proxetil tablets showed controlled release pattern, which may be attributed to the using various concentration of Chitosan, HPMC K 100 M and Sodium alginate. On the basis of in vitro release studies, the equal concentration of polymers like chitosan and sodium alginate showed better release of retarding than other combinations. The study concluded that as the amount of polymer in the tablet formulation increases, the drug release rate decreases. The drug release of nine formulations was compared with each other and the formulation F8 is considered to be the best formulation, as the drug release was retarded up to 12 hrs with 96.29% drug release. This can help to reduce the dose and frequency. Based on kinetic data it was concluded that optimized formula showed zero order release and drug release mechanism was diffusion.

 

7. ACKNOWLEDGEMENT:

The authors sincerely thank Vijaya Institute of Pharmaceutical Sciences for Women for providing necessary equipment and their support in the fulfilment of the research work successfully.

 

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Received on 14.07.2021          Modified on 02.08.2021

Accepted on 20.08.2021   ©Asian Pharma Press All Right Reserved