Formulation Development and Evaluation of Direct compressed Cefpodoxime proxetil Effervescent Tablets

 

Bibaswan Mishra*, Biswaranjan Mohanty, Chandra Sekhar Barik

Department of Pharmaceutics, Institute of Pharmacy and Technology, Salipur, Cuttack-754202, Odisha, India

 

ABSTRACT:

Cefpodoxime proxetil is an orally administered, extended spectrum, semi-synthetic antibiotic of the cephalosporin class. It belongs to BCS class IV drugs and has a limited aqueous solubility of 0.4 mg/ml. Hence the present aim of the study is to enhance the solubility of Cefpodoxime proxetil through complexation with HP-β-cyclodextrin. Binary mixture of sodium bicarbonate and citric acid to be used as effervescent materials. The disintegration to be further enhanced using superdisintegrants such as croscarmellose sodium, sodium starchglycolate and polacrilin K. Seven such formulations were prepared with varying composition and proportion of superdisintegrants. All formulations indicated a fair weight variation with in the pharmacopoeial limit. The result varies from ±1.23% to ±3.58% against ±5%. Thickness range was determined between 4mm - 4.2mm. Hardness test result revealed a good strength of more than 4.5 kg/cm² in every tablet. The percent friability was found within the specification. All formulation took fair time for completion of effervescence except F1 that don’t contain any superdisintegrant. Drug content of all formulations were found to be excellent with more than 98%. Formulation F7 showed excellent effervescent time as compare to other formulation. It showed a consistent drug release with more than 80 % drug released in just 30 minutes. In the FTIR spectra, presence of all significant peaks of drug and absence of any new peak in the formulations revealed that there was no interaction of drug with the excipients. Hence the present study could be an excellent approach to the delivery of the poorly soluble Cefpodoxime proxetil as effervescent tablet.

 

 

 

INTRODUCTION:

Solid oral formulation of drug molecules has its own importance amidst the disadvantages of slow dissolution related absorption and prolonged onset. Also the poor stability of drug in liquid oral limits their administration as liquid oral. So many modified approaches have been adopted to improve the dissolution of oral formulation. Effervescent tablets are good alternative dosage form amongst them^1,2.

 

Incorporation of effervescent compounds have been well tolerated in the last years. Some of the suitable edible organic solids such as citric acid, tartaric acid, maleic acid, ascorbic acid, adipic acid, fumaric acid etc. liberate CO₂ during the dissolution process in presence of these effervescent compounds such as sodium carbonate and sodium bicarbonate. Generally citric acid and tartaric acid, both are used along with sodium bicarbonate in the appropriate ratio in the manufacturing of effervescent tablets. The organic food acid combines with the carbonate source to form potassium, sodium, calcium or magnesium salts of the acid and buffers the solution that ease the dissolution of a variety of drug. Hence it is also helpful in dispersing poorly soluble active ingredients^3,4.

Cyclodextrins (CDs) are chemically cyclic oligosaccharides that typically consist of 6-8 glucopyranose units (namely a-, b-, g- and s-CD). They have a central hydrophobic core with a relatively hydrophilic outer surface. Many drugs were reported to form inclusion complex through host-guest interaction with hydroxypropyl b-Cyclodextrin (HP/b-CD). These complexes improve drug solubility, chemical stability, dissolution and bioavailability as well as decrease side-effects. Therefore HP b-CD has been widely used in many pharmaceutical products and considered toxicity free at moderate oral and intravenous doses⁵.

 

Cefpodoxime proxetil (Fig-1) is an orally administered, extended spectrum, semi-synthetic antibiotic of the cephalosporin class. It belongs to BCS class IV drugs and has a limited aqueous solubility of 0.4 mg/ml. The drug possesses gelling behaviour when dispersed in water. Hence the present aim of the study is to enhance the solubility of cefpodoxime proxetil through complexation with HP-β-cyclodextrin. Binary mixture of sodium bicarbonate and citric acid was used as effervescent materials. The disintegration of the tablets were further enhanced using superdisintegrants such as sodium starch glycolate and polacrilin K. The effect of various superdisintegrants on the drug release was studied^6,7,8.

 

Hence the new formulations were developed to overcome the solubility and gelling problems of Cefpodoxime proxetil. The prepared effervescent tablets can be dispersed quickly and completely in water the drug leading to faster dissolution of the drug-HP b-CD inclusion complex.

 

 

Figure-1: Cefpodoxime proxetil

 

 

 

 

 

 

MATERIALS AND METHODS:

Materials:

Cefpodoxime proxetil was received as a gift sample from Hetero drugs (Baddi, India). Mannitol, talc and magnesium stearate were purchased from S.D. Fine Chem (Mumbai, India). Sodium starch glycolate and Polacrilin potassium were received as gift samples from Colorcon Asia (Goa, India). HP b-cyclodextrin and Sodium saccharine were purchased from Hi-Media Lab (Mumbai, India). Lemon flavor were received as gift samples from Pentagon Trading Company (Ahmedabad, India). All ingredients and chemicals used were of analytical grade.

 

Methods:

Preparation of effervescent tablets:

The effervescent tablets were prepared using direct compression method. All materials were weighed accurately as presented in Table 1. They were sifted through a stainless-steel mesh of size 120 and were blended using a zipper poly packet for 15 min. Tablets were prepared by compressing powder blend using single punch compression machine (Cadmach-Ahmedabad) fitted with 8 mm round punches. 50 tablets were compressed for each formulation. The whole of the processing was carried out under the controlled conditions of humidity (relative humidity below 35%).

 

Evaluation of powder blend:

Prior to compression, the drug and the powder blends were evaluated for their flow and compressibility. Various parameters related to the flow and compressibility like bulk density, tapped density, angle of repose, compressibility index and Hausner ratio were determined. All determinations were made in triplicate and results were presented as average^9,10.

 

Physical properties of Tablets:

Weight variation for each batch were calculated by measuring 20 tablets individually (United States pharmacopoeia (USP 31 NF-26) and revision, 2008) using a digital balance (K-Roy, BW-200, Kolkata). The deviation of individual weight from average weight was calculated and weight variation was determined.

Table-1: Formulation Design

Ingredients	Formulation code
	F1	F2	F3	F4	F5	F6	F7
Cefpodoxime proxetil (mg)	50	50	50	50	50	50	50
HP β-Cyclodextrin (mg)	50	50	50	50	50	50	50
Sodium bicarbonate (mg)	40	40	40	40	40	40	40
Citric acid (mg)	30	30	30	30	30	30	30
Mannitol (mg)	50	44	42	40	44	42	40
Sodium Starch Glycolate (mg)	-	6	8	10	-	-	-
Polacrilin K (mg)	-	-	-	-	6	8	10
Sodium saccharine (mg)	4	4	4	4	4	4	4
Talc (mg)	1	1	1	1	1	1	1
Magnesium stearate (mg)	1	1	1	1	1	1	1

 

 

The thickness of 10 tablets from each formulation was measured using a slide callipers and their average and standard deviation were calculated. Mechanical strength of tablets of 10 tablets, from each formulation, was determined using a Monsanto tablet hardness tester (Praveen enterprises, Bangalore) and their mean values were calculated. Friability was determined according to official method (British Pharmacopoeias, 2008) using single drum friabilator (Veego, VFT-DV, Mumbai)^10,11,12.

 

Drug content:

Cefpodoxime proxetil contents of tablets were determined as described in B.P. (British Pharmacopoeias, 2008) using 0.1 N HCl as solvent and as blank solution. Absorbance of the sample solution and standard solution was measured at 264 nm using a double beam UV–visible spectrophotometer (Figure-9; UV pharmaspec-1700, Simadzu). The drug content was calculated by a comparison of absorbance of two solutions. All determinations were made in triplicate and their average and standard deviation were calculated¹³.

 

Effervescence time of tablets:

Effervescence time was determined by allowing one tablet to disperse completely in 250 ml of purified water at room temperature (European pharmacopoeia et al., 2005). Time required for the completion of effervescence was noted using a digital stopwatch (Sony, Japan). Effervescence time determination was performed for 6 tablets and results were presented as average^14,15.

 

Moisture content:

The moisture content of the tablet was determined using a desiccator. Powdered tablets were loaded to the desiccator and loss on drying was recorded. Determination was made in triplicate and results were presented as average¹⁶.

 

 

Wetting time of tablets:

Wetting time of the tablets from each formulation was determined by placing the tablet on a filter paper soaked in a watch glass containing 5 ml purified water. The time required for complete hydration of the tablet was noted with a digital stopwatch. The experiment was performed in triplicate for each formulation and average wetting time was calculated¹⁷.

 

Dissolution studies:

Dissolution of cefpodoxime proxetil is pH dependent; in vitro dissolution studies were carried out using USP type 2 dissolution apparatus (Paddle type; Scientific Ltd., Mumbai, India). The study was carried out in 900 ml of 0.1 N HCl. Dissolution medium was kept in a thermostatically controlled water bath, maintained at 37 ± 0.5°C. The paddle rotated at 50 rpm. At predetermined time intervals, 5 ml of samples were withdrawn and assessed for drug release spectrophotometrically at λmax 264 nm. At each withdrawal, 5 ml of fresh dissolution medium was added to dissolution jar¹⁸.

 

Infrared (IR) spectroscopy:

Infrared (IR) spectroscopy was conducted using a Fourier transform infrared spectrophotometer (Bruker Alfa, Germany) and the spectrum was recorded in the wavelength region of 4,000–600 cm⁻¹. The sample was placed on the ATR quartz sample holder, and the spectrum was recorded. All spectra were collected at a resolution of 2 cm⁻¹.

 

RESULT AND DISCUSSION:

Evaluation result of powder blend showed poor flowability of drug which was successfully improved in all the formulations to achieve uniform flow as depicted in table-2. It was revealed that the glidant concentration was sufficient enough to enhance the flow parameters of the powder blend.

Table-2: Evaluation result of powder blend

Formulation	Bulk density (g/ml)	Tapped density (g/ml)	Inter particle porosity	Hausner's ratio	Carr's index (%)
	Limit
	0-1	0-1	0-1.2	<1.2	<40
Drug	0.23	0.37	1.60	1.59	37.06
F1	0.40	0.45	0.31	1.14	12.36
F2	0.43	0.48	0.24	1.11	10.21
F3	0.42	0.48	0.31	1.15	13.04
F4	0.36	0.41	0.35	1.14	12.59
F5	0.46	0.57	0.43	1.25	19.86
F6	0.51	0.65	0.41	1.27	20.99
F7	0.50	0.63	0.43	1.27	21.45

 

All the formulations indicated a fair weight variation within the Pharmacopoeial limit. The result varies from ±1.23% to ±3.32% against ±5% as shown in Table-3. The thickness range measured by slide calipers was found between 4mm - 4.2mm. Hardness test result revealed a good strength of more than 4.5 kg/cm² in each batch of tablet formulation. This result can be attributed to the adhesive nature of the HP β-cyclodextrin used in the formulation. The percent friability was found within the specification (Table-3)¹⁹.

Table-3: Results of evaluation study of effervescent tablets

Formulation	F1	F2	F3	F4	F5	F6	F7
Appearance/shape	Round and Concave	Round and Concave	Round and Concave	Round and Concave	Round and Concave	Round and Concave	Round and Concave
Weight variation (%)	±1.23	±1.36	±2.25	±1.96	±3.30	±3.31	±3.32
Thickness (mm)	4	4.1	4.1	4	4	4.2	4.1
Hardness (kg/cm2)	4.5	4.7	5	4.8	5	4.8	4.5
Friability (%)	0.43	0.79	0.91	0.58	0.89	0.57	0.53
Effervescent time (sec)	220	120	117	119	88	82	58
Drug content (%)	98.86 ±1.84	99.45 ±1.23	100.05 ±1.39	99.39 ±1.90	100.01 ±1.09	99.78 ±2.03	98.97 ±1.53
Wetting time (min)	12.5	10.3	9.4	8.75	8.1	6.25	5
Moisture content (%)	0.549	0.629	0.437	0.814	0.482	0.448	0.394

 

All the formulation took fair time for completion of effervescence except F1 that don’t contain any superdisintegrant. The result reflects that the role of superdisintegrant has significant role in breaking the lumps formed by the drug- HP β-cyclodextrin mixture. It was observed that the effervescent time decreases with increase in the concentration of both superdisintegrants and formulations with polacrilin-K showed better result compared to formulation containing SSG. Formulation F7 showed excellent effervescent time as compare to other formulation. Drug content of all formulations were found to be excellent with more than 98 %. The wetting time and moisture content were determined for all formulations and shown in table 3.

 

The dissolution profile revealed that F7 containing polacrilin K showed a consistent drug release with more than 80% drug released in just 30 minutes. All other formulations containing superdisintegrant exhibited good dissolution profile than the F1 that don’t contain superdisintegrant. It has been observed that as the concentration of SSG was increased from 6 mg to 8 mg keeping the HP b-CD concentration constant, the cumulative percent of drug released increases from 62.16% to 92.43% and that for polacrilin K, it increases from 92.88% to 100.8%. Similarly, for the same concentration of both the superdisintegrants, keeping the amount of all other ingredients same, it was found that formulations with polacrilin K showed better dissolution profile than the formulations containing SSG as in between F2 and F5, F3 and F6, and F4 and F7.

Table-4 Dissolution profile of formulations

Time (min)	Cumulative percent drug released (mg)
	Drug	F1	F2	F3	F4	F5	F6	F7
5	19.49	3.92	12.81	11.46	5.91	29.38	28.80	29.68
15	30.12	16.74	34.52	38.41	29.47	63.07	60.06	65.39
30	42.19	28.04	45.82	65.23	57.34	73.47	68.45	81.78
45	51.80	34.44	52.21	78.75	74.25	85.83	75.67	94.56
60	59.11	44.39	62.16	86.32	92.43	92.88	98.80	100.80

 

Figure-2 Comparative dissolution profile of formulations

 

The presence of all significant peaks of drug and absence of any new peak in the formulations revealed that there was no interaction of drug with the excipients (figure-3)²⁰.

 

Figure-3 FTIR study. a) Cefpodoxime proxitel; b) HP β-cyclodextrin; c) F2; d) F7

 

CONCLUSION:

Effervescent tablets of Cefpodoxime proxetil was successfully developed. The role of superdisintegrants in the formulations has a significant role in the development of tablets as it is necessary to reduce the lumps formed by the drug-HP β-cyclodextrin inclusion complex. Formulations with polacrilin-K revealed better dissolution profile as compared to formulations with sodium starch glycolate. F-7 was found to be the best formulation as it showed a consistent release profile with 80 % of drug released in just 30 minutes. All the formulation found compatible with no evidence of drug-excipients interaction.

 

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Received on 18.12.2018          Modified on 07.02.2019

Accepted on 10.03.2019        © RJPT All right reserved