INTRODUCTION:

Oral drug delivery has been known for decades as the most widely utilized route of administration among all the routes that have been explored for the systemic delivery of drugs via various pharmaceutical products of different dosage forms. The reason that the oral route achieved such popularity may be in part attributed to its ease of administration as well as traditional belief that by oral administration the drug is as well absorbed as the food stuffs that are ingested daily.

In fact the development of pharmaceutical products for oral delivery, irrespective of physical form involves varying extents of optimization of dosage form characteristics within the inherent constraints of GI physiology.¹Therefore, a fundamental understanding of various disciplines, including GI physiology, pharmacokinetics, pharmacodynamics and formulation design are essential to achieve a systemic approach to the successful development of an oral pharmaceutical dosage form.² The more sophisticated a delivery system, the greater is the complexity of these various disciplines involved in the design and optimization of the system. Drinking water plays an important role in the swallowing of oral dosage forms. Often People experience inconvenience in swallowing conventional tablets and capsules, when water is not available, in the case of motion sickness (kinetosis), sudden episodes of coughing during the common cold, allergic conditions and bronchitis³. For these reasons, tablets which can rapidly dissolve or disintegrate in the oral cavity have attracted a great deal of attention. Rapidly dissolving or disintegrating tablets are not only indicated for people who have swallowing difficulties, but also for ideal for active people.

Cefixime is used to treat infections caused by bacteria such as pneumonia, bronchitis, gonorrhoea, and ear, lung, throat, and urinary tract infections.⁴The aim of the study was to formulate and evaluate fast dissolving tablets of Cefixime having adequate mechanical strength, rapid disintegration and fast action, to enhance the solubility and bioavailability of the drug, to determine the effect of change in superdisintegrants and their concentration on the formulation and to compare the superiority of different superdisintegrants in the formulation of FDTs of Cefixime Trihydrate

MATERIALS AND METHODS:

Cefixime trihydrate was obtained as gift sample from Dr. Reddys laboratory, Hyderabad. Croscarmellose sodium (CCS) and Sodium Starch Glycolate (SSG) was obtained as gift samples from Amree Pharmaceuticals, Karnal. All chemicals used were of analytical grade.

Compatibility studies:

DSC studies:

DSC thermo gram of pure drug (Cefixime Trihydrate), Superdisintegrants (Cross Carmellose sodium, Sodium Starch Glycollate, Cross Povidone, Plantago ovata) were taken for their endothermic reaction. Finally physical mixture of all above ingredients was scanned for DSC. DSC thermo grams of physical mixture of drug and excipients showed the melting peak of the drug at 220º C and endothermic peak at a sharp melting endotherm Physical mixture of all above ingredients showed their identical peaks at defined temperature range in the fig 1-6. Presence of all peaks indicates that all ingredients are compatible with each other means there is no incompatibility between the selected ingredients.

Table 1- Composition of Cefexime Trihydrate Fast dissolving tablets

Ing (mg)	Formulation Codes
Ing (mg)	F1	F2	F3	F4	F5	F6	F7	F8	F9
Cefixime Trihydrate	100	100	100	100	100	100	100	100	100
Plantago ovate	18	24	30	-	-	-	-	-	-
Hibiscus Rosa Saneness	-	-	-	18	24	30	-	-	-
Ac-Di-Sol	-	-	-	-	-	-	18	24	30
Micro crystalline Cellulose	120	120	120	120	120	120	120	120	120
Mannitol	28	22	16	28	22	16	28	22	16
Sodium saccharin	15	15	15	15	15	15	15	15	15
Talc	6	6	6	6	6	6	6	6	6
Magnesium stearate	3	3	3	3	3	3	3	3	3
Orange flavor	10	10	10	10	10	10	10	10	10
AVG. WEIGHT	300	300	300	300	300	300	300	300	300

Table 2- Composition of Cefexime Trihydrate Fast dissolving tablets

Ing (mg)	Formulation Codes
Ing (mg)	F10	F11	F12	F13	F14	F15
Cefixime Trihydrate	100	100	100	100	100	100
Cross Povidone	18	24	30	-	-	-
Sodium Starch Glycollate	-	-	-	18	24	30
Micro crystalline Cellulose	120	120	120	120	120	120
Mannitol	28	22	16	28	22	16
Sodium saccharin	15	15	15	15	15	15
Talc	6	6	6	6	6	6
Magnesium stearate	3	3	3	3	3	3
Orange flavor	10	10	10	10	10	10
AVG. WEIGHT	300	300	300	300	300	300

Table 3: Pre-compression evaluations of powder blend

Formulation	Bulk density (gm/cm³)	Tapped Density (gm/cm³)	Angle of Repose (θ)	Carr’s Index(%)	Hausner Ratio
F1	0.508±0.02	0.68±0.01	29.43± 1.23	25.29±1	1.24±0.03
F2	0.577±0.04	0.70±0.02	29.08±1.32	17.57±1.51	1.24±0.03
F3	0.588±0.05	0.72±0.01	22.59±1.22	18.33±1.21	1.22±0.01
F4	0.597±0.04	0.76±0.03	24.50±1.44	21.44±1.86	1.27±0.03
F5	0.610±0.05	0.82±0.02	27.24±1.33	25.60±1.47	1.34±0.02
F6	0.643±0.04	0.84±0.03	28.45±1.51	23.45±1.57	1.30±0.02
F7	0.629±0.03	0.83±0.01	27.65±1.46	24.21±1.39	1.31±0.03
F8	0.518±0.03	0.68±0.02	27.77±1.37	23.82±1.62	1.31±0.02
F9	0.508±0.02	0.69±0.01	29.70±1.45	26.37±1.45	1.35±0.03
F10	0.544±0.04	0.70±0.02	24.81±1.49	22.28±2.02	1.40±0.01
F11	0.610±0.05	0.80±0.02	21.40±1.55	23.70±2.09	1.31±0.03
F12	0.638±0.04	0.84±0.03	21.37±1.56	24.04±1.78	1.32±0.03
F13	0.625±0.02	0.83±0.02	25.60±1.19	24.69±1.39	1.33±0.02
F14	0.544±0.04	0.74±0.03	26.44±1.54	26.48±1.88	1.24±0.03
F15	0.538±0.03	0.71±0.02	22.59±1.39	24.22±1.56	1.28±0.03

Evaluation of Fast Dissolving tablets (table- 4 and5)

Table 4-Evaluation Results of Fast Dissolving tablets

Avg. weight (mg)	F1	F2	F3	F4	F5	F6	F7	F8
Avg. weight (mg)	300±0.3	300±0.5	299±0.5	298 ±0.4	298 ±0.4	303±0.7	300±0.5	30±0.2
Hardness (kg/cm²)	3.5±0.1	3.2±0.1	3.4±0.1	3.1±0.1	3.4±0.1	3.5±0.1	3.4±0.1	3.6±0.1
Thickness (mm)	4.1	4.1	4.0	4.1	4.0	4.1	4.0	4.0
Friability (%)	0.551	0.442	0.418	0.439	0.498	0.500	0.498	0.502
Disintegration time (sec.)	160	25	22	20	2	27	25	70
In-Vitro Dispersion time (sec)	67.15	24.18	21.52	21.24	22.17	22.25	21.39	26.09
Wetting time (sec)	145	52	48	52	60	62	58	51
Water absorption ratio (%)	43	40	45	35	35	50	55	60

Table 5-Evaluation Results of Fast Dissolving tablets

Avg. weight (mg)	F9	F10	F11	F12	F13	F14	F15
Avg. weight (mg)	299±0.5	299±0.5	301±0.25	302±0.5	300±0.47	301±0.52	300±0.36
Hardness (kg/cm²)	3.5±0.15	3.4±0.18	3.3±0.16	3.6±0.14	3.5±0.13	3.3±0.19	3.6±0.10
Thickness (mm)	4.1	4.0	4.0	4.0	4.1	4.0	4.0
Friability (%)	0.398	0.402	0.398	0.386	0.378	0.395	0.386
Disintegration time (sec.)	65	67	75	70	67	105	100
In-Vitro Dispersion time (sec)	28.47	30.59	37.09	33.47	33.59	37.32	34.34
Wetting time (sec)	62	66	53	54	57	53	54
Water absorption ratio (%)	53	70	60	71	64	65	71

Uniformity of Tablet Weight:

It is desirable that all the tablets of a particular batch should be uniform in weight. If any weight variation is there, that should fall within the prescribed limits.

^Hardness:

^{Hardness
or crushing strength is the force required to break a tablet in diametric
compression. Hardness of the tablets is determined by Monsanto hardness tester
which consists of a barrel with a compressible spring. The pointer moving along
the gauze in the barrel at which the tablet fractures indicates the hardness of
the tablet. Six tablets from each batch were taken randomly and their hardness
was determined.}

^Thickness:

^{Thickness
was determined for twenty pre-weighed tablets of each batch using a digital vernier scale (Mitutoyo- Digital)
and the average thickness was determined in mm. The tablet thickness
should be controlled within a ± 5% variation of a standard.6}

^Friability:

^{This
test is performed to evaluate the ability of a tablet to withstand abrasion in
packing, handling and transporting purpose. Twenty sample tablets were rotated
at 25rpm for 4 minutes by a USP-type Roche friabilator,
then reweighed after removal of fines and the percentage weight loss was
calculated according to the following formula. The tablets were found to pass
the friability test, if the percentage weight loss was found to be less than
1%.7}

% Friability= (1-Weight of tablet before the test) x 100

Weight of tablet after the test

F = (1‐ Wo/W) x 100

Where, Wo is the weight of the tablets before the test, W is the weight of the tablet after the test

Disintegrating Time:

The disintegration test is carried out in an apparatus (Electro lab, Mumbai) containing a basket rack assembly with six glass tubes of 7.75 cm in length and 2.15 mm in diameter, the bottom of which consists of a #10 mesh sieve. The basket is raised and lowered 28-32 times per minute in a medium of 900 ml which is maintained at 37±2° C. Six tablets were placed in each of the tubes and the time required for complete passage of tablet fragments through the mesh (#10) was considered as the disintegration time of the tablet. Limit for disintegration time of FDTs: not more than 3 minutes according to USP⁸.

In Vitro Dispersion Time

Tablet was added to 10 ml of phosphate buffer solution (pH 7.4) at 37±0.5°C. Time required for complete dispersion of a tablet was measured.⁹

Water Absorption ratio:

A piece of tissue paper folded twice was placed in a small Petri dish containing 6ml of water. The weight of the tablet prior to placement in the Petri dish was noted (W_b) utilizing a Shimadzu digital balance. The wetted tablet was removed and reweighed (W_a). Water absorption ratio, R, was then determined according to the following equation.

R= 100× (Wa –Wb) / Wb

Where W_aand Wb are tablet weights before and after water absorption, respectively.¹⁰

Wetting Time:

The method was followed to measure tablet wetting time. A piece of tissue paper (10.75×12 mm) folded twice was placed in a culture dish (d=6.5 cm) containing 6 ml of water. A tablet was put on the paper and the time for complete wetting was measured.¹¹

Dissolution study:

Dissolution rate was studied by using USP type-1 apparatus at 100 rpm using 900 ml of 0.05 M potassium phosphate buffer pH (7.2) as dissolution medium. Temperature of the dissolution medium was maintained at 37⁰C; aliquot of dissolution medium was withdrawn at every 5 minutes interval and filtered. The absorbance of filtered solution was measured by UV spectrophotometric method at 288 nm and concentration of the drug was determined from standard calibration curve. The results of In vitro drug release of different formulation at 6%, 8%, 10% concentration of different superdisintegrants are tabulated in Table 6and7.¹²

Table 6: In vitro drug release of different formulation at 6% concentration of different superdisintegrants.

Time (min.)	In vitro Percentage drug release (%)
Time (min.)	F1	F2	F3	F4	F5	F6	F7	F8	F9	F10
5	80.18	83.12	85.44	77.12	77.12	83.10	70.44	70.44	80.19	68.22
10	82.67	84.08	88.87	78.45	78.45	86.09	72.90	72.10	81.23	70.14
15	84.14	85.00	90.54	80.10	80.10	87.02	74.87	74.57	83.10	72.45
20	85.65	86.08	90.80	81.09	81.04	89.04	75.12	76.02	85.56	74
25	86.64	87.12	92.02	83.60	83.40	90.46	77.09	77.29	87.29	75.34
30	88	90	94	85.78	85.07	92.10	78	78.44	89.46	78
35	90.10	93.10	96.15	87	87.22	93.33	80	80.65	90	80.10
40	92.98	94.38	98.31	89.02	89.02	96.51	82.40	83.44	91.69	82.68
45	94.45	95.08	99.20	92.43	93.43	98	84.13	88.23	93.06	84.48

Table 7:In vitro drug release of different formulation at 6% concentration of different superdisintegrants

Time (min.)	In vitro Percentage drug release (%)
Time (min.)	F11	F12	F13	F14	F15
5	68.72	72.04	71.98	71.28	77.38
10	71	74.13	72.63	72.71	79. 71
15	72.55	78.55	74.19	73	81
20	74.33	80.10	75	75.56	83.43
25	75. 89	82.05	78.18	79.68	85
30	77.76	85.30	80.66	80.36	86.10
35	80.50	86.50	83.15	83.95	88.63
40	82.88	89.28	85.76	86	91
45	87	91	86.05	88.05	93.52

RESULTS AND DISCUSSION:

Oral disintegrating tablets Cefixime trihydrate were prepared by direct compression method using Plantago ovata, Hibiscus rosa sinensis as natural superdisintegrants and Croscarmellose sodium (CCS), Cross povidone and Sodium Starch Glycolate (SSG) as synthetic superdisintegrants in different concentration. A total of 16 formulations were prepared.The FTIR spectra and DSC studies of formulation shows that no interaction between drug and excipient. It reflects drug and superdisintegrants used are compatible with each other. The powder blend of 16 formulations was evaluated for Angle of repose, Bulk density, Tapped density, Compressibility and Hausner’s ratio, which showed the pre-compressed blend, has good flow property. Bulk density was found to be between 0.50 and 0.643 gm/cm³and tapped density between 0.68 and 0.84 gm/cm³ for all Formulations. Angle of repose was found to be in the range of 21.37 and 29.70. Hausner ratio was found below 1.45. The husk of Plantago ovata showed very high percentage of swelling index as compared to the other superdisintegrating agents. The tablets obtained had drug contents in the range of 98 to 100%. This is within the acceptable limit. Hardness of tablet was found to be in the range of 3.1 to 3.6 kg/cm². Friability was found to be below 1% which indicates good mechanical strength of the tablets. Water absorption ratio and wetting time which are critical parameters for evaluation of performance of ODT’s were found to be less than 62 seconds respectively. which facilitate the faster dispersion. Based on the in-vitro disintegration time, formulation containing natural superdisintegrants like Plantago ovata, Hibiscus rosa saneness (Formulation no. F2-F7) was found to be promising and showed a disintegration time of less than 30 seconds. In vitro dissolution study on an optimized formulation revealed that more than 90% drug was released within 15 minutes. The stability study shows that no significant changes in tablets after 3 months study.

CONCLUSION:

The observations have shown that different superdisintegrants were used in their ability to disintegrate model tablet into their primary particles when used at the same w/w percentage concentration. It can be concluded that super disintegrates like husk of Plantago ovata; Hibiscus rosa saneness showed better disintegrating property than the most widely used super disintegrates like Sodium starch glycollate (SSG), Cross carmellose sodium (Ac-Di-Sol) and Cross Povidone (CP) in the formulations of FDTs.

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Received on 23.02.2015 Modified on 20.03.2015

Res. J. Pharm. Dosage Form. & Tech. 7(2): April-June, 2015; Page 118-124

DOI: 10.5958/0975-4377.2015.00017.8