OPTIMIZATION OF STARCH GLYCOLATE AS NOVEL SUPERDISINTEGRANT IN THE FORMULATION OF GLIPIZIDE FAST DISSOLVING TABLETS THROUGH 2 3 FACTORIAL DESIGN

Objective: To synthesize, characterize and evaluate starch glycolate as a superdisintegrant in the formulation of Glipizide fast dissolving tablets by employing 2 3 factorial designs. Methods: Starch glycolate was prepared and its physical and micromeritic properties were performed to evaluate it. The fast dissolving tablet of Glipizide was prepared by employing starch crotonate as a superdisintegrant in different proportions in each case by direct compression method using 2 3 factorial design for the evaluation of tablet parameters like disintegration and dissolution efficiency in 5 min. Results: The starch glycolate prepared was found to be fine, free-flowing and amorphous. Starch glycolate exhibited good swelling in water with a swelling index (10%). The study of starch glycolate was shown by fourier transform infrared spectra (FTIR). The drug content (100±5%), hardness (3.5–4 kg/sq. cm), and friability (<0.15%) was been effective with regard to all the formulated fast dissolving tablets employing starch glycolate. The disintegration time of all the formulated tablets was found to be in the range of 13±0.015 to 180±0.014 sec. The optimized formulation F8 had the least disintegration time i.e., 13±0.015 sec. The wetting time of the tablets was found to be in the range of 8±0.015 to 95±0.013 sec. The In vitro wetting time was less (i.e., 8±0.015s) in optimized formulation F8. The water absorption ratio of the formulated tablets was found to be in the range of 75±0.012 to 150±0.014%. The percent drug dissolved in the optimized formulation F8 was found to be 99.95% in 5 min. Conclusion: Starch glycolate was an efficient superdisintegrant for fast-dissolving tablets. The disintegration and dissolution efficiency of the fast dissolving tablets of glipizide was good and depended on the concentration of superdisintegrant employed i.e., starch glycolate, sodium starch glycolate, crospovidone. The formulated fast dissolving tablets of glipizide exhibited good dissolution efficiency in 5 min which can be used for the fast therapeutic action of glipizide.


INTRODUCTION
Fast dissolving tablets emerge as one of the popular and widely accepted dosage forms, especially for pediatric patients because of incomplete development of the muscular and nervous system and a case of geriatric patients suffering from Parkinson's disorder or hand tremors. Few solid dosage forms like capsules and tablets are present days facing the problems like difficulty in swallowing (dysphagia), resulting in many incidences of non-compliance and making the therapy ineffective [1]. Oral dosage form and oral route are the most preferred route of administration for various drugs that had limitations like first-pass metabolism, psychiatric patients, bedridden and uncooperative patients [2]. FDTs are disintegrating or dissolve quickly in the saliva without a need of water. Fast dissolving tablets are designed to dissolve in saliva remarkably faster, within a few secs (less than 60 secs), and those are real fastdissolving tablets [3]. FDTs formulations contain super disintegrants to enhance the disintegration rate of a tablet in the buccal cavity [4]. FDTs have advantages such as easy portability and manufacturing, accurate dosing, good chemical and physical stability and an ideal alternative for geriatric and paediatric patients [5]. FDTs have disintegrated quickly, absorb faster so, in vitro drug release time improves and this property of drugs (dosage form) enhanced bioavailability [6]. FDT formulations have the advantage of both conventional tablet formulation and liquid dosage form [7]. There are several technologies that are conventional or patented based on spray drying, cotton candy process, sublimation, melt granulation, direct compression freezes drying/lyophilisation, phase transition process, mass extrusion, etc. have been developed for manufacturing of FDTs [8]. This review contains brief information about FDTs including definition, advantages, needs or requirements of FDTs, salient features of FDTs, limitations, challenges in developing FDT [9], etc.
Glipizide; a second-generation sulfonylurea, act by stimulating the release of insulin from the pancreas, reducing blood glucose level in humans [10]. The present investigation deals with a systematic formulation approach for optimization of glipizide fast dissolving tablets employing starch glycolate, sodium starch glycolate, and crospovidone sodium as superdisintegrants. A 2 3 factorial design was applied to investigate the main and interaction effects of the three formulation variables i.e., starch glycolate (A), sodium starch glycolate (B), crospovidone (C) in each case to find the formula with less disintegration time and more dissolution efficiency 5 min and to permit arbitrary selection of tablets with immediate release of drug within 5 min. The result of formulation, optimization and evaluation of Glipizide fast dissolving tablets are described in this article.

Preparation of starch glycolate (a novel superdisintegrant)
Initially, 10 parts of potash starch were slurried in 10 parts of distilled water and 10 parts of starch glycolate were dissolved in distilled water. Both are stirred continuously for 30 min. adjust the pH to 3.5 by using 10M NaOH and stirred for 16 h at 25 °C. After 16 h it was filtered and washed with distilled water. The I In nt te er rn na at ti io on na al l J Jo ou ur rn na al l o of f A Ap pp pl li ie ed d P Ph ha ar rm ma ac ce eu ut ti ic cs s product was kept in the oven at 60 °C for 2 h. The product obtained was ground and sieved [11].

Characterization of starch glycolate
The starch glycolate prepared was evaluated for the following

pH
The pH of 1% w/v slurry was measured [12].

Melting point
Melting point was determined by using the melting point apparatus [12].

Viscosity
Viscosity of 1% dispersion in water was measured using Ostwald Viscometer [12].

Swelling index
Starch glycolate (200 mg) was added to 10 ml of water and light liquid paraffin taken in two Different graduated test tubes and mixed. The dispersion in the tubes was allowed to stand for 12 h. The volumes of the sediment in the tubes were recorded [12]. The swelling index of the material was calculated as follows.

Test for gelling property
The gelling property (gelatinization) of the starch and starch glycolate prepared was evaluated by heating a 7% w/v dispersion of each in water at 100 °C for 30 min [12].

Particle size
Particle size analysis was done by sieving using standard sieves [12].

Density
Density (g/cc) was determined by the liquid displacement method using benzene as a liquid [12].

Bulk density
Bulk density (g/cc) was determined by the three-tap method in a graduated cylinder [12].

Angle of repose
Angle of repose was measured by the fixed funnel method [12].

Compressibility index
Compressibility index (CI) was determined by measuring the initial volume (V0) and final volume (V) after hundred tapings of a sample of starch lactate in a measuring cylinder [12]. CI was calculated using the equation.
Compressibility index (CI) = X 100 Where, V0= initial volume of powder, V= final volume of powder

Fourier transform infrared (FTIR) spectroscopy
FTIR spectra of starch glycolate were recorded on samples prepared in Potassium Bromide (KBr) disks using a BRUKER FT-IR, (Tokyo, Japan). Samples were prepared in (KBr) disks by means of a hydrostatic press at 6-8 tons pressure [12]. The scanning range was 500 to 3000 cm -1 .

Ester test
To 1 mg of Starch glycolate, 2m of ethanol and 1 ml of 0.1 ml NaOH were added. To this, a phenolphthalein indicator was added [12]. The colour change was observed.

Preparation of glipizide fast dissolving tablets
The tablets were prepared by direct compression method. The composition of different formulations of glipizide fast dissolving tablets was shown in table no 1. For uniformity in particle size, each ingredient was passed through # 80 meshsized screen before mixing. Starch glycolate, sodium starch glycolate, crospovidone, mannitol and microcrystalline cellulose were accurately weighed and mixed using mortar and pestle and then added to glipizide. Finally, talc and magnesium stearate were added to the powder mixture [13]. Finally, the mixed blend was compressed by using an eightstation rotator Karnavathi machinery Pvt, ltd., Ahmedabad, India.

Hardness
The tablet hardness, which is the force that requires breaking in a diametric compression force. The hardness tester used in the study was the Monsanto hardness tester, which applies force to the tablet diametrically with the help of an inbuilt spring and expressed in kg/cm 2 [14].

Uniformity of weight
Weight variation test was done with 20 tablets. It is the individual variation of tablets weighed from the average weight of 20 tablets [14].
Average weight of the tablet % Deviation 80 mg or less ±10 More than 80 mg or less than 125 mg ±7.5 125 mg or less ±5

Friability
The friability of tablets was measured using a Roche friabilator. Tablets were rotated at 25 rpm for 4 min or up to 100 revolutions. The tablets were then reweighed after removal of fines and the percentage of weight loss was calculated [14].

Drug content uniformity
For content uniformity, ten tablets were weighed and powdered a quantity of powder equivalent to 10 mg of Glipizide was extracted into 7.4 phosphate buffer and filtered. The Glipizide content was determined by measuring the absorbance spectrophotometrically at 254 nm after appropriate dilution with 7.4 phosphate buffer. The drug content was calculated as an average of three determinations [14].

Wetting time
The wetting time of tablets was measured using a very simple procedure five circular tissue papers of 10 cm diameter were placed in a petri dish with a 10 cm diameter. Ten ml of water containing a water-soluble dye (Amaranth) was added to the petri dish. A tablet was carefully placed on the tissue paper. Time required for water to reach the upper surface of the tablet was noted as wetting time [14].

Water absorption ratio
A piece of tissue paper folded twice in a small petri dish containing 5 ml of water. A tablet was put in the tissue paper allowed to completely wet. The wetted tablet was then weighed [14]. Water absorption ration R was determined using the following equation.
Wb = weight of tablet before water absorption.

In-vitro disintegration time
Disintegration time for FDTs was determined using USP disintegration apparatus using pH 7.4 phosphate buffer. The volume of the medium was 900 ml and the temperature was 37±0.2 °C. The time in second taken for complete disintegration of the tablet with no palatable mass remaining in the apparatus was measured [14].

In-vitro dissolution rate studies
The in vitro dissolution rate studies of glipizide Fast Dissolving Tablets were performed using 8 stage dissolution test apparatus (Electrolab TDT-08L) fitted with paddles (50 rpm) at 37±0.5 °C, using 7.4 phosphate buffer (900 ml) as a dissolution media. At the predetermined time intervals, 5 ml samples were withdrawn, filtered through 0.45µ membrane filter, diluted and assayed at 275 nm using a shimadzu UV/Visible double beam Spectrophotometer. Cumulative percentage release was calculated using standard absorbance from the calibration curve. All the dissolution experiments were conducted in triplicate (n = 3) [14].

Drug-excipients compatibility studies
The compatibility of Starch glycolate with the selected drug (Glipizide) was evaluated in DSC and FTIR.

Differential scanning calorimetry (DSC)
DSC thermograms of Glipizide and their mixtures (1: 1) with starch glycolate were recorded on Perkin Elmer Thermal Analyzer Samples (2-5 mg) were sealed into aluminum pans and scanned at a heating rate of 10 °C min -1 over a temperature range 30-350 °C [15].

Infrared spectroscopy
FTIR spectra of Glipizide and their mixtures (1: 1) with starch glycolate were recorded on a Perkin Elmer, IR Spectrophotometer model: Spectrum RXI, using KBr disc as reference [15].

RESULTS AND DISCUSSION
The starch glycolate prepared was found to be a fine, free-flowing amorphous powder. The physical and micromeritic properties of the starch glycolate are summarized in table 2. It was insoluble in aqueous solvents and insoluble in organic solvents tested (methanol, petroleum ether, dichloromethane, and chloroform) the pH of 0.1% aqueous dispersion was 3.83 Starch glycolate exhibited good swelling in water. The swelling index was 10% all micrometric properties indicated good flow and compressibility needed for solid dosage from manufacturing. The density of starch glycolate was found to be 0.76 g/cc. The FTIR spectrum of starch and starch glycolate was shown in fig. 1, 2. The presence of peaks absorption at 1727.18 cm-1 characteristic peaks of ester, so from FTIR studies it was concluded that starch glycolate (ester) was formed when starch was allowed to react with formic acid. The X-ray diffraction pattern ( fig. 3) of starch glycolate showed characteristic peaks, which indicates that the structure was slightly crystalline. The disappearance of the pink color in the ester test confirmed the presence of ester, i.e., starch glycolate.
As the starch glycolate was slightly crystalline and it had got all the characteristics of superdisintegrants it was concluded that starch glycolate can be used as novel superdisintegrants in the formulation of fast dissolving tablets.

Evaluation of tablets
Fast dissolving tablets each containing 100 mg of glipizide could be prepared by employing starch glycolate and other known superdisintegrants, sodium starch glycolate and crospovidone by direct compression method.

Hardness
Hardness of the tablet was in the range of 3.5-4 kg/sq. cm. it indicates good strength with a capability to resist physical and prefunctionary stress conditions during handling. The hardness was much less in comparison to tablets having the hardness in the range of 5.1±0.11 to 6.4±0.11, prepared by Asmaa A. Bayoumi [16].

Friability
Weight loss on the friability test was less than 0.15 % in all cases which is less in comparison to the tablets having 0.42% friability, prepared by Amrita Sony and et al. [17].

Drug content
All the fast dissolving tablets prepared contained glipizide within 100±5% of the labeled claim which is more when compared to the tablets having drug content 97.05 to 99.13, prepared by S Jaya and et al. [18].

Wetting time and water absorption ratio
The result of wetting time and water absorption ratio was found to be within the prescribed limits and satisfy the criteria of the dissolving tablets ( fig. 8). The wetting time was less in F8 i. e 8±0.015 secs which consists of a combination of 5 % starch glycolate, 5 % sodium starch glycolate and 5 % crospovidone. It is less when compared to the tablets having a wetting time of 17.75±1.67 secs, prepared by Rasha Khalid Dhahir and et al. [19].
The water absorption ratio of the formulation F8 was observed to more i. e 125±0.015 % which is relatively more when compared to the tablets having water absorption ratio in the range of 73.2 to 94.38%, prepared by Bandaru Nagajyothi and et al. [20].

In vitro disintegration time
The disintegration time of all the formulated tablets was found to be in the range of 13±0. 03 to 124±0.03 secs as indicated in the table 3. The disintegration time was relatively less when compared to the tablets with a disintegration time of 20±10 secs, prepared by Mangesh M Kumare and et al. [21].

In vitro dissolution rate studies
The drug dissolution from the glipizide fast dissolving tablets employing starch glycolate and other known superdisintegrants were in table 4. and fig. 9, 10. The dissolution parameters of the formulation from (F1-F8) which were made by direct compression method were shown in the table 5. In all these cases the PD5 (percent dissolved in 5 min) was more i. e 99.95±0.03% in F8 which consists at 5 % Starch glycolate, 5 % Sodium starch glycolate and 5 % crospovidone. The percent drug release is much more when compared to the tablets having the release of 96. 94±0.47% for 30 min, prepared by Krishna Mohan Chinnala and et. al. [22]. The same was in the case of DE5 % (dissolution efficiency in 5 min). The PD5 and DE5 % revels that starch glycolate was effective at 5% starch glycolate, 5% sodium starch glycolate, and 5 % crospovidone when the formulations were made by direct compression using these superdisintegrants. The number of folds increases in DE5% was given to table 5. From the results, it was concluded that starch glycolate (new superdisintegrant) could be used as superdisintegrant in the formulation of fast dissolving tablets of glipizide.
Fast dissolving tablets formulated employing starch glycolate (5%), sodium starch glycolate (5%) and crospovidone (5%) as superdisintegrants exhibited in disintegration and dissolution efficiency in 5 min. Formulation 8 gave a release of 99% in 5 min fulfilling the official specification, based on disintegration time and dissolution efficiency in 5 min. Formulation 8 is considered as a good fast dissolving tablet formulation of glipizide.     n= 3±SD (Standard deviation), PD5-Percent dissolved in 5 min, DE5%-Dissolution efficiency in 5 min

CONCLUSION
From the results obtained the following conclusions are drawn, all the fast dissolving tablets formulated employing starch glycolate were of good quality with regard to drug content, hardness and friability and fulfilled the official (IP/USP) requirements of compressed tablets with regard to the above mentioned physical properties.
With glipizide, drug release from the fast dissolving tablets formulated employing starch glycolate (5%) by direct compression was fast and within 5 min. Overall, starch glycolate was found to be a superdisintegrant that can be used along with sodium starch glycolate and crospovidone, and hence it could be used in the formulation of fast dissolving tablets to provide immediate release of the contained drug within 5 min. Hence, starch glycolate was recommended as a novel superdisintegrant in fast dissolving tablets for obtaining an immediate release of the poorly soluble drugs.