Formulation and Evaluation of Ibuprofen Fast Dissolving Tablets Employing Starch Malonate (Modified Starch) as a Superdisintegrant

Aim: The goal of the study was to prepare a superdisintegrant named starch malonate followed by its evaluation for physicochemical properties. Prepared starch malonate was optimized in the preparation of fast dissolving tablets of ibuprofen by using 2 3 factorial designs. Methods: Compatibility studies like FTIR, TLC and DSC were performed to check any interaction between starch malonate and ibuprofen. Fast dissolving tablets were compressed by direct compression method and subjected to various official tests like hardness, friability, drug content, dissolution etc. Wetting time and water absorption ratio were also performed. At last response surface plot and contour plot was plotted to check the effects of starch malonate, croscarmellose sodium and crospovidone (independent variables) on disintegration time and dissolution efficiency in 5 minutes (dependent variables). Stability studies were also performed to check the stability of prepared fast dissolving tablets of ibuprofen. Results: Results of the studies showed that all the results are within acceptable limits and complying with the criteria of fast dissolving tablets. Drug content was found to be (100±5%), hardness of all tablets were found in between 3.8 -4 kg/cm 2 , friability was found less than 0.15%. Optimized formulation has showed less wetting time, less disintegration time followed by enhanced Original Research Article Kumari and Kumar; JPRI, 33(48B): 176-198, 2021; Article no.JPRI.74299 177 drug release. Among all formulation, formulation F2 has shown least disintegration time and enhanced drug release (99.89%) as compared to other formulations. We can conclude that starch malonate can be used as a novel superdisintegrant.


INTRODUCTION
Drugs solubility is the important and critical step in the formulations of any dosage form. Bioavailability and stability of the dosage forms depends on the solubility of the drug. [1,2]. Poorly soluble drug when formulated into oral dosage forms having low bioavailability because of its low solubility. Different dosage forms like oral solid dosage forms, liquid dosage forms, parenteral, rectal, nasal, buccal etc are available in market with their own advantages and disadvantages [3]. The oral route is the most common, stable, economical route compared to other dosage forms preferred by the major population [4]. Literature study has shown that conventional oral solid dosage forms (tablets or capsules) has shown the problem of swallowing, dysphasia (nausea), chocking and its difficult to administer to mentally ill, bed-ridden and unconscious patients [5]. To overcome these problems fast dissolving systems are in boom. They are named "fast dissolving systems" as they are characterized by their property to disintegrate within seconds as soon it comes in contact with saliva which results in fast release of drugs. Fast dissolving tablets and fast dissolving films are available under these systems. [6]. In market many conventional and parented technologies are available for the preparation of fast dissolving tablets. Researchers are still going on so that these fast dissolving tablets should be available for types of disease. In this competitive world, fast onset of action is first choice by every individual. If we consider patient comfort, fast dissolving tablets are first choice by doctors. They have already proved that fast dissolving tablets have high rate of acceptable for pediatrics, geriatrics, psychotic and bedridden patients. It is also easy to administer to patients who are travelling and forget to carry water [7]. Different methods are available for the preparation of fast dissolving tablet. But in among different methods, direct compression method in which superdisintegrant are added are the easy method, have less processing step and have low cost [8]. Superdisintegrant are the agents which help in the quick disintegration of tablets within seconds as it comes in contact with saliva. They are used in very low concentration [9]. Superdisintegrant helps to enhance the drug release of poorly soluble drugs have been already proved by literature survey [10]. In this current work our main aim is to prepare novel modified starch named starch malonate by esterification reaction which will be used as superdisintegrant in order to enhance the drug release of poorly soluble drug. Concentration of starch malonate alone or in combination with other known superdisintegrant (Croscarmellose sodium, Crospovidone) are optimized by using 2 3 factorial designs and fast dissolving tablets of Ibuprofen was prepared.

Materials
Ibuprofen, Croscarmellose sodium, Crospovidone, starch and potato starch were purchased from Yarrow chemicals, Mumbai. Sodium hydroxide and Mannitol were obtained from Finar chemicals Ltd, Ahmadabad. Malonic acid was purchased from Liha Life sciencesHyderabad.Microcrystalline cellulose was procured from Qualigens fine chemicals, Mumbai. Magnesium stearate and Talc was purchased from molychem, Mumbai.

Preparation of a starch malonate
Initially, ten parts of malonic acid and ten parts of potato starch were dissolved in 25 parts of distilled water. Then, the pH of the solution was checked. If pH was not 3.5, the 10 Molar NaOH solution was added to make up to pH 3.5. This solution was then conditioned for 16 hrs. It was kept in the oven at 60º C until it got dried. The mass was washed with distilled water to remove the unreacted malonic acid. The product was held in an oven at 60°C until it got dried. The product obtained was ground and sieved (#120) [11].

Drug -Excipient compatibility studies
Drug excipient compatibility studies are the most important preformulation aspect as excipients used in the formulation should not react with the drug used. Starch malonate compatibility was studied with the ibuprofen by performing FTIR and DSC studies.

Infrared spectroscopy
Mixture of ibuprofen with starch malonate was prepared in the ratio of 1:1. IR spectrum was recorded by using IR Spectroscopy, model: RXI, using KBr disc as reference [12].

Differential Scanning Calorimetry (DSC)
DSC thermograms of ibuprofen and their mixtures (1: 1) with starch malonate were recorded on Perkin Elmer Thermal Analyser. Samples (2-5 mg) were sealed into aluminium pans and scanned at a heating rate of 100C min -1 over a temperature range of 30 -350°C [13].

TLC STUDIES
Thin layer chromatography (TLC) study Stationary Phase: Silica gel G (pre-coated TLC plates).
Mobile Phase: Toluene: n-Hexane: Ethyl Acetate: Glacial Acetic Acid (75:25:5) Procedure: Mobile phase was prepared as per ratio given and kept in TLC chamber undisturbed for 24 hours in order to saturate the chamber. With the help of narrow capillary tube, pure drug, drug with excipient were spotted on the activated silica plate. The spotted plates were kept in the thin layer chromatography (TLC) chamber and allowed to run mobile phase. The plates were dried and kept in iodine chamber to develop the spots. Determine the retardation factor (Rf) by using the formula given below: Retardation factor (R F ) = Distance travelled by sample / Distance travelled by solvent front.

Preparation of fast dissolving tablets of ibuprofen
Ibuprofen fast dissolving tablets composition formulas are given in below Table 1. Formula was optimized by using 2 3 factorial designs. First all the ingredients are weighed properly and then each ingredient was passed through mesh # 120 for uniformity in particle size. In a mortar pestle, an accurately weighed amount of starch malonate, crospovidone, croscarmellose sodium, and microcrystalline cellulose was added and triturated properly for uniform mixing and then drug (ibuprofen) was added to it. Talc and magnesium stearate were added to the powder mixture at last. [14]. Finally mixed blend was compressed by using an eight-station rotary press Karnavati Machinery Pvt, Ltd., Ahmadabad, India). Wetting Time: Five pieces of circular tissue paper were placed in Petri plate having 10 cm diameter. Ten ml of water containing a watersoluble dye (amaranth) was added to the petri dish. Carefully one tablet was kept in the petri plate in and the time taken by colored water to reach the upper surface of the tablet was noted as wetting time [17].

Evaluation of Ibuprofen fast dissolving tablets
Water absorption ratio: The tissue paper was folded twice as per the diameter of the petri dish and 6 ml of water was added to the petri dish. A tablet was kept on the tissue paper and allowed to wet thoroughly and the wetted tablet was weighed. Water absorption ratio was calculated by using the given Equation: Where, W d = Tablet weight after water absorption W e = Tablet weight before water absorption

Stability Studies
Stability studies for the formulation F2 was conducted as per ICH guidelines. The F2 formulation was packed in a screw capped bottle and stored for 6 months at accelerated storage condition (40 0 C ± 2 0 C and 75% RH). The formulation was evaluated for drug content and drug dissolution after storage for 6 months.

RESULTS AND DISCUSSION
The prepared new superdisintegrant starch malonate was found as slightly crystalline free flowing fine powder.
The starch malonate prepared was found to be fine, free flowing slightly crystalline powder. It was insoluble in aqueous solvents and insoluble in organic solvents tested (methanol, petroleum ether, dichloromethane, and chloroform). The pH of 1% w/v aqueous dispersion was checked and it was 3.15. In melting point study, it was found that starch malonate got charred at 270º C which indicates that it can be used in wet granulation method as it can resist temperature. Viscosity of 1% w/v aqueous dispersion was checked and found 1.022cps. Starch malonate exhibited good swelling in water. The swelling index was 83.95%. All micrometric properties indicated good flow and compressibility needed for solid dosage form manufacturing. The density of starch malonate was found to be 1.008 g/cc. The angle of repose and compressibility index showed good flow properties of starch malonate.
The evaluation results for all the tests performed (solubility, pH, swelling index, density) are given in Table 2.
Drug -Excipient compatibility studies: FTIR spectrum of starch malonate and potato starch showed in Fig. 1 and Fig. 2

Fig. 1. FTIR spectra of potato starch
Figs. 4 and 5 shows the scanning electron microscopic (SEM) image of potato starch and starch malonate. The morphological structure of starch malonate was found slightly crystalline form when compared with potato starch which is amorphous in nature.
Compatibility of starch malonate with ibuprofen was evaluated by conducting Fourier-transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), thin layer chromatography (TLC). Fig. 6 and Fig. 7 showed FTIR spectra of Ibuprofen and ibuprofen with starch malonate FTIR spectra. The characteristic peak of carboxylic group (-OH and C=O) present in FTIR spectra of ibuprofen plus starch malonate. This indicates that no interaction between starch malonate and drug selected (ibuprofen).
The DSC thermograms of ibuprofen and ibuprofen starch malonate exhibited endothermic peaks at 78.48 0 C and 77.53 0 C respectively. These melting peaks of ibuprofen and ibuprofenstarch malonate correspond to the melting points of ibuprofen (75-78 0 C). The peaks observed in the DSC thermograms of ibuprofen and ibuprofenstarch malonate mixtures correspond to the melting points of the respective drug indicating no interactions between the selected drug and starch malonate. Fig. 8 and Fig. 9 shows the DSC thermograms of ibuprofen and ibuprofen-starch malonate. In this study, single spots were observed for a pure drug (ibuprofen) as well as their mixture with starch malonate (1:1). The R f values of pure drug and their mixture were found to be close. R f values of pure drug and their mixture were close, which indicate no interactions between the drug and starch malonate. Hardness of tablets determines its capability to withstand physical stress during handling and transportation.

Parameters Observation
Percentage friability was determined by performing friability of the randomly selected tablets from each formulation. Weight loss of the friability was found to be less than 0.15% of all formulations. As per IP, percent friability below 1% is an indication of good mechanical resistance of the tablets. Thus, it was proved that tablets could withstand the pressure, mechanical shocks during handling, transportation, storage and manufacturing processes.
Drug content of randomly selected tablets from each formulation was determined and it was found within 100 ±5% of the labeled amount. Drug content test signifies the all the prepare tablets are having accurate amount of drug and uniform Hence, it can be concluded that all the formulations are having an accurate amount of drug and it should fulfill the official criteria as per IP.
The disintegration time of all the formulated tablets was found to be in the range of 24± 0.02 to 3200± 0.02 seconds, given in the table 3. The water absorption ratio was in between 65.0±0.22-172±0.13. The wetting time found between 20±0.015-202±0.011 seconds. Results of water absorption ratio and wetting time of all formulations are given in Table 4 and wetting time of ibuprofen fast dissolving tablet are shown in Fig. 11. Formulation F2 showed less wetting time i.e. 20±0.0015s as compared to other formulations.  ANOVA of disintegrating time (Table 7), ANOVA of percent dissolved in 5 min (Table 8), ANOVA of wetting time (Table 9), ANOVA of water absorption ratio (Table 10) and ANOVA of dissolution efficiency in 5 min (Table 11) indicated that the individual and combined effect of three factors (Croscarmellose sodium, starch malonate, Crospovidone). ANOVA results indicates that effect were significant (P<0.05) on disintegration time, percent dissolved in 5 min, wetting time, water absorption ratio and dissolution efficiency in 5 min.
On comparison with the marketed formulation, the optimized F2 formulation gave release of 99.89% in 5 min fulfilling the official specification based on the disintegration time, percent drug dissolved in 5 min, wetting time, water absorption ratio and dissolution efficiency in 5 min.
The optimized formulation F2 showed enhanced drug release with least disintegration time found to be comparable with marketed formulation. The starch malonate can be used a novel superdisintegrant

Design Expert Study (Response Surface plot study)
Response surface plots and contour plots were plotted using design Expert 7.11 version. polynomial regression algorithm equation was developed to co-relate the independent variables (starch malonate (A), Croscarmellose sodium (B) and Crospovidone (C)) with dependent variables (disintegration time and dissolution efficiency in 5 minutes).
Below are the equations 1 and 2 representing polynomial equation for disintegration time and dissolution efficiency in 5 minutes. Effect of starch malonate (A), Croscarmellose sodium (B) and Crospovidone (C) and their interaction on disintegration time and dissolution efficiency in 5 minutes are given in below Table  12.

Effect of Different Superdisintegrant on Disintegration Time
Starch malonate (A) in combination with Croscarmellose Sodium (B) has showed a linear relation on disintegration time. When the concentration of starch malonate and Croscarmellose increases, disintegration time of tablet decreases. Tablets will disintegrate more rapidly.
Starch malonate (A) in combination with Crospovidone (C) has showed a linear relation on disintegration time. When the concentration of starch malonate and Crospovidone (C) increases, disintegration time of tablet decreases. Tablets will disintegrate more rapidly.
Croscarmellose Sodium (B) in combination with Crospovidone (C) has showed a linear relation on disintegration time. When the concentration of Croscarmellose Sodium and Crospovidone increases, disintegration time of tablet decreases. Tablets will disintegrate more rapidly. Fig. 13, Fig. 14

Effect of Different Superdisintegrant on Dissolution Efficiency in 5 Minutes
Effect of combination AB (Starch malonate with Croscarmellose Sodium), AC (Starch malonate with Crospovidone) and BC (Croscarmellose Sodium with Crospovidone) was found to be nonlinear on dissolution efficiency in 5 minutes. In combination these superdisintegrant are not showing good drug release profile. Starch malonate with Croscarmellose Sodium and Crospovidone has showed linear relation means when concentration will increases it will enhance the dissolution efficiency in 5 minutes. Fig. 16, Fig. 17 and Fig. 18 showed the response and contour plot of effect of different superdisintegrant on disintegration time of Ibuprofen fast dissolving tablets employed starch malonate.
After storing period of 6 months, no physical changes was observed in the formulation. Drug content and dissolution profile was evaluated. Drug content was not found different after stability testing. The drug dissolution profiles of the fast-dissolving tablets before and after storage are given in Table 13. Drug content and drug dissolution rate of the fast dissolving tablets formulated employing starch malonate were quite stable.

DISCLAIMER
The products used for this research are commonly and predominantly use products in our area of research and country. There is absolutely no conflict of interest between the authors and producers of the products because we do not intend to use these product s as an avenue for any litigation but for the advancement of knowledge. Also, the research was not funded by the producing company rather it was funded by personal efforts of the authors.

CONSENT
It is not applicable.

ETHICAL APPROVALS
We