Optimization Combination of Suweg Starch (Amorphophallus campanulatus Decne) and Gembili Starch (Dioscorea esculenta (Lour.) Burk.) as Filler of Ibuprofen Tablet by Simplex Lattice Design Method

Tablet is pharmaceutical dosage form that simple and efficient in drug delivery system. Ibuprofen tablet is usually taken along with food or milk to reduce side effects on the gastrointestinal tract. Starch of Suweg and Gembili are not yet widely developed as excipients in tablet formulation. Based on Biopharmaceutics Classification Systems, ibuprofen includes in BCS class II with high permeability and low solubility. This study want to formulate ibuprofen tablets using combination of suweg and gembili starch with wet granulation method. However, the optimum proportion of starch composition is not yet known, so optimization is needed with the simplex lattice design method using Design Expert software. Obtained 8 formulas with physical response: granule flow time, tablet weight uniformity and disintegration time of tablets. The optimization shows that the optimum composition of suweg and gembili starch are 51.809%: 48.191%. The result of statistical analysis [t-test] physical parameters of granule and tablet of ibuprofen optimum formula were not significantly different (p-value > 0.05) with Design Expert prediction. Based on the requirements of Pharmacopeia Indonesia 4th Edition the results of optimum formula test provide good physical test with granule flow time 3.583±0.130 seconds; tablet weight uniformity 498.333±5.080 mg, hardness tablet 4.780±0.130 Kg, friability vvof tablets 0.904% and the disintegration time of tablets 6.833±0.750 minutes. The dissolution profile of the optimum formula showed %DE at 60 minutes is 76.975±0.037%. Consentration of ibuprofen in tablet is 191.755±5.847 mg and percentage of ibuprofen in tablet is 95.877±2.293%.


Introduction
Tablet is one of the most commonly used drug dosage forms because efficient, practical, and ideal for administering orally active substances [1] . Tablet is solid preparation, made in flat or double convex press, generally round, containing one type of drug with or more with or without additives. Additional substances used can function as filler substances, developer substances, and wetting agents [2]. The filler (diluent) functions to increase the volume of the mass to be easily made. The filler material is added if the active ingredient was small or difficult to press. For example lactose, starch, dibase calcium phosphate, and microcrystalline cellulose [3].
Various types of tubers are spread in all regions in Indonesia which have the potential to produce starch, including those that have not been widely developed and the utilization is not optimal is suweg  [4] showed that A. campanulatus Decne tuber starch had low amylose (19%) and high peak viscosity (700 BU) so that it was well developed for thickening and filling materials. Gembili tubers with high starch yield (21.44%) are also very potential to be developed into starch products. The use of a combination of fillers in the tablet preparation formulation will affect the physical properties of tablets produced because the filler material has a large portion of the overall weight of the tablet.
Ibuprofen tablets are usually taken along with food or milk to reduce the side effects of the drug. Therefore, a new idea was developed to replace the components of tablet fillers with natural ingredients as well as food ingredients, namely suweg tubers (A.campanulatus Decne) and gembili (D. esculenta (Lour.) Burk.), the aim that Ibuprofen tablets are produced better and could helped minimize the side effects of the drug. Comparison of the filler composition in the formulation of a tablet Ibuprofen preparation can determine the physical properties of the tablets produced. Therefore, the research was optimized to obtain the optimum composition of tuber starch filler mixture with the simplex lattice design method using Design Expert software.

Methods 2.2.1. Isolation of Tuber Suweg and Gembili
Determination of suweg and gembili tubers was carried out at the Biology Laboratory of the Mathematics and Natural Sciences Faculty, Universitas Sebelas Maret, Surakarta, Indonesia. The process of making starch from tubers is done by extracted with water solvent twice (1:3 and 5:3) for 15 minutes. After 15 minutes, the extract is filtered so that liquid starch is obtained, then dried using an oven with a temperature of 50±2 ⁰C for 6 hours. Dry starch is ground and sieved using 70 and 90 mesh [4] then organoletics test.
The sample of 1.0 g of tuber starch was flattened above the pan of the Moisture Analyzer. The tool will heat the sample at 105 ⁰C until it shows a constant readable water content value (± 3-5 minutes).

Wet Granulation and Evaluation
Ibuprofen tablets are made using wet granulation method. The ingredients are weighed according to the desired weight in each formula (Table 1). First, the binder (10% gelatine) is made by 10 g gelatine powder diluted with hot water ad 100 mL. Active substances (ibuprofen), crushers (amprotab) and fillers (suweg and gembili starch) are mixed and ground until homogeneous. Then the binder (10% gelatin) is added until a moist mass can be obtained. When the granule is passed on a 16 mesh sieve, the granule is dried in oven at 60 ⁰C for 2 hours. Dry granules are sieved again with 18 mesh sieve, then mixed with lubricant (Mg stearate and talc) and stirred until homogeneous.
Granule evaluation includes : Flow time test of granule, weighed 50 g of granule and poured into a funnel with stem closed. The stem is opened and the granule is allowed to flow until it runs out. The

Tableting and Evaluation
Tablet pressed with each tablet weigh 500 mg with a dose of 200 mg ibuprofen was performed using a single punch tablet pressed. Tablets that have been press then evaluation including :

Weight uniformity test
Weighed 20 tablets one at a time with an analytical scale, then the average weight and deviation of each tablet were weighed. The deviation of the weight of two tablets should not be more than 5% of the average weight and none of the tablets deviate more than 10% of the average.

Hardness test
The tablet is placed on the hardness tester with the tablet standing, then the tool lever is fully pressed. The scale achieved when a broken tablet is read. The test was repeated 3 times.

Fragility test
Weighed a total of 20 tablets, then put into the cylinder friabilator. The friabilator test equipment is run for 4 minutes or 100 rounds. Then the tablet is taken and released again, the tablet is weighed again and the difference in weight is calculated before and after testing. % Fragility = (initial weight-end weight)/(initial weight) x 100% (1)

Disintegration time
Inserted 6 tablets one at a time into the tube of disintegration test equipment, then the device moved up and down regularly 30 times per minute in medium water temperature of 36-38⁰C. Tablets are disintegrated if there are no tablet parts left behind. Tablet

Tablet dissolution
Pour of 900 mL dissolution medium into a vessel, then heated at temperature of 37±0.5°C. The ibuprofen tablet was put into the dissolution vessel then rotated at a speed of 50.0 rpm. Samples were taken as much as 10.0 mL at intervals of 0, 2, 5, 10, 15, 20, 30, 45, and 60 minutes. Each sample taken is then replaced with 10.0 mL dissolution medium. The absorbed sample is measured at it's maximum wavelength. According to the Indonesian Pharmacopeia 5th Edition [5], within 60 minutes it must dissolve not less than 80% C13H18O2 of the amount indicated on the label.

Data Analysis
Optimum formula was obtained by Simplex Lattice Design methods using Design Expert software. Data on the physical properties of tablets obtained by measurement of time until the granules flow out for flow time, calculation of the Coefficients of Variation (CV), balancing tablet weight of 5% and 10% for tablet weight uniformity, average scale value on hardness tester tools for tablet hardness, calculation of tablet fragility%, tablet disintegration time with disintegration test equipment.
Profiles of dissolution of ibuprofen tablet optimum formula for the combination composition of tuber starch fillers was obtained by comparing the dissolution test results with the requirements listed in Indonesian Pharmacopeia 5th Edition (2014).
The data obtained were analyzed statistically using a T-Test for one sample (one sample T-Test) with a 95 % confidence level. Test results are compared with predictive results.

Results and Discussion
The results of the determination in the Biology Laboratory of the Mathematics and Natural Sciences Faculty, Sebelas Maret University Surakarta, Indonesia based on Flora of Java book stated that the plants used in this study were Suweg (A. campanulatus Decne) and Gembili (D. esculenta (Lour.) Burk.).
High moisture content can increase the growth of microbes and enzymes that cause damage to starch. The limit of microbial water content can still grow is 14-15% . Water content of tuber starch with replications resulted in an average water content in suweg tuber starch (A. campanulatus Decne) which was 16.6% and gembili tuber starch (D. esculenta (Lour.) Burk.) was 18.7%. The test results of water content in tuber starch showed high values can be made possible due to environmental conditions when the research is still entering the rainy season so the air is more humid. From the optimization results, it was made ibuprofen tablets with the same method with ibuprofen tablets made for optimization. Furthermore, ibuprofen tablets with the optimum formula composition combination of suweg starch and gembili starch were obtained from the optimization using Simplex Lattice Design method from the physical properties of granules and tablet.
The uniformity of ibuprofen tablet weight of the optimum formula test results were significantly different from the predictive results (p>0.05), but it was acceptable because it was still included in the requirements of tablet weight uniformity. The deviation of the weight of two tablets no more than 5 % of the average weight of 20 tablets and none of the tablets deviate more than 10 % from an average of 20 tablets. The test results of determining the optimum formula levels of ibuprofen tablets using UV-VIS spectrophotometer show that on average each tablet contains of 191.76 ±5.85 mg ibuprofen with concentration of 95.88±2.29 % ibuprofen. According to the requirements listed [5], ibuprofen tablets are not less than 90% and not more than 110 %, so that the optimum level of the active ingredient of ibuprofen each tablet meets the requirements. From the results of the analysis showed that the optimum formula ibuprofen tablet had dissolution profiles which meet the requirements of Indonesian Pharmacopoeia 5th edition (2014) with %DE (Disolution Efficiency) which was not less than 80 % within 60 minutes which was 94.85±0.037 %.