OPTIMIZATION OF NON-EFFERVESCET FLOATING TABLETS RANITIDINE HCl FORMULA USING DURIAN SEED MATRIX (Durio zibethinus Murr) FULLY GELATINIZED MODIFIED USING SIMPLEX LATTICE DESIGN METHOD

This study investigated the use of fully gelatinated durian seed starch as an excipient in Ranitidine HCl Non-Effervescent Buoyancy Tablets (NEFT). The simplex lattice design method was used to formulate the optimum composition of the formula, including fully gelatinated durian seed starch, PVP K30, and magnesium stearate. Physically modified durian seed starch is expected to increase the release time of active substances in the body. The experiment was conducted for six months by measuring the physical properties of the granule, tablet hardness, solubility, and friability. Results showed that the optimum formula (27.74 mg durian seed starch, 1.5 mg PVP K30, 0.76 mg magnesium stearate) produced ranitidine HCl NEFT tablets with optimal properties. This research may contribute to the development of effective tablet formulations


INTRODUCTION
Along with the progress of time, all fields in life are experiencing rapid advancements, including the pharmaceutical field.With this progress, pharmacists are required to continuously develop drug formulation, drug manufacturing methods, and drug delivery systems.The oral route of drug administration is the most preferred by the public due to several advantages, such as easy use, high flexibility, http://eduvest.greenvest.co.idSecondly, it aims to ascertain the optimal composition of the matrix, comprising fully gelatinized durian seed starch, PVP K30, and magnesium stearate, required in the NEFT tablet formula.This is essential for producing a pharmaceutical preparation with the most favorable characteristics.
The overarching goals of this study are two-fold.Firstly, it endeavors to generate a standardized excipient from fully gelatinized durian seed starch, specifically designed for effective use in NEFT tablets.Secondly, it aims to identify the optimal composition of the matrix, involving fully gelatinized durian seed starch, PVP K30, and magnesium stearate, within the NEFT tablet formula.The ultimate objective is to create a pharmaceutical preparation with properties that are deemed optimal for pharmaceutic purposes.

RESEARCH METHOD
This research is experimental in nature and aims to evaluate the use of fully gelatinized Durian Seed starch as an excipient in Non-Effervescent Floating Tablets (NEFT).Additionally, the study aims to determine the optimum formula for the matrix of fully gelatinized Durian Seed starch, magnesium stearate, and PVP K30 in NEFT using the Simplex Lattice Design method in the Design Expert software.The research locations include the National Research and Innovation Agency (BRIN), Eka Karya Botanical Garden in Bali, and the Pharmaceutical Laboratory, Faculty of Mathematics and Natural Sciences, Udayana University.The research is conducted over a period of six months.
Various tools are utilized in the research, including a blender, analytical balance, oven, sieves, mortar and pestle, as well as testing equipment such as Tablet Hardness Tester, Tablet Friability Tester, and Tablet Disintegration Tester.Materials involved comprise ranitidine HCl, Durian Seeds, magnesium stearate, PVP K30, distilled water, 70% ethanol, and hydrochloric acid.
Independent variables involve the composition of fully gelatinized Durian Seed starch, PVP K30, and magnesium stearate, while dependent variables include the physical properties of granules and the characterization of ranitidine HCl tablets, including NEFT properties.Controlled variables encompass the preparation process of fully gelatinized Durian Seed starch, granule formation, and tablet manufacturing.
Research procedures encompass the determination of Durian Seed plants, submission of ethical clearance, collection of materials, production of natural and fully gelatinized Durian Seed starch, tablet optimization using Simplex Lattice Design, granule production, and physical properties testing of granules.Tablet evaluation includes hardness testing, friability testing, dissolution testing, and NEFT testing in rat stomachs.
The optimum formula is chosen based on NEFT tablet testing and analyzed using mathematical models such as linear, quadratic, and special cubic approaches.Desirability assessment is conducted using the Design Expert software.

Plant Determination
The plant used to make amylum fully gelatinized in this study is Durian Seed plant (Durio zibethinus Murr).The determination was carried out at the Characterization Laboratory of the Botanical Garden "Eka Karya" Bali.The method used is direct identification and comparison with literature.Plant determination aims to find out the truth of a plant used and there are no errors in sampling as material (La et al., 2021

Ethical Clearance
Ethical clearance or feasibility of research ethics is a written statement given by the research ethics commission for research involving living things (humans, animals, and plants) stating that a research proposal is feasible to be carried out after meeting certain requirements (Insani et al., 2013).Ethical clearance is submitted to the Veterinary Ethics Committee of the Faculty of Veterinary Medicine, Udayana University.The ethical clearance certificate can be seen in Appendix 2.

Collection of Materials
The plant part used in this study was durian seeds.Durian seeds Durian seeds are obtained in Wongaya Gede Village, Tabanan Regency, Bali.The color of the durian seed shell, which is blackish brown with the color of white durian seeds.The selected durian seeds are durian seeds that are 10 months old.Durian seeds harvested in physiological mature conditions (10 months) will produce maximum durian seed sizes with blackish-brown durian seed color and less mucus content in durian seeds (Lopulalan et al., 2021).While the active substance of NEFT tablets in this study, namely ranitidine HCl was obtained from Kimia Farma Batukarut, Arjasari District, Bandung, West Java.Certificate of Analysis of ranitidine HCl can be seen in appendix 3.

Making Natural Amylum (Native Starch)
Making natural amylum is done by means of durian seeds Durian seeds are peeled and then washed with clean water.Then, durian seeds are cut into small pieces and crushed using a blender that has added aquaades.Cutting durian seeds into small aims to facilitate the grinding process, while the use of a blender aims to create a mechanical collision between the solvent (aquades) and durian seeds.After that, the result is squeezed and filtered.Filtering aims to separate the pulp with filtrate liquid containing amylum (Rahmatullah et al., 2021).The liquid from the mixture of Durian seeds and aquades is precipitated for 48 hours in a closed http://eduvest.greenvest.co.id container.The goal is that the amylum can settle and not remain in the filtrate liquid so that the resulting amylum ration is better.
After 48 hours, the resulting supernatant liquid is removed and washed with aquades until only amylum from Durian seeds remains.The resulting precipitate has a smooth but mushy texture because there is still water content, so drying is carried out in the oven at a temperature of 50ºC until dry so that the resulting amylum avoids the growth of microorganisms.The amylum produced after drying is in the form of dry lumps with a smooth texture.Sieving is carried out using a mesh sieve of 100 to obtain fine powder in accordance with the requirements of amylum in the Indonesian Pharmacopoeia (INDRAWATI, n.d.;Kiptiyah et al., 2021).
Fully Gelatinized Amylum Manufacturing Making fully gelatinized amylum is done by mixing natural amylum with aquades (1: 2) b / v. Then the mixture is heated using water vapor at a temperature of 90ºC for 15 minutes until a viscous mass is obtained.The use of a temperature of 90ºC because the temperature is the peak temperature of gelatinization (Jatmiko & Estiasih, 2014;Kuntari et al., 2017;Polnaya et al., 2015).In addition, based on previous research shows that the temperature of 90ºC is the optimum temperature in the modification of Durian Seed amylum.This is evidenced by the lowest amylose levels produced by gelatinization at a temperature of 90ºC so that at that temperature it produces amylum with the highest amylopectin levels.The temperature of 90ºC was also chosen because of the yield of the smallest percentage of crystallinity and the greatest morphology of the granule.The result of heating is a bone-white gel which is then dried in the oven at 60ºC for 48 hours.The heating results of fully gelanitized amylum obtained a hard shape so it is necessary to reduce the particle size by grinding and sifting with a mesh sieve 20.

Granule Manufacturing
Granule manufacturing is carried out using the wet granulation method.Wet granulation is a process of mixing active substance particles and excipients into larger particles by adding a binder in the right amount to form a moist mass that can be granulated.This method forms granules by binding powder using a binder as a substitute for compaction.The principle of wet granulation is to wet the mass or mixture of active substance and excipients with a binding solution until a certain level of moisture is obtained (Gopalan & Gozali, 2019).
The granule manufacturing process begins by mixing ranitidine HCl, fully gelatinized Durian Seed starch, and lactose (Mixture 1).The mixing process is done gradually from the least to the most abundant material to produce a homogeneous mixture (Wirasti et al., 2021).Afterward, PVP K30 mucilage is prepared by dissolving it in 70% ethanol as needed.The mixture of ethanol and PVP K30 generally produces better granules than adding PVP directly in dry conditions.Additionally, the volatile nature of ethanol facilitates the granule drying process.The mucilage is added to Mixture 1 until a moist mass that can be kneaded is obtained.The moist mass is then passed through a 10-mesh sieve to form granules.The moist mass is sieved with a mesh sieve 10 to increase the surface area of particles, making the drying process easier at a temperature of 40ºC-60ºC (Hajrin et al., 2021).The formed granules are dried using an oven at a temperature of 50ºC until the water content meets the requirements.The dried granules are then passed through a number 20 mesh sieve, mixed with a lubricant (magnesium stearate), and stirred until homogeneous.The resulting dry granules are sieved using a number 20 mesh sieve to ensure uniform size, allowing them to fill tablet molds evenly (Hidayat et al., 2021).526,23 ± 1,92 Particle size distribution testing was conducted using the sieving method.Sieving is the most common method used to measure particle size distribution because it is inexpensive, simple, and fast with little variation between operators (Gumbara et al., 2015).This method is performed by using four mesh sieves arranged in sequence, where the coarsest sieve is placed at the top (Jannah et al., 2018).Granule formulas can be considered good if they have a narrow particle size distribution, and the amount of fines is not more than 10% (ZAIDAN et al., 2016).This testing is essential because particle size can affect the flowability of a granule.A wide particle size distribution results in uneven flow into the compression chamber, affecting tablet weight uniformity (Mariyani et al., 2012).Based on the results of particle size distribution testing (Table 4), the particle size of all formula granules falls within the range of 426.75 µm to 720.69 µm.The formula with the smallest average particle size is Formula 5, measuring 426.75 µm, while the formula with the largest average particle size is Formula 9, measuring 720.69 µm.These results indicate that all formulas are predominantly retained on a 40-mesh sieve due to the granulation process being conducted using a 20-mesh sieve.Compressibility testing aims to determine whether the material can form a stable and compact mass when subjected to pressure.The results of compressibility testing (Table 6) show that the compressibility index percentage of all formulas meets the requirements, which is less than 20%.A low compressibility index value for a material indicates better flow properties compared to a high compressibility index value.The extent of compressibility is influenced by the granule size and shape (Akbar & Febriani, 2019;Husni et al., 2020).Good compressibility is indicated by uniform particle size and shape, facilitating compression and producing compact tablets during printing (Kholidah et al., 2014).

Formula
Formula Flow Time (seconds) (Mean ± SD) 1 9,15 ± 0,28 2 9,57 ± 0,23 3 9,69 ± 0,11 4 9,51 ± 0,27 5 9,60 ± 0,10 6 9,43 ± 0,28 7 9,30 ± 0,39 8 9,68 ± 0,09 9 9,46 ± 0,47 10 9,40 ± 0,23 11 9,42 ± 0,41 12 9,25 ± 0,27 13 9,66 ± 0,08 Flow time is the time required for a certain amount of granules to flow through a funnel, expressed as the number of granules flowing per unit of time.Flow time testing aims to determine the flow properties of granules by calculating their flow rate.Flow properties are influenced by particle shape, size, and cohesion between particles.Good granules are those that can flow freely and can be compressed into tablets.The lower the concentration of binding agents, the smaller the size, viscosity, and density of the preparation, resulting in increased cohesive forces between granule particles.High cohesive forces make granules difficult to flow freely.A small density means a small molecular weight, reducing the influence of gravity on the mass because cohesive forces are higher than gravitational forces, preventing granules from flowing freely (Elisabeth, 2018;Ririn & Balfas, 2020).Granules have good flow properties if 100 g of granules have a flow time of ≤ 10 seconds or a flow rate of 10 g/second ( (Soemarie et al., 2017).The flow time testing results range from 9.15 to 9.69 seconds (Table 7).Based on these results, it can be concluded that all formulas have good flow times as they meet the requirements.27,1195 The angle of repose is the maximum angle formed by the granule surface on the horizontal surface.The powder will form a cone, and the flatter the cone produced, the smaller the angle of repose will be.The size of the angle formed is influenced by particle size, the strength of attraction and friction between particles.The smaller the particle size, the higher the cohesive forces.High cohesion makes granules difficult to flow and results in a larger angle of repose (Dewi et al., 2021;Mulyadi et al., 2016).

56-65
Extremely Poor >66 Based on the results of granule angle of repose testing (Table 8), all formulas, except Formula 2, have an excellent angle of repose, while Formula 2 has a good angle of repose.If the angle of repose is ≤ 30°, the granules can flow well, but if ≥ 40°, the flow properties become less favorable.The smaller the angle of repose value, the better the flow properties of the granules, resulting in uniformly weighted tablets.The angle of repose value is related to flow time, where a faster flow time corresponds to a smaller angle of repose formed.Granule formulations with higher concentrations of binding agents show that granules can flow more freely because the particle size is larger compared to formulations with lower concentrations of binding agents (Rohmani & Rosyanti, 2019).1,88 ± 0,06 Testing the moisture content of granules aims to determine the amount of volatile components, including water, present in the granules due to the heating process during drying (Husni et al., 2020).A moisture content above 5% indicates significant degradation of the preparation.This can occur because the concentration of binding agents is too low, resulting in small size and density of the preparation.Conversely, if the moisture content is <1%, capping may occur, which is the splitting of the tablet at the top (Elisabeth et al., 2018).Based on the results of granule moisture content testing (Table 10), all formulas meet the requirements for good granule moisture content, which is 1-5%, ensuring stability and quality during storage (Rowe et al., 2009).

Tablet Making
Tablets can be made based on the results of previous tests on the physical properties of granules.Based on the test results, the entire formula has met the requirements of a good granule so that it can be printed into tablets.The granules are printed into tablets using a single punch tablet felt.The main requirement for making tablets is that the components are easy to print and easy to flow (Putra & Jaya, 2023).The results of making tablets can be seen in figure 5. http://eduvest.greenvest.co.id 169,4 ± 1,48 Hardness in tablets is used to describe the tablet's strength to withstand mechanical pressures during distribution, manufacturing, packaging, and storage (Rohmani & Rosyanti, 2019).Sufficient tablet hardness is one of the essential requirements for a tablet.Factors influencing tablet hardness include compression pressure and the properties of the compressed material.Hardness is used as a measure of compression pressure, and increasing the pressure during compression will enhance tablet hardness (Banne et al., 2012) Hadisoewignyo, 2010).Based on the tablet hardness test results, it can be observed that higher concentrations of binding agents in the formula can strengthen the particle bonds within the tablet, resulting in a more compact tablet (Devi et al., 2018).
From the response data of the hardness test, a linear graph for the hardness test of NEFT ranitidine HCl tablets was obtained, with significant results reflected in a p-value <0.0001 (less than 0.05).This value indicates that the equation model used can describe the conditions of the hardness response.This is further supported by the insignificant prediction error of the model, i.e., 0.8894 (greater than 0.05).The response also yields coefficient equations A (+180.54513), B (+144.12160), and C (+71.79219).
Based on the Cook's distance graph, it is illustrated that hardness test data for all formulas is good, as none of the data surpasses the Cook's distance value.The coefficient values obtained explain that the composition of fully gelatinized Durian seed starch, PVP K30, and magnesium stearate can increase the hardness of NEFT ranitidine HCl tablets.The hardness test calculation results can be seen in Equation 4. Meanwhile, the relationship analysis between the combination of fully gelatinized Durian seed starch, PVP K30, and Mg stearate with the hardness test results is depicted in a contour plot shown.
From the response data of the friability test, a linear graph for the friability test of NEFT ranitidine HCl tablets was obtained, with significant results reflected in a p-value <0.0001 (less than 0.05).This value indicates that the equation model used can describe the conditions of the friability response.This is further supported by the insignificant prediction error of the model, i.e., 0.2028 (greater than 0.05).The response also yields coefficient equations A (-0.013591), B (+0.092291), and C (+0.511115).
Based on the Cook's distance graph, it is illustrated that friability test data for all formulas is good, as none of the data surpasses the Cook's distance value.The coefficient values obtained explain that fully gelatinized Durian seed starch can reduce the friability of NEFT ranitidine HCl tablets, while magnesium stearate can increase the friability value of the tablet.The friability test calculation results can be seen in Equation 5.Meanwhile, the relationship analysis between the combination of fully gelatinized Durian seed starch, PVP K30, and Mg stearate with the friability test results is depicted in a contour plot.

Dissolution
Dissolution is a process in which a solid substance dissolves in its carrier medium, producing a homogeneous solution (Almuksiti et al., 2010).Dissolution testing is an important parameter to provide information in the development of a dosage form with optimal therapeutic efficacy (Anggraini et al., 2016).The purpose of dissolution testing is to determine the release profile of the active drug substance from its dosage form in the specified conditions and ensure continuous product quality.In vitro dissolution testing shows a good correlation to estimate the bioavailability of the dissolved active drug substance in vivo (Umar & Lucida, 2023).
Based on the dissolution test results, a maximum wavelength of 224 nm was obtained.The linear regression equation obtained from the measurement of various concentrations of the serial solution is y = 0.0605x + 0.0089 with an r-value of 0.993.The data from the dissolution test show that all formulas have similar dissolution profiles.The slowest drug release process is observed in formula 9, with a dissolution percentage of 71.16%.
From the response data of the dissolution test, a linear graph for the dissolution test of NEFT ranitidine HCl tablets was obtained, with significant results reflected in a p-value <0.0001 (less than 0.05).This value indicates that the equation model used can describe the conditions of the dissolution response.This is further supported by the insignificant prediction error of the model, i.e., 0.1979 (greater than 0.05).The response also yields coefficient equations A (+69.58337), B (+103.51748), and C (+130.87278).
Based on the Cook's distance graph, it is illustrated that dissolution test data for all formulas is good, as none of the data surpasses the Cook's distance value.The coefficient values obtained explain that the composition of fully gelatinized Durian seed starch, PVP K30, and magnesium stearate can increase the dissolution of NEFT ranitidine HCl tablets.The dissolution test calculation results can be seen in Equation 6.Meanwhile, the relationship analysis between the combination of fully gelatinized Durian seed starch, PVP K30, and Mg stearate with the dissolution test results is depicted in a contour plot.

Determination of Optimal Formula
The software used to analyze the data of NEFT ranitidine HCl tablets is Design Expert 13.0.5.0.The data obtained from the tablet testing is processed using this software to generate the optimum formula for NEFT ranitidine HCl tablets.Before obtaining the optimum formula, the criteria for the desired optimum formula need to be established.
Based on the analysis, the optimum formula obtained is number 1 with the composition of fully gelatinized Durian seed starch 27.74 mg, PVP K30 1.5 mg, and magnesium stearate 0.76 mg, as it produces the best hardness, friability, and dissolution test correlation values.The hardness test value produced by the design expert is 175.968N, while the hardness test value produced in the real test is 174.733N, friability test value is 0.005%, whereas the value produced in the test is 0.008%, dissolution value is 72.833% whereas the real test result is 71.98%, and the desirability value produced is 0.936.

CONCLUSION
The conclusion in this study is that natural Durian Seed Amylum modified into fully gelatinized Durian Seed amylum can be used as NEFT tablet excipient.This is evidenced in this study, namely the resulting ranitidine HCl NEFT tablets.The amylum formula of fully gelatinized Durian Seeds, PVP K30, and magnesium stearate with a ratio of (27.74:1,5:0.76)was determined as the optimum formula with a desirability value of 0.936.It is recommended to conduct further research on in vivo test and stability test of the NEFT tablet formula ranitidine HCl using the excipient amylum Durian Seeds fully gelatinized as a binder.

Table 4 .
Results of Particle Size Distribution Measurement

Table 5 .
Particle Size Range for Each Sieve Number(MoH RI, 2020)

Table 6 .
Compressibility Measurement Results

Table 8 .
Angle of Repose Measurement Results

Table 9 .
Relationship Between Flow Properties and Angle of Repose(USP, 2015)

Table 10 .
Moisture Content Measurement Results