Title Science and Technology Indonesia e-ISSN:2580-4391 p-ISSN:2580-4405 Vol. 6, No. 3, July 2021 Research Paper Tablet Formula Optimization From Helminthostachys Zaylanica Extract Using A Simplex Lattice Design Fitrya1*, Najma Annuria Fithri1, Budi Untari1, Aprililianti1, 1Department of Pharmacy, Universitas Sriwijaya, Palembang, South Sumatera *Corresponding author: fitrya@unsri.ac.id Abstract Helminthostachys zeylanica extract has pharmacological activities such as antioxidant, antiinflamatory, and antihyerucemia. Thisextract is nontoxic substance from the acute and subchronic toxicity tests. This extract has a potency to be formulated into tabletdosage forms. This study aims to optimize a tablet formula from Helminthostachys zeylanica extract. Disintegrant and binderconcentrations were independent variables, while physical properties and dissolution time of the tablets were dependent variables.The tablet was prepared by a wet granulation method. Formula was optimized by Simplex Lattice Design. Physicochemical propertiesof granule, physical properties and dissolution of tablet were then analyzed with One Way ANOVA (p = 0.05). Based on granuleanalysis, specification of physicochemical parameters, such as hausner’s ratio, compressibility index, flowability, repose angle, andwater content, met standard British Pharmacopeia. In addition, the starch and PVA concentrations influenced thickness, weightvariation, hardness, friability, disintegration time and dissolution of the tablets (p <0.05), except for friability (p> 0.05). Based on thisstudy, the starch and PVA concentrations for the optimum tablet formula were 19.5% and 1.05%, respectively. Keywords Helmynthostachis zeylanica, Tablet, Optimization, Simplex Lattice Design Received: 9 March 2021, Accepted: 11 June 2021 https://doi.org/10.26554/sti.2021.6.3.131-136 1. INTRODUCTION Helminthostachys zeylanica known as Tunjuk Langit (TL), has active components, such as ugonstilben A-D and avonoids ugonin E-M (Chen et al., 2003; Fitrya, 2010; Wu et al., 2017) Pharmacological activities of the extract of TL has been re- ported as an antioxidant (Huang et al., 2003), anti inamma- tory (Huang et al., 2017; Su et al., 2016), hepatoprotective (Suja et al., 2004), antihyperuricemia (Fitrya and Muharni, 2014) and antidiabetic (Chang et al., 2019; El Ridhasya et al., 2020). Based on a toxicity test of the extract, it was reported to be safe for consumption (Fitrya, 2017). Nowadays, the use of herbal medicine is becoming more popular. Extract formulations into pharmaceutical dosage forms are increasingly developed for both topical and oral uses. The most popular-oral dosage is a tablet form because it is easy for consumption and is better stability (de Souza et al., 2007; Nguyen et al., 2013). Several studies on tablet formulations of the herbal extracts were reported such as tablets from Morus alba extract (Son et al., 2018), Ginger dry extract (Malek et al., 2020); Pachyrrhizus erosus extract (Kharisma et al.); Curcuma longa exctract (Ermawati et al., 2017); and Phillanthus niruri extract (de Souza et al., 2007). The herbal extracts tend to be high hygroscopic because they are composed from carbohydrates as a major component. The hygroscopic properties of the extract inuence the ow properties. Furthermore, these ow properties cause tablet compactibility if they are formulated to a tablet dosage form. Therefore, the determination of the type and concentration of the excipient will determine the qualityof the tablets (Son et al., 2018). In the preliminary study we have prepared three tablet formulations of the TL rhizome ethanol extract using dierent disintegrant and binder combinations, i.e., formula A: Starch & Polyvinyl Alcohol (PVA); formula B: AvicelrPH102 and Polyvinyl Pirolidone (PVP); and formula C: sodium alginate & methylcellulose. Based on physical properties and dissolution of the tablets, formula A had the best physical properties and dissolution(Fitrya, 2016). The main function of disintegrant is contrary to binder eciency but the disintegrant and binder are essential components which determine an ability of tablet disintegration. The stronger the binder, the more eective the disintegrant must be for the tablets to release its medicine. Disintegrant plays an important role of water absorption into the tablet matrix, so that the tablets turn into granules and sub- sequentlybecome primaryparticles. The formation of primary https://crossmark.crossref.org/dialog/?doi=10.26554/sti.2021.6.3.131-136&domain=pdf https://doi.org/10.26554/sti.2021.6.3.131-136 Fitrya et. al. Science and Technology Indonesia, 6 (2021) 131-136 particles increases the dissolution rate and bioavailability of the drug (Desai et al., 2016; Dilebo and Gabriel, 2019). There- fore, the type and concentration of disintegrant and binder are important to ensure a good bioavailability of drug (Bhowmik et al., 2010). This study aims to determine optimum disinte- grant and binder concentration in a tablet formula. Optimum concentration was determined by Simplex Lattice Design (SLD) using software Design Expertr8 (DXr8) 2. EXPERIMENTAL SECTION 2.1 Material The active ingredient was ethanol extract of the TL rhizome. This rhizome was collected from Ogan Ilir area, South Sumat- era. All chemicals are in analytical grade. 2.2 Methods Design of Optimum Formula Tablets were made according to the best formula from previous studies using starch as a disintegrant and PVA as a binder (Fit- rya, 2016). Optimization of tablet formula was designed using a simplex lattice design (DXr8 software, USA). The independent variables are the concentration of binder and disintegrant while the dependent variables are the physical properties and disso- lution of tablets. The starch is in a range of 5-20% (Bhowmik etal.,2010) andPVAis less than2%(Saxena,2004). Therefore, PVA is 1% and 2% for low and high levels, respectively. Based on the simplex latice design, 8 tablet formulas were produced (Table 1). The extract was mixed with lactoce until reaching homogen. The disintegrant, adsorbent, and binder were added sequently. Producedgranulesweredriedat40-50◦Cuntil constantweight, and they were then sieved with No. 14. The dry granule was added magnesium stearate and talcum as lubricant. The re- sulting granules were evaluated for their physical properties, such as the hausner’s ratio, compressibility index, owability, angle of repose and water content (Ermawati et al., 2017). The granules were evaluated following the British Pharmacopoeia, 2008. Finally, the granules were pressed into tablets by tablet- ingmachine (DTR4). Anoptimimumformulawasdetermined based on a formula producing tablets with the best physical properties and dissolution. The PhysicalProperties Evaluation of Tablets The physical properties of tablet studies included organoleptic, thickness, weight variation, hardness, friability, disintegration time, and dissolution (Kharisma et al.; Mishra, 2019). The friability of tablet referred to the British Pharmacopoeia, 2008 using friability tester (CS-1 Friability Tester). Tablet unifor- mity and disintegration time were determined referring to Indonesian Pharmacopeia 4nd by disintegration tester (BJ-3 Disintegration Tester), while tablet hardness was determined referring to the United States Pharmacopeia 32nd, 2009 by a hardness tester (YD-1 Hardness Tester). Experiment results were statistically analyzed by SPSSr21. Figure 1. Tablet run 1-8 In Vitro Dissolution Study The optimum formula dissolution was tested referring to the British Pharmacopoeia, 2008 using the dissolution tester (RC- 3 Dissolution Tester) by determining a total phenolic content as a marker. The total phenolic content was measured by the Folin-Ciocalteu’s method. 3. RESULTS AND DISCUSSION 3.1 Granules Properties Experimental design of tablet formula using DXr8 software was produced eight formulas (F1-F8) showed in Table 1. A wet ganulation method was used based on considera- tion of characteristics of the extract, such as viscousity and hygroscopy. In addition, by the wet granulation method, ow properties and compressibility of powder can be improved so that the powder can be more easily compressed into tablets. Quality all of granule formulas, that is determined by re- pose angle, hausner ratio and compressibility index, can be categorized from good to excellent in their ow properties as presented on Table 2 (Mishra, 2019). Moreover, the plant ex- tracts tend to be more hygroscopic and low owability. These excellentowpropertiesbecomeamainspecicationforweight uniformity during compression of tablets (Son et al., 2018). 3.2 Physical Properties of Tablets Tablet formulas1–8fromtheexperimentaldesignareshownin Figure 1. The physical properties of these tablets are presented in Table 3. Weight variations of these eight formula tablets were in a range of 0.50–0.52 g. These variations indicated all batches in weight uniformity, and each batch content is uniform. The mathematical models for responses as tablet characteristics from the DXr8 software are presented in Table 4. As indicated in Table 4, starch and PVA concentration in- uenced tablet characteristics (except friability) i.e., weight, thickness, hardness, and disintegration time. In the math- ematical models, a positive coecient inuenced responses synergistically, while a negative coecient showed an antago- nistic eect on the responses (Rao et al., 2009). Moreover, the starch and PVA concentration individually inuenced weight and thickness responses while the interaction between both concentration did not have eects. Increase in starch and PVA © 2021 The Authors. Page 132 of 136 Fitrya et. al. Science and Technology Indonesia, 6 (2021) 131-136 Table 1. Experimental Design of Optimized Formula Runs Concentration (%) Extract Lactose Aerosilr Talc Mg Stearate Starch PVA (mg) (mg) (%) (%) (%) F1 17.5 1.25 135 260.49 0.5 1 0.5 F2 12.5 1.75 135 282.99 0.5 1 0.5 F3 10 2 135 294.24 0.5 1 0.5 F4 15 1.5 135 271.74 0.5 1 0.5 F5 20 1 135 249.24 0.5 1 0.5 F6 15 1.5 135 271.74 0.5 1 0.5 F7 20 1 135 249.24 0.5 1 0.5 F8 10 2 135 294.24 0.5 1 0.5 Table 2. The Granules Properties Evaluation Results Formula Hausner ratio Compressibility Flowability Angle of repose Water content (Runs) ± SD index (%) ± SD (10 g/s) ± SD (◦) ± SD (%) ± SD 1 1.14 ± 0.06 12.23 ± 4.78 1.62 ± 0.16 28.0 ± 2.92 7.92 ± 3.67 2 1.10 ± 0.00 9.02 ± 0.12 1.97 ± 0.06 26.7 ± 1.05 8.05 ± 1.40 3 1.15 ± 0.01 12.9 ± 0.42 2.20 ± 0.26 30.07 ± 2.29 5.88 ± 1.40 4 1.10 ± 0.03 9.42 ± 2.16 2.20 ± 0.26 29.58 ± 3.48 7.19 ± 0.51 5 1.14 ± 0.02 11.9 ± 1.16 2.30 ± 0.10 31.07 ± 1.89 6.18 ± 1.47 6 1.10 ± 0.03 9.42 ± 2.16 2.20 ± 0.26 29.58 ± 3.48 7.19 ± 0.51 7 1.14 ± 0.02 11.9 ± 1.16 2.30 ± 0.10 31.07 ± 1.89 6.18 ± 1.47 8 1.15 ± 0.01 12.9 ± 0.42 2.20 ± 0.26 30.07 ± 2.29 5.88 ± 1.40 concentration would increase weight of tablets because molec- ular weights of the starch and PVA are 300–1000 g/mol and 20.000–200.000g/mol, respectively(Roweetal.,2009). Mean while, the dierences in the tablet thickness were due to the dierences in pressure during the pressing process (Rao et al., 2009). Friability was tested to assess eects of friction and shocks, which may often cause breaking, capping, or cracking tablet (Hardenia et al., 2016; Zade et al., 2009). According to BP 2008 a good friability value is less than 0.8%, the tablets were therefore indicated agood mechanical resistance. Lowfriability indicated that the tablet has resistance to friction and is able to maintain its shape. While the tablet surface has been eroded in high friability (Kharisma et al.). Furthermore, hardness was tested to describe tablet endurance through good mechan- ical resistance for packing and distribution. The individual component of the starch and PVA and their interactions sig- nicantly increased hardness and disintegration time. On the other hand, factor of disintegrant and binder and interaction of both could insignicantly reduce the friability of tablet. The starch has more eect on tablet hardness compared to PVA. The hardness can also be inuenced by a compression force during manufacturing, pressing speed, and a height - diameter ratio of the tablets (Adeleye et al., 2015). As starch tend to deform, increasing the starch concentration allows blends more compact (Bhowmik et al., 2010). In addition, the using more PVAcaused an increase in hydroxyl groups to binding the other tablet component. Based on response equations in Table 4, starch concentration become a dominant factor inuencing hardness. Increasing starch, PVA, and their interaction accelerated the disintegration time. Based on their coecients, PVA had the most eect on disintegration time compared to starch and their interaction. During the disintegration process, the capil- lary bridges were formed causing adjacent particles to attract each other. The disintegration capability must exceed interpar- ticulate forces and destruct the bonds. Penetration of liquid into tablet pores is the rst step and often determines the rate of tablet disintegration (Markl and Zeitler, 2017). Increasing starch concentration would also improve a wicking mechanism and deformation recovery, resulting in a faster disintegration time. PVA has a high tendency to swell in water and biological liquid (Kadajji and Betageri, 2011). The hydroxyl groups in the PVA molecules which are close each other will interact to form intra and intermolecular hydrogen bonds. This hydrogen bond results in crystal formation. Increase in crystallinity in the swelling polymer reduces the disintegration ability (Mup- palaneni, 2013; Markl and Zeitler, 2017). 3.3 In Vitro Dissolution Study A drug release prole of tablets in vitro was observed by per- centages of the drugrelease for60minutes (DE60) aspresented in Figure 2. © 2021 The Authors. Page 133 of 136 Fitrya et. al. Science and Technology Indonesia, 6 (2021) 131-136 Table 3. The Physical Properties of Tablets Batch Weight Thickness Friability Hardness Disintegration time (g) ± SD (mm) ± SD (%) (N) ± SD (mnt) ± SD 1 0.51 ± 0.01 3.36 ± 0.15 0.3 19.33 ± 3.15 11.79 ± 1.88 2 0.52 ± 0.01 3.32 ± 0.06 0 27.33 ± 1.65 16.47 ± 1.87 3 0.51 ± 0.01 3.56 ± 0.13 0 17.53 ± 3.02 28.67 ± 2.12 4 0.52 ± 0.01 3.48 ± 0.07 0 29.18 ± 2.17 29.16 ± 1.13 5 0.51 ± 0.02 3.41 ± 0.16 0 35.52 ± 4.04 15.65 ± 1.10 6 0.52 ± 0.02 3.48 ± 0.05 0 30.53 ± 3.62 29.24 ± 2.64 7 0.50 ± 0.01 3.36 ± 0.11 0.15 34.52 ± 3.12 15.93 ± 1.24 8 0.51 ± 0.02 3.58 ± 0.10 0 13.92 ± 0.77 30.93 ± 4.23 Table 4. Mathematical Models of Responses Respons (Y) SLD actual component equation P valueModels of respons Weight variation Y = 0.50 (A) + 0.51(B) + 0.020.05 (A)(B) Thickness Y = 3.38(A) + 3.57(B) + 1.00(A)(B) + 0 0.70(A)(B)(A-B) - 3.96(A)(B)(A-B)2 Friability Y=0.07(A) + 0.00(B) - 1.00(A)(B) + 0.11 1.40(A)(B)(A-B) - 3.00(A)(B)(A-B)2 Hardness Y= 35.02(A) + 15.72(B) + 56.31(A)(B) – 0 94.12(A)(B)(A-B) - 153.62(A)(B)(A-B)2 Disintegration Y= 15.79(A) + 29.80(B) + 25.62(A)(B) + 0Time 12.40(A)(B)(A-B) – 287.33(A)(B)(A-B)2 A = starch concentration and B = PVA concentration Figure 2. Dissolution Curve of Formula 1–8 The mathematical model recommended was quartic with p value less than 0.05 This model indicates that two components (Aand B) have a signicant eect on DE60 of tablets. The SLD actual components are given in Equation 1. Y = 67.21(A) + 42.65(B) + 46.71(A)(B)˘118.71 (A)(B)(A − B) + 469.11(A)(B)(A − B)2 (1) From Eq. 1, starch and PVA increase DE60 of tablets, and starch has more signicant eects than PVA. Increasing starch concentration formed capillary pathways that were getting big- ger. Moreover, the starch became more liquid penetrating into the tablet, and disintegration time of tablet was then faster. In addition, an increase in starch concentration resulted in more disintegrating particles undergoing deformation. Increasing the distintegration time accelerated the dissolution rate of the tablet (Kumar et al., 2016). 3.4 Optimum Formula Optimum formula was determined based on dependent vari- able responses. Responses priority are from 1 (low) to 5 (high). The weight, thickness, friability, and disintegration time of tablets responses were selected in a minimum priority, while the hardness response was selected for level 3 (medium). The less weight and thickness tablet was, the easier it swallowed. If the tablet was too hard, tablet disintegration was postponed and dissolution was bad. Meanwhile, less hard tablets would be easier to break down them for packing and distributing. The faster disintegration time of tablets was, the better the disso- lution of tablets would be. The tablet dissolution is selected in a maximum priority, because the dissolution prole is im- portant parameter ensuring a drug bioavailability. The faster dissolution rate would result in better drug absorptions. © 2021 The Authors. Page 134 of 136 Fitrya et. al. Science and Technology Indonesia, 6 (2021) 131-136 DXr8 analysis obtained three proposional combinations of the starch and PVA, and the largest desirability value (0.777) was selected. This optimum composition consisted of 19.5% starch and 1.05% PVA. If the starch concentration was under this optimum level, capilariy pathways would be not formed. In contrast, if the concentration was too much, the tablet com- pressibility became too bad (Bhowmik et al., 2010). Disintegration time of tablet was long when the PVA con- centration was 2%. The PVA has many hydroxyl groups in its structure, so that it has a capabilityas binder. Therefore, higher concentration of PVA resulted in more hydroxyl groups inter- acting with the extract components. The PVA binded either the extract or other components of tablet by hydrogen bonds, dipole-dipole interactions, and van der waals’s bonds. 4. CONCLUSIONS The starch and PVA concentration signicantly inuenced the tablet characteristics. Based on characteristics and dissolution analysis, the optimum concentration of the starch and PVA on tablet formula are 19.5% and 1.05%, respectively. In order to use dryextracts formakinga tablet, we suggest to reduce extract moisture and to improve ow properties of the granules. 5. 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Page 136 of 136 INTRODUCTION EXPERIMENTAL SECTION Material Methods RESULTS AND DISCUSSION Granules Properties Physical Properties of Tablets In Vitro Dissolution Study Optimum Formula CONCLUSIONS ACKNOWLEDGEMENT