Title Science and Technology Indonesia e-ISSN:2580-4391 p-ISSN:2580-4405 Vol. 7, No. 3, July 2022 Research Paper Synthesis of Cellulose–Polylactic Acid Microcapsule as a Delivery Agent of Rifampicin Suripto Dwi Yuwono1*, Ridho Nahrowi1, Andi Setiawan1, Ni Luh Gede Ratna Juliasih1, Irza Sukmana2, Wasinton Simajuntak1, Sutopo Hadi1* 1Department of Chemistry, Faculty of Mathematics and Natural Sciences, Universitas Lampung, Bandar Lampung, 35145, Indonesia2Department of Mechanical Engineering, Faculty of Engineering, Universitas Lampung, Bandar Lampung, 35145, Indonesia *Corresponding author: suripto.dwi@fmipa.unila.ac.id, sutopo.hadi@fmipa.unila.ac.id AbstractIn medicinal field, delivery agent is a very important substance to improve the efficiency of drug used by improving the stability andpreventing the degradation of drug during the medical treatment. Due to these important roles of the drug delivery agent, the searchof effective agent is continuously in progress. In this respect, this current research was carried out to synthesize cellulose–polylacticacid (cellulose-PLA), as a potential delivery agent of rifampicin for the curing of tuberculosis. Cellulose was isolated from cassavabagasse, while PLA was obtained from commercial supplier. The two raw materials were used to synthesize cellulose–PLA in 3.5%HCl as solvent under magnetic stirring. The product obtained was then characterized by Fourier-Transform Infrared spectroscopy(FTIR), Particle-Size Analysis (PSA), and Scanning Electron Microscopy (SEM). The FT-IR result showed the presence of hydroxy(3446 to 3429 cm−1) and carbonyl (1757 to 1759 cm−1), confirming the formation new bond between cellulose and PLA. ThePSA characterization displays a particle-sizes of PLA are in the range of 960–92780 nm, while cellulose–PLA are in the rangeof 100–17730 nm demonstrating that cellulose-PLA combined to form more compact structures. The results of SEM analysisindicate the distinct feature of cellulose-PLA, and combination of the features in the cellulose and PLA image. The results of thedissolution test carried out two different concentrations of rifampicin revealed that the optimum dissolution (8.42%) was achievedwith cellulose–PLA of 0.3%, dissolution time of 12 h, and pH of 7.4. KeywordsCellulose, Cellulose-PLA, Dissolution Test, Polylactic Acid Received: 21 January 2022, Accepted: 5 May 2022 https://doi.org/10.26554/sti.2022.7.3.263-268 1. INTRODUCTION Asides from the human immunodeciency virus, tuberculosis (TB) is one of the leading causes of death worldwide. In 2014, relatively 9.6 million new TB cases were recorded globally. Besides, approximately 1.5 million deaths have been recorded as a result of this disease (World Health Organization, 2016). One of the causes of the high death rate is TB cycle irregularity (Patel et al., 2013). However, continuous TB treatment leads to resistance to the antibiotic drugs administered. In addition, inappropriate administration of drugs leads to increased bac- terial survival in host cells (Patel et al., 2013). Therefore, an innovation to reduce the death caused bythis disease is urgently required. Besides, for relatively 20 years, nanomaterial has been de- veloped worldwide due to the wide range of applications, espe- cially in the pharmaceutical eld, owing to its numerous advan- tages. This is based on the fact that the nanomaterial design adapts to individual drug requirements. It serves as a controlled release of drug encapsulation, enhances therapeutic ecacy, and reduces side eects (Amirah et al., 2014; Miricescu et al., 2019). The commonly used nanomaterials such as cellulose are natural polymers that are abundant in nature. Cellulose is a polysaccharide used in various applications due to its advan- tages, such as being non-toxic and renewable, and aordable processing cost (Guo et al., 2012). In addition, cellulose is a strong and rigid polymer that has a high potential to be used as a biopolymer reinforcing agent such as polylactic acid (PLA) (Rahman et al., 2014). Fortunately, PLA serves as a drug re- lease because it is a biodegradable polymer that in vitro has good biocompatibility and bio-absorbability (Dev et al., 2010). Moreover, it has an aliphatic polyester structure (Guo et al., 2012). The active component of the drug bound to the PLA molecule is highly resistant to degradation, thereby improving its eectiveness (Kadian, 2018). This led to the synthesis of cellulose–PLA, used in the encapsulation of rifampicin. The steps performed during the process included micro PLA, cellulose–PLA, and microcapsule https://crossmark.crossref.org/dialog/?doi=10.26554/sti.2022.7.3.263-268&domain=pdf https://doi.org/10.26554/sti.2022.7.3.263-268 Yuwono et. al. Science and Technology Indonesia, 7 (2022) 263-268 syntheses using rifampicin drug. Furthermore, FTIR, SEM, and dissolution test analyses as well as PSA were conducted. 2. EXPERIMENTAL SECTION 2.1 Materials The materials utilized comprise PLA, hydrochloric acid, and chloroform obtained from Merck & Co (NJ, USA). Cellulose was extracted from cassava bagasse through delignication and applied without further treatment. Rifampicin was obtained from a local drug store and was used as purchased. 2.2 Synthesis of Micro PLA The synthesis of micro PLA was conducted by dissolving 5 g of PLA in 50 mL of chloroform. The solution was stirred with a magnetic stirrer for 4 h. Furthermore, 50 mL of ethanol was added, and the solution was stirred using a magnetic stirrer (Stuart Magnetic Stirrer, China) for another 4 h. The solu- tion was evaporated with a rotary evaporator (Buchi Rotary Evaporator, Switzerland) until only a small amount of solvent was left. Subsequently, 25 mL of distilled water was added and evaporated to get rid of the organic solvent. Finally, the micro PLA obtained was freeze-dried (ScanVac-Freeze dryers, Denmark). 2.3 Synthesis of Cellulose–PLA The synthesis of cellulose–PLA was carried out by combining several methods reported in various studies (Dev et al., 2010; Jeevitha and Kanchana, 2014). Firstly, 1 g of cellulose was suspended in 50 mL HCl 3.5 M and stirred with a magnetic stirrer for 2 h at 50◦C. Secondly, 5 g of PLA was dissolved in 50 mL of chloroform and stirred for 4 h. Subsequently, 50 mL of ethanol was added to the PLA solution, which was further mixed with the initially prepared cellulose suspension. The cellulose–PLA mixture was stirred for 4 h at room tem- perature and then transferred into a separating funnel. The upper layer, which comprises the chloroform, was removed using a bulb pipette, while the remaining cellulose–PLA was ltered with a lter paper and then freeze-dried. The sample was analyzed using FTIR (Agilent Carry 630, CA, USA), PSA (Fritsch, Germany), SEM (Zeiss Evo MA10, Germany). 2.4 Synthesis of Microcapsule Meanwhile, approximately 0.65 g of cellulose–PLA was dis- solvedin6mLofchloroform. Consequently, rifampicin(0.002 5 and 0.005 g) was added to the solution, followed by the addi- tion of 50 mL polyvinyl alcohol 0.5%. It should be mentioned that the concentration of rifampicin used is much lower than the normally used dose for curing purpose, since the main objective of this study is to study the potential application of cellulose-PLA synthesized as delivery agent. The mixture was stirred for 1 h and dispersed in 250 mL of distilled water. Fi- nally, the mixture was stirred for another 1h and then ltered. The solid obtained was then dried for 24 h (Chang, 1984). 2.5 Slow Release Test The slow-release test was carried out by dissolving 0.2 g of mi- crocapsules into 500 mL of a buer solution (pH 1.2 KCl-HCl buer, andpH7.4phosphatebuer) withapHofrelatively1.2 and 7.4. Therefore, for every 3 h interval, 5 mL of each solu- tion, with triplicate sampling at pH of 1.2 and 7.4 was collected and diluted with 25 mL of buer solution. The concentration was measured using a UV–Vis Shimadzu UV-245 Spectropho- tometer (Japan) at a wavelength of 244 nm (Derakhshandeh and Soleymani, 2010; Ciobanu et al., 2013; Siqueira et al., 2010). The drug dissolution rate was further measured using the following formula (1) %D = M × fp × v × 11,000,000 w × 100% (1) Where Exp: % D (percent dissolution), M (concentration), fp (dilution factor), V (volume), W (mass of microcapsules used). 2.6 Characterizations TheIRspectrawererecordedonKBrdiscswithinthewavenum- ber range of 4000 to 400 cm−1. The particle size distribution of PLA and cellulose–PLA were determined using the wet dispersion using water as solvent. SEM characterization was conducted on gold coated sample to increase the conductivity. 3. RESULTS AND DISCUSSION 3.1 Synthesis of Micro PLA and Cellulose–PLA Besides, during the synthesis of micro PLA, mechanical treat- ment was adopted. Conversely, for the cellulose–PLA, a com- bination of mechanical and acid hydrolysis treatments was utilized. Micro PLA synthesis was carried out using a magnetic stirrer at a constant rotational speed. One advantage of the mechanical treatment is that the surface charge of the nanoma- terial is equivalent to that of the raw material (Chang, 1984). Conversely, acid hydrolysis treatment was conducted using 3.5 M HCl solution. The acidic solution was used to break down the heterocyclic ether bond between the monosaccharide monomers (Siqueira et al., 2010; Laopaiboon et al., 2010). The ionic strength of the HCl solution decreased the viscos- ityofcellulose, therebyreducingthesizeof themacromolecules (Czechowska-Biskup et al., 2007). Although, before mixing the PLA and cellulose solution, ethanol was added to the PLA solution, which acted as an emulsier. It accumulated on the surface of the HCl and chloroform solution, thereby, causing ethanol to be adsorbed in the solution. In addition, ethanol also decreases the surface and interface strains of each solvent. Additionally, during the emulsion process, the molecules of cellulose and PLAwere collided, therebyfreely interacting with each other (Tadros, 2013). The collision frequency increased during the stirring process. Electromagnetic induction, which generated rotational motion at a constant angular velocity, en- hanced the reaction rate of cellulose and PLA (Szajnar et al., 2014). © 2022 The Authors. Page 264 of 268 Yuwono et. al. Science and Technology Indonesia, 7 (2022) 263-268 3.2 FTIR Analysis of Cellulose-PLA FTIR analysis was carried out to determine the functional groups of materials synthesized. The FTIR spectra are shown inFigure1. Figure1(a) shows theabsorptionat3446cm−1 due to the presence of OH from cellulose. In addition, the absorp- tion at 2900 and 1429 cm−1 indicates the C-H bond from the cellulose. These results show that pure cellulose was obtained through the delignication process. This was evidenced by the absence of absorption at 1170 and 1082 cm−1. Meanwhile, the absorption of the pyranose ring originated from hemicellulose. In addition, the absence of an alkyl aryl ether bond at 1232 cm−1 indicated that no lignin was bound to the cellulose (Yang et al., 2007). This was proven by the absence of absorption at 1599 and 1511 cm−1, indicating a phenylpropanoid ring of lignin (Adapa et al., 2011). Figure 1(b) shows that the carbonyl group PLA is evident at 1757 cm−1, CH3 at 2999 cm−1, and C–H at 2949 and 1458 cm−1. The cellulose–PLA spectrum is shown in Figure 1(c). Furthermore, the presence of absorption at 1759 cm−1 indi- cates the presence of carbonyl derived from PLA. In addition, absorption at 3429 cm−1 implies that a hydroxyl group was derived from the cellulose. The presence of a hydroxy group is indicated by the presence of a band at relatively 3446 and 3429 cm−1 and carbonyl at approximately 1757 and 1759 cm−1, thereby conrming the formation of a bond between the cellulose and PLA, while retaining theirbasic functional groups. Rahman et al. (2014) reported that the shift in wavenumbers was caused by the intermolecular hydrogen bonds between the cellulose and PLA. 3.3 PSA of Cellulose–PLA Besides being used to detect particle size, PSA was also used to determine the eect of mechanical and acid hydrolysis treat- ments on micro-particle synthesis. The results of the eect of PSA on PLA and cellulose–PLA is shown in Figure 2. In accordance with Figure 2(a), PLA has 3 clusters of particles. The particle sizes in the rst cluster range within 0.36 and 2.86 `m, with a relative percentage of 11.75%. The second cluster overlappedwith the thirdandtheparticle sizes rangingbetween 7.74 and 205`m, with a relative percentage of 87.18%. How- ever, considering the cellulose–PLA (Figure 2(b)), the result showed that the sample size is much smaller while displaying a slightly narrower distribution. Based on the diagram, the particle size of the main cluster in the sample ranges within 8.30 to 37.86`m with a relative percentage of 90.55%. This nding suggests that cellulose and PLA were combined to form a more compact material leading to the collapse of overlapping due to the mechanical and hydrolysis treatment during the preparation process. In respect to this, it was proven that a combination of mechanical and acid hydrolysis treatments im- proved the eectiveness of micro material synthesis. Mechan- ical treatment increased the frequency of polymer collisions in a solvent, thereby accelerating solvation. Acid hydrolysis treatment accelerated bonding by protonating polymer bonds. In this study, it is evident that the particle size of the pre- Figure 1. FTIR Spectra of (a) Cellulose, (b) PLA, (c) Cellulose- PLA pared sample is within the micrometer (`m) range and signif- icantly larger than the ndings of the research carried out by Kumar et al. (2012), which reported that the preparation of co-ethyl cellulose–PLA had particle sizes within the nanometer (nm) range. These signicantly dierent results were most likely realized due to the dissimilarities in the starting materials utilized. 3.4 SEM Analysis of Cellulose-PLA SEM analysis was carried out to conrm the result of the cellu- lose–PLAsynthesis morphologically, shown in Figure 3. Based on Figure 3(a), PLA has sheet morphology; this was due to the addition of chloroform. This solvent was diused and ad- sorbed in the PLA 3-dimensional network, thereby breaking thecross-link. Toconrmthisnotion, itwasdiscovered that the density between PLA sheets was quite high. The chloroform disconnected the intermolecular, both physically and chemi- cally. Figure 3(b) shows that the cellulose obtained throughthe delignication process has a rod-like structure. In addition, its intermolecular density was extremely high, indicating that the cellulose possesses a microcrystalline structure. Cellulose poly- mers possess uniform agglomeration due to the intramolecular © 2022 The Authors. Page 265 of 268 Yuwono et. al. Science and Technology Indonesia, 7 (2022) 263-268 Figure 2. PSA Analysis (a) PLA, (b) Cellulose-PLA Figure 3. SEM Analysis (a) PLA, (b) Cellulose, (c) Cellulose- PLA hydrogen bonds. Meanwhile, the cellulose microcrystal was composedofhundredsofagglomerationofcellulosenanobrils with a rod-like structure (Rahman et al., 2014). Based on Figure 3(c), the cellulose bounded into PLA par- ticles has a smooth surface. The cellulose suspension process in the HCl was stirred in order to reduce agglomeration by hydrolyzing and breaking the intramolecular hydrogen bonds, thereby causing the inter-particle spacing to become more ten- uous than that in Figure 3(b). It was also discovered that the density of the PLA particles attached to the cellulose was more tenuous than that in Figure 3(a) due to the HCl solvent hy- drolyzed ether bonds on the PLA. The acid solution used was capable of hydrolyzing the long-chain cellulose in the amor- phous part, thereby producing a crystalline structure. On the contrary, the crystalline part was resistant to acid attack (Khoo et al., 2016). The addition of cellulose caused the PLA struc- ture to become more fragile than pure one (Sullivan et al., 2015), thereby increasing its dissolution ability in the body. 3.5 Dissolution Test The dissolution test was carried out using rifampicin to deter- mine the extent of its detachment from the micro material. Figure 4. Dissolution Test of Rifampicin Concentration (a) 0.3% and (b) 0.6% Rifampicin was selected because of its easy accessibility. The dissolution test was carried out at apH of 1.2, which is regarded as a simulation of the stomach and intestinal pH of 7.4, carried out for 15 h. The dissolution test results are shown in Figure 4. Figure 4(a) shows the percentage dissolution of PLA-cellu- lose-drug 0.3% at a pH of 7.4 and 1.2. The optimum time for drug dissolution at the same pH was 12 h. Furthermore, relatively 8.42% and 3.81% of the drugs were dissolved at a pH of 7.4, and 1.2 respectively. In addition, drug dissolution occurred more at a pH of 7.4 than 1.2. The percentage disso- lution of PLA-cellulose-drug of 0.6%, is shown in Figure 4(b). The optimum time fordrug dissolution at a pH of 7.4 was 15 h. In addition, approximately 2.03% of the drugs were dissolved. Conversely, the optimum time for drug dissolution at a pH of 1.2 was 12 h. Furthermore, approximately 6.69% of the drugs were dissolved. Therefore, the drug dissolution occurred more at pH 1.2 than 7.4. An eective microcapsule used for TB treatment is cellulo- se-PLA-drug 0.3%. Conversely, several nanomaterial drugs were not degraded in the stomach, they were easily degraded in the lungs. The presence of a nanomaterial improved the eec- tiveness of the treatment and reduced the TB drug resistance causedbygeneticmutations (Shakyaetal.,2012). Basedonthe data in Figure 4, the optimum dissolution time for rifampicin is 12 h. This is consistent with the studycarried out bySarfaraz et al. (2010) which stated that after 12 h, approximately 69% to 91% of rifampicin was deformed. Amirah et al. (2014) re- ported that the optimum dissolution time for rifampin is 10 h. The dissolution rate on the rst day was aected by several fac- tors, such as diusion through the cellulose–PLA channel. In addition, terminal carboxylic acids improved water absorption, thereby accelerating swelling and cellulose–PLA degradation © 2022 The Authors. Page 266 of 268 Yuwono et. al. Science and Technology Indonesia, 7 (2022) 263-268 (Fonseca et al., 2002). The dissolution rate was also aected by the large surface area of the material (Nag et al., 2016). 4. CONCLUSIONS In this research cellulose-PLA was successfully synthesized from cellulose isolated from cassava bagasse and commercial PLA.Theformationofbondbetweenthe twostartingmaterials was conrmed by FT-IR analysis as indicated by the presence of absorption bands at 3445 and 3429 cm−1 associatied with hydroxyl group and the band at 1757 and 1759cm−1 associated with carbonyl group. PSA analysis indicated the reduction of particle size of cellulose-PLA compared to those of cellulose and PLA, conrming the formation of cellulose-PLA micro- capsule. 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Characteristics of Hemicellulose, Cellulose and Lignin Py- rolysis. Fuel, 86(12-13); 1781–1788 © 2022 The Authors. Page 268 of 268 INTRODUCTION EXPERIMENTAL SECTION Materials Synthesis of Micro PLA Synthesis of Cellulose–PLA Synthesis of Microcapsule Slow Release Test Characterizations RESULTS AND DISCUSSION Synthesis of Micro PLA and Cellulose–PLA FTIR Analysis of Cellulose-PLA PSA of Cellulose–PLA SEM Analysis of Cellulose-PLA Dissolution Test CONCLUSIONS ACKNOWLEDGMENT