The Optimum Conditions of Carboxymethyl Chitosan Synthesis on Drug Delivery Application and Its Release of Kinetics Study

Parsaoran Siahaan(1*), Nadira Cahyaning Mentari(2), Ustera Octovindra Wiedyanto(3), Dwi Hudiyanti(4), Suci Zulaikha Hildayani(5), Marlyn Dian Laksitorini(6)

(1) Diponegoro University
(2) Department of Chemistry, Diponegoro University
(3) Department of Chemistry, Diponegoro University
(4) Department of Chemistry, Diponegoro University
(5) Department of Chemistry, Diponegoro University
(6) Department of Pharmaceutics, Faculty of Pharmacy, Universitas Gadjah Mada
(*) Corresponding Author


In this paper, carboxymethyl chitosan (CMC) was synthesized and studied as a carrier to encapsulate vitamin (as drug model) and controlled release. Chitosan (CS) is a polycationic derivated from chitin, which suitable for active substance carrier system on biomedical function. CS has good properties such as non-toxic, biodegradable, and biocompatible. However, CS insoluble in an aqueous solvent so CS was modified chemically into CMC. CMC was formed by reacting CS and monochloroacetic acid with sodium hydroxide (NaOH) as a catalyst. Optimation was performed by varying the NaOH concentration during alkalizing the CS and the temperature reaction. The functional group and crystallinity of CS and CMC were estimated by FTIR and XRD. The degree substitution of carboxymethylation has an average value of 0.60. The results show optimum temperature reaction and NaOH concentration were 60 °C and 40% (w/v). The nicotinamide (NA), a hydrophilic vitamin, was loaded within CMC matrix system through in vitro precipitation method. To confirm the encapsulation of NA in CMC and the release kinetics of NA from CMC in distilled water was studied through UV-Vis spectrophotometry. The release profile of NA from CMC matrix system carried out for 3 h and 12 h. The rate of NA release from CMC increases with increasing time and the follows a zero order, Higuchi, and Korsmeyer-Peppas kinetics rules.


carboxymethyl chitosan; temperature reaction; NaOH concentration; encapsulation; release kinetics

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[1] Peniche, H., and Peniche, C., 2011, Chitosan nanoparticles: A contribution to nanomedicine, Polym. Int., 60 (6), 883–889.

[2] Vemmer, M., and Patel, A.V., 2013, Review of encapsulation methods suitable for microbial biological control agents, Biol. Control, 67 (3), 380–389.

[3] van der Lubben, I.M., Verhoef, J.C., Borchard, G., and Junginger, H.E., 2001, Chitosan for mucosal vaccination, Adv. Drug Delivery Rev., 52 (2), 139–144.

[4] Koppolu, B.P., Smith, S.G., Ravindranathan, S., Jayanthi, S., Suresh Kumar, T.K., and Zaharoff, D.A., 2014, Controlling chitosan-based encapsulation for protein and vaccine delivery, Biomaterials, 35 (14), 4382–4389.

[5] Mizrahy, S., and Peer, D., 2012, Polysaccharides as building blocks for nanotherapeutics, Chem. Soc. Rev., 41 (7), 2623–2640.

[6] Siafaka, P.I., Titopoulou, A., Koukaras, E.N., Kostoglou, M., Koutris, E., Karavas, E., and Bikiaris, D.N., 2015, Chitosan derivatives as effective nanocarriers for ocular release of timolol drug, Int. J. Pharm., 495 (1), 249–264.

[7] Cheng, X., Liu, R., and He, Y., 2010, A simple method for the preparation of monodisperse protein-loaded microspheres with high encapsulation efficiencies, Eur. J. Pharm. Biopharm., 76 (3), 336–341.

[8] Rinaudo, M., 2006. Chitin and chitosan: Properties and applications, Prog. Polym. Sci., 31 (7), 603–632

[9] Ye, Z., Guo, J., Wu, D., Tan, M., Xiong, X., Yin, Y., and He, G., 2015, Photo-responsive shell cross-linked micelles based on carboxymethyl chitosan and their application in controlled release of pesticide, Carbohydr. Polym., 132, 520–528.

[10] Vakili, M., Rafatullah, M., Ibrahim, M.H., Abdullah, A.Z., Salamatinia, B., and Gholami, Z., 2016, Chitosan hydrogel beads impregnated with hexadecylamine for improved reactive blue 4 adsorption, Carbohydr. Polym., 137, 139–146.

[11] Kouchak, M., Avadi, M., Abbaspour, M., Jahangiri, A., and Boldaji, S.K., 2012, Effect of different molecular weights of chitosan on preparation and characterization of insulin loaded nanoparticles by ion gelation method, Int. J. Drug Dev. Res., 4 (2), 271–277.

[12] Berger, J., Reist, M., Mayer, J.M., Felt, O., Peppas, N.A., and Gurny, R., 2004, Structure and interactions in covalently and ionically crosslinked chitosan hydrogels for biomedical applications, Eur. J. Pharm. Biopharm., 57 (1), 19–34.

[13] Bernkop-Schnürch, A., and Dünnhaupt, S., 2012, Chitosan-based drug delivery systems, Eur. J. Pharm. Biopharm., 81 (3), 463–469.

[14] Mourya, V.K., Inamdar, N.N., and Tiwari, A., 2010, Carboxymethyl chitosan and its application, Adv. Mater. Lett., 1 (1), 11–33.

[15] Mourya, V.K., and Inamdar, N.N., 2009, Trimethyl chitosan and its applications in drug delivery, J. Mater. Sci. - Mater. Med., 20 (5), 1057–1079.

[16] Mourya, V.K., and Inamdar, N.N., 2008, Chitosan-modifications and applications: Opportunities galore, React. Funct. Polym., 68 (6), 1013–1051.

[17] Chen, L., Du, Y., and Zeng, X., 2003, Relationships between the molecular structure and moisture-absorption and moisture-retention abilities of carboxymethyl chitosan: II. Effect of degree of deacetylation and carboxymethylation, Carbohydr. Res., 338 (4), 333–340.

[18] Chen, L., Tian, Z., and Du, Y., 2004, Synthesis and pH sensitivity of carboxymethyl chitosan-based polyampholyte hydrogels for protein carrier matrices, Biomaterials, 25 (17), 3725–3732.

[19] Mi, Y., Su, R., Fan, D.D., Zhu, X.L., and Zhang, W.N., 2013, Preparation of N,O-carboxymethyl chitosan coated alginate microcapsule and their application to Bifidobacterium longum BIOMA 5920, Mater. Sci. Eng., C, 33 (5), 3047–3053.

[20] Teng, Z., Luo, Y., and Wang, Q., 2013, Carboxymethyl chitosan-soy protein complex nanoparticles for the encapsulation and controlled release of Vitamin D3, Food Chem., 141 (1), 524–532.

[21] Kurniasih, M., Purwati, P., Hermawan, D., and Zaki, M., 2014, Optimum conditions for the synthesis of high solubility carboxymethyl chitosan, Malay. J. Fundam. Appl. Sci., 10 (4), 189-194.

[22] Jyothi, N.V., Prasanna, P.M., Sakarkar, S.N., Prabha, K.S., Ramaiah, P.S., and Srawan, G.Y., 2010, Microencapsulation techniques, factors influencing encapsulation efficiency, J. Microencapsulation, 27 (3), 187–197.

[23] Agnihotri, S.A., Mallikarjuna, N.N., and Aminabhavi, T.M., 2004, Recent advances on chitosan-based micro- and nanoparticles in drug delivery, J. Controlled Release, 100 (1), 5–28.

[24] Kashyap, P.L., Xiang, X., and Heiden, P., 2015, Chitosan nanoparticle based delivery systems for sustainable agriculture, Int. J. Biol. Macromol., 77, 36–51.

[25] Maiese, K., Chong, Z.Z., Hou, J., and Shang, Y.C., 2009, The vitamin nicotinamide: Translating into clinical nutrition care, Molecules, 14 (9), 3446–3485.

[26] Lappas, M., and Permezel, M., 2011, The anti-inflammatory and antioxidative effects of nicotinamide, a vitamin B3 derivative, are elicited by FoxO3 in human gestational tissues: implications for preterm birth, J. Nutr. Biochem., 22 (12), 1195–1201.

[27] Aiping, Z., Jianhong, L., and Wenhui, Y., 2006, Effective loading and controlled release of camptothecin by O-carboxymethylchitosan aggregates, Carbohydr. Polym., 63 (1), 89–96.

[28] Souza, J.M., Caldas, A.L., Tohidi, S.D., Molina, J., Souto, A.P., Fangueiro, R., and Zille, A., 2014, Properties and controlled release of chitosan microencapsulated limonene oil, Rev. Bras. Farmacogn., 24 (6), 691–698.

[29] Mhlanga, N., and Ray, S.S., 2015, Kinetic models for the release of the anticancer drug doxorubicin from biodegradable polylactide/metal oxide-based hybrids, Int. J. Biol. Macromol., 72, 1301–1307.

[30] Vaghani, S.S., Patel, M.M., Satish, C.S., Patel, K.M., and Jivani, N.P., 2012, Synthesis and characterization of carboxymethyl chitosan hydrogel: Application as site specific delivery for lercanidipine hydrochloride, Bull. Mater. Sci., 35 (7), 1133–1142.

[31] de Abreu, F.R., and Campana-Filho, S.P., 2009, Characteristics and properties of carboxymethylchitosan, Carbohydr. Polym., 75 (2), 214–221.

[32] Rahmawati, H., and Iskandar, D., 2014, Sintesis karboksimetil kitosan terhadap pengaruh konsentrasi natrium hidroksida dan rasio kitosan dengan asam monokloroasetat, Jurnal Teknologi Technoscientia., 6 (2), 145–155.

[33] Wijaya, H.G., Eko, S., and Lukman, A., 2010, Analisis termal gravimetri film gelatin komersial kitosan, Prosiding, Kimia FMIPA ITS, 1–8.

[34] Patale, R.L., and Patravale, V.B., 2011, O,N-Carboxymethyl chitosan-zinc complex: a novel chitosan complex with enhanced antimicrobial activity, Carbohydr. Polym., 85 (1), 105–110.

[35] Siepmann, J., and Peppas, N.A., 2011, Higuchi equation: derivation, applications, use and misuse, Int. J. Pharm., 418 (1), 6–12.


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