Oryza sativa hydroxypropylated crosslinked starch as disintegrant in tablet

J. Pharm. Pharmacogn. Res., vol. 10, no. 4, pp. 701-716, July-August 2022.

Original Article

Application of hydroxypropylated crosslinked starch from the grains of Oryza sativa L. as potential disintegrant in compressed solid dosage form

[Aplicación de almidón reticulado hidroxipropilado de los granos de Oryza sativa L. como desintegrante potencial en forma de dosificación sólida comprimida]

Elizabeth A. Pagtalunan1,2,3*, Judson Lowie T. Ramos4, Gerard Q. De Guzman5

1Graduate School, Adamson University, Manila, Philippines.

2Belo Medical Group, San Juan, Manila, Philippines.

3School of Pharmacy, Saint Jude College, Manila, Philippines.

4School of Chemical, Biological and Materials Engineering, and Sciences, Mapua University, Manila, Philippines.

5Department of Pharmacology and Toxicology, College of Medicine, University of the Philippines, Manila, Philippines.

*E-mail: elizabeth.pagtalunan@adamson.edu.ph


Context: The modification of starch from the grains of NSICRc222 rice variety may provide a new material with enhanced disintegrating functionality in compressed solid dosage forms.

Aims: To synthesize hydroxypropylated crosslinked rice starch that may possess characteristics of a good disintegrant.

Methods: Starch was isolated by the wet milling method. The crosslinking was performed using trisodium trimetaphosphate as crosslinking agent, and successively hydroxypropylated by using phosphorous oxychloride. The evidences of chemical modifications were determined by FTIR, TGA, and DSC. The application of modified rice starch as a disintegrant was evaluated by determining the dissolution profile, and was compared to the performance of commercially available disintegrants. The compatibility of modified rice starch was employed using FTIR, and the stability of the formulation was subjected to an accelerated stability study.

Results: The changes in infrared spectra and thermogram confirmed successful chemical modification of rice starch. Allopurinol and modified starch mixture staged from 0 to 3 months showed no significant changes in the infrared spectra, which suggest compatibility of HCR with allopurinol. The dissolution rate of allopurinol tablets at pH 1.2, pH 4.5, and pH 6.8 with various superdisintegrants were comparable to the dissolution rate that utilized hydroxypropylated crosslinked rice starch as disintegrant. The accelerated stability study showed no significant changes from 0th to 3rd month, and no degradation products were detected in the HPLC analysis.

Conclusions: The chemical modification of rice starch through crosslinking and hydroxypropylation yielded a novel material comparable to the commercially available superdisintegrants.

Keywords: crosslinking; disintegrant; hydroxypropylation; immediate release; NSIC Rc222-Tubigan 18; rice starch.



Contexto: La modificación del almidón de los granos de la variedad de arroz NSIC RC 222 puede proporcionar un nuevo material con una funcionalidad de desintegración mejorada en formas de dosificación sólidas comprimidas.

Objetivos: Sintetizar almidón de arroz reticulado hidroxipropilado que pueda poseer características de un buen desintegrante.

Métodos: El almidón se aisló por el método de molienda húmeda. El entrecruzamiento se realizó con trimetafosfato trisódico como agente de entrecruzamiento, y sucesivamente se hidroxipropiló utilizando oxicloruro de fósforo. Las evidencias de modificaciones químicas fueron determinadas por FTIR, TGA y DSC. La aplicación de almidón de arroz modificado como desintegrante se evaluó determinando el perfil de disolución y se comparó con el desempeño de los desintegrantes disponibles comercialmente. La compatibilidad del almidón de arroz modificado se empleó mediante FTIR y la estabilidad de la formulación se sometió a un estudio de estabilidad acelerado.

Resultados: La caracterización por FTIR reveló una modificación exitosa del almidón de arroz según los cambios de espectros. Los cambios en los termogramas confirmaron la modificación exitosa del almidón de arroz. La mezcla de alopurinol y almidón modificado en etapas de 0 a 3 meses no mostró cambios significativos en los espectros infrarrojos, lo que sugiere compatibilidad de HCR con alopurinol. La velocidad de disolución de las tabletas de alopurinol a pH 1,2, pH 4,5 y pH 6,8 con varios superdesintegrantes fue comparable a la velocidad de disolución de HCR. El estudio de estabilidad acelerada no mostró cambios significativos del mes O al 3, y no se detectaron productos de degradación en el análisis HPLC.

Conclusiones: La modificación química del almidón de arroz a través de la reticulación y el hidroxipropilado produjo un material novedoso comparable a los superdesintegrantes disponibles comercialmente.

Palabras Clave: almidón de arroz; desintegrante; hidroxipropilado; liberación inmediata; NSIC Rc222-Tubigan 18; reticulado.


Citation Format: Elizabeth AP, Judson Lowie TR, Gerard QDG (2022) Application of hydroxypropylated crosslinked starch from the grains of Oryza sativa L. as potential disintegrant in compressed solid dosage form. J Pharm Pharmacogn Res 10(4): 701–716.

ASEAN Guideline on Stability of Drug Product (2005) In Update (Issue February): 6-9.

Bindar Y, Efan A, Rahmi (2013) Sodium hydroxide (NaOH) concentration and steeping time duration effects on starch production from dry-milled low quality rice IR 64 grade 3 flour using alkaline-protease enzyme digestion method. Int Food Res J 20(3): 1353–1358.

Casper Pharma LLC (2018) Product information. Zyloprim® (allopurinol). Reference ID: 4357411. 1-9.

Changdeo JS, Vinod M, Shankar KB, Rajaram CA (2011) Physicochemical characterization and solubility enhancement studies of allopurinol solid dispersions. Braz J Pharm Sci 47(3): 513–523.

Chen CR, Lin YH, Cho SL, Yen SY, Wu HLS (1997) Investigation of the dissolution difference between acidic and neutral media of acetaminophen tablets containing a superdisintegrant and a soluble excipient. Chem Pharm Bull 45(3): 509-512.

Colussi R, Pinto VZ, Halal SLME, Vanier NL,Villanova FA, Silva RM, Zavareze EDR, Dias ARG (2014) Structural, morphological, and physicochemical properties of acetylated high-, medium-, and low-amylose rice starches. Carbohydr Polym 103: 405-413.

Dai XL, Yao J, Wu C, Deng JH, Mo YH, Lu TB, Chen, J M (2020) Solubility and permeability improvement of allopurinol by cocrystallization. Cryst Growth Des 20(8): 5160–5168.

Desai PM, Liew CV, Heng PWS (2016) Review of disintegrants and the disintegration phenomena. J Pharm Sci 105(9): 2545–2555.

Feng K, Wen G (2017) Absorbed Pb2+ and Cd2+ ions in water by crosslinked starch xanthate. Int J Polymer Sci 2017: 6470306.

Furrer P (2013) The central role of excipients in drug formulation. Eur Pharm Rev: 1–13.

Granza AG, Travalini AP, Farias FO, Colman TAD, Schnitzler E, Demiate IM (2015) Effects of acetylation and acetylation–hydroxypropylation (dual-modification) on the properties of starch from Carioca bean (Phaseolus vulgaris L.). J Therm Anal Calorim 119: 769–777.

Hausler O, Rowe R, Shesky P, Quinn ME (2009) Starch. Handbook of Pharmaceutical Excipients. 6th Edition. Pharmaceutical Press, pp. 685-691.

Hu X, Xie Y, Jin Z, Xu X, Chen H (2014) Effect of single- , dual- , and triple-retrogradation treatments on in vitro digestibility and structural characteristics of waxy wheat starch. Food Chem 157: 373–379.

Iftikhar SA, Dutta H (2019) Status of polymorphism, physicochemical properties and in vitro digestibility of dual retrogradation-annealing modified rice starches. Int J Biol Macromol 132: 330–339.

Kar M, Chourasiya Y, Maheshwari R, Tekade RK (2019) Chapter 2 – Current Developments in Excipient Science: Implication of Quantitative Selection of Each Excipient in Product Development, pp. 29-83.

Karthik V (2016) Excipients used in the formulation of tablets. Research and reviews. J Chem 5(2): 143–154.

Kunle O (2019) Starch source and its impact on pharmaceutical applications. In: Volume Chemical Properties of Starch, Emeje M, ed. DOI: 10.5772/intechopen.89811.

Lawal OS (2004) Composition, physicochemical properties and retrogradation characteristics of native, oxidised, acetylated and acid-thinned new cocoyam (Xanthosoma sagittifolium) starch. Food Chem 87(2): 205–218.

Lenaerts V, Beck RHF, Bogaert EV, Chouinard F, Höpcke R, Désévaux C (2003) Crosslinked high amylase starch for use in controlled-release pharmaceutical formulations and processes for its manufacture. United States Patent US 6,607,748 B1: 13-15.

Li HH, Gao YH, Zhang LH, Li N, Liu ZF (2020) Synthesis and adsorption properties of crosslinked carboxymethyl starch (CMS). J Phys Conf Ser 1605: 012130.

Liu J, Wang B, Jin L, Zhang J, Liu W, Xie J (2013) Functional, physicochemical properties and structure of crosslinked oxidized maize starch. Food Hydrocoll 36: 45-52.

Liu J, Wang B, Lin L, Zhang J, Liu W, Xie J, Ding Y (2014) Functional, physicochemical properties and structure of cross-linked oxidized maize starch. Food Hydrocoll 36: 49–51.

Liu X, Lan C, Al A, Yu L, Zhou S (2016) Preparation of cross-linked high amylose corn-starch and its effects on self-reinforced starch films. Int J Food Eng 12(7): 673–680.

NDA – New Drug Application (2017) Multidisciplinary Review and Evaluation Lesinurad/Allopurinol (Duzallo). Application Number: 209203Orig1s000. U.S. FDA Center for Drug Evaluation and Research: 40.

Neha D (2017) Immediate release tablets. A review. World J Pharm Pharm Sci 10(8): 595–611.

Pahwa R, Gupta N (2011) Superdisintegrants in the development of orally disintegrating tablets: A review. Int J Pharm Sci Res 2(11): 2767–2780.

Prathyusha CH, Murthy TEGK (2013) Compatibility studies of donepezil with different excipients by using HPLC and FTIR. J Adv Pharm Educ Res 3(3): 273–278.

Radhakrishnan A, Palanisamy V, Sanphui P (2020) Organic molecular salts of allopurinol with improved solubility. Mater Today Proc 40(suppl. 1): S210–S215.

Rahaju MR, Fardiaz D, Kusnandar F, Candra Sunarti T (2014) Characterization of chemical and physical properties of hydroxypropylated and crosslinked arrowroot (Marantha arundinacea) starch. J Eng Technol Sci 45(3): 207–221.

Ravenelle F, Rahmouni M (2006) Contramid: High-amylose starch for controlled drug delivery. ACS Symposium Series 934: 79-104.

Runa F, Sarkar MR, Sultana R, Jahan K, Labu ZK (2013) Study on dissolution improvement of allopurinol by co-grinding and fusion method using solid dispersion technique. J Biomed Pharm Res 2(3): 1–7.

Shangraw R, Mitrevej A, Shah M (1980) A new era of tablet disintegrants. Pharm Tech 4(10): 49–57.

Shen Y, Yao Y, Wang Z, Wu H (2021) Hydroxypropylation reduces the gelatinization temperature of corn starch for textile sizing. Cellulose 28: 5123–5134.

Singh AV, Nath LK (2011) Synthesis and evaluation of physicochemical properties of crosslinked Phaseolus aconitifolius starch. Starch 63: 655–660.

Tiwari A (2015) Practical Biochemistry: A Student Companion. LAP Lambert Academic Publishing, p. 6.

Troy D, Beringer P (2006) Tablet Characteristics. Remington: The Science and Practice of Pharmacy. 21st Edition. Lippincott Williams & Wilkins, pp. 916-918.

US FDA – United States Food and Drugs Administration (2019) Guidance for Industry: Dissolition Testing of Immediate Release Solid Oral Dosage Forms. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/dissolution-testing-immediate-release-solid-oral-dosage-forms [Updated October 2019].

USP-NF – United States Pharmacopeia and National Formulary (2021). Allopurinol Tablets. https://online.uspnf.com/uspnf/document/1_GUID-3CF9976A-F17A-4434-9E24-7109F20A161F_1_en-US [Updated October 2019].

Usman M, Ishfaq MT, Malik SR, Iqbal, M, Ishfaq B (2014) Alkaline extraction of starch from broken rice of Pakistan. Int J Innov Appl Res 7(1): 146–152.

Xiao HX, Lin QL, Liu GQ, Yu FX (2012) A comparative study of the characteristics of crosslinked, oxidized and dual-modified rice starches. Molecules 17(9): 10946–10957.

Xie Y, Zhang B, Li MN, Chen HQ (2019) Effects of cross-linking with sodium trimetaphosphate on structural and adsorptive properties of porous wheat starches. Food Chem 289: 187–194.

Zaidul ISM, Absar N, Kim S, Suzuki T (2008) DSC study of mixtures of wheat flour and potato, sweet potato, cassava, and yam starches. J Food Eng 86: 68–73.

Zarmpi P, Flanagan T, Meehan E., Mann J, Fotaki N (2020) Biopharmaceutical understanding of excipient variability on drug apparent solubility based on drug physicochemical properties. Case study: Superdisintegrants. AAPS J 22: 46.

Zhao X, Li Z, Wang L, Lai X (2008) Synthesis, characterization, and adsorption capacity of crosslinked starch microspheres with N,N1-Methylene bisacrylamide. J Appl Polym Sci 109: 2571–2575.

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