Formulation, Development and Scale-Up of Fixed-Dose Combination Tablets Containing Zidovudine, Lamivudine and Nevirapine

Author(s): Zênia Maria Maciel Lavra, Flávia Patrícia Morais de Medeiros, Rosali Maria Ferreira da Silva, Talita Atanazio Rosa, Victor de Albuquerque Wanderley Sales, Laysa Creusa Paes Barreto Barros Silva, André Luiz Moreira Domingues de Sousa, Leduar Guedes de Lima, Larissa Araújo Rolim, Pedro José Rolim Neto*

Journal Name: Current HIV Research

Volume 17 , Issue 5 , 2019

Become EABM
Become Reviewer
Call for Editor

Graphical Abstract:


Background: The development of antiretroviral associations in a single dosage form aims to ensure improved efficacy, low costs and better adherence to treatment.

Objective: This work performed the pharmacotechnical development, coating, and stability studies of fixed-dose combination tablets of zidovudine, lamivudine and nevirapine (300 + 200 + 150 mg, respectively).

Methods: Qualitative and quantitative planning of diluents (101 and 250 microcrystalline cellulose, spray-dried monohydrate lactose and corn starch) and coating polymers (Opadry white II HP® and Instacoat Aqua Moistshield II®) were analyzed, and direct compression (DC) and wet granulation (WG) methods were tested aiming the development of the pharmaceutical form. Quality control was carried out according to the specifications set by official compendia. The chosen formulation was scaled-up and the industrial batches were submitted to accelerated and long-term stability studies.

Results: The batches obtained by WG met the requirements, using 101 microcrystalline cellulose, corn starch and Opadry white II HP® as excipients. The DC trial was not possible due to the need of a greater ratio of excipients to improve formulation properties.

Conclusion: Thus, this study brings a new therapeutic alternative for HIV treatment, contributing to the development of another possibility to simplify drug administration.

Keywords: Drug stability, highly active antiretroviral therapy, coating polymers, tablet, HIV, AIDS.

Singh B, Garga B, Bhatowa R, et al. Systematic development of a gastroretentive fixed dose combination of lamivudine and zidovudine for increased patient compliance. J Drug Deliv Sci Technol 2017; 37: 204-15.
Perelson AS, Essunger P, Cao Y, et al. Decay characteristics of HIV-1-infected compartments during combination therapy. Nature 1997; 387(6629): 188-91.
[] [PMID: 9144290]
Cohen MS, Chen YQ, McCauley M, et al. Prevention of HIV-1 infection with early antiretroviral therapy. N Engl J Med 2011; 365(6): 493-505.
[] [PMID: 21767103]
Wilson DP, Law MG, Grulich AE, Cooper DA, Kaldor JM. Relation between HIV viral load and infectiousness: a model-based analysis. Lancet 2008; 372(9635): 314-20.
[] [PMID: 18657710]
Violari A, Cotton MF, Gibb DM, et al. Early antiretroviral therapy and mortality among HIV-infected infants. N Engl J Med 2008; 359(21): 2233-44.
[] [PMID: 19020325]
Marrazzo JM. HIV prevention: opportunities and challenges. Top Antivir Med 2017; 24(4): 123-6.
[PMID: 28208119]
Günthard HF, Saag MS, Benson CA, et al. Antiretroviral drugs for treatment and prevention of HIV infection in adults: 2016 recommendations of the International Antiviral Society-USA Panel. JAMA 2016; 316(2): 191-210.
[] [PMID: 27404187]
Brasil. Protocolo clínico e diretrizes terapêuticas para manejo da infecção pelo HIV em adultos. Brasília (DF): Ministério da saúde; 2017.
WHO. World Health Organization. Zidovudine, Lamivudine and Nevirapine Tablets: Final text for addition to The International Pharmacopoeia 2009. Available from: [Accessed 19 June 2017].
HIV/AIDS. World Health Organization. Fact sheet, 2019. Available from: [Accessed August 27, 2019.]
Carrasco DA, Straten MV, Tyring SK. A review of antiretroviral drugs. Dermatol Ther 2000; 13: 305-17.
Handa T, Jhajra S, Bhagat S, Bharatam PV, Chakraborti AK, Singh S. Molecular insight into atypical instability behavior of fixed-dose combination containing amlodipine besylate and losartan potassium. J Pharm Biomed Anal 2017; 136: 66-80.
[] [PMID: 28064090]
Erle G, Lovise S, Stocchiero C, et al. A comparison of preconstituted, fixed combinations of low-dose glyburide plus metformin versus high-dose glyburide alone in the treatment of type 2 diabetic patients. Acta Diabetol 1999; 36(1-2): 61-5.
[] [PMID: 10436254]
Hoffman C, Rockstroh J, Kamps BS. HIV Therapy. HIV Med 2003; 4: 163-93.
Crane JT, Kawuma A, Oyugi JH, et al. The price of adherence: qualitative findings from HIV positive individuals purchasing fixed-dose combination generic HIV antiretroviral therapy in Kampala, Uganda. AIDS Behav 2006; 10(4): 437-42.
[] [PMID: 16636892]
Bangalore S, Shahane A, Parkar S, Messerli FH. Compliance and fixed-dose combination therapy. Curr Hypertens Rep 2007; 9(3): 184-9.
[] [PMID: 17519122]
Pan F, Chernew ME, Fendrick AM. Impact of fixed-dose combination drugs on adherence to prescription medications. J Gen Intern Med 2008; 23(5): 611-4.
[] [PMID: 18288541]
Arnum PV. Medicamentos de combinação: somando oportunidades. Pharm Technol 2012; 17: 6-11.
Moulding T, Dutt AK, Reichman LB. Fixed-dose combinations of antituberculous medications to prevent drug resistance. Ann Intern Med 1995; 122(12): 951-4.
[] [PMID: 7755232]
Mandal U, Pal TK. Formulation and in vitro studies of a fixed-dose combination of a bilayer matrix tablet containing metformin HCl as sustained release and glipizide as immediate release. Drug Dev Ind Pharm 2008; 34(3): 305-13.
[] [PMID: 18363146]
Bailey CJ, Day C. Fixed-dose single tablet antidiabetic combinations. Diabetes Obes Metab 2009; 11(6): 527-33.
[] [PMID: 19175373]
Gerbino PP, Shoheiber O. Adherence patterns among patients treated with fixed-dose combination versus separate antihypertensive agents. Am J Health Syst Pharm 2007; 64(12): 1279-83.
[] [PMID: 17563050]
Food and drug administration (FDA). Department of Health and Human Services. Approved and Tentatively Approved Antiretrovirals in Association with the President's Emergency Plan. United States. 2018. Available from: international programs/pepfar/ucm119231.htm [Accessed 10 July 2018.]
Chokephaibulkit K, Cressey TR, Capparelli E, et al. Pharmacokinetics and safety of a new paediatric fixed-dose combination of zidovudine/lamivudine/nevirapine in HIV-infected children. Antivir Ther (Lond) 2011; 16(8): 1287-95.
[] [PMID: 22155910]
Sam AP, Fokkens JG. Drug delivery system: adding therapeutic and economic value to pharmacoterapy. Part 2. Pharm Tech Eur 1997; 9: 58-6.
Gohel MC, Jogani PD. A review of co-processed directly compressible excipients. J Pharm Pharm Sci 2005; 8(1): 76-93.
[PMID: 15946601]
Dalziel G, Nauka E, Zhang F, Kothari S, Xie M. Assessment of granulation technologies for an API with poor physical properties. Drug Dev Ind Pharm 2013; 39(7): 985-95.
[] [PMID: 22656190]
United States. United States Pharmacopeia. 37th ed. Rockville: United States Pharmacopeial Convention 2014.
Brasil. The Brazilian Health Regulatory Agency. RE n. 01, 29 July 2005. Available from: [Accessed 03 December 2017].
Leane M, Pitt K, Reynolds G. A proposal for a drug product Manufacturing Classification System (MCS) for oral solid dosage forms. Pharm Dev Technol 2015; 20(1): 12-21.
[] [PMID: 25162770]
Farmacopeia brasileira, 5 ed. ANVISA, Brasília 2010.
Brasil. The Brazilian Health Regulatory Agency. RE n. 899, 29 May 2003. Available from: [Accessed 20 November 2017.]
Lavra ZMM, Rolim-Neto PJ, Silva RMF, Medeiros FPM. Desenvolvimento e validação de método analítico para determinação simultânea de lamivudina, zidovudina e nevirapina em comprimidos dose-fixa combinada por cromatografia líquida de alta eficiência. Quim Nova 2008; 31: 969-74.
Lima AC, Nabarretti BH. FM 14. Desenvolvimento e produção de comprimidos de azitromicina por compactação direta. Ver Ciênc Farm Básica Apli 2015; 36(1): 178. Availble from:
Šantl M, Ilić I, Vrečer F, Baumgartner S. A compressibility and compactibility study of real tableting mixtures: the impact of wet and dry granulation versus a direct tableting mixture. Int J Pharm 2011; 414(1-2): 131-9.
[] [PMID: 21605646]
Jivraj I, Martini LG, Thomson CM. An overview of the different excipients useful for the direct compression of tablets. Pharm Sci Technol Today 2000; 3(2): 58-63.
[] [PMID: 10664574]
Capece M, Huang Z, Davé R. insight into a novel strategy for the design of tablet formulations intended for direct compression. J Pharm Sci 2017; 106(6): 1608-17.
[] [PMID: 28283431]
Bolhuis G, Kussendrager K, Langridge J. New developments in spray-dried lactose. Pharm Technol 2004; 22: 26-31.
Nakamura S, Nakagawa M, Tanaka C, et al. Utility of microcrystalline cellulose to prevent drug segregation in direct powder compression. J Drug Deliv Sci Technol 2019; 52: 386-92.
Schaller BE, Moroney KM, Castro-Dominguez B, et al. Systematic development of a high dosage formulation to enable direct compression of a poorly flowing API: A case study. Int J Pharm 2019; 566: 615-30.
[] [PMID: 31158454]
Chattoraj S, Sun CC. Crystal and Particle Engineering Strategies for Improving Powder Compression and Flow Properties to Enable Continuous Tablet Manufacturing by Direct Compression. J Pharm Sci 2018; 107(4): 968-74.
[] [PMID: 29247737]
Abe H, Yasui S, Kuwata A, Takeuchi H. Improving powder flow properties of a direct compression formulation using a two-step glidant mixing process. Chem Pharm Bull (Tokyo) 2009; 57(7): 647-52.
[] [PMID: 19571406]
Rosiaux Y, Girard JM, Desvignes F, Miolane C, Marchaud D. Optimizing a wet granulation process to obtain high-dose sustained-release tablets with Compritol 888 ATO. Drug Dev Ind Pharm 2015; 41(10): 1738-44.
[] [PMID: 25652358]
Morin G, Briens L. A comparison of granules produced by high-shear and fluidized-bed granulation methods. AAPS PharmSciTech 2014; 15(4): 1039-48.
[] [PMID: 24839117]
Remington GAR. A Ciência e a Prática da Farmácia. Rio de Janeiro: Guanabara Koogan 2004; pp. 923-32.
Mustapha MA, Oseremen AA, Ihunde JE. Formulation development and quality profiling of paracetamol – ibuprofen combination tablets. Int J Pharm Sci Res 2014; 5: 964-9.
Lachman L, Lieberman HA, Kanig JL. Teoria e prática na indústria farmacêutica. Lisboa: Calouste Gulbekian 2001; pp. 563-76.
Mallick S, Pradhan SK, Mohapatra R. Effects of microcrystalline cellulose based comilled powder on the compression and dissolution of ibuprofen. Int J Biol Macromol 2013; 60: 148-55.
[] [PMID: 23732329]
Pachuau L, Dutta RS, Roy PK, et al. Propriedades físico-químicas e desintegrantes do amido glutinoso de arroz de Mizoram, Índia. Int J Biol Macromol 2017; 95: 1298-304.
[] [PMID: 27840214]
Sakwanichol J, Sungthongjeen S, Puttipipatkhachorn S. Preparation and characterization of chitosan aqueous dispersion as a pharmaceutical film forming material. J Drug Deliv Sci Technol 2019; 54101230
Aulton ME, Taylor KMG. Delineamento de formas farmacêuticas. Porto Alegre: Artmed 2005.
Maddineni S, Chandu B, Ravilla S, et al. Dissolution Research- a Predictive Tool for Conventional and Novel Dosage Forms. Asian Journal of Pharmacy and Life Science 2012; 2: 119-34.
ICH. Quality Guidelines. 2003. Available from: [Accessed August 27, 2019].
Joshi A, Gbadero D, Esseku F, Adesanya OJ, Adeyeye MC. A randomized two-way crossover bioequivalence study in healthy adult volunteers of paediatric zidovudine/lamivudine/nevirapine fast-disintegrating fixed-dose combination tablet. J Pharm Pharmacol 2017; 69(4): 463-70.
[] [PMID: 27859251]

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2019
Published on: 04 December, 2019
Page: [360 - 367]
Pages: 8
DOI: 10.2174/1570162X17666190927162155
Price: $65

Article Metrics

PDF: 28