PHARMACOTECHNICAL DEVELOPMENT AND OPTIMIZATION OF MULTILAYERED TABLETS: AN UPDATED INDUSTRIAL REVIEW WITH EMPHASIS ON BILAYER TABLETS

Authors

  • AHMED M. AGIBA Formulation Department, Research and Development Directorate, IDI Pharmaceutical, East of Al Tafreah, Port Said Governorate, Egypt, Pharmaceutics Department, Faculty of Pharmacy, Sinai University Kantara Campus, Ismailia, Egypt https://orcid.org/0000-0003-3635-9093
  • SOHA SAYED ABUL-ELLA Pharmaceutics Department, College of Pharmaceutical Sciences and Industrial Pharmacy, Misr University for Science and Technology, 6th of October City, Egypt
  • REHAB A. ABD EL-MONEM Industrial Pharmacy Department, College of Pharmaceutical Sciences and Industrial Pharmacy, Misr University for Science and Technology, 6th of October City, Egypt

DOI:

https://doi.org/10.22159/ijap.2021v13i4.41528

Keywords:

Fixed-dose combination formulations, Multilayered tablets, Novel approaches, Manufacturing improvement, Process parameters, Characterization tests

Abstract

Fixed-dose combination formulations are multilayered platforms designed for solving complex medication regimens and overcoming polypharmacy problems especially in chronic diseases with geriatric patients. Multilayered tablets are considered promising avenues to combine different active pharmaceutical ingredients (APIs) for a synergic therapeutic effect, or different formulations of the same API in order to achieve a specific drug release profile. Besides, multilayered tablets can extensively help in avoiding possible interactions between different drugs, as well as optimizing each formulation individually in terms of pharmacokinetics and manufacturability. This review article discusses the most suitable materials used in the manufacturing of multilayered tablets, describes novel approaches to manufacturing improvement and process parameters, the influence of process parameters on layer adhesion, and the characterization tests of multilayered tablets.

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Author Biography

AHMED M. AGIBA, Formulation Department, Research and Development Directorate, IDI Pharmaceutical, East of Al Tafreah, Port Said Governorate, Egypt, Pharmaceutics Department, Faculty of Pharmacy, Sinai University Kantara Campus, Ismailia, Egypt

Agiba, A.M. has a bachelor's degree in pharmaceutical sciences and industrial pharmacy from Misr University for Science and Technology (Egypt) with a general grade of Excellent First-Class Honors, a master of pharmaceutical sciences with a specialization in pharmaceutics from Ain Shams University (Egypt), and a master of science in biotechnology from University of Chemical Technology and Metallurgy (Bulgaria) and University of Oviedo (Spain) with a general grade of Excellent (Erasmus Mundus Scholarship).

Agiba, A.M. was granted two research fellowships: Joint NAM S&T Centre ICCBS Research Fellowship at ICCBS, University of Karachi (Pakistan) and FCT Research Grant at CICECO Aveiro Institute of Materials (Portugal), plus an internship at Bajcsy-Zsilinszky Krhz s Rendelintzet (Hungary).

Agiba, A.M has worked for top leading pharmaceutical industries in the Middle East, Africa, and worldwide: SIGMA Pharmaceutical Industries as a product development senior specialist at Formulation R&D, Egyptian Armed Forces Pharmaceutical Factory as a principal researcher, Pharco-B International, a member of Pharco Corporation, as a R&D section head at Formulation R&D, and October Pharma as R&D section head at Formulation R&D.  

Agiba, A.M has 6 international research/review articles in high-quality, peer-review journals, 8 international conference papers and 2 theses.

References

Efentakis M, Peponaki C. Formulation study and evaluation of matrix and three-layer tablet sustained drug delivery systems based on carbopols with isosorbite mononitrate. AAPS PharmSciTech 2008;9:917–23.

Vaithiyalingam SR, Sayeed VA. Critical factors in manufacturing multilayered tablets–assessing material attributes, in-process controls, manufacturing process and product performance. Int J Pharm 2010;398:9–13.

Nirmal J, Saisivam S, Peddanna C, Muralidharan S, Nagrarajan M. Bilayer tablets of atrovastatin calcium and nicotinic acid: formulation and evaluation. Chem Pharm Bull 2008;56:1455–8.

Shiyani B, Gattani S, Surana S. Formulation, and evaluation of bi-layer tablet of metoclopramide hydrochloride and ibuprofen. AAPS PharmSciTech 2008;9:818–27.

La Force C, Gentile DA, Skoner DP. A randomized, double-blind, parallel-group, multicenter, placebo-controlled study of the safety and efficacy of extended-release of guaifenesin/pseudoehphedrine hydrochloride for symptom relief as adjunctive therapy to antibiotic treatment of acute respiratory infections. Post Grad Med 2008:120:53–9.

Gavate NT, Gondkar SB, Saundaga RS. Multilayer tablet: a new trend in solid dosage forms. World J Pharm Pharm Sci 2013;2:271-84.

Qiu Y, Chidambaram N, Flood K. Design, and evaluation of layered diffusional matrices for zero-order sustained-release. J Controlled Release 1998;51:123-30.

Yadav G, Bansak M, Thakur N, Khare SP. Multilayer tablets and their drug release kinetic models for oral controlled drug delivery system. Middle-East J Sci Res 2013;16:782-95.

Maroni A, Zema L, Carea M, Sangalli ME. Oral pulsatile drug delivery systems. Expert Opin Drug Delivery 2005;2:855-71.

More S, Ghodekar S, Rane B, Bavaskar K, Patil M, Jain A. Multilayered tablet: a novel approach for oral drug delivery. Int J Pharm Sci Rev Res 2015;9:872-82.

Charman SA, Charman WN. Oral modified-release delivery systems. In: Rathbone MJ, Hadgraft J, Roberts MS. (Eds.) Modified-release drug delivery technology. Informa Healthcare; 2002. p. 1–19.

Abdul S, Poddar SS. A flexible technology for modified release of drugs: multi-layered tablets. J Controlled Release 2004;97:393-405.

Ozeki Y, Ando M, Watanabe Y, Danjo K. Evaluation of novel one-step dry-coated tablets as a platform for delayed-release tablets. J Controlled Release 2004;95:51-60.

Akseli I, Dey D, Cetinkaya C. Mechanical property characterization of bilayered tablets using nondestructive air-coupled acoustics. AAPS PharmSciTech 2010;1:90-102.

Klinzing G, Zavaliangos A. Understanding the effect of environmental history on bilayer tablet interfacial shear strength. Pharm Res 2013;30:1300-10.

Desai D, Wang J, Wen H, Li X, Timmins P. Formulation design, challenges, and development considerations for fixed dose combination (FDC) of oral solid dosage forms. Pharm Dev Technol 2013;18:1265-76.

Abebe A, Akseli I, Sprockel O, Kottala N, Cuitino AM. Review of bilayer tablet technology. Int J Pharm 2014;461:549-58.

Kottala N, Abebe A, Sprockel O, Bergum J, Nikfar F, Cuitino A. Evaluation of the performance characteristics of bilayer tablets: part I. Impact of material properties and process parameters on the strength of bilayer tablets. AAPS PharmSciTech 2012;13:1236–42.

Sinka IC, Pitt KG. Tabletting. In: Salman AD, Hounslow M, Seville JPK. (Eds.). Handb Powder Technol Granulation Elsevier; 2006. p. 735–78.

Diarra H, Mazel V, Busignies V, Tchoreloff P. Investigating the effect of tablet thickness and punch curvature on density distribution using finite elements method. Int J Pharm 2015;493:121–8.

Wu CY, Seville JPK. A comparative study of compaction properties of binary and bilayer tablets. Powder Technol 2009;189:285–94.

Podczeck F. Theoretical and experimental investigations into the delamination tendencies of bilayer tablets. Int J Pharm 2011;408:102–12.

Cazes R. A QbD approach to shorten tablet development time. Pharm Technol Solid Dos Drug Dev Manuf 2018;Suppl 42:16–20.

Akseli I, Iyer S, Lee HP, Cuitino AM. A quantitative correlation of the effect of density distributions in roller-compacted ribbons on the mechanical properties of tablets using ultrasonics and x-ray tomography. AAPS PharmSciTech 2011;12:834–53.

Akseli I, Ladyzhynsky I, Katz J, He X. Development of predictive tools to assess capping tendency of tablet formulations. Powder Technol 2013;236:139–48.

Mazel V, Busignies V, Diarra H, Tchoreloff P. Lamination of pharmaceutical tablets due to air entrapment: direct visualization and influence of the compact thickness. Int J Pharm 2015;478:702–4.

Garr JSM, Rubinstein MH. An investigation into the capping of paracetamol at increasing speeds of compression. Int J Pharm 1991;72:117–22.

Van Veen B, Maarschalk KVDV, Bolhuis GK, Zuurman K, Frijlink HW. Tensile strength of tablets containing two materials with a different compaction behaviour. Int J Pharm 2000;203:71–9.

Heckel RW. Density-pressure relationships in powder compaction. Trans Metall Soc AIME 1961;221:671–5.

Jain S. Mechanical properties of powders for compaction and tableting: an overview. Pharm Sci Technol Today 1999;2:20–31.

Roberts RJ, Rowe RC. Mechanical properties. Pharmaceut Taylor and Francis; 1995.

Asgharnejad M, Storey DE. Application of a compaction simulator to the design of a high-dose tablet formulation. Part I. Drug Dev Ind Pharm 1996;22:967–75.

Inman SJ, Briscoe BJ, Pitt KG. Topographic characterization of cellulose bilayered tablets interfaces. Chem Eng Res Dis 2007;85:1005-12.

Peleg M. Flowability of food powders and methods for its evaluation-a review. J Food Process Eng 1977;1:303–28.

Aulton E, Taylor K. Particle science and powder technology. In: Elsevier Health Sciences (Ed.). Aulton’s Pharm Des Manuf Med; 2013. p. 187–98.

Mullarney MP, Hancock BC, Carlson GT, Ladipo DD, Langdon BA. The powder flow and compact mechanical properties of sucrose and three high-intensity sweeteners used in chewable tablets. Int J Pharm 2003;257:227–36.

Lindberg NO, Palsson M, Pihl AC, Freeman R, Freeman T, Zetzener H, et al. Flowability measurements of pharmaceutical powder mixtures with poor flow using five different techniques. Drug Dev Ind Pharm 2004;30:785–91.

Amidon GE, Houghton ME. The effect of moisture on the mechanical and powder flow properties of microcrystalline cellulose. Pharm Res 1995;12:923–9.

Li Q, Rudolph V, Weigl B, Earl A. Interparticle van der waals force in powder flowability and compactibility. Int J Pharm 2004;280:77–93.

Tye CM, Sun C, Amidon GE. Evaluation of the effects of tableting speed on the relationships between compaction pressure, tablet tensile strength and tablet solid fraction. J Pharm Sci 2005;94:465–72.

Sugisawa K, Kaneko T, Sago T, Sato T. Rapid quantitative analysis of magnesium stearate in pharmaceutical powders and solid dosage forms by atomic absorption: method development and application in product manufacturing. J Pharm Biomed Anal 2009;49:858-61.

Yamamura T, Ohta T, Taira T, Ogawa Y, Sakai Y, Moribe K, et al. Effects of automated external lubrication on tablet properties and the stability of eprazinone hydrochloride. Int J Pharm 2009;370:1-7.

Blicharski T, Swiader K, Serefko A, Kulczycka Mamona S, Kolodziejczyk M, Szopa A. Challenges in technology of bilayer and multi-layer tablets: a mini-review. Curr Issues Pharm Med Sci 2019;32:229-35.

Akseli I, Abebe A, Sprockel O, Cuitino AM. Mechanistic characterization of bilayer tablet formulations. Powder Technol 2013;3236:30-6.

Lacombe R. Adhesion measurement methods: theory and practice. CRC Press; 2005.

Cremer K, Asmussen B. Novel controlled-release tablet with erodible layers. Proc Int Controlled Release Bioact Mater 1995;22:732-3.

Dietrich P, Cremer K, Bauer Brandl A, Schubert R. Complex layer tablets-aspects of a new tabletting technology. Pharm Sci 1998;1:318.

Dietrich P, Cremer K, Bauer Brandl A, Schubert R. Adhesion strength in two-layer tablets. Pharm Res 1997;14:429.

Fell JT, Newton JM. Determination of tablet strength by the diametral-compression test. J Pharm Sci 1970;59:688–91.

Pitt KG, Newton JM, Richardson R, Stanley P. The material tensile strength of convex-faced aspirin tablets. J Pharm Pharmacol 1989;41:289–92.

Li SP, Karth MG, Feld KM, Di Paolo LC, Pendharkar CM, Williams RO. Evaluation of bilayer tablet machines-a case study. Drug Dev Ind Pharm 1995;21:571-90.

Yang L, Venkatesh G, Fassihi R. Compaction simulator study of a novel triple-layer tablet matrix for industrial tableting. Int J Pharm 1997;152:45-52.

Karehill PG, Glazer M, Nyström C. Studies on direct compression of tablets. XXIII. The importance of surface roughness for the compatibility of some directly compressible materials with different bonding and volume reduction properties. Int J Pharm 1990;64:35-43.

Takeuchi H, Yasuji T, Yamamoto H, Kawashima Y. Spray-dried lactose composite particles containing an ion complex of alginate-chitosan for designing a dry-coated tablet having a time-controlled releasing function. Pharm Res 2000;17:94-9.

Muzzio FJ, Lerapetritou M, Portillo P, Llusa M, Levin M, Morris KR, et al. A forward-looking approach to process scaleup for solid dose manufacturing. In pharmaceutical dosage forms tablets. CRC Press 2008;3:135-68.

Podczeck F. Methods for the practical determination of the mechanical strength of tablets—from empiricism to science. Int J Pharm 2012;436:214-32.

Klinzing G, Zavaliangos A. Understanding the effect of environmental history on bilayer tablet interfacial shear strength. Pharm Res 2013;30:1300-10.

Park CR, Munday DL. Development and evaluation of a biphasic buccal adhesive tablet for nicotine replacement therapy. Int J Pharm 2002;237:215-26.

Singh SD. Bilayer tablet technology: an overview. J Appl Pharm Sci 2011;1:43-7.

Conley R, Gupta SK, Sathyan G. Clinical spectrum of the osmotic-controlled release oral delivery system (OROS), an advanced oral delivery form. Curr Med Res Opin 2006;22:1879-92.

Lende LKLK, Banerjee SK, Gadhave MV, Gaikwad DD, Gaykar AJ. Review on: bilayer floating tablet. Asian J Pharm Res Dev 2013;1:31-9.

Ijaz H, Qureshi J, Danish Z, Zaman M, Abdel Daim M, Bashir I. Design, and evaluation of bilayer matrix tablet of metoprolol tartrate and lisinopril maleate. Adv Polym Technol 2017;36:152-9.

Kamila MM, Mondal N, Ghosh LK, Gupta BK. Multiunit floating drug delivery system of rosiglitazone maleate: development, characterization, statistical optimization of drug release and in vivo evaluation. AAPS PharmSciTech 2009;10:887.

Rekhi GS. Advances in solid dose oral drug delivery. ON Drug Delivery: Oral Drug Delivery and Advanced Excipients; 2010. p. 14-8.

Rayakwar N, Dangi YS. Development and characterization of controlled release bilayered tablets of citicoline sodium. J Drug Dev Ther 2019;9:125-31.

Hu L, Hu Q, Kong D. Formulation and in vitro evaluation of aspirin and isosorbide 5-mono-nitrate sustained bilayer tablets. Int J Pharm Life Sci 2014;5:799.

Melocchi A, Parietti F, Loreti G, Maroni A, Gazzaniga A, Zema L. 3D printing by fused deposition modeling (FDM) of a swellable/erodible capsular device for oral pulsatile release of drugs. J Drug Delivery Sci Tech 2015;30:360-7.

Gopinath C, Bindu VH, Nischala M. An overview on bilayered tablet technology. J Global Trends Pharm Sci 2013;4:1077-85.

Nagaraju R, Kaza R. Formulation and evaluation of bilayer sustained-release tablets of salbutamol and theophylline. Int J Pharm Sci Nanotech 2009;2:638-46.

Kumar V, Prasad G, Ganesh B, Swathi C, Rashmi A, Reddy A. Development, and evaluation of guaifenesin bilayer tablet. Int J Pharm Sci Nanotech 2010;3:1122-8.

Yeole PG, Khan S, Patel VF. Floating drug delivery systems: need and development. Indian J Pharm Sci 2005;67:265.

Busignies V, Mazel V, Diarra H, Tchoreloff P. Role of the elasticity of pharmaceutical materials on the interfacial mechanical strength of bilayer tablets. Int J Pharm 2013;457:260-7.

Akhtar M, Jamshaid M, Zaman M, Mirza AZ. Bilayer tablets: a developing novel drug delivery system. J Drug Delivery Sci Tech 2020:102079.

Louie Helm J, Berner B. Formulation of an erodible, gastric retentive oral dosage form using in vitro disintegration test data. United States Patent 10,281,284; 2003.

Demiri V, Stranzinger S, Rinner P, Piller M, Sacher S, Lingitz J, et al. Gluing pills technology: a novel route to multilayer tablet manufacturing. Int J Pharm 2018;548:672-81.

Paudel A, Raijada D, Rantanen J. Raman spectroscopy in pharmaceutical product design. Adv Drug Delivery Rev 2015;89:3-20.

Zhang Y, McGeorge G. Quantitative analysis of pharmaceutical bilayer tablets using transmission raman spectroscopy. J Pharm Innov 2015;10:269-80.

Seo KS, Han HK. Multilayer-coated tablet of clopidogrel and rosuvastatin: preparation and in vitro/in vivo characterization. Pharmaceutics 2019;11:313.

Agiba AM, Eldin AB. Insights into formulation technologies and novel strategies for the design of orally disintegrating dosage forms: a comprehensive industrial review. Int J Pharm Pharm Sci 2019;11:8-20.

Agiba AM, Abdel-Hamid S, Nasr M, Geneidi AS. Geriatric oriented high dose nutraceutical ODTs: formulation and physicomechanical characterization. Curr Drug Delivery 2018;15:267-77.

Khan KA. The concept of dissolution efficiency. J Pharm Pharmacol 1975;27:48-9.

Agiba AM. Liquisolid technology: a state-of-the-art review on the current state, challenges, new and emerging technologies for next generation. Curr Drug Delivery 2020;17:736-54.

Agiba AM, Hakeem WA, Zayed AG. Modulatory effect of polymer type and concentration on drug release from sustained release matrix tablets of ranolazine: a comparative release kinetic study. Asian J Pharm Clin Res 2020;13:132-40.

Podczeck F. Comparison of in vitro dissolution profiles by calculating mean dissolution time (MDT) or mean residence time (MRT). Int J Pharm 1993;97:93-100.

Wagner JG. Interpretation of percent dissolved-time plots derived from in vitro testing of conventional tablets and capsules. J Pharm Sci 1969;58:1253-7.

Higuchi T. Rate of the release of medicaments from ointment bases containing drugs in suspension. J Pharm Sci 1961;50:874-5.

Hixon AW, Crowell JH. Dependence of reaction velocity upon surface and agitation. Ind Eng Chem 1931;23:923-31.

Korsmeyers RW, Gumy R, Doelker EM, Buri P, Peppas NA. Mechanism of solute release from porous hydrophilic polymers. Int J Pharm 1983;15:25-35.

Karudumpala S, Gnanaprakash K, Venkatesh B, Sankar P, Balaji G, Vidya Sagar N. Formulation, and evaluation of gastro-retentive floating bilayer tablets of nifedipine. AJADD 2013;20131:341-57.

Center for Drug Evaluation and Research (U. S.). Orange book: approved

of bilayer technology: a novel approach. J Pharm Pharm Sci 2015;2:148-61.

Cunha Filho M, Gelfuso GM, Gratieri T. Subdivision of modified-release tablets: state-of-the-art and future perspectives. Ther Delivery 2020;11:5.

Rantanen J, Khinast J. The future of pharmaceutical manufacturing sciences. J Pharm Sci 2015;104:3612-38.

Published

07-07-2021

How to Cite

AGIBA, A. M., ABUL-ELLA, S. S., & EL-MONEM, R. A. A. (2021). PHARMACOTECHNICAL DEVELOPMENT AND OPTIMIZATION OF MULTILAYERED TABLETS: AN UPDATED INDUSTRIAL REVIEW WITH EMPHASIS ON BILAYER TABLETS. International Journal of Applied Pharmaceutics, 13(4), 55–64. https://doi.org/10.22159/ijap.2021v13i4.41528

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Review Article(s)