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Critical Reviews™ in Therapeutic Drug Carrier Systems
IF: 2.9 5-Year IF: 3.72 SJR: 0.736 SNIP: 0.818 CiteScore™: 4.6

ISSN Print: 0743-4863
ISSN Online: 2162-660X

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Critical Reviews™ in Therapeutic Drug Carrier Systems

DOI: 10.1615/CritRevTherDrugCarrierSyst.2020032040
pages 229-269

Systematic Development of Drug Nanocargos Using Formulation by Design (FbD): An Updated Overview

Bhupinder Singh
University Institute of Pharmaceutical Sciences, UGC Centre of Advanced Studies, Panjab University, Chandigarh, India 160014; UGC-Centre of Excellence in Applications of Nanomaterials, Nanoparticles and Nanocomposites (Biomedical Sciences), Panjab University, Chandigarh, India 160014
Teenu Sharma
University Institute of Pharmaceutical Sciences, UGC Centre of Advanced Studies, Panjab University, Chandigarh, India 160014
Sumant Saini
University Institute of Pharmaceutical Sciences, UGC Centre of Advanced Studies, Panjab University, Chandigarh, India 160014
Ranjot Kaur
University Institute of Pharmaceutical Sciences, UGC Centre of Advanced Studies, Panjab University, Chandigarh, India 160014; School of Pharmacy and Biomedical Sciences, University of Central Lancashire, Preston PR1 2HE, United Kingdom
Atul Jain
UGC-Centre of Excellence in Applications of Nanomaterials, Nanoparticles and Nanocomposites (Biomedical Sciences), Panjab University, Chandigarh, India 160014
Kaisar Raza
Department of Pharmacy, School of Chemical Sciences and Pharmacy, Central University of Rajasthan, Bandar Sindri, Distt. Ajmer, Rajasthan, India 305 817
Sarwar Beg
Department of Pharmaceutics, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, India 110062


Nanostructured drug delivery formulations have lately gained enormous attention, contributing to their systematic development. Issuance of quality by design (QbD) guidelines by ICH, FDA, and other federal agencies, in this regard, has notably influenced the overall development of drug products, enabling holistic product and process understanding. Owing to the applicability of QbD paradigms, a science lately christened as formulation by design (FbD) has been dedicated exclusively to QbD-enabled drug product development. Consisting of the principal elements of design of experiments (DoE), quality risk management (QRM), and QbD-enabled product comprehension as the fundamental tools in the implementation of FbD, a variety of drug nanocargos have been successfully developed with FbD paradigms and reported in the literature. FbD aims to produce novel and advanced systems utilizing nominal resources of development time, work effort, and money. A systematic FbD approach envisions the entire developmental path through pivotal milestones of risk assessment, factor screening and optimization (both using appropriate experimental designs), multivariate statistical and optimum search tools, along with response surface modeling, usually employing suitable computer software. The design space is one of the fundamental elements of FbD providing the most sought-after regulatory flexibility to pharma companies, postapproval. The present paper provides a bird's eye view of the fundamental aspects of FbD terminology, methodology, and applications in the development of a wide range of nanocargos, as well as a discussion of trends from both technological and regulatory perspectives.


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  118. Tripathi CB, Beg S, Kaur R, Shukla G, Bandopadhyay S, Singh B. Systematic development of optimized SNEDDS of artemether with improved biopharmaceutical and antimalarial potential. Drug Deliv. 2016;23(9):3209-23.

  119. Garg B, Katare OP, Beg S, Lohan S, Singh B. Systematic development of solid self-nanoemulsifying oily formulations (S-SNEOFs) for enhancing the oral bioavailability and intestinal lymphatic uptake of lopinavir. Colloids Surf B Biointerfaces. 2016;141:611-22.

  120. Bandyopadhyay S, Katare OP, Singh B. Optimized self nano-emulsifying systems of ezetimibe with enhanced bioavailability potential using long chain and medium chain triglycerides. Colloids Surf B Biointerfaces. 2012;100:50-61.

  121. Garg V, Kaur P, Singh SK, Kumar B, Bawa P, Gulati M, Yadav AK. Solid self-nanoemulsifying drug delivery systems for oral delivery of polypeptide-k: Formulation, optimization, in-vitro and in-vivo antidiabetic evaluation. Eur J Pharm Biopharm. 2017;109:297-315.

  122. Beg S, Sandhu PS, Batra RS, Khurana RK, Singh B. QbD-based systematic development of novel optimized solid self-nanoemulsifying drug delivery systems (SNEDDS) of lovastatin with enhanced biopharmaceutical performance. Drug Deliv. 2015;22(6):765-84.

  123. Beg S, Swain S, Singh HP, Patra C, Rao MEB. Development, optimization, and characterization of solid self-nanoemulsifying drug delivery systems of valsartan using porous carriers. AAPS PharmSciTech. 2012;13(4):1416-27.

  124. Jain A, Kaur R, Beg S, Kushwah V, Jain S, Singh B. Novel cationic supersaturable nanomicellar systems of raloxifene hydrochloride with enhanced biopharmaceutical attributes. Drug Deliv Transl Res. 2018;8(3):670-92.

  125. Beg S, Sharma G, Thanki K, Jain S, Katare OP, Singh B. Positively charged self-nanoemulsifying oily formulations of olmesartan medoxomil: Systematic development, in vitro, ex vivo and in vivo evaluation. Int J Pharm. 2015;493(1):466-82.

  126. Sharma G, Beg S, Thanki K, Katare OP, Jain S, Kohli K, Singh B. Systematic development of novel cationic self-nanoemulsifying drug delivery systems of candesartan cilexetil with enhanced biopharmaceutical performance. RSC Adv. 2015;5(87):71500-13.

  127. Chavan RB, Modi SR, Bansal AK. Role of solid carriers in pharmaceutical performance of solid supersaturable SEDDS of celecoxib. Int J Pharm. 2015;495(1):374-84.

  128. Singh G, Pai RS. Trans-resveratrol self-nano-emulsifying drug delivery system (SNEDDS) with enhanced bioavailability potential: Optimization, pharmacokinetics and in situ single pass intestinal perfusion (SPIP) studies. Drug Deliv. 2015;22(4):522-30.

  129. Ozdemir S, Qelik B, Turkoz Acar E, Duman G, Uner M. Eplerenone nanoemulsions for treatment of hypertension. Part I: Experimental design for optimization of formulations and physical characterization. J Drug Deliv Sci Technol. 2018;45:357-66.

  130. Argenta DF, de Mattos CB, Misturini FD, Koester LS, Bassani VL, Simoes CO, Teixeira HF. Factorial design applied to the optimization of lipid composition of topical antiherpetic nanoemulsions containing isoflavone genistein. Int J Nanomed. 2014;9:4737-47.

  131. Sood S, Jain K, Gowthamarajan K. Optimization of curcumin nanoemulsion for intranasal delivery using design of experiment and its toxicity assessment. Colloids Surf B Biointerfaces. 2014; 113:330-37.

  132. Dordevic SM, Radulovic TS, Cekic ND, Randelovic DV, Savic MM, Krajisnik DR, Milic JR, Savic SD. Experimental design in formulation of diazepam nanoemulsions: Physicochemical and pharmacokinetic performances. J Pharm Sci. 2013;102(11):4159-72.

  133. Maher PG, Fenelon MA, Zhou Y, Kamrul Haque M, Roos YH. Optimization of P-Casein stabilized nanoemulsions using experimental mixture design. J Food Sci. 2011;76(8):1108-17.

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  135. Karakucuk A, Celebi N, Teksin ZS. Preparation of ritonavir nanosuspensions by microfluidization using polymeric stabilizers: I. A design of experiment approach. Eur J Pharm Biopharm. 2016;95:111-21.

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  141. Singh G, Pai RS. Optimized PLGA nanoparticle platform for orally dosed trans-resveratrol with enhanced bioavailability potential. Expert Opin Drug Deliv. 2014;11(5):647-59.

  142. Kharia AA, Singhai AK. Screening of most effective variables for development of gastroretentive mucoadhesive nanoparticles by Taguchi design. ISRN Nanomaterials. 2013;2013:1-8.

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  146. Shamekhi F, Tamjid E, Khajeh K. Development of chitosan coated calcium-alginate nanocapsules for oral delivery of liraglutide to diabetic patients. Int J Biol Macromol. 2018;120:460-67.

  147. Garala KC, Shinde AJ, More HN. Solubility enhancement of aceclofenac using dendrimer. Res J Pharm Dosage Forms Technol. 2009;1(2):94-6.

  148. Zarandi MA, Zahedi P, Rezaeian I, Salehpour A, Gholami M, Motealleh B. Drug release, cell adhesion and wound healing evaluations of electrospun carboxymethyl chitosan/polyethylene oxide nanofibres containing phenytoin sodium and vitamin C. IET Nanobiotechnol. 2015;9(4):191-200.

  149. Nadia AA, Leila R, Mohammad I, Ismaeil H. Fabrication of PLA/PEG/MWCNT electrospun nanofibrous scaffolds for anticancer drug delivery. J Appl Polym Sci. 2015;132(3):1-9.

  150. Asfaram A, Ghaedi M, Purkait K. Novel synthesis of nanocomposite for the extraction of sildenafil citrate (Viagra) from water and urine samples: Process screening and optimization. Ultrason Sonochem. 2017;38:463-72.

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  153. Raviadaran R, Chandran D, Shin LH, Manickam S. Optimization of palm oil in water nano-emulsion with curcumin using microfluidizer and response surface methodology. LWT. 2018;96:58-65.

  154. Avasatthi V, Pawar H, Dora CP, Bansod P, Gill MS, Suresh S. A novel nanogel formulation of methotrexate for topical treatment of psoriasis: Optimization, in vitro and in vivo evaluation. Pharm Dev Technol. 2016;21(5):554-62.

  155. Water JJ, Kim YT, Maltesen MJ, Franzyk H, Foged C, Nielsen HM. Hyaluronic acid-based nanogels produced by microfluidics-facilitated self-assembly improves the safety profile of the cationic host defense peptide novicidin. Pharm Res. 2015;32(8):2727-35.

  156. Ishak RAH, Mostafa NM, Kamel AO. Stealth lipid polymer hybrid nanoparticles loaded with rutin for effective brain delivery-comparative study with the gold standard (Tween 80): Optimization, characterization and biodistribution. Drug Deliv. 2017;24(1):1874-90.

  157. Yalcin TE, Ilbasmis-Tamer S, Takka S. Development and characterization of gemcitabine hydrochloride loaded lipid polymer hybrid nanoparticles (LPHNs) using central composite design. Int J Pharm. 2018;548(1):255-62.

  158. Dave V, Yadav RB, Kushwaha K, Yadav S, Sharma S, Agrawal U. Lipid-polymer hybrid nanoparticles: Development & statistical optimization of norfloxacin for topical drug delivery system. Bioact Mater. 2017;2(4):269-80.

  159. Sengel-Turk CT, Hascicek C. Design of lipid-polymer hybrid nanoparticles for therapy of BPH: Part I. Formulation optimization using a design of experiment approach. J Drug Deliv Sci Technol. 2017;39:16-27.

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  164. Leopold L, Zhao C, McConnachie L, Khurana RK, Sharma T, Singh B, Ho RJY. Surface engineered nanomaterial: Environmental and safety considerations in pharmaceutical and medicinal products. In: Singh B, Kanwar JR, Garg S, editors. NanoBioEngineering. Boca Raton, FL: CRC Press; 2018. p. 297-310.

  165. Mody VV, Siwale R, Singh A, Mody HR. Introduction to metallic nanoparticles. J Pharm Bioallied Sci. 2010;2(4):282-89.

  166. Baughman RH, Zakhidov AA, De Heer WA. Carbon nanotubes-the route toward applications. Science. 2002;297(5582):787-92.

  167. Sun YP, Fu K, Lin Y, Huang W. Functionalized carbon nanotubes: properties and applications. Acc Chem Res. 2002;35(12):1096-104.

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  170. Sathigari SK, Ober CA, Sanganwar GP, Gupta RB, Babu RJ. Single-step preparation and deagglomeration of itraconazole microflakes by supercritical antisolvent method for dissolution enhancement. J Pharm Sci. 2011;100(7):2952-65.

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  172. Alshweiat A, Katona G, Csoka I, Ambrus R. Design and characterization of loratadine nanosuspension prepared by ultrasonic-assisted precipitation. Eur J Pharm Sci. 2018;122:94-104.

  173. Alshweiat A, Ambrus R, Katona G, Csoka I. QbD based control strategy of loratadine nanosuspensions and dry nanoparticles stabilized by soluplus. Farmacia. 2019;67:729-35.

  174. Pallagi E, Ambrus R, Szabo-Revesz P, Csoka I. Adaptation of the quality by design concept in early pharmaceutical development of an intranasal nanosized formulation. Int J Pharm. 2015; 491(1-2):384-92.

  175. Ismail R, Sovany T, Gacsi A, Ambrus R, Katona G, Imre N, Csoka I. Synthesis and statistical optimization of poly (lactic-co-glycolic acid) nanoparticles encapsulating GLP1 analog designed for oral delivery. Pharm Res. 2019;36(7):99.

  176. Chung N-O, Lee MK, Lee J. Mechanism of freeze-drying drug nanosuspensions. Int J Pharm. 2012;437(1-2):42-50.

  177. Niu L, Panyam J. Freeze concentration-induced PLGA and polystyrene nanoparticle aggregation: Imaging and rational design of lyoprotection. J Control Release. 2017;248:125-32.

  178. Gajera BY, Shah DA, Dave RH. Investigating a novel hot melt extrusion-based drying technique to solidify an amorphous nanosuspension using design of experiment methodology. AAPS PharmSciTech. 2018;19(8):3778-90.

  179. Kassem MAA, ElMeshad AN, Fares AR. Enhanced solubility and dissolution rate of lacidipine nano-suspension: Formulation via antisolvent sonoprecipitation technique and optimization using Box-Behnken design. AAPS PharmSciTech. 2017;18(4):983-96.

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  181. Kumar S, Gokhale R, Burgess DJ. Quality by design approach to spray drying processing of crystalline nanosuspensions. Int J Pharm. 2014;464(1):234-42.

  182. Nakarani M, Misra AK, Patel JK, Vaghani SS. Itraconazole nanosuspension for oral delivery: Formulation, characterization and in vitro comparison with marketed formulation. Daru. 2010;18(2):84-90.

  183. Yiamsawas D, Boonpavanitchakul K, Kangwansupamonkon W. Optimization of experimental parameters based on the Taguchi robust design for the formation of zinc oxide nanocrystals by solvothermal method. Mater Res Bull. 2011;46(5):639-42.

  184. Yue PF, Li Y, Wan J, Wang Y, Yang M, Zhu WF, Wang CH, Yuan H. Process optimization and evaluation of novel baicalin solid nanocrystals. Int J Nanomed. 2013;8:2961-73.

  185. Koradia DK, Parikh HR. Dissolution enhancement of albendazole through nanocrystal formulation. J Pharm Bioallied Sci. 2012;4(1):62-3.

  186. Shah S, Parmar B, Soniwala M, Chavda J. Design, optimization, and evaluation of lurasidone hydrochloride nanocrystals. AAPS PharmSciTech. 2016;17:1150-58.

  187. Adena SKR, Upadhyay M, Vardhan H, Mishra B. Development, optimization, and in vitro characterization of dasatinib-loaded PEG functionalized chitosan capped gold nanoparticles using Box-Behnken experimental design. Drug Deliv Ind Pharm. 2018;44(3):493-501.

  188. Lohan S, Raza K, Mehta SK, Bhatti GK, Saini S, Singh B. Anti-Alzheimer's potential of berberine using surface decorated multi-walled carbon nanotubes: A preclinical evidence. Int J Pharm. 2017;530(1):263-78.

  189. Farahani BV, Behbahani R, Javadi N. Functionalized multi walled carbon nanotubes as a carrier for doxorubicin: Drug adsorption study and statistical optimization of drug loading by factorial design methodology. J Braz Chem Soc. 2016;27(4):694-05.

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