Nano-sizing Crystals: An Exquisite Way of Drug Conveyance

Author(s): Jaimini Gandhi*, Pooja Golwala, Shyam Madheshiya, Pranav Shah

Journal Name: Nanoscience & Nanotechnology-Asia

Volume 10 , Issue 3 , 2020

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Graphical Abstract:


Extensive attempts have been made to decipher the problem associated with the solubility of drugs for maximizing bioavailability at targeted sites. More than 40% NCEs (new chemical entities) emerged through modern technology like high throughput screening, combinatorial chemistry, computer-aided drug design etc. and the drug discovery process has been dramatically accelerated. Fabrication of materials into the nanodimension changes their physical properties which depicts a vivid shift from lab scale optimization studies to scale up focused studies. In addition, this comprehensive review covers physics behind the drug nanocrystals and their properties, different technologies and methods of drug nanocrystal preparation and its stabilization along with theapplication of nanocrystals. This review also covers factors affecting nanoformulations, post-production processing and future prospects.

Keywords: Nanocrystal, solubility, nanosuspension, bottom up, top down, stabilizers.

Chavhan, S.S.; Petkar, K.C.; Sawant, K.K. Nanosuspensions in drug delivery: Recent advances, patent scenarios, and commercialization aspects. Crit. Rev. Ther. Drug Carrier Syst., 2011, 28(5), 447-488.
Liu, Y.; Xie, P.; Zhang, D.; Zhang, Q. A mini review of nanosuspensions development. J. Drug Target., 2012, 20(3), 209-223.
Shah, D.A.; Murdande, S.B.; Dave, R.H. A review: Pharmaceutical and pharmacokinetic aspect of nanocrystalline suspensions. J. Pharm. Sci., 2016, 105(1), 10-24.
Carrier, R.L.; Miller, L.A.; Ahmed, I. The utility of cyclodextrins for enhancing oral bioavailability. J. Control. Release, 2007, 123(2), 78-99.
Mishra, I. Dendrimer: A novel drug delivery system. J. Drug Deliv. Thera., 2011, 1(2), 333-392.
Chaudhary, A.; Nagaich, U.; Gulati, N.; Sharma, V.K.; Khosa, R.L. Enhancement of solubilization and bioavailability of poorly soluble drugs by physical and chemical modifications: A recent review JAPER, 2012, 2(1), 32-67.
Junghanns, J.U.; Muller, R.H. Nanocrystal technology, drug delivery and clinical applications. Int. J. Nanomed., 2008, 3(3), 295-309.
Patravale, V.; Date, A.; Kulkarni, R. Nanosuspensions: A promising drug delivery strategy. J. Pharm. Pharmacol., 2004, 56, 827-840.
Vishal, P.; Abhale, V.N. Nanocrystal technology: A particle engineering formulation strategy for the poorly water soluble drugs. Pharm. Lett, 2016, 8, 384-392.
Prabhakar, C.; Krishna, K. A review on nanosuspensions in drug delivery. Int. J. Pharm. Bio. Sci., 2011, 2, 549-558.
Peltonen, L.; Hirvonen, J. Pharmaceutical nanocrystals by nanomilling: Critical process parameters, particle fracturing and stabilization methods. J. Pharm. Pharmacol., 2010, 62(11), 1569-1579.
Chogale, M.M.; Ghodake, V.N.; Patravale, V.B. Performance parameters and characterizations of nanocrystals: A brief review. Pharmaceutics, 2016, 8(3) E26
Zhou, Y.; Du, J.; Wang, L.; Wang, Y. Nanocrystals technology for improving bioavailability of poorly soluble drugs: A mini-review. J. Nanosci. Nanotechnol., 2017, 17(1), 18-28.
Boles, M.A.; Ling, D.; Hyeon, T.; Talapin, D.V. The surface science of nanocrystals. Nat. Mater., 2016, 15(2), 141-153.
Kumar, S.; Dilbaghi, N.; Rani, R.; Bhanjana, G. Nanotechnology as emerging tool for enhancing solubility of poorly water-soluble drugs. BioNanoScience, 2012, 2, 4.
Kandil, M. The role of nanotechnology in electronic properties of materials, 2016. Availabale from:.
Burda, C.; Chen, X.; Narayanan, R.; El-Sayed, M.A. Chemistry and properties of nanocrystals of different shapes. Chem. Rev., 2005, 105(4), 1025-1102.
Sutradhar, K.; Khatun, S.; Luna, I. Increasing possibilities of nanosuspension. J. Nanotechnol., 2013, 2013 346581
Gora, S.; Mustafa, G.; Sahni, J.K.; Ali, J.; Baboota, S. Nanosizing of valsartan by high pressure homogenization to produce dissolution enhanced nanosuspension: Pharmacokinetics and pharmacodyanamic study. Drug Deliv., 2016, 23(3), 940-950.
High pressure homogenizer applications. Avialable from:. (Accessed on: 20/01/2019).
Salazar, J.; ller, R.H.; Schwitzer, J.P. Combinative particle size reduction technologies for the production of drug nanocrystals. J. Pharm. (Cairo), 2014, 2014, 14.
Patrignani, F.; Lanciotti, R. Applications of high and ultra high pressure homogenization for food safety. Front. Microbiol., 2016, 7, 1132.
de Waard, H.; Frijlink, H.W.; Hinrichs, W.L.J. Bottom-up preparation techniques for nanocrystals of lipophilic drugs. Pharm. Res., 2011, 28(5), 1220-1223.
Chang, T-l.; Zhan, H.; Liang, D.; Liang, J. Nanocrystal technology for drug formulation and delivery. Front Chem. Sci. Eng, 2015, 9, 1-14.
Prasanna, L.; Giddam, A.K. Nano-suspension technology: A review. Int. J. Pharm. Pharm. Sci., 2010, 2, 35-40.
Geetha, G.; Poojitha, U.; Khan, A. Various techniques for preparation of nanosuspension-a review. Pharm. Res., 2014, 3, 30-37.
de Waard, H.; De Beer, T.; Hinrichs, W.L.; Vervaet, C.; Remon, J.P.; Frijlink, H.W. Controlled crystallization of the lipophilic drug fenofibrate during freeze-drying: Elucidation of the mechanism by in-line Raman spectroscopy. AAPS J., 2010, 12(4), 569-575.
Moschwitzer, J.; Muller, R.H. New method for the effective production of ultrafine drug nanocrystals. J. Nanosci. Nanotechnol., 2006, 6(9-10), 3145-3153.
Chin, W.W.; Parmentier, J.; Widzinski, M.; Tan, E.H.; Gokhale, R. A brief literature and patent review of nanosuspensions to a final drug product. J. Pharm. Sci., 2014, 103(10), 2980-2999.
Shegokar, R.; Muller, R.H. Nanocrystals: Industrially feasible multifunctional formulation technology for poorly soluble actives. Int. J. Pharm., 2010, 399(1-2), 129-139.
Salazar, J.; Muller, R.H.; Moschwitzer, J.P. Performance comparison of two novel combinative particle-size-reduction technologies. J. Pharm. Sci., 2013, 102(5), 1636-1649.
Teagarden, D.L.; Baker, D.S. Practical aspects of lyophilization using non-aqueous co-solvent systems. Eur. J. Pharm. Sci., 2002, 15(2), 115-133.
Shete, G.; Bansal, A.K. NanoCrySP technology for generation of drug nanocrystals: Translational aspects and business potential. Drug Deliv. Transl. Res., 2016, 6(4), 392-398.
Bansal, S.; Kumria, R. Nanocrystals: Current strategies and trends. Int. J. Res. Pharmaceut. Biomed. Sci., 2012, 3(1), 407-419.
Jacobs, C.; Muller, R.H. Production and characterization of a budesonide nanosuspension for pulmonary administration. Pharm. Res., 2002, 19(2), 189-194.
Bhatia, S. Natural polymer drug delivery systems: Nanoparticles, plants, and algae. In: Nanoparticles, Plants, and Algae; Switzerland: Springer International Publishing, 2016; pp. 1-225.
Blunk, T.; Hochstrasser, D.F.; Sanchez, J.C.; Muller, B.W.; Muller, R.H. Colloidal carriers for intravenous drug targeting: Plasma protein adsorption patterns on surface-modified latex particles evaluated by two-dimensional polyacrylamide gel electrophoresis. Electrophoresis, 1993, 14(12), 1382-1387.
Blunk, T.; Luck, M.; Calvor, A.; Hochstrasser, D.F.; Sanchez, J.C.; Muller, B.W.; Muller, R.H. Kinetics of plasma protein adsorption on model particles for controlled drug delivery and drug targeting. Eur. J. Pharm. Biopharm., 1996, 42, 262-268.
Wallis, K.H.; Muller, R.H. Determination of the surface hydrophobicity of colloidal dispersions by mini-hydrophobic interaction chromatography. Pharm. Ind., 1993, 55, 1124-1128.
Kocbek, P.; Baumgartner, S.; Kristl, J. Preparation and evaluation of nanosuspensions for enhancing the dissolution of poorly soluble drugs. Int. J. Pharm., 2006, 312(1-2), 179-186.
Tuomela, A.; Hirvonen, J.; Peltonen, L. Stabilizing agents for drug nanocrystals: Effect on bioavailability. Pharmaceutics, 2016, 8(2), 16.
Lai, F.; Pini, E.; Angioni, G.; Manca, M.L.; Perricci, J.; Sinico, C.; Fadda, A.M. Nanocrystals as tool to improve piroxicam dissolution rate in novel orally disintegrating tablets. Eur. J. Pharm. Biopharm., 2011, 79(3), 552-558.
Tuomela, A. Nanocrystals for Drug Delivery Applications. Doctoral dissertation (article-based), University of Helsinki. 2015.
Abdelwahed, W.; Degobert, G.; Stainmesse, S.; Fessi, H. Freeze-drying of nanoparticles: formulation, process and storage considerations. Adv. Drug Deliv. Rev., 2006, 58(15), 1688-1713.
Nagalingam, A.; Deecaraman, M.; Rani, C. Nanosuspension Technology and its applications in drug delivery. Asian J. Pharmaceut, 2009, 3, 3.
Kayser, O.; Olbrich, C.; Yardley, V.; Kiderlen, A.F.; Croft, S.L. Formulation of amphotericin B as nanosuspension for oral administration. Int. J. Pharm., 2003, 254(1), 73-75.
Mauludin, R.; Muller, R.H.; Keck, C.M. Development of an oral rutin nanocrystal formulation. Int. J. Pharm., 2009, 370(1-2), 202-209.
Merisko-Liversidge, E.; Liversidge, G.G.; Cooper, E.R. Nanosizing: A formulation approach for poorly-water-soluble compounds. Eur. J. Pharm. Sci., 2003, 18(2), 113-120.
Kayser, O. Nanosuspensions for the formulation of aphidicolin to improve drug targeting effects against leishmania infected macrophages. Int. J. Pharm., 2000, 196(2), 253-256.
Gao, L.; Liu, G.; Ma, J.; Wang, X.; Zhou, L.; Li, X. Drug nanocrystals: In vivo performances. J. Control. Release, 2012, 160(3), 418-430.
Chingunpituk, J. Nanosuspension technology for drug delivery. Walailak J. Sci. Technol., 2011, 4(2), 15.
Rabinow, B.E. Nanosuspensions for parenteral delivery. In: Nanoparticulate Drug Delivery Systems; Thassu, M.D.; Pathak, Y., Eds.; Informa Healthcare: London, 2015; pp. 33-49.
Zhang, Q.; Shen, Z.; Nagai, T. Prolonged hypoglycemic effect of insulin-loaded polybutylcyanoacrylate nanoparticles after pulmonary administration to normal rats. Int. J. Pharm., 2001, 218(1-2), 75-80.
Gao, L.Z.; Dianrui, Z.; Chen, M. Drug nanocrystals for the formulation of poorly soluble drugs and its application as a potential drug delivery system. J. Nanopart. Res., 2008, 10, 845-862.
Kassem, M.A.; Abdel Rahman, A.A.; Ghorab, M.M.; Ahmed, M.B.; Khalil, R.M. Nanosuspension as an ophthalmic delivery system for certain glucocorticoid drugs. Int. J. Pharm., 2007, 340(1-2), 126-133.
Romero, G.B.; Keck, C.M.; Muller, R.H.; Bou-Chacra, N.A. Development of cationic nanocrystals for ocular delivery. Eur. J. Pharm. Biopharm., 2016, 107, 215-222.
Katara, R.; Sachdeva, S.; Majumdar, D.K. Design, characterization, and evaluation of aceclofenac-loaded Eudragit RS 100 nanoparticulate system for ocular delivery. Pharm. Dev. Technol., 2019, 24(3), 368-379.
Pignatello, R.; Ricupero, N.; Bucolo, C.; Maugeri, F.; Maltese, A.; Puglisi, G. Preparation and characterization of Eudragit Retard nanosuspensions for the ocular delivery of cloricromene. AAPS PharmSciTech, 2006, 7(1), E192-E198.
Lu, Y.; Li, Y.; Wu, W. Injected nanocrystals for targeted drug delivery. Acta. Pharm., 2016, 6(2), 106-113.
Hao, L.; Luan, J.; Zhang, D.; Li, C.; Guo, H.; Qi, L.; Liu, X.; Li, T.; Zhang, Q. Research on the in vitro anticancer activity and in vivo tissue distribution of Amoitone B nanocrystals. Colloids Surf. B Biointerfaces, 2014, 117, 258-266.
Han, M.; Liu, X.; Guo, Y.; Wang, Y.; Wang, X. Preparation, characterization, biodistribution and antitumor efficacy of hydroxycamptothecin nanosuspensions. Int. J. Pharm., 2013, 455(1-2), 85-92.
Schöler, N.; Krause, K.; Kayser, O.; Müller, R.H.; Borner, K.; Hahn, H.; Liesenfeld, O. Atovaquone nanosuspensions show excellent therapeutic effect in a new murine model of reactivated toxoplasmosis. Antimicrob. Agents Chemother., 2001, 45(6), 1771-1779.
Bhusnure, O.G.; Gholve, S.B.; Bhange, M.M.; Pentewar, R.S. Formulation of nanosuspension and nanoemulsion as a new approach for the delivery of poorly soluble drugs. IAJPR, 2015, 5(11), 11.
Taheri, A.; Mohammadi, M. The use of cellulose nanocrystals for potential application in topical delivery of hydroquinone. Chem. Biol. Drug Des., 2015, 86(1), 102-106.
Pyo, S.; Meinke, M.; Keck, C.; Müller, R. Rutin—Increased antioxidant activity and skin penetration by nanocrystal technology (smartCrystals). Cosmetics, 2016, 3(1), 9.
Kobierski, S.; Ofori-Kwakye, K.; Muller, R.H.; Keck, C.M. Resveratrol nanosuspensions for dermal application--production, characterization, and physical stability. Pharmazie, 2009, 64(11), 741-747.
Pathak, D.T.; Deleers, M. Pharmaceutical applications of nanoparticulate drug-delivery systems. In: Nanoparticulate Drug Delivery Systems; Informa Healthcare: London, 2015; pp. 185-212.
Hecq, J.; Deleers, M.; Fanara, D.; Vranckx, H.; Amighi, K. Preparation and characterization of nanocrystals for solubility and dissolution rate enhancement of nifedipine. Int. J. Pharm., 2005, 299(1-2), 167-177.
Lockman, P.R.; Koziara, J.M.; Mumper, R.J.; Allen, D.D. Nanoparticle surface charges alter blood-brain barrier integrity and permeability. J. Drug Target., 2004, 12(9-10), 635-641.
Alyautdin, R.N.; Petrov, V.E.; Langer, K.; Berthold, A.; Kharkevich, D.A.; Kreuter, J. Delivery of loperamide across the blood-brain barrier with polysorbate 80-coated polybutyl-cyanoacrylate nanoparticles. Pharm. Res., 1997, 14(3), 325-328.
Schroder, U.; Sabel, B.A. Nanoparticles, a drug carrier system to pass the blood-brain barrier, permit central analgesic effects of i.v. dalargin injections. Brain Res., 1996, 710(1-2), 121-124.
Muller, R.H.; Jacobs, C. Buparvaquone mucoadhesive nanosuspension: Preparation, optimisation and long-term stability. Int. J. Pharm., 2002, 237(1-2), 151-161.
Möschwitzer, J.; Müller, R.H. Spray coated pellets as carrier system for mucoadhesive drug nanocrystals. Eur. J. Pharm. Biopharm., 2006, 62(3), 282-287.

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Article Details

Year: 2020
Page: [203 - 218]
Pages: 16
DOI: 10.2174/2210681209666190220130824
Price: $25

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