Generic placeholder image

Pharmaceutical Nanotechnology

Author(s): Maria L.A.D. Lestari, Rainer H. Müller and Jan P. Möschwitzer *

DOI: 10.2174/2211738507666190401142530

DownloadDownload PDF Flyer Cite As
The Scalability of Wet Ball Milling for The Production of Nanosuspensions

Page: [147 - 161] Pages: 15

  • * (Excluding Mailing and Handling)

Explore Articles
About Journal
For Authors
For Editors
For Reviewers

Abstract

Background: Miniaturization of nanosuspensions preparation is a necessity in order to enable proper formulation screening before nanosizing can be performed on a large scale. Ideally, the information generated at small scale is predictive for large scale production.

Objective: This study was aimed to investigate the scalability when producing nanosuspensions starting from a 10 g scale of nanosuspension using low energy wet ball milling up to production scales of 120 g nanosuspension and 2 kg nanosuspension by using a standard high energy wet ball milling operated in batch mode or recirculation mode, respectively.

Methods: Two different active pharmaceutical ingredients, i.e. curcumin and hesperetin, have been used in this study. The investigated factors include the milling time, milling speed, and the type of mill.

Results: Comparable particle sizes of about 151 nm to 190 nm were obtained for both active pharmaceutical ingredients at the same milling time and milling speed when the drugs were processed at 10 g using low energy wet ball milling or 120 g using high energy wet ball milling in batch mode, respectively. However, an adjustment of the milling speed was needed for the 2 kg scale produced using high energy wet ball milling in recirculation mode to obtain particle sizes comparable to the small scale process.

Conclusion: These results confirm in general, the scalability of wet ball milling as well as the suitability of small scale processing in order to correctly identify the most suitable formulations for large scale production using high energy milling.

Keywords: High energy wet ball milling, low energy wet ball milling, nanosuspension, scalability, screening, wet ball milling.

Graphical Abstract

[1]
Eerdenbrugh BV. Mooter GVd, Augustijns P. Top-down production of drug nanocrystals: nanosuspension stabilization, miniaturization and transformation into solid products. Int J Pharm 2008; 364: 64-75.
[2]
Merisko-Liversidge EM, Liversidge GG. Drug nanoparticles: formulating poorly water-soluble compounds. Toxicol Pathol 2008; 36: 43-8.
[3]
Kesisoglou F, Panmai S, Wu Y. Nanosizing - Oral formulation development and biopharmaceutical evaluation. Adv Drug Deliv Rev 2007; 59: 631-44.
[4]
Lee J. Drug nano and microparticles processed into solid dosage forms: physical properties. J Pharm Sci 2003; 92(10): 2057-68.
[5]
Liversidge GG, Cundy KC. Particle size reduction for improvement of oral bioavailability of hydrophobic drugs: I. Absolute oral bioavailability of nanocrystalline danazol in beagle dogs. Int J Pharm 1995; 125: 91-7.
[6]
Juhnke M, Berghausen J, Timpe C. Accelerated formulation development for nanomilled active pharmaceutical ingredients using a screening approach. Chem Eng Technol 2010; 33(9): 1412-8.
[7]
Cunningham J, Liversidge E, Cooper ER, Liversidge GG. Milling microgram quantities of nanoparticulate candidate compoundsUnited States patent US 2004/0173696 A1, 2004 Sept 9
[8]
Eerdenbrugh BV, Stuyven B, Froyen L, et al. Downscaling drug nanosuspension production: processing aspects and physicochemical characterization. AAPS PharmSciTech 2009; 10(1): 44-53.
[9]
Niwa T, Miura S, Danjo K. Universal wet-milling technique to prepare oral nanosuspension focused on discovery and preclinical animal studies - Development of particle design method. Int J Pharm 2011; 405: 218-27.
[10]
Haskell RJ. Laboratory scale milling process World Intellectual Property Organization patent WO/2002/ 045691, 2002 June 13
[11]
Siewert C, Moog R, Alex R, Kretzer P, Rothenhäusler B. Process and scaling parameters for wet media milling in early phase drug development: a knowledge based approach. Eur J Pharm Sci 2018; 115: 126-31.
[12]
Sharma RA, Gescher AJ, Steward WP. Curcumin: the story so far. Eur J Cancer 2005; 41: 1955-68.
[13]
Tonnesen HH, Karlsen J. Studies on curcumin and curcuminoids. Z Lebensm Unters Forsch 1985; 180: 402-4.
[14]
DiMauro TM. Use of nitrogen-containing curcumin analogs for the treatment of alzheimers diseaseUnited States patent US 2009/0326275 A1, 2009 Dec 31
[15]
Fugita RA, Gálico DA, Guerra RB, et al. Thermal behaviour of curcumin. Braz J Therm Anal 2012; 1(1): 19-23.
[16]
Sigma-Aldrich.Safety Data Sheet Hesperetin, 2018. Available at: https: //www.sigmaaldrich.com/MSDS/MSDS/DisplayMSDSPage.do?country=ID&language=en&productNumber=W431300&brand=ALDRICH&PageToGoToURL=https%3A%2F%2Fwww.sigmaaldrich.com%2Fcatalog%2Fproduct%2Faldrich%2Fw431300%3Flang%3Den.
[17]
Jovanovic SV, Steeden S, Tosic M, Marjanovic B, Simic MG. Flavonoids as antioxidants. J Am Chem Soc 1994; 116: 4846-51.
[18]
Tsai Y-H, Lee K-F, Huang Y-B, Huang C-T, Wu P-C. In vitro permeation and in vivo whitening effect of topical hesperetin microemulsion delivery system. Int J Pharm 2010; 388: 257-62.
[19]
Chebil L, Humeau C, Anthoni J, Dehez F, Engasser J-M, Ghoul M. Solubility of flavonoids in organic solvents. J Chem Eng Data 2007; 52: 1552-6.
[20]
Lestari MLAD, Müller RH, Möschwitzer JP. Systematic screening of different surface modifiers for the production of physically stable nanosuspensions. J Pharm Sci 2015; 104(3): 1128-40.
[21]
George M, Ghosh I. Identifying the correlation between drug/stabilizer properties and critical quality attributes (CQAs) of nanosuspension formulation prepared by wet media milling technology. Eur J Pharm Sci 2013; 48: 142-52.
[22]
Peltonen L, Hirvonen J. Pharmaceutical nanocrystals by nanomilling: critical process parameters, particle fracturing and stabilization methods. J Pharm Pharmacol 2010; 62: 1569-79.
[23]
Afolabi A, Akinlabi O, Bilgili E. Impact of process parameters on the breakage kinetics of poorly water-soluble drugs during wet stirred media milling: a microhydrodynamic view. Eur J Pharm Sci 2014; 51: 75-86.
[24]
Gubskaya AV, Lisnyak YV, Blagoy YP. Effect of cryogrinding on physico-chemical properties of drugs. i. theophyline: evaluation of particle sizes and the degree of crystallinity, relation to dissolution parameters. Drug Dev Ind Pharm 1995; 21(17): 1953-64.