Solid formulations by a nanocrystal approach: critical process parameters regarding scale-ability of nanocrystals for tableting applications.
Nanocrystallization is among the foremost drug delivery platform approaches for the commercial development of poorly soluble drugs. There exists an urge to enable a universal shift of the production of the solid nanocrystal formulations from laboratory scale to industrially feasible scale. The success of any formulation development depends on its transferability to large scale manufacture. The objectives of the study were to increase the nanocrystallization batch size and to screen and optimize parameters for industrially feasible itraconazole (ITC) and indomethacin (IND) nanocrystal composition for tablet formulation. Thus, ITC and IND were transformed into nanocrystal suspensions, using an increased batch size of a wet milling process, freeze-dried, and further developed into both direct compression (DC) and granulated (G) tableting masses. According to the investigated powder and tablet properties (true density, flowability, dose uniformity, maximum upper punch force, crushing strength, dissolution and disintegration) and stability testings, it was clear that the amount of the nanocrystals in the solid tablet formulation is critical in order to fully utilize the benefits of the nanocrystals, i.e., fast dissolution, and to produce high-quality tablets. The DC designs of both the model drugs with compositions including 40% of freeze-dried nanocrystalline drug powder outperformed the corresponding granulated tablets in all parameters after the stability surveillance.
Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland. Electronic address: annika.tuomela@helsinki.fi.
Annika
A
Tuomela
Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland.
Timo
T
Laaksonen
Orion Pharma R&D, Formulation Research, Espoo, Finland.
Johanna
J
Laru
Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland.
Osmo
O
Antikainen
Orion Pharma R&D, Formulation Research, Espoo, Finland.
Juha
J
Kiesvaara
Oy Medfiles Ltd., Kuopio, Finland.
Jukka
J
Ilkka
Santen Oy, Tampere, Finland.
Olli
O
Oksala
School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland.
Seppo
S
Rönkkö
School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland.
Kristiina
K
Järvinen
Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland.
Jouni
J
Hirvonen
Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland.
Leena
L
Peltonen
D002626:Chemistry, Pharmaceutical; D003460:Crystallization; D005079:Excipients / Q000737:chemistry; D005612:Freeze Drying; D007213:Indomethacin / Q000737:chemistry*; D017964:Itraconazole / Q000737:chemistry*; D007700:Kinetics; D053758:Nanoparticles; D036103:Nanotechnology; D011208:Powders; D012212:Rheology; D012995:Solubility; D013607:Tablets; D013678:Technology, Pharmaceutical / Q000379:methods*
D005079:Excipients; D011208:Powders; D013607:Tablets; D017964:Itraconazole; D007213:Indomethacin
Freeze-drying; Granulation; Scale-up; Solid nanocrystal formulation; Tableting; Wet milling