(776b) Microfluidization as an Enabling Technology for Solubility Enhancement

Sá Couto, C., Hovione
Duarte, Í., iMed.ULisboa, Faculty of Pharmacy, University of Lisbon
Porfirio, T., Hovione
Vicente, J., Hovione
Temtem, M., Hovione FarmaCiência SA

as an enabling technology for solubility enhancement

Iris Duarte, Clara Sa
Couto, Tiago Porfirio, João Vicente and Marcio Temtem

R&D Drug Product
Development, Hovione Farmaciência S.A, Sete Casas, 2674-506 Loures, Portugal


Emerging drugs are essentially poorly
water-soluble and such limited aqueous solubility has been one of the major
hurdles in the development of oral-dosage forms, as poor solubility typically hinders
oral bioavailability. This challenge has been addressed with different
formulation strategies and enabling technologies, including: complexation with
cyclodextrines (CD), production of amorphous solid dispersions (ASD) or particle-size
reduction, such as the production of nanosuspensions and/or nanocrystals [1].

This work describes a technique
which encompasses a microfluidization followed by a spray drying step, to
produce nano- to microparticles of crystalline drug-alone, cyclodextrins
complexes or amorphous solid dispersions. Three different case-studies will be
detailed in this work. The manufacturing process is scalable to industrial
scales and can operate either in batch or continuous manufacturing mode as
benchmarked in the current work.

The microfluidization step is
defined as a dynamic high-pressure process where two liquid streams, solution
or suspension, pass through micro-channels toward an impingement area through
which the fluids flow and interact [2]. The microfluidization step renders in
either a liquid solution or liquid suspension that is typically followed by a
spray drying step to remove the solvents and produce the dried particulate
system. A schematic illustration of the process train is shown in Figure 1. This
process was successfully demonstrated using fluticasone propionate as drug
alone, itraconazole (ITZ) / Eudragit L-100 amorphous solid dispersions and ITZ /
cyclodextrins inclusion complexes.

Case study I:
production of micro / nanocrystals using microfluidization:
Fluticasone propionate was dissolved in
acetone. As anti-solvent, a mass of deionized water corresponding to 10 times
that of the solvent was used. The two solutions were fed and mixed using PureNanoTM
in a single passage. The particle size of the isolated product was
characterized through scanning electron microscopy, SEM (Figure 2). Roughly,
particles with nano-scale were obtained [3].

Case study II:
complexation of a poorly water soluble API using cyclodextrines
ITZ was dissolved in DCM and SBE-β-CD dissolved in water. The two solutions
were fed and mixed using PureNanoTM in a single passage. Two
different trials at different temperatures were done, a filtration step was
done prior to the spray dryer to remove the API not complexed. 3% was the
maximum drug load obtained in the dried product [4].



Case study III:
co-precipitation of nano-solid dispersions
and Eudragit L-100, in a mass proportion 1:9 and 40:60, were dissolved in a
mixture of ethanol / acetone in a volume proportion of 1:1. Acidified cold
water (pH=2) was used as anti-solvent with a ratio solvent:anti-solvent of 1:10
w/w. The results indicated that amorphization of ITZ was successful when using
the present method (Figure 4) [5].



This work demonstrates that the technique
herein described, consisting in a microfluidization step followed by an
isolation step via spray drying is able to produce drug-alone nano-crystals,
cyclodextrins complexes and amorphous solid dispersions. The process is
scalable to industrial scales.



1 - Experimental set-up for the batch and continuous
controlled precipitation process.


2 -
SEM of spray dried particles of fluticasone



3 -
i) X-ray diffractograms of ITZ solid dispersion
at two different ratios and its crystalline form and ii) SEM of spray dried
dispersion of ITZ.

[1] Perrie Y., Rades T. “Pharmaceutics - Drug
Delivery and Targeting”, Pharmaceutical Press, 2010;

[2] Rakesh P. Patel, Ashok H Baria, Nikunjana A
Patel, An overwiew of size reduction technologies in the field of
pharmaceutical manufacturing, Asian Journal of Pharmaceutics October-December
(2008) 216-220.

[3] Fonseca, T., Duarte, I., Vicente, J.,
Temtem, M. “Continuous production of particles”, Patent No. WO2016156841 A1,

[4] Lisboa, H., Santos, F., Vicente, J.,
Temtem, M. “Continuous complexation of active pharmaceutical ingredients”, Portuguese
Patent No. 109117, 2016.

[5] Temtem, M., Pereira, R., Vicente, J.,
Duarte, I., Gaspar, F., Duarte, I. “A method of preparing amorphous solids dispersions
in submicron range by co-precipitation”, Patent No. WO2016016665 A1, 2016.