(442t) Particle Engineering through Continuous Solvent Precipitation

Particle
Engineering through continuous solvent precipitation

T. Porfirio¹, I. Duarte¹, J.
Vicente¹, M. Temtem¹

¹Hovione Farmaciencia SA, Sete Casas, Portugal

Up to 90% of the active pharmaceutical substances
under development are poorly water soluble, usually resulting in low
bioavailability (BCS class II and class IV). To overcome this issue, different engineering
and formulation approaches have been developed. Among the different strategies,
the use of cocrystals and amorphous solid dispersions is becoming an
increasingly relevant platform. It is also known by a skilled in the art that
the dissolution rate may be enhanced by increasing the surface area of the
particles through size reduction.

Most particle size-reduction methods rely on a
top-down approach, where larger particles are mechanically processed by milling
or high shear processing. In these cases the size of particles is reduced by
impact which can introduce impurities and limits the flexibility in controlling
particle morphology.

In opposition, on bottom-up approaches the control of
the particle properties (size, morphology, crystallinity, etc.) is easily
achieved due to molecular arrangements. An example is the liquid antisolvent
precipitation which allows particle formation through
crystallization/precipitation by using a suitable solvent/antisolvent system.
The liquid antisolvent precipitation has been used in the production of single
drug particles, cocrystals or amorphous solid dispersions. [1, 2, 3]

The present work discloses a new continuous process
that makes use of a micro-reaction technology to control precipitation in order
to produce single drug particles, cocrystals or amorphous solid dispersions in
the particulate form. The benefits of this technology are associated with the
capacity to achieve homogeneous and rapid mixing of the two or more fluids thus
enabling the control of particle characteristics (e.g. particle size,
morphology, polymorphic form).

Figure 1 ? Simplified scheme of the process [4]

Firstly, the solvent and antisolvent mixtures are
prepared, that are able to form precipitates under preferred process conditions.
Then both solvent and antisolvent are delivered to an intensifier pump and mixed
under controlled conditions in a microreactor to produce a suspension, as
depicted in Fig. 1. The said suspension is feed to a membrane system to obtain
a concentrate stream which is supplied to a spray drying unit in order to
obtain the product in particulate form. [4]

The feasibility of using this process was successfully
demonstrated using carbamazepine/ saccharin co-crystals and fluticasone
propionate as single drug.

In the case of carbamazepine-saccharin cocrystals, the
raw materials were dissolved in a molar proportion 1:1 in methanol. As
antisolvent, a mass of deionized water corresponding to 2 times that of the
solvent was measured. The co-precipitation in the form of cocrystal was
performed micro-fluidizer reactor processor. The intensifying pump was set to
impose a pressure higher than 1 kPsi.

The resulting suspension was fed to an in-line filter.
The suspension was also analyzed by X‑ray powder diffraction
characterization and presented the target crystalline form of carbamazepine‑saccharin
cocrystal as described by Porter III et al. [5]. Fig. 2 depicted
the X-ray powder diffraction of the analysis and the corresponding raw
materials. The concentrate stream was supplied to a lab scale spray dryer. The
obtained product presents the same target crystalline form of carbamazepine‑saccharin
cocrystal that was obtained before drying.

Figure 2 ? XRPD patterns and normalized
intensity of carbamazepine, saccharin and carbamazepine-saccharin cocrystal

In the case of the fluticasone propionate, the API was
dissolved in acetone. The mass of antisolvent (deionized water) was set as 10
times that of the solvent. The trial was performed with the same setup. The
particle size of the isolated product was characterized through scanning
electron microscopy. A representative image of the particles is shown in Fig.
3. Roughly, particles with nano- and micro-scale were obtained.

Figure 3 ? SEM of spray dried particles of
fluticasone propionate

As mentioned above, the present work is also suitable
for the production of amorphous solid dispersions overcoming the challenges
with intermediate stability of the amorphous materials produced using a
co-precipitation approach.

In conclusion, the present work proposes a continuous
process to overcome the shortcoming identified in the art mainly because: i)
includes a new separation approach during the isolation of materials produced
by co-precipitation; ii) enables a better control of particle characteristics;
iii) reduces the use of excipients in the formulation (such as surfactants),
iv) supports the continuous production of single drug particles, cocrystals or
amorphous solid dispersions in the particulate form in the micro- and/or
nano-range, and v) is scalable to high production scales.

References