(489f) Production of Amorphous Nano-Solid Dispersions Using a Solvent Controlled Precipitation Process – Benchmarking with the Spray Drying Process

Production
of amorphous nano-solid dispersions using a solvent
controlled precipitation process – benchmarking with the spray drying
process

Iris
Duarte^1,2, Pedro Serodio¹, M. Luisa Corvo², Joao
Vicente¹, Joao F. Pinto², Marcio Temtem^1*

¹ Hovione FarmaCiencia
SA, Sete Casas, 2674-506 Loures, Portugal; ^*mtemtem@hovione.com or
+351 219 847 569

²iMed.ULisboa, Faculdade
de Farmácia da Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003, Lisboa,
Portugal

            Current pharmaceutical
pipelines are highly populated with new molecules presenting poor
physicochemical properties, which typically translate into solubility issues.
Poor solubility is one of the major concerns in the oral-drug delivery field,
mainly because it limits bioavailability. Among the different formulation strategies applied to address this
issue, the use of amorphous solid dispersions (ASDs) is a popular technology,
with a large number of amorphous-based medicines reaching the market.

            Bioavailability enhancement
may be achieved by improving the dissolution kinetics - applicable to Class IIa compounds, according to the recent Developability Classification System (DCS) - and/or
by increasing the maximum concentration of the active compound in solution - applicable
to DCS Class IIb compounds [1]. In the particular
case of DCS class IIa drugs the particle size can play an important role in the enhancement of the
dissolution rate. Although
various methods are reported in literature for the preparation of solid
dispersions (e.g. spray drying,
freeze drying, hot melt extrusion, etc), the state of
the art is scarce in technologies that enable both control of the particle size
in the submicron range while maintaining the amorphous state.

            In order to address this, the purpose of this work was to evaluate the
feasibility of using a solvent controlled precipitation (SCP) process to produce nano-sized ASDs [2]. Moreover, the
influence of varying the formulation and process conditions on the co-precipitated
products was assessed.

          Carbamazepine (anhydrous, Form
III), a DSC Class IIa molecule, was the model drug
selected to conduct this feasibility study. Solvent controlled precipitation
experiments were undertaken using Microfluidics Reaction Technology,
followed by a spray-drying step to isolate the particles [3]. Figure 1
represents the half-factorial design 2^3-1 + 2 central points
conducted to study the effect of critical formulation variables [i.e.
type of polymer, drug load and feed solids concentration (C_feed)]
on typical critical quality attributes (CQAs) of ASDs (e.g. physical
stability, particle size and morphology, bulk powder rheology, dissolution/supersaturation potential, in vivo bioavailability).
Among the API/Polymer systems
tested, the ones that resulted in true amorphous solutions were also produced
using spray-drying (SD), for benchmarking purposes. 

 

Figure 1. Half-factorial
design (2^3-1) + 2 central points for the solvent controlled
precipitation process study.
            Figure 2, on the left,
shows the XRPD diffractograms obtained for the
different co-precipitated products. These results indicated that drug's solid-state and physical stability was mainly dependent on the
type of stabilizing polymer and drug load in the formulation. For the CBZ:HPMCAS systems, a
gradual increase in the relative intensity of the characteristic peaks of CBZ
with increasing drug loading was observed, which indicated that glass solutions
were not obtained. By opposition, for the CBZ:Eudragit^®
L100 systems, Test #4 resulted in a glass solution while Test #5 and #6
resulted in crystalline suspensions of CBZ within the polymer, indicated by the
absence and presence of CBZ characteristic peaks, respectively. C_feed had no significant effect in the amorphization and physical
stability of the products.

Figure 2. Left: XRPD diffractograms corresponding to Test#1 to Test#6. Right: SEM micrographs corresponding to Tests #4 and #6 and Tests #1 and #2.

            On
the right hand side of Figure
2 are represented the SEM results obtained for Tests #1 and #3 and Tests #4 and
#6, at 5000x magnification. In relation to particle size and morphology,
agglomerated and spherical particles were obtained among all tests, varying in
a size range of 5-10μm, regardless the drug-polymer system or drug load.
However, in terms of number distribution in each sample, a higher number of
particles with a larger diameter were observed in the samples corresponding to
high solids' concentration in solution, and vice-versa. These results indicated
that bulk particle size was mainly dependent on the feed solids concentration,
and both variables varied proportionately. Finally,
the observation of the particles surface under high magnification revealed that
the agglomerates consisted of individual particles, most of them with a
diameter below 100nm (inserts). Moreover, these nano-particles were more
individualized in case of low drug load formulations, and more
entangled/fused with each other for higher drug load formulations.
Consequently, formulations with lower drug load presented a higher superficial
area, which is believed to have a positive influence on the dissolution profile
of a BCS/DCS Class IIa drugs.

            To assess the in vitro performance of the amorphous nanocomposite particles
produced by SCP (Test #4) powder dissolution experiments were conducted (Figure
3). For benchamrking purposes, two additonal CBZ-based formulations were
produced: (1) 60 wt% CBZ:Eudragit^® L100 by SCP and (2) 20 wt%
CBZ:Eudragit^®
L100 by SD, both at 8 wt% C_feed.
The former formulation resulted in a crystalline suspension of CBZ within the
polymer (similar to Test #6) and maintained its nano-features,
while the latter resulted in a true glass solution, but in the form of microparticles. Figure 3, on the right, shows these
differences, in terms of particle size/morphology.

Figure 3. Left: Dissolution profiles of different CBZ:Eudragit^®
L100 formulations, either produced by SCP or SD and pure crystalline CBZ (n=1).
Right: respective SEM micrographs of CBZ:Eudragit^®
L100 formulations tested.

            When compared with spray-dried ASDs, the rapid dissolution of
high-surface area nanoparticles produced by SCP favoured the creation and
maintenance of higher supersaturated levels. Differences
between the NanoCrystalline and NanoAmorphous
formulations may be related with different powder wetting properties;
nevertheless additional dissolution experiments will be conducted (n=3) to
better understand these differences. Moreover, the ongoing in vivo studies will also support a greater
understanding of this synergistic effect (nano +
amorphous) in absorption and bioavailability of DCS Class IIa
drugs.

            To
assess the bulk powder rheology of the amorphous nanocomposite
particles produced by SCP (Test #4), a FT4 powder rheometer was used. Similarly,
and for comparison, the respective amorphous spray-dried formulation (20 wt% CBZ:Eudragit^® L100, C_feed at 8 wt%) was also tested.

Figure 4. Left: Permeability as a function of normal stress at
constant air velocity of 2 mm/s. Right: Compressibility (i.e. % of bulk density change) as a function of normal stress.

            Figure 4 shows the results from the permeability
and compressibility tests at 15 kPa. Permeability
is a measure of how easily the powder can transmit air through its bulk, while compressibility is a measure of the volume change in a powder as a consequence of
an applied consolidating stress [4]. The NanoAmorphous
formulation showed to be less permeable, and consequently more compressible
than the MicroAmorphous formulation. These
differences are clearly related with the different particle
properties of both powders, namely particle size, shape, surface properties,
amount of fines, etc.   

References:

[1] Butler J. and Dressman
J., The Developability Classification System:
Application of Biopharmaceutics Concepts to Formulation Development, J Pharm Sci,
2010, 99 (12), pp. 4940-54;

[2] Provisional patent application:
PT107846;

[3] Panagiotou T., PureNano? and MRT Applications, Microfluidics,
2012;

[4] Freeman Technology Limited, An Introduction to powders, 2014.