(550a) Particle Engineering of Cocrystals Using a Solvent-Free Approach By Spray Congealing

Duarte,, Hovione Farmaciência SA
Pinto, J. F., iMed.ULisboa, Faculty of Pharmacy, University of Lisbon
Temtem, M., Hovione FarmaCiência SA

engineering of cocrystals using a solvent-free
approach by spray congealing

Duarte1,2, Joao F. Pinto2, Marcio Temtem1*

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

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

            Around 90% of the new chemical entities emerging from the
drug discovery phase present, at least, solubility constraints (BCS Class
II+IV). Among the different solubilization strategies that have been applied to
address this issue, the use of pharmaceutical cocrystals emerged as
an alternative crystal-engineering platform to enhance the poor physicochemical
properties of these challenging molecules
            Pharmaceutical cocrystals are stable
multicomponent crystals, typically comprising two molecules, e.g. an API, or the salt of an API, and a coformer. The
coformer can be an active or non-active ingredient (e.g. pharmaceutical excipients, vitamins, minerals, amino acids,
other APIs) that has a favorable intermolecular interaction with the API,
promoting hydrogen bonding, van der Wall forces or pi-stacking [2].

            In general, and despite
the great potential of cocrystallization, producing
cocrystals with high efficiency at industrial scales is challenging due to the
tight thermodynamic and kinetic crystallization windows necessary to achieve
the desired crystalline form. Specifically referring to the pharmaceutical
field, the wide application of cocrystals
is still limited due, in part, to the scarcity of suitable large-scale
production methods and lack of robust and cost-effective processes.

            In order to address some of these challenges, spray congealing has recently emerged as new process for the preparation
of cocrystals [3]. Spray congealing, which is a hybrid technology governed by similar principles of spray drying and hot melt extrusion, consists in feeding a molten mixture to an
atomizer, which then breaks the liquid feed into small droplets, and those
droplets are cooled thanks to a co-current stream of cooling gas (Figure 1).
advantages of this method are the fact it can be conducted in the same
apparatus of spray drying, with minor modifications, thus making the commercial
scale of the process readily available; for being a solvent free technique, cocrystallization via spray congealing will also comply with green chemistry
requirements and, most importantly, it can be used to
produce ?engineered? cocrystals (i.e. with the desired properties) in a
particulate form, in a single stage operation without
the need of any downstream processing.

            The feasibility of using spray congealing to produce
pharmaceutical cocrystals was successfully demonstrated using three model API:coformer systems (Table 1).

Figure 1. Schematic representation of the spray congealing set up used.

Table 1. Case-studies and respective process variables defined for the tests. The flow rate of the congealing (F_gas) was set at 0.35m3/min.


Molar Proportion

Process Variables


ΔT [ºC]*

F_atom [L/min]**

Caffeine:Glutaric acid






Caffeine:Salicylic acid












* ΔT: difference between the mixture melting temperature observed inside the beaker (TM,mix) and the inlet temperature of the congealing gas (Tin, gas);

**F_atom: flow of the atomization gas.


the final products obtained with spray congealing presented DSC thermal
profiles and XRPD diffractograms characteristic of the respective cocrystals
and different from the pure components or physical mixtures. As an example, Figure 2 shows the results
obtained for the 1:1 Caffeine: Salicylic Acid system.


 ISD.HQ00005 5000x 2.tif

Figure 2. Results obtained for the 1:1 CAF:SAL
system. From left to right: DSC, XRPD and SEM.

and for one specific case-study,
i.e. 1:1 Caffeine:Glutaric acid (CAF:GLU), a DoE with 2 parameters at 2 levels + 1 central point was conducted, to assess the effect of process variables on the final cocrystal particle and bulk
powder properties. The parameters or process variables (i.e. ΔT and
F_atom) were varied according to the ranges shown in
Table 1. 

            According to Figure 3 it can be observed
that particle properties (size, morphology, shape) can be adjusted, in situ, as part of the spray congealing
process, without compromising cocrystal formation (DSC
and XRPD data not shown).

particle properties are known to affect the bulk behaviour of powders, which
can impact subsequent downstream processing (i.e. blending, capsule filling, tableting, etc.) [8]. In order to
evaluate this, bulk (i.e,
compressibility and permeability) and shear properties of the powders produced
were measured using a FT4 powder rheometer. Figure 4 shows the results from the permeability
and compressibility tests at 15 kPa, and the shear
cell test on samples that have been pre-consolidated at 9kPa normal stress.

Figure 3. SEM results (right) and number-based circular equivalente diameter (CED) distributions (above) for the 1:1 CAF:GLU systems produced, when varying ΔT and F_atom.

            Shear testing
classified the powders as identical, whilst the permeability and
compressibility tests show they are significantly different. The shear data
suggest that the powders may behave similarly in a moderate to high stress
environment, such as in a hopper, but it does not necessarily mean that they
will behave similarly when aerated or flowing under low stress. The different
tendencies of the permeability and compressibility results are clearly a
consequence of the influence of multiple variables or particle properties (e.g. particle size, shape, surface
properties, amount of fines, etc.) on the bulk powder rheology.

Figure 4. From left to right: permeability
as a function of normal stress at constant air velocity of 2 mm/s, compressibility
(i.e. % of bulk density change) as a
function of normal stress and shear stress as a function of applied normal


[1] Blagden N. et
, Pharmaceutical co-crystals - are we there yet?.
2014, 16, pp. 5753-5761;

[2] Qiao, N. et al., Pharmaceutical
cocrystals: An overview. International Journal of Pharmaceutics, 2011, 419, pp. 1-11;

[3] Duarte, I., et al. Synthesis and particle engineering of cocrystals. WO2015/036799A1 (2015);

[4] Trask et
, Solvent-drop grinding: green polymorph control of cocrystallization.
Chem. Commun.,
2004, 7, 890-891;

[5] Lu et al.,
A rapid thermal method for cocrystal screening. CrystEngComm, 2008, 10,

[6] Chieng et al., Formation Kinetics and Stability of
Carbamazepine - Nicotinamide Cocrystals Prepared by Mechanical
Activation. Cryst. Growth Des., 2009, 9(5), 2377- 2386;

[7] Liu et al., Improving the Chemical Stability of
Amorphous Solid Dispersion with Cocrystal Technique by Hot Melt Extrusion. Pharm. Res., 2012, 29, 806-817;

[8] Freeman R.,
Measuring the flow properties of consolidated, conditioned and aerated powders
– a comparative study using a powder rheometer
and rotational shear cell. Powder Technology, 2007, 174, pp. 25-33.