British Association For Crystal Growth Annual Conference 2017
Crystallization in composite hydrogels for controlling polymorphism
M.A. Reus,1 H.J.M. Kramer,1 H.B. Eral,1
1
Delft University of Technology, Process & Energy Department, The Netherlands
[email protected]
Introduction
In the case of class II pharmaceuticals (medicine with a low bioavailability), reducing the crystals to the
submicron size can greatly enhance the dissolution rate and therefore the effectiveness of the API in the
body. However, apart from the crystal size, the polymorph also influences the solubility and dissolution rate.
Therefore, control of polymorphism of the nanocrystals is of vital importance. This study aims to control the
polymorphism in model API nanocrystals through interplay of confinement and interactions between
surfactant molecules at liquid-liquid interfaces. Thereto, an emulsion crystallization of the model API is
performed, while the emulsion is immobilized by a composite hydrogel. Griseofulvin (GRIS), an antifungal
drug with poor water solubility, was used as a model compound.
Production of drug laden composite hydrogels
For the production of the particles containing the immobilized emulsion, first the disperse and continuous
phases were prepared. The disperse phase consists of a hydrophobic solvent (e.g. dichloromethane (DCM),
Anisole (ANI)) saturated with GRIS, the continuous phase consists of water containing 2 % w/v sodium
alginate and 1% w/v surfactant (e.g. pluronic F68, SDS, Tween20). The solutions were premixed (10% v/v
dispersed phase) and sonicated to obtain a nanoemulsion, which was dripped in a cross-linking bath
containing 6% w/v CaCl2 for solidification. Then, the particles were sieved and dried in an oven at 50°C for 4
days.
Results
To investigate the effect of the crystallization in the particles of immobilized emulsion on the polymorphism,
GRIS was crystallized in particles as well as in bulk solvents of different compositions and subsequently
analyzed using XRPD and DSC. In figure 1 the XRPD patterns are given (top to bottom) of composite
particles with DCM/Tween20/GRIS (1st), composite particles with DCM/F68/GRIS (2nd), composite particles
with ANI/SDS/GRIS and separate SDS (3rd) and raw GRIS (4th). The raw GRIS from the stock was form I,
as compared to results from Mahieu et al. [1].
Crystallizing from the bulk in ANI and DCM yielded form I and the solvate GRIS:DCM 1:1 (compared to the
results of Shirotani et al. [2]), respectively, regardless of any dissolved surfactant, dispersed hydrogel, etc.
When the GRIS was crystallized in the particles, however, the XRPD pattern was significantly different from
any of the known forms. For different combinations of solvent and surfactant, droplet size, etc. the unknown
form prevailed. These experiments indicate that neither the solvent, the hydrogel matrix nor the emulsion
droplet size influence the polymorphism of the GRIS. However, crystallizing GRIS in the particles containing
DCM with Tween20 as surfactant yielded form I. This indicates that the surfactant bound on the surface does
have an influence on the polymorphism.
Fig. 1: from top to bottom: XRPD patterns of composite particles with DCM/Tween20/GRIS (1st), composite particles with
DCM/F68/GRIS (2nd), composite particles with ANI/SDS/GRIS and separate SDS (3rd) and raw GRIS (4th)(Form I, compared with
Mahieu et al.[1]).
British Association For Crystal Growth Annual Conference 2017
To confirm this effect, an experiment was performed where GRIS was crystallized from a DCM droplet
evaporating through a layer of water, without the use of any surfactant. The resulting XRPD pattern was
again different from all others. The crystals form on the DCM-water interface and then grow out. This
indicates that the surface functionality is the main rudder for the steering of polymorphs.
Conclusions and outlook
The production of Griseofulvin nanocrystals using composite hydrogels was explored to improve the
dissolution rate and control the morphology of the produced crystals. Comparison of the resulting crystal
forms revealed that the functionality at the surface can be used to influence the resulting polymorph. A
thorough understanding of the effect that the surface functionality has enables control over the crystallization
of the desired polymorph. Further efforts will be directed to gaining more understanding and developing a
control strategy that can also be utilized for the crystallization of other compounds.
References:
[1] A. Mahieu, J.-F. Willart, E. Dudognon, M.D. Eddleston, W. Jones, F. Danede, and M. Descamps, Journal of
Pharmaceutical Sciences, 2013, 102, 462-468.
[2] K.-I. Shirotani, E. Suzuki, Y. Morita and K. Sekiguchi, Chemical & Pharmaceutical Bulletin, 1988, 36, 4045-4054.