Towards a better understanding of the role of stabilizers in QESD crystallizations
Quasi-emulsion solvent-diffusion crystallization (QESD) is a type of spherical crystallization which can be used as a particle design method to improve the flowability and micromeritic properties of drugs or excipients. Spherical particles are generated by dispersing a solvent phase in an antisolvent so that a transient emulsion is formed. Within the droplets the material can crystallize and agglomerate into spherical, hollow particles.
Surfactants, such as surface-active polymers like hypromellose, are often required to stabilize the quasi-emulsion. To gain further understanding for the role of the stabilizer, a new screening-method was developed which compared different surface active polymers in solution at similar dynamic viscosities rather than at a set concentration. The dynamic viscosities of a low-viscosity grade hypromellose solution used in the previous publications describing the QESD crystallization of metformin hydrochloride by the authors was used as a target value.
QESD crystallizations of metformin hydrochloride (MF) and celecoxib showed that the type of stabilizer and whether it is dissolved in the solvent or antisolvent has an effect on the agglomerates. For MF, the type of hypromellose used can have a significant influence on the properties of the agglomerates. More polymers could be used to stabilize the transient emulsion of celecoxib than previously found in literature. Furthermore, QESD crystallizations seem to be more robust when the stabilizer is dissolved in the antisolvent, however this can lead to a reduced drug load of the agglomerates.
About this article: Hansen, J., Kleinebudde, P. Towards a better understanding of the role of stabilizers in QESD crystallizations. Pharm Res (2022). https://doi.org/10.1007/s11095-022-03212-2
Materials
The QESD crystallizations of metformin hydrochloride (MF, Auro Laboratories Ltd., India), pramipexole dihydrochloride (Chr. Olesen, Denmark), selegilin hydrochloride (BASF, Germany), metoprolol tartrate (Microsin, Romania) and salbutamol sulfate (Caelo, Germany) were performed by dissolving the API in demineralized water and crystallizing in technical-grade acetone. Drugs with a poor solubility in water, celecoxib (CEL, Cadila Pharmaceuticals Limited, India) and naproxen sodium (NP, Divi’s Laboratories Limited, India) were dissolved in technical-grade acetone and crystallized in demineralized water. A variety of pharmaceutical grade polymers and surfactants (Table I) were added to the aqueous phase. For this screening hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), hydroxyethylcellulose (HEC), polyvinylpyrrolidone (PVP), polyvinylpyrrolidone/vinyl acetate copolymer (PVPVA), polyvinyl alcohol-polyethylene glycol graft copolymer (PVA-PEG) and polysorbate 80 (PS80) were used (Table I).
Table I Polymers used as QESD-stabilizers
