(124c) Crystal Polymorphism of Particles Formed Via Monodisperse Droplet Evaporation

Snyder, R. C. - Presenter, Bucknell University
Karakis, V., Bucknell University
Carver, K. M., Bucknell University
Trauffer, D., Bucknell University
Maassel, A., Bucknell University
For small molecule active pharmaceutical ingredients, almost all are isolated as crystalline materials and over 80% are formulated in a crystalline and particulate form. When forming crystalline products, identifying the polymorph space and forming the desired polymorph are of critical importance in terms of drug properties including bioavailability, stability and patentability. There are a variety of methods used to identify polymorphs of crystals including using varied solvents and anti-solvents, adding other chemicals, crystallizing from the melt, or using specific substrates. In addition to traditional crystal formation methods, particles can also be formed via droplet evaporation which industrially takes place through spray drying. While spray drying often is utilized with the goal of forming amorphous products, it can be used to produce crystalline products. Further, monodisperse droplet generation (MDG) offers a useful tool for providing more controlled droplet evaporation by eliminating the droplet size distribution in spray dryers. Additionally, MDGs have low flow rates leading to increased droplet dispersion and faster droplet evaporation. This faster droplet evaporation leads to a larger chemical potential driving force for the formation of solids in the droplet before nucleation can occur leading to the potential to form metastable polymorphs that are otherwise unexpected with similar chemistries.

In this talk, we will highlight our recent work on producing unexpected polymoprhs of crystalline particles via evaporation of monodisperse droplets using a vibrating orifice aerosol generator (VOAG). Varied particle morphologies will also be presented. Several organic molecular crystal systems will be presented including succinic acid, glycine, and suberic acid. As with other crystallization methods, the solvent is crucial in impacting both the resulting particle crystal polymorph(s) and the particle morphologies. For succinic acid we will demonstrate the formation of the alpha polymorph at room temperature and pressure using water as the solvent (Carver and Snyder, 2012), whereas it otherwise has previously only been isolated at elevated temperatures. For glycine, we will highlight the ability to form the beta polymorph from water solutions (Trauffer, Maassel and Snyder, 2016), whereas additional chemicals or modifiers typically are needed to form the beta polymorph. Last, we will present a preliminary potentially new polymorph of suberic acid. The use of a chemical additive to enhance or inhibit some of these polymorph formations also will be considered. Finally, we will consider the challenges and opportunities for using this technique both in other research applications as well as industrially.


Kelly M. Carver and Ryan C. Snyder; Industrial and Engineering Chemistry Research, 2012; 51: 15720-15728.

David I. Trauffer, Anna K. Maassel and Ryan C. Snyder; Crystal Growth and Design, 2016; 16: 1917–1922.