Solvent Influence on Organic Crystal Agglomeration
Advancing the chemical engineering fundamentals
Crystallization (T2-9P)
Keywords: crystallization, polymorphs, solvents, pharmaceutical
The crystallization process is a critical step in the manufacture of pharmaceutical compounds. In this step properties such as the polymorphic form, particle size, crystal habit, surface properties and mechanical strength can be controlled and secured to achieve an expected product quality. Among important parameters like supersaturation generation, feed and mixing conditions the selection of solvent is crucial. The solvent very much determines the productivity and yield of the process, but also the crystal size, shape and agglomeration. Agglomeration is in principal a three steps process: crystals collide, adhere and grow together. After collision, physico-chemical and fluid mechanical forces compete and determine the time available for crystalline bridging between crystal faces. All three steps are influenced by the properties of the solvent.
In previous work the influence of solvent composition on crystal agglomeration of paracetamol was studied [1-3]. The agglomeration behaviour in the crystallization experiments correlated to large extent to the solvent polarity and to the free energy of adhesion between crystal faces in various solvents. The paracetamol product is less agglomerated and the agglomerates are weaker when the crystallization is carried out in polar solvents where the crystal-solvent interactions are stronger, e g in water. The paracetamol crystal has different faces where the molecules are differently arranged but still expose a rather similar hydrogen bonding ability. In the present work the agglomeration behaviour of (RS)-ibuprofen crystals, exposing a more pronounced difference in surface chemistry and hydrogen bonding ability of different faces, is investigated.
Fully seeded isothermal crystallization experiments are conducted in pure solvents. Particles from each experiment are examined by image analysis and multivariate data evaluation. Each particle is characterized for the number of crystals per particle using a set of calibration particles. Consistently the product particles are to some extent agglomerated and hence differently from the results of paracetamol the agglomeration behaviour of ibuprofen is independent of solvent. Surfaces of large, well grown ibuprofen crystals are characterized by contact angle measurements. The surface free energy components of different faces are determined by using three probe liquids and the Lifshitz-van der Waals acid-base theory [4]. The free energy of adhesion between different crystal faces can then be calculated and used to explain the observed agglomeration in different solvents.
[1] Ålander, E; Uusi-Penttilä, M; Rasmuson, Å, Ind. Eng. Chem. Res. (2004), 43, 629-637.
[2] Ålander, E; Rasmuson, Å, Ind. Eng. Chem. Res. (2005), 44, 5788-5794.
[3] Ålander, E; Rasmuson, Å, (2006), submitted to AlChE J.
[4] van Oss, C J; Good , R J; Chaudhury, M K, Langmuir (1988), 4, 884-891.
Presented Wednesday 19, 13:30 to 15:00, in session Crystallization (T2-9P).
