Direct Production of Active Pharmaceutical Ingredients from Multi-Component Solutions by Membrane-Based Crystallization Technology

This work aimed to develop a versatile method for the direct formulation of cocrystals of active pharmaceutical ingredients (APIs) and conformers from multicomponent solutions. In more detail, membrane crystallization,[1] operated in antisolvent configuration,[2] has been used to obtain solid crystalline products from solutions containing carbamazepine (CBZ) and saccharin (SAC), from water and ethanol as solvent mixtures. Results demonstrated that, depending on the solution composition, the preferential crystallization of the API (CBZ) or a co-crystal of the two component molecules can be obtained. In the case of water/ethanol mixtures containing 1:1 initial molar ratio of the two components, the selective crystallization of CBZ was observed. Among the four known phases of carbamazepine, the precipitate contained the triclinic form I ( , lattice parameters: a = 20.57, b = 5.17, c = 22.25, α = 88.0, β = 84.1, γ = 85.2), with a polymorphic purity exceeding 90%, while the remaining part form IV (C-centered monoclinic cell - C2/c, lattice parameters: a = 26.609, b = 6.9269, c = 13.957, α = 90.0, β = 109.702, γ = 90.0) was obtained as byproduct. When increasing the molar amount of co-crystal former (SAC) in the right combination with respect to CBZ, the CBZ-SAC I co-crystals were exclusively (phase purity > 99%) obtained (CBZ-SAC phase I, , lattice parameters: a = 7.5, b = 10.5, c = 12.7, α = 83.6, β = 85.7, γ = 75.4). These results demonstrated that membrane-based crystallization technology, working in antisolvent configuration, can be suitable to achieve direct product formulation of co-crystals even in the crystallization from multi-component (solvents mixture) systems.