Purification of amoxicillin trihydrate by impurity-coformer complexation in solution†
In this work, we demonstrated the purification of amoxicillin trihydrate (AMCT) by the formation of 4-hydroxyphenylglycine (4HPG)-coformer complex in solution. Without advanced knowledge of cocrystal formation of 4HPG, a workflow was established to choose the optimal coformer and the amount of coformer to add for a specific target/impurity system. Forty-seven compounds were chosen and screened due to their functional groups having the potential to form heterosynthons with the functional groups on 4HPG. Using solid-state grinding, eleven compounds were selected as coformers for separation experiments because they can form cocrystals with 4HPG but not AMCT. Four compounds, 2-picolinic acid, L-lysine, L-leucine, and L-isoleucine were shown to enhance AMCT purity the most. The purities of the AMCT crystals crystallized from solutions with a 1 : 10 4HPG : AMCT ratio and with these four compounds were significantly greater than that without the addition of coformer and greater than that obtained from a second crystallization from fresh solvent. By varying the coformer-to-4HPG ratio, we can correlate the purification results to the level of complexation in the solution. In addition, the proposed separation method has practical uses and can be applied to expensive products where low yield is unacceptable.