The purification of structurally
similar compounds was investigated
using selective impurity complex formation in solution followed by
crystallization of the target compound. Two systems of structurally
similar compounds, benzamide/benzoic acid (BAM/BA) and cinnamamide/cinnamic
acid (CAM/CA), were chosen. Three reported co-formers that form co-crystals
with both BA and CA were selected: isonicotinamide (INA), 2-amino-4,6-dimethylpyrimidine
(DMP), and dimethylglyoxime (DMG). The addition of DMG to the BAM/BA
system demonstrated the largest improvement of BAM purity. The amount
of BA did not decrease with increasing amount of DMG added. For the
CAM/CA system, adding DMP resulted in the largest CAM purity increase.
Phase solubility diagrams were measured to calculate binding constants
for 1:1 complexes. These binding constants were used as indications
of the complexation level in the solution. For the CAM/CA system,
the more complex formed in solution, the purer the CAM. This result
was not seen in the BAM/BA system. The results indicate that, for
difficult to purify compounds where the structurally similar impurities
substitute in the crystal lattice, the use of additives which have
the potential to complex with the impurity in solution can result
in an increase in crystal purity. However, the correlation between
the level of complexation and the purification result needs further
verification.
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.
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