Paper
CrystEngComm
these four coformers and 4HPG. High levels of complexation
contributed to the enhancement of purification.
most: 2-picolinic acid, L-leucine, L-isoleucine, and L-lysine. The
amounts of 4HPG incorporated in AMCT in these four systems
were lower than that in an initial crystallization and a second
crystallization. We were able to correlate purification results to
the level of complexation by varying the amount of coformer
added.
The purification results obtained from a single crystal-
lization reduced the impurity concentration to as low as
0.12(¡0.01) wt% from 0.98(¡0.07) wt% when no coformer
was added. In addition, crystals obtained from a second
crystallization without the addition of coformer were still
significantly less pure than crystals made from a single
crystallization with the coformer. This indicates the potential
usefulness of the method. The most common way to improve
product purity is to recrystallize the compound of interest.
However, by doing so, the yield is sacrificed to increase the
purity. On the other hand, in our separation method, in
addition to the high purity gained, the yield was not sacrificed.
Our proposed separation method has the potential to be
applied on expensive products when low yield is unacceptable.
We can correlate the level of complexation to the purifica-
tion results with the addition of various coformer amounts. At
r = 0.1, no significant decrease was observed in any system.
This can be due to the lack of complex formation. For the
2-picolinic acid and L-lysine systems, best purifications were
achieved at r = 0.5 and additional coformers cannot further
decrease the amount of 4HPG in AMCT crystal lattice. This fact
suggested that the level of complexation increased when r was
increased from 0.1 to 0.5 and the maximum level of
Acknowledgements
The support of Novartis for this research is gratefully
acknowledged.
Notes and references
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Conclusions
The practical use of the proposed separation method with a
real drug/impurity system was evaluated. Forty-seven com-
pounds were selected because they have functional groups that
can form heterosynthons with functional groups on 4HPG.
Eleven were confirmed to form cocrystal with 4HPG but not
AMCT using solid-state grinding. Separation experiments were
performed and four compounds were found to decrease the
amount of 4HPG incorporated into AMCT crystal lattice the
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CrystEngComm
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