Purification of Structurally Similar Compounds by the Formation of Impurity Co-Former Complexes in Solution

Abstract

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.

Impurity incorporation in solution crystallization: diagnosis, prevention, and control

“…A novel method to tackle impurity incorporation during crystallization was initially demonstrated by Hsi et al for the purification of benzamide and cinnamamide from structurally similar impurities. 115 Most of the aforementioned mechanisms require impurity molecules to interact with the growing crystal so that they can be incorporated at the surface or lattice. In this context, Hsi et al hypothesized that co-formers that can form a co-crystal with the impurities will also form a complex in solution, preventing those impurities from incorporating in the growing crystals.…”

“…121 For known impurity systems, the Cambridge Crystallographic Data Centre (CCDC) can be used to find co-formers that would form co-crystals with the impurity, and use those as early candidates for screening. 115 The measurement of solution interaction energies for potential candidates, and the use of computational models, can facilitate the selection of potential co-formers. 121 However, for systems with large numbers of unknown impurities, screening for the right co-formers can take a significant amount of time and resources.…”

TOF-SIMS analysis of curcuminoids and curcumin crystals crystallized from their pure and impure solutions

“…Such impurities often introduce undesirable effects that includes the modification of the crystal habit, increased mosaicity, altered crystal growth rate, and can ultimately decrease the purity of the final crystals. [1][2][3][4][5] Additionally, structurally similar impurities can also replace atoms on the crystal lattice, modifying its intrinsic properties. 6,7 Depending on the type and nature of the impurities, as well as experimental conditions, impurities can alter the properties of the final crystals in terms of the crystal structure, and even other commonly encountered factors such as crystal agglomeration, attrition, overall crystal morphology, and yield.…”

Continuous Crystallization with Impurity Complexation and Nanofiltration Recycle

“…Impurity complexation can improve purity without compromising the yield and is therefore an effective solution to this issue. In this process, a complexing agent which can selectively bind with the impurity but not with the API is added to the solution prior to crystallization.…”