Abstract
This paper describes the application of a novel antisolvent crystallization approach to rapid production of tunable solid solutions of hydrophobic amino acids, comprising l-leucine, l-isoleucine, and l-valine. The antisolvent approach provides an alternative to other crystallization routes, e.g., ball-milling, liquid-assisted grinding, and slurry methods, to achieve the required multicomponent solid phases. We report new crystal structures of l-leucine/l-isoleucine and l-leucine/l-valine, and confirm a recent report on a new form of l-isoleucine/l-valine. We used these multicomponent complexes as a test set of materials to demonstrate translation of small scale batch antisolvent crystallization to a continuous production process.
Highlights
Multicomponent complexes (MCCs) are materials that have two or more different molecules in the same crystal lattice.[1,2] MCCs can be classified into many different subsets that include cocrystals, solvates, and solid solutions
The interest in MCCs recently led to cocrystals being classified by the U.S Food and Drug Administration for the first time to clarify their legal status.[3,4]
This study has shown that we are able to control the formation of tunable solid solutions of hydrophobic amino acids using a novel antisolvent crystallization approach
Summary
Multicomponent complexes (MCCs) are materials that have two or more different molecules in the same crystal lattice.[1,2] MCCs can be classified into many different subsets that include cocrystals, solvates, and solid solutions. Previous work by Kurosawa et al.[42] and Isakov et al.[43] has shown that the three amino acids, L-leucine, L-isoleucine, and L-valine, formed solid solutions via the interpretation of the (0 0 1) reflection from the PXRD patterns and HPLC methods. The continuous process provided steady-state yields (based on the total amount of amino acids in the inlet feed) of 70% for 1, 50% for 2, and 70% for 3 were observed after experimental running times of 20, 3, and 10 min, respectively (Table 1 and Figure 2) These yields can be further improved by varying the solvent to antisolvent ratio. The diffraction and composition data for compound 2 from our study fits well with previous work showing a linear change of the d-spacing with the composition of the solid; at 10% leucine the structure reverts to the valine structure as identified by the unit cell parameters. The solubility of the solid solution was shown by Isakov to be higher than the isoleucine solubility, the reason that we observe the mixed phase in the solid
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