In this work, we demonstrate a semibatch solid-state deracemization process for N-(2-chlorobenzylidene)­henylglycine amide­ (NCPA), a complex chiral polymorphic system that involves three types of crystalline racemates (racemic compound and conglomerate forms I and II). In this process, gradually fed metastable racemic compound crystals are converted in situ to crystals of the preferred (seeded) enantiomer under grinding conditions through a series of solvent-mediated transformations in a racemizing solution. The phase diagram for this system shows that while conglomerate form II is stable under the conditions examined (acetonitrile at 21 °C), form I crystals of a single enantiomer (used as seeds) are unstable at (nearly) racemic compositions and convert to the racemic compound upon addition of the racemization catalyst. Thus, care needs to be exercised in order to fully convert form I to form II before addition of the racemization catalyst in order to prevent the undesired crystallization of the racemic compound. This can be achieved by adding a small amount of water, which is found to enhance the nucleation and growth kinetics of the most stable conglomerate form II, eventually leading to complete deracemization. Importantly, we show that this special deracemization process can be easily monitored online by Raman spectroscopy, which gives access to the evolution of the solid-phase composition. For the studied system, this information can in turn be used to directly estimate the solid-phase enantiomeric excess online throughout the process, as long as conglomerate crystals of the counter enantiomer do not form.

Multicomponent crystals such as co-crystals, salts, and solid solutions can be used to modify physical properties of active pharmaceutical ingredients. Phase diagrams of such multicomponent crystals are essential for crystallization process development, especially in the case where multiple solid phases may coexist. However, additional components and solid phases make phase diagrams more complex and their determination more time consuming. We propose to accelerate this process by identifying the eutectic points and constructing the rest of the phase diagram using thermodynamic models, informed by further measurements, if necessary. In this work, a novel solution addition method is proposed for determining the eutectic points in a cocrystal system. This method implements gradual compositional changes to traverse various regions of the phase diagram. Phase boundaries are determined by monitoring changes in the liquid phase (UV−vis) and solid phase (Raman), and eutectic points are obtained from intersection of phase boundaries. The results from solution addition are compared to those of an equilibration method, which combines gravimetry, XRPD, and NMR to identify the eutectic solution composition starting from a composition in the three-phase region of a co-crystal phase diagram. Both methods were able to locate all eutectic points, allowing construction of the ternary phase diagrams of benzoic acid and isonicotinamide in ethanol.

Chiral molecules are challenging for the pharmaceutical industry because although physical properties of the enantiomers are the same in achiral systems, they exhibit different effects in chiral systems, such as the human body. The separation of enantiomers is desired but complex, as enantiomers crystallize most often as racemic compounds. A technique to enable the chiral separation of racemic compounds is to create an asymmetry in the thermodynamic system by generating chiral cocrystal(s) using a chiral coformer and using the solubility differences to enable separation through crystallization from solution. However, such quaternary systems are complex and require analytical methods to quantify different chiral molecules in solution. Here, we develop a new chiral quantification method using ultraviolet-circular dichroism spectroscopy and multivariate partial least squares calibration models, to build multicomponent chiral phase diagrams. Working on the quaternary system of (R)- and (S)-2-(2-oxopyrrolidin-1-yl)butanamide enantiomers with (S)-mandelic acid in acetonitrile, we measure accurately the full quaternary phase diagram for the first time. By understanding the phase stabilities of the racemic compound and the enantiospecific cocrystal, the chiral resolution of levetiracetam could be designed due to a large asymmetry in overall solubility between both sides of the racemic composition. This new method offers improvements for chiral molecule quantification in complex multicomponent chiral systems and can be applied to other chiral spectroscopy techniques.