Screening Approach for Identifying Cocrystal Types and Resolution Opportunities in Complex Chiral Multicomponent Systems

Self Cite

Pharmaceutical cocrystals are highly interesting due to their effect on physicochemical properties and their role in separation technologies, particularly for chiral molecules. Detection of new cocrystals is a challenge, and robust screening methods are required. As numerous techniques exist that differ in their crystallization mechanisms, their efficiencies depend on the coformers investigated. The most important parameters characterizing the methods are the (a) screenable coformer fraction, (b) coformer success rate, (c) ability to give several cocrystals per successful coformer, (d) identification of new stable phases, and (e) experimental convenience. Based on these parameters, we compare and quantify the performance of three methods: liquid-assisted grinding, solvent evaporation, and saturation temperature measurements of mixtures. These methods were used to screen 30 molecules, predicted by a network-based link prediction algorithm (described in Cryst. Growth Des. 2021, 21(6), 3428−3437) as potential coformers for the target molecule praziquantel. The solvent evaporation method presented more drawbacks than advantages, liquid-assisted grinding emerged as the most successful and the quickest, while saturation temperature measurements provided equally good results in a slower route yielding additional solubility information relevant for future screenings, single-crystal growth, and cocrystal production processes. Seventeen cocrystals were found, with 14 showing stability and 12 structures resolved.

Section: Introductionmentioning

confidence: 99%

Comparing and Quantifying the Efficiency of Cocrystal Screening Methods for Praziquantel

Charpentier

Devogelaer²,

Tijink³

et al. 2022

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“…The quasi-binary phase diagrams (Q-BPDs) of type I and II successfully avoid complex considerations of melting and decomposition. Nonetheless, predicting the resolution accessibility with Q-BPDs depends on specific operating conditions . For example, an improper selection of the initial solvent ratio may even fatally affect the qualitative consequence.…”

Section: Results and Discussionmentioning

confidence: 99%

Thermodynamic and Molecular Recognition Mechanism of Diastereomeric Salt/Cocrystal-Induced Chiral Separation

Sui

Wang

et al. 2022

To better understand the thermodynamics and molecular self-assembly mechanism of diastereomeric salt/cocrystalinduced chiral separation, a series of 1:1 cocrystals and salts consisting of chiral valines (VAL) and tartaric acid derivatives were synthesized via different methods. Powders of these as-screened cocrystals/salts were characterized by PXRD, TGA, DSC, FT-IR, and Raman spectroscopy. The crystal structures of the five cocrystals/salts were determined and analyzed. It was found that both DBTA and DTTA form diastereomeric salt pairs with VAL enantiomers. Interestingly, L-DMTA cocrystallizes with D-VAL and L-VAL via hydrogen bonding and proton transfer, respectively. Considering this particularity, the differential isothermal (10 °C) ternary phase diagrams (TPDs) of D-DMTA and L-VAL (D-VAL) cocrystals (salt) were constructed in the mixed solvent of MeOH/ H 2 O. Moreover, a pure L-VAL:D-DMTA cocrystal and D-VAL:D-DMTA:0.5CH 4 O:0.25H 2 O salt were prepared via equimolar slurry conversion at 10 °C. In situ Raman spectroscopy was applied to monitor the molecular assembly process during the incubation of the cocrystal/salt. Molecular dynamics simulation was employed to rationalize the molecular recognition mechanism, demonstrating the excellent chirality preference of L-DMTA toward L-VAL instead of D-VAL. Calculations of density functional theory approved the synergistic instead of antagonistic effects of binding energy and solvation free energy toward chiral separation.

“…A racemic conglomerate, as the outcome of the crystallization of a chiral racemate, termed spontaneous resolution, is much less probable than the formation of a racemic compound, reaching ∼5–10% of the cases. , The spontaneous resolution of racemic compounds is generally unpredictable. This context has driven the development of new crystallization-based resolution techniques. − …”

Section: Introductionmentioning

confidence: 99%

Spontaneous Resolution of RS-Fluoxetine to a Racemic Conglomerate upon Salt Formation with Oxalic Acid

Carvalho

Diniz

Cardoso

et al. 2022

Fluoxetine (Flx), an important active pharmaceutical ingredient (API) for the treatment of depression, is commercially available as a racemic hydrochloride salt. Interestingly, the spontaneous resolution of RS-Flx occurred upon salt formation with oxalic acid (H2Oxa). Single crystals of Flx hydrogen-oxalate salt (Flx HOxa) have been obtained by slow evaporation from solution. They have been examined by single-crystal and powder X-ray diffraction, chiral chromatography, thermal analysis, and equilibrium solubility, revealing that Flx HOxa salt crystallizes as a racemic conglomerate. In the salt structure, the Flx+··· HOxa– ionic pairs assemble in 21-helical chains in the Sohncke space group P21 and Z’ = 1, through N+H···O– H-bonds. Additional cationic homochiral chains are formed in the crystals through noncovalent interactions between helicoidal motifs. It was shown that Flx HOxa conglomerates are as thermally stable as the hydrochloride salt of Flx, confirmed by thermal analysis. The identification of Flx HOxa salt conglomerates is a crucial step for the further chiral resolution process for the API and is also a novel multicomponent crystal with promising properties for a new drug formulation.