Tuning Physicochemical Properties of Antipsychotic Drug Aripiprazole with Multicomponent Crystal Strategy Based on Structure and Property Relationship

X-ray photoelectron spectroscopy (XPS) is used to understand the nature of acid–base crystalline solids, to know whether the product is a salt (proton transfer, O–···H–N+) or a cocrystal (neutral adduct, O–H···N). The present study was carried out to explore if intermediate states of proton transfer from COOH to nitrogen (the proton resides between hydrogen bonded to O and N, O···H···N, quasi state) can be differentiated from a salt (complete proton transfer, N+–H··· O–) and cocrystal (no proton transfer, O–H···N) using N 1s XPS spectroscopy. The intermediate states of proton transfer arise when the pK a difference between the acid and the conjugate base is between −1 and 4, −1 < ΔpK a < 4, a situation common with COOH and pyridine functional groups present in drug molecules and pharmaceutically acceptable coformers. Complexes of pyridine N bases with aromatic COOH molecules in nine salts/cocrystals were cocrystallized, and their N 1s core binding energies in XPS spectra were measured. The proton state was analyzed by single-crystal X-ray diffraction for confirmation. Three new complexes were crystallized and analyzed by XPS spectra (without knowledge of their X-ray structures), to assess the predictive ability of XPS spectra in differentiating salt–cocrystal intermediate states against the extremities. The XPS results were subsequently confirmed by single-crystal X-ray data. Complexes of 3,5-dinitrobenzoic acid and isonicotinamide in 1:1 and 1:2 ratios exist as a salt and a salt–cocrystal continuum, respectively, as shown by the N 1s core binding energies. The proton states of the crystalline solids by XPS are in good agreement with the corresponding crystal structures. Other complexes, such as those of 3,5-dinitrobenzoic acid with 1,2-bis(4-pyridyl)ethylene, exhibit a salt–cocrystal continuum, maleic acids with 1,2-bis(4-pyridyl)ethylene and acridine are salts, 2-hydroxybenzoic acid and acridine is a salt, and the complex of 3,5-dinitrobenzoic acid and 3-hydroxypyridine is a salt and salt–cocrystal continuum, while fumaric acids with 1,2-bis(4-pyridyl)ethylene and acridine are cocrystals. Furthermore, three new acid–base complexes of 3,5-dinitrobenzoic acid with phenazine, 4-hydroxypyridine, and 4-cyanopyridine were studied initially by XPS and then confirmed by X-ray diffraction. In summary, since the N 1s binding energies cluster in a narrow range as cocrystals (398.7–398.9 eV) and salts (400.1–401.1 eV), it is clearly possible to differentiate between cocrystals and salts, but the salt–cocrystal continuum values in XPS spectra are clustered in an intermediate range of cocrystals and salts but overlap with those of cocrystal or salt binding energies.

Section: Discussionmentioning

confidence: 99%

Can We Identify the Salt–Cocrystal Continuum State Using XPS?

Tothadi

Shaikh

Gupta

et al. 2021

“…Through the slow solvent evaporation method, 10 new multicomponent crystals, The proton transfers in 10 new multicomponent crystals were determined through the comparison of the bond length difference between C−O bonds in carboxyl group of coformers. 19,56 In salts, the bond length difference (ΔD C−O ) is small, while in cocrystals, it is large. The bond lengths of C−O bonds (D C−O ) in the carboxyl group and ΔD C−O are listed in Table 5 to identify the formation of salts or cocrystals.…”

Section: Resultsmentioning

confidence: 99%

Evaluation on Cocrystal Screening Methods and Synthesis of Multicomponent Crystals: A Case Study

Zhang

Yao

et al. 2021

Self Cite

Screening of suitable coformers is a major challenge during the development of cocrystals. To guide and simplify the cocrystal synthesis process, we evaluated three different predictive methods as well as their combinations during the cocrystallization of 2-amino-4,6-dimethoxypyrimidine (MOP) with 63 components. The conductor-like screening model for the real solvents (COSMO-RS) approach offered the best predictive results among three methods with an overall success rate of 84.1%. When combined with molecular complementarity (MC) analysis, the success rate was up to 85.7%. The Hansen solubility parameters (HSP) method did not deliver a satisfying outcome no matter if used individually or in combination for the MOP system. In addition, based on the screened results, 21 new solid phases of MOP were experimentally observed. Among them, the crystal structures of 10 multicomponent crystals (cocrystals and salts) were revealed by single crystal X-ray diffraction analysis (SCXRD), and their thermodynamic and spectroscopy properties were also characterized. The Hirshfeld surface analysis and the molecular electrostatic potential (MEP) surface analysis were conducted to explore the interactions in multicomponent crystals and the origin for salts and cocrystals. The cases in this study not only enriched the solid forms of MOP, evidenced the feasibility of the combined screening method, but also set an effective example for choosing potential coformers to prepare multicomponent crystals.

“…The bond length difference between two C−O bonds in the carboxylate group ΔD C−O is useful to determine the proton transfer. 61 The small ΔD C−O value indicates the transfer of proton and the formation of salt, while the large value suggests the formation of cocrystal. In Table 2, 3c).…”

Section: Resultsmentioning

confidence: 99%

New Salts and Cocrystals of Pymetrozine with Improvements on Solubility and Humidity Stability: Experimental and Theoretical Study

Xiao

et al. 2021

Self Cite

For the purpose of enhancing the solubility and humidity stability of pymetrozine (PMZ), a highly active but nonbiocidal pesticide, new multicomponent crystals were developed based on the connotation of crystal engineering. In the coformer screening process, a combined method, the Conductor-like Screening Model for Realistic Solvents (COSMO-RS) approach together with Cambridge Structural Database (CSD) analysis, was employed to shorten the screening process. Further, seven single crystals of PMZ’s new multicomponent solids were obtained including three cocrystals and four salts. Single-crystal X-ray diffraction together with Hirshfeld surface analysis clarified the detailed structure and the molecular interactions in these new crystals. Thermodynamic properties and spectral data were characterized by thermogravimetric analysis, differential scanning calorimetry, and Fourier-transform infrared spectroscopy. Hygroscopicity and solubility of the seven cocrystals/salts were investigated by dynamic vapor sorption and equilibrium solubility measurement, respectively. Multicomponent crystals not only exhibit better stability against humidity and but also higher water solubility than PMZ. Meanwhile, the insecticidal activity of PMZ was preserved during the formation of cocrystals/salts. On this basis, we conducted the atoms-in-molecules (AIM) analysis and the molecular electrostatic potential surfaces (MEPs) analysis to assess the strength of hydrogen bonds and reveal the origins of salt/cocrystal formation. So, the variations and origins of these physicochemical properties were rationalized and explained on the atomic scale. On the whole, the efficiency of the novel combined coformers screening method was verified and new multicomponent crystalline forms of PMZ were successfully obtained to prevent the parent compound from hydrating transformation.