Salt Cocrystal Research Articles

Trimesic Acid as a Building Block for Ternary and Quaternary Salts and Salt Cocrystals

Trimesic Acid as a Building Block for Ternary and Quaternary Salts and Salt Cocrystals

Supramolecular architectures in multicomponent crystals of imidazole-based drugs and trithiocyanuric acid.

The structures of three multicomponent crystals formed with imidazole-based drugs, namely metronidazole, ketoconazole and miconazole, in conjunction with trithiocyanuric acid are characterized. Each of the obtained adducts represents a different category of crystalline molecular forms: a cocrystal, a salt and a cocrystal of salt. The structural analysis revealed that in all cases, the N-H...N hydrogen bond is responsible for the formation of acid-base pairs, regardless of whether proton transfer occurs or not, and these molecular pairs are combined to form unique supramolecular motifs by centrosymmetric N-H...S interactions between acid molecules. The complex intermolecular forces acting in characteristic patterns are discussed from the geometric and energetic perspectives, involving Hirshfeld surface analysis, pairwise energy estimation, and natural bond orbital calculations.

Influence of O-H⋅⋅⋅Pt interactions on photoluminescent response in the (Et4N)2{[Pt(bph)(CN)2][phenylene-1,4-diresorcinol]} framework.

Tunable photoluminescence (PL) is one of the hot topics in current materials science, and research performed on the molecular phases is at the forefront of this field. We present the new (Et4N)2[PtII(bph)(CN)2]⋅rez3⋅1/3H2O (Pt2rez3) (bph=biphenyl-2,2'-diyl; rez3=3,3",5,5"-tetrahydroxy-1,1':4',1"-terphenyl, phenylene-1,4-diresorcinol coformer, a linear quaternary hydrogen bond donor) co-crystal salt based on the recently appointed promising [PtII(bph)(CN)2]2- luminophore. Within the extended hydrogen-bonded subnetwork [PtII(bph)(CN)2]2- complexes and rez3 coformer molecules form two types of contacts: the rez3O-H⋅⋅⋅Ncomplex ones in the equatorial plane of the complex and non-typical rez3O-H⋅⋅⋅Pt ones along its axial direction. The combined structural, PL, and DFT approach identified the rez3O-H⋅⋅⋅Pt synthons to be crucial in promoting the noticeable uniform redshift of bph ligand centered (LC) emission compared to the LC emission of the (Et4N)2[PtII(bph)(CN)2]⋅H2O (Pt2) precursor, owing to the direct interference of the phenol group with the PtII-bph orbital system via altering the CT processes within. The high-resolution emission spectra for Pt2 and Pt2rez3 were successfully reproduced at 77 K by using the Franck-Cordon expressions. The possibility to tune PL properties along the plausible continuum of rez3O-H⋅⋅⋅Pt synthons is indicated, considering various scenarios of molecular occupation of the space above and below the complex plane.

A Highly Electrostrictive Salt Cocrystal and the Piezoelectric Nanogenerator Application of Its 3D-Printed Polymer Composite.

Ionic cocrystals with hydrogen bonding can form exciting materials with enhanced optical and electronic properties. We present a highly moisture-stable ammonium salt cocrystal [CH3C6H4CH(CH3)NH2][CH3C6H4CH(CH3)NH3][PF6] ((p-TEA)(p-TEAH)·PF6) crystallizing in the polar monoclinic C2 space group. The asymmetry in (p-TEA)(p-TEAH)·PF6 was induced by its chiral substituents, while the polar order and structural stability were achieved by using the octahedral PF6- anion and the consequent formation of salt cocrystal. The ferroelectric properties of (p-TEA)(p-TEAH)·PF6 were confirmed through P-E loop measurements. Piezoresponse force microscopy (PFM) enabled the visualization of its domain structure with characteristic "butterfly" and hysteresis loops associated with ferro- and piezoelectric properties. Notably, (p-TEA)(p-TEAH)·PF6 exhibits a large electrostrictive coefficient (Q33) value of 2.02 m4 C-2, higher than those found for ceramic-based materials and comparable to that of polyvinylidene difluoride. Furthermore, the composite films of (p-TEA)(p-TEAH)·PF6 with polycaprolactone (PCL) polymer and its gyroid-shaped 3D-printed composite scaled-up device, 3DP-Gy, were prepared and evaluated for piezoelectric energy-harvesting functionality. A high output voltage of 22.8 V and a power density of 118.5 μW cm-3 have been recorded for the 3DP-Gy device. Remarkably, no loss in voltage outputs was observed for the (p-TEA)(p-TEAH)·PF6 devices even after exposure to 99% relative humidity, showcasing their utility under extremely humid conditions.

Synthon Approach in Crystal Engineering to Modulate Physicochemical Properties in Organic Salts of Chlorpropamide.

The formulation of drug with improved bioavailability is always challenging and indispensable in the field of pharmaceutics. The control of intermolecular interactions via crystal engineering approach and solid-state molecular recognition results in the formation of active drug molecules with modulated pharmacological benefits. Therefore, with the aim to improve the solubility and dissolution rate of the drug chlorpropamide (CPA), the mechanochemical liquid-assisted grinding (LAG) of the drug with several pharmaceutically accepted excipients was performed. This contributed to the discovery of six novel solid phases, namely salts, salt cocrystals and salt cocrystal hydrate─the salt of CPA with 3, 4-diaminopyridine (DAP); salt and salt cocrystal (SC) polymorph (Z″=3) with 1, 4-diazabicyclo [2.2.2] octane (DABCO); a salt, SC polymorph (Z″=9), and a SC hydrate (Z″=9) with piperazine (PIP). The formation of these salts and salt cocrystals are mainly guided by the strong hydrogen bonds with tunable strength having high electrostatic contribution. This attractive interaction brings the donor and the acceptor atoms close to each other for a facile proton transfer. Furthermore, the conformational constraints on the drug molecules, provided by the excipients via strong and directional hydrogen bonds, are quite impressive as this leads to the identification and characterization of "new conformational isomers" for the CPA molecules. The new crystalline phases exhibit enhanced intrinsic dissolution rate in comparison to that of the pure drug, the magnitude being 7, 131, and 120 folds for CPADAP, CPADABCO_II, and CPAPIP_III, respectively. Furthermore, it is interesting to note that the order of solubility is enhanced by 2.7-, 3-, and 7-fold, respectively, for the abovementioned salts. This also mirrors the trends in the magnitude of the binding energy, the higher magnitude being reflected in the lower solubility. Additionally, the in vivo experiments performed in SD rats results in the enhancement of the magnitude of the pharmacokinetic properties, when compared to the pristine drug. The concentration of the drug in CPADABCO_II and CPAPIP_III formulations exhibits 6- and 4-fold increments, respectively. Indeed, these results corroborate to the trends observed in the structural characterization, intermolecular energy calculations, solubility, and in vitro dissolution assessments.

Gefitinib salts/cocrystals with phenolic acids as a promising solid-state approach to improve solubility

In this study, we designed and synthesized a series of gefitinib (GEF) salts and cocrystals with phenolic acids, comprising two salts, one cocrystal, and two salt cocrystals. All these forms exhibited significant improvements in solubility compared to pure GEF.

Correction: Chemical shift tensors as probes of chalcogen bonds: solid-state NMR study of telluradiazole-XCN− (X = O, S, Se) salt cocrystals

Correction: Chemical shift tensors as probes of chalcogen bonds: solid-state NMR study of telluradiazole-XCN− (X = O, S, Se) salt cocrystals

A zwitterionic salt–cocrystal: in vitro insights from niraparib tosylate, an anti-cancer drug

Schematic representation showing nomenclature of different cocrystals.

THEDES as a drug product intermediate for improved melt-extrusion processibility of thermally labile active ingredients

Hot melt extrusion (HME) is extensively employed in the pharmaceutical industry, but its utilization of heat raises concerns over drugs’ thermal stability. Strategies to improve stability and processibility of thermolabile materials via salt formation and co-crystals engineering are found in the literature. In this work, it was attempted to use therapeutic deep eutectic solvents (THEDES) as a mean to achieve improved drug thermal stability through the formation of a charge-assisted strong hydrogen boding network. Thermogravimetric studies on THEDES formed using a thermolabile drug, lidocaine, with different non-steroidal anti-inflammatory agents (NSAIDs) were employed to test this hypothesis. The resulted three THEDESs in this study were all tested to be more thermally stable than the corresponding parent compounds, confirming the stabilizing effect from the THEDES bonding network. This investigation reintroduces THEDES as a drug product intermediate with improved processibility for HME.  

Nonlinear and Emissive {[MIII(CN)6]3-···Polyresorcinol} (M = Fe, Co, Cr) Cocrystals Exhibiting an Ultralow Frequency Raman Response.

Optically active functional noncentrosymmetric architectures might be achieved through the combination of molecules with inscribed optical responses and species of dedicated tectonic character. Herein, we present the new series of noncentrosymmetric cocrystal salt solvates (PPh4)3[M(CN)6](L)n·msolv (M = Cr(III), Fe(III), Co(III); L = polyresorcinol coformers, multiple hydrogen bond donors: 3,3',5,5'-tetrahydroxy-1,19-biphenyl, DiR, n = 2, or 5'-(3,5-dihydroxyphenyl)-3,3″,5,5″-tetrahydroxy-1,19:3',1″-terphenyl, TriRB, n = 1) denoted as MDiR and MTriRB, respectively. The hydrogen-bonded subnetworks {[M(CN)6]3-;Ln}∞ of dmp, neb, or dia topology are formed through structural matching between building blocks within supramolecular cis-bis(chelate)-like {[M(CN)6]3-;(H2L)2(HL)2} or tris(chelate)-like {[M(CN)6]3-;(H2L)3} fragments. The quantum-chemical analysis demonstrates the mixed electrostatic and covalent character of these interactions, with their strength clearly enhanced due to the negative charge of the hydrogen bond acceptor metal complex. The corresponding interaction energy is also dependent on the geometry of the contact and size matching of its components, rotational degree of freedom and extent of the π-electron system of the coformer, and overall fit to the molecular surroundings. Symmetry of the crystal lattices is correlated with the local symmetry of coformers and {complex;(coformer)n} hydrogen-bonded motifs characterized by the absence of the inversion center and mirror plane. All compounds reveal second-harmonic generation activity and photoluminescence diversified by individual UV-vis spectral characteristics of the components, and interesting low-frequency Raman scattering spectra within the subterahertz spectroscopic domain. Vibrational (infrared/Raman), UV-vis electronic absorption (experimental and calculated), and 57Fe Mössbauer spectra together with electrospray ionization mass spectrometry (ESI-MS) data are provided for the complete description of our systems.

Ionic salt cocrystals studied via multinuclear solid-state magnetic resonance: a case study of lithium 4-methoxybenzoate:L-proline polymorphs

Lithium salts continue to find pharmaceutical applications, particularly as psychiatric medications. As with any active pharmaceutical ingredient, structural polymorphism is an important concern for lithium-based medications that can influence solubility and other physicochemical properties. Here we report a 13C, 1H, and 7Li magic-angle spinning solid-state nuclear magnetic resonance (MAS SSNMR) study of two 1:1 polymorphic ionic cocrystals of lithium 4-methoxybenzoate and L-proline (L4MPRO(α) and L4MPRO(β)). One-dimensional 13C cross-polarization MAS and two-dimensional heteronuclear correlation NMR spectra hint at differential mobilities of the proline and benzoate moieties for the two polymorphs. Five key resonances differ in 13C chemical shift by more than 1 ppm between the two polymorphs, clearly distinguishing between them. Gauge-including projector-augmented-wave density functional theory calculations of 13C and 1H magnetic shielding constants correlate strongly with the experimental chemical shifts for both polymorphs. R2 and root-mean-square deviation metrics are shown to be insufficient in the case of 13C, but sufficient in the case of 1H, for differentiating between the polymorphs. 7Li satellite-transition MAS NMR of both polymorphs are identical, as are the computed lithium magnetic shielding constants, demonstrating the insensitivity of 7Li NMR to polymorphism in these samples. This work highlights the utility of solid-state NMR spectroscopy for examining ionic salt cocrystals and also highlights some caveats in this regard.

Cocrystallization-Driven Double-Optimized Stratagem toward Directional Self-Assembly for the First Ternary Salt Cocrystal of Cardiotonic Drug Milrinone with Different Phenolic Acids Exhibits Optimal In Vitro/Vivo Biopharmaceutical Peculiarities.

The current research leverages the structural features and property superiorities along with benefits in protecting cardiovascular system of gallic acid (GLC) and gentisic acid (HGA) to optimize in vitro/vivo peculiarities of cardiotonic drug milrinone (MIL) through developing a stratagem of cocrystallization-driven double-optimized ternary salt cocrystal. This strategy assembles MIL ternary salt cocrystal by shaping a cocrystallization moiety relying on noncovalent interplays with GLC to obtain permeability advancement and molding a salt segment via the salification of proton transfer between HGA and MIL molecules to facilitate solubility enhancement. While the ameliorative in vitro properties further modulate the in vivo pharmacokinetic behaviors, thus fulfilling a dual optimization of MIL's biopharmaceutical characteristics on both in vitro and in vivo aspects. Along this line, the first MIL ternary salt cocrystal, viz., [HMIL+-GA-]-MIL-GLC-H2O (denoted as MTSC hereinafter), has been satisfactorily constructed and precisely structurally identified by diversified techniques. The single-crystal X-ray diffraction experiment validates that a molecular salt [HMIL+-GA-] species cocrystallizes with one neutral MIL, two GLC, and five solvent water molecules, among which the organic constituents compose laminated hydrogen bond networks, and then are self-assembled by water molecules to a 3D supramolecular structure. The unique structural feature and stacking pattern of MTSC make both the permeability and solubility be respectively enhanced by 9.69 times and 5.17- to 6.03-fold compared with the parent drug per se. The experimental outcomes are powerfully supported by associated calculations based on density functional theory. Intriguingly, these optimal in vitro physicochemical natures of MTSC have been potently converted into strengths of in vivo pharmacokinetics, showcasing the elevated drug plasma concentration, elongated half-life, alongside advanced bioavailability. Consequently, this presentation not just contributes a brand-new crystalline form with utility values, but ushers in a new dimension of ternary salt cocrystals for improving in vitro/vivo limitations of poor drug bioavailability.

A method for improving the properties of famotidine

According to crystal engineering, the pharmaceutical intermediate m-nitrobenzoic acid (MNBA), which contains a carboxylic acid group, was selected as a coformer (CCF) for drug cocrystallization with famotidine (FMT), and a new stable FMT salt cocrystal was synthesized. The salt cocrystals were characterized by scanning electron microscopy, differential scanning calorimetry, thermogravimetric analysis, infrared spectroscopy, powder X-ray diffraction and X-ray single crystal diffraction. A single crystal structure of FMT–MNBA (1:1) was successfully obtained, and then the solubility and permeability of the newly synthesized salt cocrystal were studied. The results showed that, compared with free FMT, the FMT from the FMT–MNBA cocrystal showed improved permeability. This study provides a synthetic method to improve the permeability of BCS III drugs, which will contribute to the development of low-permeability drugs.

Approach to Di/Triorganotin(IV) Cations via Hydrolysis of Stannate Salts Bearing Alkanesulfonate Ligands

An in-depth study of the class of organotin cations bearing weakly coordinating trifluoromethanesulfonate/arylsulfonate has led to key insights into their stability, structural aspects, and role as catalysts. Related chemistry with alkanesulfonate ligands remains a missing link due to the strong Sn-O bond. The study reported herein describes the scope of diorganostannates, [n-Bu4N][R2Sn(OSO2R1)3] (R = n-Bu, R1 = Me(1), Et(2); R = Ph, R1 = Me(3)), as reactive substrates in the presence of adventitious water to afford [n-Bu2SnOH(OSO2Me)] (4), [n-Bu2Sn(H2O)4][n-Bu4N][OSO2Et]3·H2O (5), and [Ph2Sn(H2O)4][n-Bu4N]2[OSO2Me]4 (6), respectively, the latter two being the first examples of salt cocrystals comprising tetra(aqua)diorganotin cations. Hydrolysis of 3 in the presence of 1,4-bis((1H-imidazol-1-yl)methyl)benzene (bix) as the N-donor ligand proceeds via disproportionation and yields [Ph3Sn(bix)](OSO2Me) (7) along with an insoluble solid, likely derived from the hydrolysis of PhSn(OSO2Me)3. Direct evidence of this phenomenon can be gleaned from ESI-MS of 3, which identifies mass clusters corresponding to [Ph3Sn(OSO2Me)2]- and [PhSn(OSO2Me)3-H+]-. X-ray crystallographic studies of 1-7 are reported to establish their structural identity and the role of alkanesulfonate anions in the formation of supramolecular assemblies.

Chemical shift tensors as probes of chalcogen bonds: solid-state NMR study of telluradiazole-XCN− (X = O, S, Se) salt cocrystals

We report experimental 125Te magic-angle spinning solid-state nuclear magnetic resonance (MAS NMR) measurements of the tellurium chemical shift (CS) tensors in three [K(18-crown-6)]+ 3,4-dicyano-1,2,5-telluradiazole-XCN− (X = O, S, Se) salt cocrystals featuring chalcogen bonds. These data are compared to those for pure 3,4-dicyano-1,2,5-telluradiazole (1). A reduction in the span of the 125Te CS tensor is consistently noted in the salt cocrystals compared to pure 1. Isotopically 15N-labelled [K(18-crown-6)]+[1-OC15N]−, which features a chalcogen bond between Te and the cyanate nitrogen atom, is synthesized using KOC15N, and the nitrogen CS tensors are measured for both samples via 15N slow MAS NMR spectroscopy. Possible dynamic disorder of the cyanate ions in KOCN is ruled out. Two crystallographically distinct nitrogen sites are resolved for the salt cocrystal. Upon formation of [K(18-crown-6)]+[1-OC15N]−, the 15N isotropic CS and CS tensor span both decrease relative to the values for pure KOC15N, and the axial symmetry of this tensor is lost. These findings are supplemented with a series of density functional theory calculations of magnetic shielding tensors using cluster models or periodic boundary conditions. Inclusion of spin–orbit relativistic effects in the calculation of tellurium shielding tensors is particularly important in achieving agreement with experiment.

Improving Solubility and Avoiding Hygroscopicity of Tetrahydropalmatine by Forming a Pharmaceutical Salt Cocrystal via CAHBs

AbstractIn order to improve the solubility of tetrahydropalmatine (THP), an unreported THP‐sulfosalicylic acid (THP‐SSA) pharmaceutical salt cocrystal is designed and synthesized. Structural analysis shows that the building unit of THP‐SSA is composed of two THP cations, two SSA anions and one ethyl acetate molecule. Meanwhile, 1D chain, 2D layered structure, 3D hydrogen bond network, and Supramolecular motif R1110(48) of THP‐SSA are connected by stable charge‐assisted hydrogen bonds (CAHBs) N+‐H···O‐, π–π packing, and hydrogen bond. As expected, the maximum solubility of THP‐SSA in water is about 60 times that of THP, probably due to the protonation of the N atom on the piperidine ring in THP forms a pharmaceutical salt cocrystal, which greatly improves the solubility of THP. However, to the surprise, the hygroscopicity of THP‐SSA is also effectively reduced compared with THP, probably because the hydrogen bonds between THP and SSA have been formed, preventing the entry of water molecules. In addition, THP‐SSA also has higher antibacterial activity than THP. This suggests that forming a pharmaceutical salt cocrystal by cocrystal technology can not only improve the solubility of THP and avoid the hygroscopic property, but also improve the antibacterial activity of THP in vitro.

Crystal Structure of a New 1:1 Acridine-Diclofenac Salt, Obtained with High Yield by a Mechanochemical Approach

The liquid-assisted grinding (LAG) approach was exploited to efficiently produce a new salt cocrystal with a minimum expenditure of reagents and energy, with possible application in the pharmaceutical field. LAG was applied to the acridine/diclofenac couple, and a new cocrystal was obtained with a 1:1 ratio of reagents and its structure resolved by X-ray powder diffraction (XRPD). The XRPD analysis confirmed that the yield is higher than 90% and the limited use of solvents and the absence of waste generally makes the synthesis very efficient and with the minimum possible environmental impact. The crystal structure of the title compound was compared to a previously solved 1:2 cocrystal, also with the aid of Hirshfeld’s surface analysis and calculations of the energy framework. The packing of the 1:1 structure is stabilized by a strong H-bond and partial π⋯π-stacking interactions. It differs considerably from that of the previously identified cocrystal, in which two strong hydrogen bonds and a perfect interlocking of the molecules thanks to the the π⋯π stacking induce a much higher stability, as confirmed by energy framework calculations. DSC analysis confirmed its purity and a melting point at 140 °C, which is different from those of the two reactants.

Directional Self-Assembly of Ofloxacin and Syringic Acid: The First Salt Cocrystal of Ofloxacin with Phenolic Acid Displays Superior In Vitro/Vivo Biopharmaceutical Property and Enhanced Antibacterial Activity

A cocrystallization tactic of double optimization and synergistic enhancement efficacy has been proposed, aiming at maximizing the benefits of phenolic acid nutriment syringic acid (HSA) to perfect biopharmaceutical features of antibacterial drug ofloxacin (OA). This strategy utilizes the salt-forming function and cocrystallization ability of HSA interplaying with OA to assemble into a salt cocrystal, thus ameliorating OA’s physicochemical properties in vitro, which, in turn, can optimize its pharmacokinetic characteristics in vivo, making OA’s pharmaceutical peculiarities be doubly optimized on both in vivo and in vitro levels. Ulteriorly, the antibacterial potency of OA is heightened by stimulating the auxiliary antibacterial ability of HSA, fulfilling the cooperativeness of OA and HSA in antibacterial efficacy. Taking this tactic as orientation, the first OA– nutriment salt cocrystal, viz., [HOA+-SA–]-HSA-H2O, is directionally synthesized and structurally identified. Single-crystal X-ray diffraction substantiates that the salt cocrystal has a bilayer hole structure, wherein, a hexahelical hydrogen-bonding motif of [HOA+-SA–] salts situates outside with a double spiral of neutral HSA and H2O molecules inside, thus endowing the salt cocrystal with the capacity to simultaneously enhance solubility and permeability compared with OA itself, which achieves positive correlations with theoretical investigations. Intriguingly, the strengthened in vitro properties of the salt cocrystal have been effectually turned into in vivo pharmacokinetic advantages, displaying an advanced peak plasma concentration and protracted half-life along with raised relative bioavailability. More meaningfully, the antibacterial capacity of the salt cocrystal has also attained significant enhancement owing to the congenerous antibacterial action of OA and HSA. Therefore, this investigation not only offers a novice strategy for optimizing in vitro/vivo pharmaceutical characteristics and concurrently elevating antibacterial efficacy of OA through formation of the salt cocrystal but also fulfills a breakthrough in developing new salt cocrystal systems of antibacterial drugs.

Improving the solubility, hygroscopicity and permeability of enrofloxacin by forming 1:2 pharmaceutical salt cocrystal with neutral and anionic co-existing p-nitrobenzoic acid

With the purpose of improving the solubility and reducing the hygroscopicity of enrofloxacin (ENR), an unreported pharmaceutical salt cocrystal of enrofloxacin with both neutral and anionic p-nitrobenzoic acid (PNB) (ENR-PNB, C19H23FN3O3·C7H4NO4·C7H5NO4) was designed and synthesized by changing the reaction molar ratio (1:2) of ENR and coformer PNB on the basis of summarizing the past experience of our group, and its crystal structure was characterized. Single-crystal X-ray diffraction (SCXRD) analysis revealed that the salt cocrystal consists of ENR+, PNB− and PNB neutral molecule in a 1:1:1 ratio. The two asymmetric units that become centrosymmetric form an X-shaped structure centered on the ENR dimer R22(20). The adjacent X-shaped structures are interconnected by hydrogen bonds to form 1D chain and form the octamer R88(42) at the same time. As we expected, the formation of the salt cocrystal ENR-PNB results in a simultaneous improvement in the solubility and hygroscopicity of ENR. This may be the fact that ENR and PNB depend on CAHBs to raise the hydrous enthalpy of salt cocrystal. And the presence of PNB neutral molecules lower hygroscopicity of ENR in high humidity environments. Unexpectedly, the permeability of ENR-PNB was also increased compared to that of pure ENR. It is speculated that the number of polar sites in the system is greatly reduced because of hydrogen bonds formation, which increases the permeability of the ENR salt cocrystal. In addition, the in vitro antibacterial activities of ENR-PNB are enhanced at different concentrations compared to ENR. The present study implies that it is possible to improve the solubility, hygroscopic stability, permeability and antibacterial activity of enrofloxacin by changing the chemical reaction molar ratio to form salt cocrystal containing both neutral and anionic coformers, which provides a new strategy and insight to simultaneously improve the solubility and hygroscopicity and even permeability of the active ingredients of solid drugs.

Physicochemical aspects and comparative analysis of Voxelotor and its salt and cocrystal

Voxelotor (VOX) is a BCS (Biopharmaceutical classification system) Class II drug (poor solubility and high permeability) and is issued for the treatment of sickle cell disease. The VOX free base, VOX-HCl salt and succinic acid (VOX-SC) cocrystals were crystallized and their crystal structures were determined by the Single Crystal X-ray diffraction technique (SCXRD). Further, solid-state characterization techniques such as Nuclear magnetic resonance (NMR) and Fourier transform Infra-red spectroscopy(FT-IR) were carried out. In all three structures, the VOX molecules exhibit an intramolecular S(6)-motif formed by O-H⋅⋅⋅O hydrogen bond. In VOX free base, only weak C-H⋅⋅⋅O, C-H⋅⋅⋅π and π⋅⋅⋅π interactions were observed, which lead to the formation of two-dimensional hydrogen-bonded sheets. In VOX-HCl salt, N-H⋅⋅⋅Cl hydrogen bond along with the C-H⋅⋅⋅π and π⋅⋅⋅π interactions form a discrete dimeric unit. In VOX-SC cocrystal, the VOX and SC molecules were connected through N-H⋅⋅⋅O, O-H⋅⋅⋅O and C-H⋅⋅⋅O interactions and generate a two-dimensional hydrogen-bonded network. Thermal analysis of VOX-SC cocrystal resulted in melting points intermediate to that of API and coformer, while VOX-HCl salt yielded a higher melting point than the parent VOX. Both VOX-HCl and VOX-SC cocrystal showed better solubility compared to VOX free base. The stress analysis revealed that in VOX-SC cocrystal, no physical transformations of solid-phase was observed. Enhancement in solubility and stability was observed in the obtained VOX-SC cocrystal in comparison to the free base.