Synthesis of cocrystals of sulfonyl urea class drug using suitable coformers for enhancement of aqueous solubility

The pharmaceutical cocrystals and its engineering is widely accepted phenomenon regarding to the enhancement of aqueous solubility of poorly soluble drugs. The pharmaceutical cocrystals have the great ability to improve the physicochemical properties of drug substance. Cocrystals are formed by the stoichiometric combination of drug substance and the coformer. The drug glimepiride is a third generation oral hypoglycemic sulfonylurea class. Glimepiride is a drug which is get classified as biopharmaceutical classification system (BCS) class II which indicates the glimepiride having low aqueous solubility and high permeability. Cocrystal engineering is a perfect way to increases glimepiride solubility without changing its therapeutic property. The cocrystals were synthesized by the solvent drop grinding as a green chemistry approach. The coformers used to form the cocrystals are succinic acid (SA), Theobromine (TB), caffeine (CF). The synthesized cocrystals are get characterized by vibrational spectroscopy, thermal analysis, molecular crystallography, and optical microscopy. The obtained results shows the formation of cocrystal phase between the drug glimepiride and its coformers.

Drug-drug cocrystals:Opportunities and challenges

Recently,drug-drug cocrystal attracts more and more attention.It offers a low risk,low-cost but high reward route to new and better medicines and could improve the physiochemical and biopharmaceutical properties of a medicine by addition of a suitable therapeutically effective component without any chemical modification.Having so many advantages,to date,the reported drug-drug cocrystals are rare.Here we review the drug-drug cocrystals that reported in last decade and shed light on the opportunities and challenges for the development of drug-drug cocrystals.

NIR-II Organic Photothermal Cocrystals with Strong Charge Transfer Interaction for Flexible Wearable Heaters

The organic cocrystal strategy has provided a convenient and efficient platform for preparing organic photothermal materials.However,the rapidly directional preparation of cocrystals with desirable photothermal properties remains challenging due to a lack of suitable design ideas.Here,two new photothermal cocrystals,MTC and MFC,based on acceptor molecules(TCNQ and F4TCNQ)with different electron-withdrawing capacities were quickly prepared by the coprecipitation method,aiming to explore the effect of charge transfer(CT)interaction on photothermal properties.Compared with MTC,the stronger intermolecular CT interaction in MFC facilitates extending the absorption range(from the NIR-I to the NIR-II region)and enhancing the non-radiative transition process.Under the 808 nm laser irradiation,the photothermal conversion efficiency(PCE)of MFC is 54.6%,whereas MTC displays a mere 36.8%.The MFC cocrystal was further combined with a flexible polymer substrate(HPDMS)to prepare a flexible wearable heater(HPDMS@MFC),which exhibits excellent NIR-II photothermal performance.This work points out a research direction for the rapid assembly of efficient photothermal cocrystals and additionally provides an extensive application prospect for organic photothermal cocrystals in the field of wearable devices.

Cocrystals of carbamazepine:Structure,mechanical properties,fluorescence properties,solubility,and dissolution rate

Carbamazepine(CBZ)is an anticonvulsant with very low water solubility,presenting as a white crystalline powder with poor mechanical properties and is hard to bend.To enhance CBZ's physicochemical properties,such as water solubility and mechanical properties,we selected six cocrystal coformers(CCFs):nicotinamide(NIC),benzamide(BZM),salicylic acid(SCA),fumaric acid(FMA),trimesic acid(TMA),and hesperetin(HPE).Six CBZ cocrystals were successfully prepared using the solution method.Fourier transform infrared spectroscopy(FT-IR),powder X-ray diffraction(PXRD),differential scanning calorimetry(DSC),and single crystal X-ray diffraction(SCXRD)were used to characterize the crystal structures and gain comprehensive insights into the six cocrystals.The mechanical,fluorescence,and solubility properties of the six cocrystals were tested.The results reveal that most of the prepared cocrystals exhibit improved water solubility and mechanical properties when compared to CBZ.Among them,the dissolution rate of cocrystals excluded from CBZ-HPE has increased by an average of 3 or 4 times compared to CBZ,while CBZ-HPE exhibits superior mechanical properties.Moreover,all six cocrystals possess better fluorescence performance than CBZ.We thoroughly evaluated the mechanical properties of the cocrystals through both experimental and theoretical approaches.This work provides a new direction for studying drug cocrystals to improve the physicochemical properties of drugs.

Organic stoichiometric cocrystals with a subtle balance of charge-transfer degree and molecular stacking towards high-efficiency NIR photothermal conversion

Charge-transfer(CT)stoichiometric cocrystals are promising choice of organic materials for unveiling the structure-property relationship.However,due to the contradiction between large CT degree required for strong NIR absorption and flexible molecular stacking,construction of stoichiomorphism-based cocystals with near-infrared(NIR)photothermal property remains challenging.Herein,the first example of stoichiomorphism-based photothermal cocrystals were accomplished through the adaptive assembly of 3,3,5,5-tetramethylbenzidine(TMB)donor and 1,2,4,5-tetracyanobenzene(TCNB)acceptor.The selective cocrystallization could be controlled by varying the donor-acceptor stoichiometries via a surfactantassisted method,resulting in two cocrystals with 1:1(T1C1)and 1:2(T2C1)stoichiometries.The absorbance intensity of T1C1 at 808 nm was nearly twice that of T2C1,while the photothermal conversion efficiency(PCE)of the former was 60.3%±0.6%,approximately 80%of that for the latter(75.5%±2.6%),which might be caused by the different intermolecular interactions in distinct molecular stacking patterns.Notably,both excellent PCEs of stoichiometric cocrystals were attributed to the nonradiative transition process,including internal conversion and charge dissociation processes,as elucidated by femtosecond transient absorption spectroscopy measurements.Furthermore,T1C1 was used as an NIR heater for preparing agarose-based photothermal hydrogel,showing great potential for light-controlled in-situ gelation.This strategy of balancing the CT degree and molecular packing orientation not only uncovered the relationship between stoichiometric stacking and photothermal property,but also provided an opportunity to develop advanced organic optoelectronic materials.

Organic cocrystals:From high-performance molecular materials to multi-functional applications

Advancements in organic electronics are propelling the development of new material systems,where organic materials stand out for their unique benefits,including tunability and cost-effectiveness.Organic single crystals stand out for their ordered structure and reduced defects,enhancing the understanding of the relationship between structure and performance.Organic cocrystal engineering builds upon these foundations,exploring intermolecular interactions within multicomponent-ordered crystalline materials to combine the inherent advantages of single-component crystals.However,the path to realizing the full potential of organic cocrystals is fraught with challenges,including structural mismatches,unclear cocrystallization mechanisms,and unpredictable property alterations,which complicate the effective cocrystallization between different molecules.To deepen the understanding of this promising area,this review introduces the mechanism of organic cocrystal formation,the various stacking modes,and different growth techniques,and highlights the advancements in cocrystal engineering for multifunctional applications.The goal is to provide comprehensive guidelines for the cocrystal engineering of highperformance molecular materials,thereby expanding the applications of organic cocrystals in the fields of optoelectronics,photothermal energy,and energy storage and conversion.

Pharmaceutical cocrystals: A review of preparations, physicochemical properties and applications

Pharmaceutical cocrystals are multicomponent systems in which at least one component is an active pharmaceutical ingredient and the others are pharmaceutically acceptable ingredients.Cocrystallization of a drug substance with a coformer is a promising and emerging approach to improve the performance of pharmaceuticals,such as solubility,dissolution profile,pharmacokinetics and stability.This review article presents a comprehensive overview of pharmaceutical cocrystals,including preparation methods,physicochemical properties,and applications.Furthermore,some examples of drug cocrystals are highlighted to illustrate the effect of crystal structures on the various aspects of active pharmaceutical ingredients,such as physical stability,chemical stability,mechanical properties,optical properties,bioavailability,sustained release and therapeutic effect.This review will provide guidance for more efficient design and manufacture of pharmaceutical cocrystals with desired physicochemical properties and applications.

Cocrystal engineering:towards high-performance near-infrared organic phototransistors based on donor-acceptor charge transfer cocrystals

Near-infrared organic phototransistors have wide application prospects in many fields.The active materials with the high mobility and near-infrared response are critical to building high-performance near-infrared organic phototransistors,which are scarce at present.Herein,a new charge transfer cocrystal using 5,7-dihydroindolo[2,3-b]carbazole(5,7-ICZ)as the donor and 2,2’-(benzo[1,2-b:4,5-b’]dithiophene-4,8-diylidene)dimalononitrile(DTTCNQ)as the acceptor is properly designed and prepared in a stoichiometric ratio(D:A=1:1),which not only displays a high electron mobility of 0.15 cm^(2)V^(-1)s^(-1) and very low dark current,but also can serve as the active layer materials in the region of near-infrared detection due to the narrowed band gap and good charge transport properties.A high photosensitivity of 1.8×10^(4),the ultrahigh photoresponsivity of 2,923 A W-1and the high detectivity of 4.26×10^(11)Jones of the organic near-infrared phototransistors are obtained.

The smart precursors of energetic–energetic cocrystals from eutectic precursors

The selected 18 energetic compounds were theoretically investigated by using the density functional theory（DFT） quantum mechanical code,DMol3,and the Hansen solubility parameters（HSPs） analyses.The results showed that 4-nitrotoluene,4-nitrophenol,N N0-dimethyl-N N0-diphenylurea and N N0-diethyl-N N0-diphenylurea contain relatively electron-rich aromatic rings.Four satisfactory energetic precursors with electron-rich rings were quickly and effectively found by electrostatic potential（ESP）surfaces and HSPs analyses.The results also indicated that the absolute value of the lowest unoccupied molecular orbital（LUMO） of the energetic precursors with electron-rich rings often was less than3.00 eV,and the absolute value of LUMO of the energetic precursors with electron deficient rings was often more than 3.00 eV.Additionally,we found that with at least two eutectic points was a prerequisite for two precursors to form a cocrystal.

The effects of pH, surfactant, ion concentration,coformer, and molecular arrangement on the solubility behavior of myricetin cocrystals

Pharmaceutical cocrystals are a promising technology that can be used to improve the solubility of poor aqueous compounds. The objective of this study was to systematically investigate the solubility of myricetin(MYR) cocrystals, including their kinetic solubility, thermodynamic solubility, and intrinsic dissolution rate(IDR). The effects of pH, surfactant, ion concentration, and coformers on the cocrystal solubility were evaluated. Furthermore, single crystal structures of MYR, myricetin–isonicotinamide(MYR–INM) and myricetin–caffeine(MYR–CAF) cocrystals were analyzed to discuss the possible reasons for the enhancement of cocrystal solubility from the perspective of the spatial structure.The results indicated that the kinetic solubility of MYR cocrystals was modulated by pH and cocrystal coformer(CCF) ionization in buffer solution, while it primarily depended on the CCF solubility in pure water. In addition, the solubility of MYR cocrystals was increased in a concentration dependent fashion by the surfactant or ion concentration. The thermodynamic solubility of MYR–INM(1:3) cocrystals decreased with the increases of the pH value of the dissolution media. The IDR of MYR cocrystals was faster than that of MYR in the same medium and extremely fast in pH 4.5 buffer. The improved solubility of MYR cocrystals was probably related to the alternate arrangements of MYR and INM/CAF molecules and increased intermolecular distance. The present study provides some references to investigate the solubility behavior of pharmaceutical cocrystals.

Organic cocrystals:the development of ferroelectric properties

Organic cocrystals are crystalline,single-phase materials composed of two or more molecular and/or ionic compounds,generally,in a stoichiometric ratio.A feature of organic cocrystals is that special optoelectronic properties such as ferroelectricity are easy to realize in these materials.In this perspective,we systematically introduce the recent research advances in organic cocrystal ferroelectrics,and we study in depth the molecular structure and self-assembling behaviors of cocrystals for ferroelectric applications.Finally,combined with an understanding of recent progress and achievements in this field,we discuss the challenges and opportunities for ferroelectric materials based on organic cocrystals,as well as the promising applications of these materials.

Polymorph and anisotropic Raman spectroscopy of Phz-Hca cocrystals

The nucleation and growth mechanism and polymorph-property correlations in the molecular cocrystal field are widely sought but currently remain unclear. Herein, a new wire-like morphology of phenazine(Phz)-chloranilic acid(H2ca) cocrystal(PHC) is demonstrated for the first time, and the self-assembly of Phz and H2ca is controlled to selectively prepare kinetically stable wires and thermodynamically stable plates. Specifically, low precursor concentration is beneficial for one-dimensional(1D) self-assembly along the [010] crystallographic direction, while only supersaturation can trigger 2D self-assembly along the [100] and [010] directions, respectively. This is understandable in terms of the(020) face showing the largest attachment energy(Eatt) and the(002) face possessing the smallest surface energy(Esurf). Moreover, anisotropic Raman spectra related to the mode symmetry and atomic displacements in two types of PHCs are revealed, and the same Raman-active vibrational bands of PHC wire and plate show different polarization responses, which is intrinsically ascribed to their different molecular orientations.Overall, this is the first case that morphologies of cocrystal are precisely tuned with comprehensive investigations of their anisotropic vibrational characteristics.

A nano-cocrystal strategy to improve the dissolution rate and oral bioavailability of baicalein

Baicalein(BE) is one of the main active flavonoids representing the variety of pharmacological effects including anticancer, anti-inflammatory and cardiovascular protective activities, but it's very low solubility, dissolution rate and poor oral absorption limit the therapeutic applications. In this work, a nano-cocrystal strategy was successfully applied to improve the dissolution rate and bioavailability of BE. Baicalein-nicotinamide(BE-NCT) nanococrystals were prepared by high pressure homogenization and evaluated both in vitro and in vivo. Physical characterization results including scanning electron microscopy, dynamic light scattering, powder X-ray diffraction and differential scanning calorimetry demonstrated that BE-NCT nano-cocrystals were changed into amorphous state with mean particle size of 251.53 nm. In the dissolution test, the BE-NCT nano-cocrystals performed 2.17-fold and 2.54-fold enhancement than BE coarse powder in FaSSIF-V2 and FaSSGF. Upon oral administration, the integrated AUC0-t of BE-NCT nano-cocrystals(6.02-fold) was significantly higher than BE coarse powder(1-fold), BE-NCT cocrystals(2.87-fold) and BE nanocrystals(3.32-fold). Compared with BE coarse powder, BE-NCT cocrystals and BE nanocrystals, BENCT nano-cocrystals possessed excellent performance both in vitro and in vivo evaluations.Thus, it can be seen that nano-cocrystal is an appropriate novel strategy for improving dissolution rate and bioavailability of poor soluble natural products such as BE.

Crystal Structures, Stability, and Solubility Evaluation of a 2:1 Diosgenin-Piperazine Cocrystal

A cocrystal of diosgenin with piperazine in 2:1 stoichiometry was successfully synthesized.The solid form was prepared by liquid assisted grinding,slurry and crystallization methods.The cocrystal was characterized by powder X-ray diffraction,differential scanning calorimetry,thermogravimetric analysis,Fourier transform infrared spectroscopy,and structure determined by single crystal X-ray diffraction,the hydrogen bonds formed into fish bone structure along the[010]direction and all the molecules packed into 3D layer structure along a axis.After formation of cocrystal,the solubility of diosgenin was improved,and the solubility value in 0.2%SDS solution was approximately 1.5 times as large as that of the parent material.

Theoretical predict structure and property of the novel CL-20/2,4-DNI cocrystal by systematic search approach

Cocrystallization integrates the merits of high energy and insensitivity between energetic molecules to obtain energetics with satisfying performance.However,how to obtain supramolecular synthons accurately and rapidly for predicting the structure and property of cocrystal remains a challenging problem.In this research,an efficient systematic search approach to predict CL-20/2,4-DNI cocrystal has been proposed that 2,4-DNI revolves around CL-20 with a stoichiometric ratio of 1:1 in accordance with the specified rules(hydrogen bond length:2.2-3.0 Å;search radius:6.5 Å;the number of hydrogen bond:1-3).Eight possible supramolecular synthons were obtained by combining quantum chemistry with molecular mechanics.Crystal structure prediction indicated that there are four structures in cocrystal,namely P21/c,P212121,Pbca and Pna21,and CL-20/2,4-DNI cocrystal is likely to be P21/c and the corresponding cell parameters are Z=4,a=8.28 Å,b=12.17 Å,c=20.42 Å,α=90°,β=96.94°,γ=90°,and ρ=1.9353 g/cm^(3).To further study the intermolecular interaction of CL-20/2,4-DNI cocrystal,a series of theoretical analyses were employed including intermolecular interaction energy,electrostatic potential(ESP),Density of State(DOS),Hirshfeld surface analysis.The C-H…O hydrogen bonds are demonstrated as the predominant driving forces in the cocrystal formation.The mechanical properties and detonation properties of CL-20/2,4-DNI cocrystal implies that the cocrystal shows better ductility and excellent detonation performances(9257 m/s,39.27 GPa)and can serve as a promising energetic material.Cocrystal structure predicted was compared with the experimental one to verify the accuracy of systematic search approach.There is a less than 8.8%error between experiment and predict results,indicating the systematic search approach has extremely high reliability and accuracy.The systematic search approach can be a new strategy to search supramolecular synthons and identify structures effectively and does have the potential to promote the development of energetic cocrystal by theoretical design.

Intermolecular Interactions, Thermodynamic Properties, Detonation Performance, and Sensitivity of TNT/CL-20 Cocrystal Explosive

Intermolecular interactions and properties of TNT（2,4,6-trinitrotoluene）/CL-20（2,4,6,8,10,12-hexanitrohexaazaisowurtzitane） cocrystal were studied by density functional theory（DFT） methods. Binding energy, natural bond orbital（NBO）, and atom in molecules（AIM） analysis were performed to investigate the intermolecular interactions in the cocrystal. Results show that the unconventional CH···O type hydrogen bond plays a key role in forming the cocrystal. The variation tendency of entropy and enthalpy shows that the formation of the cocrystal is an exothermic process and low temperature will be benefit for the assembling of complexes. The calculated detonation velocity of the cocrystal agrees well with the experimental value which is higher than that of the physical mixture of TNT and CL-20. In addition, bond dissociation energies（BDEs） of the weakest trigger bond in TNT/CL-20 complex were calculated and the results show that the TNT/CL-20 complex is thermally stable. Finally, first-principles calculations were performed and analysis of the nitro group Mulliken charge indicates that the cocrystal is less sensitive than pure CL-20.

Crystal Structure and Characterization of Salicylic Acid-benzene Azimide Cocrystal

A new single crystal of 1：1 salicylic acid-benzene azimide was determined and cha-racterized. It belongs to space group P21/n with a = 13.8085（13）, b = 5.3846（4）, c = 16.7063（13） A and β = 102.331（9）°. Crystals of the title compound, C7H6O3·C6H5N3, were obtained by cocrys- tallization. FT-IR, Raman spectroscopy and TGA-DTA were applied to characterize the title compound as supplemental evidence to prove the formation of the crystal. Our work describes the solubility of the crystal by considering the equilibria between the crystal, components, and solution mixture.

Crystal Structure, Hirshfeld Surface Analysis and Quantum Mechanical Study of a Cocrystal Based on 1,3-Di（4-pyridyl）propane and 3-（（4~′-Carboxybenzyl）oxy） Benzoic Acid

A cocrystal based on 1,3-di（4-pyridyl）propane and 3-（（4′-carboxybenzyl）oxy）benzoic acid,C13H14N2·C15H12O5,has been synthesized and characterized by single-crystal X-ray diffraction.The compound crystallizes in monoclinic,space group P21 /c with a = 11.639（4）,b = 9.808（3）,c = 20.854（6）,β = 91.242（7）°,V = 2380.0（13）3,C28H26N2O5,Mr = 470.51,Dc = 1.313 g/cm3,μ（MoKα） = 0.091 mm-1,F（000） = 992,Z = 4,the final R = 0.0677 and wR = 0.1477 for 4175 observed reflections（I 2σ（I））.Intermolecular N H···O hydrogen bonds link two kinds of components into a one-dimensional chain in [10-1] direction and adjacent chains are further arranged into a two-dimensional network by π···π and C H···π interactions.Investigation of intermolecular interactions and crystal packing via Hirshfeld surface analysis reveals that the close contacts are mainly focused on weak interactions.The theoretical investigations with HF/6-31G（d） method were performed,and its stability,frontier molecular orbital composition and Mulliken charge distribution were also discussed.

Theoretical Insight into the Influence of Molecular Ratio on the Stability, Mechanical Property, Solvent Effect and Cooperativity Effect of HMX/DMI Cocrystal Explosive

Molecular dynamics method was employed to study the binding energies of the selected crystal planes of the 1,3,5,7-tetranitro-1,3,5,7-tetrazacyclooctane（HMX）/1,3-dimethyl-2-imidazolidinone（DMI） cocrystal in different molecular molar ratios. The mechanical properties were estimated in different molar ratios. Solvent effects were evaluated and the cooperativity effects were discussed in the HMX···HF···DMI ternary by using the M06-2x/6-311＋G（2df,2p） and MP2（full）/6-311＋G（2df,2p） methods. The results indicate that the substituted patterns（020） and（100） own the highest binding energies. The stabilities of cocrystals in the 1：1 and 2：1 ratios are the greatest, and thus the HMX/DMI cocrystals prefer cocrystallizing in the 1：1 and 2：1 molar ratios, which have good mechanical properties. The sensitivity change of cocrystal originates from not only the formation of intermolecular interaction but also the increment of bond dissociation energy of the N–NO2 bond. The cooperativity effect appears in the linear complex while the anti-cooperativity effect is found in the cyclic system. DMI binding to HMX is not energetically and structurally favored in the presence of HF. This is perhaps the reason that the solvent with large dielectric constant weakens the stability of the HMX/DMI cocrystals. Therefore, the solvents with low dielectric constants should be chosen in the preparation of HMX/DMI cocrystals.

Optimized solubility and bioavailability of genistein based on cocrystal engineering

With various potential health-promoting bioactivities,genistein has great prospects in treatment of a series of complex diseases and metabolic syndromes such as cancer,diabetes,cardiovascular diseases,menopausal symptoms and so on.However,poor solubility and unsatisfactory bioavailability seriously limits its clinical application and market development.To optimize the solubility and bioavailability of genistein,the cocrystal of genistein and piperazine was prepared by grinding assisted with solvent based on the concept of cocrystal engineering.Using a series of analytical techniques including single-crystal X-ray diffraction,powder X-ray diffraction,Fourier transform infrared spectroscopy,differential scanning calorimetry and thermogravimetric analysis,the cocrystal was characterized and confirmed.Then,structure analysis on the basis of theoretical calculation and a series of evaluation on the stability,dissolution and bioavailability were carried out.The results indicated that the cocrystal of genistein and piperazine improved the solubility and bioavailability of genistein.Compared with the previous studies on the cocrystal of genistein,this is a systematic and comprehensive investigation from the aspects of preparation,characterization,structural analysis,stability,solubility and bioavailability evaluation.As a simple,efficient and green approach,cocrystal engineering can pave a new path to optimize the pharmaceutical properties of natural products for successful drug formulation and delivery.