The objective of this study was to predict,screen,synthesize,and investigate cocrystals of poorly soluble flavonoids that are commonly found in dietary supplements with bipolar compound picolinic acid(PA).To improve t...The objective of this study was to predict,screen,synthesize,and investigate cocrystals of poorly soluble flavonoids that are commonly found in dietary supplements with bipolar compound picolinic acid(PA).To improve the efficiency and success rate of experimental screening,two virtual tools based on hydrogen bond propensity(HBP)and modified molecular electrostatic potential(MEP)maps were used.The prediction accuracy of HBP and MEP is 58.82%and 94.11%,respectively,presenting that the MEP model is very powerful in the discovery of pharmaceutical cocrystals.Among the 12 successfully obtained cocrystals,4 single crystals of PA with luteolin(LUT),genistein(GEN),taxifolin(TAX),dihydromyricetin(DHM)were obtained for the first time.Charged-assisted O-H…O and N-H…O hydrogen bonds appear as main hydrogen bonding synthons,and PA adopts a zwitterionic form after cocrystallization.GEN-PA,TAX-PA,and DHM-PA showed higher DPPH'radical-scavenging capacities;LUT-PA and DHM-PA showed higher ABTS^(+)radical-scavenging capacities;GEN-PA and DHM-PA possessed better protective effects on H9c2 cells from hypoxic injury caused by CoCl_(2)than corresponding pure flavonoids.展开更多
Herein,a first example of energetic-energetic cocrystal polymorphs with a 1:1 M ratio was discovered by cocrystallizing CL-20(2,4,6,8,10,12-hexanitro-2,4,6,8,10,12-hexaazaisowurtzitane)with 1,3-DNP(1,3-dinitropyrazole...Herein,a first example of energetic-energetic cocrystal polymorphs with a 1:1 M ratio was discovered by cocrystallizing CL-20(2,4,6,8,10,12-hexanitro-2,4,6,8,10,12-hexaazaisowurtzitane)with 1,3-DNP(1,3-dinitropyrazole).These two energetic cocrystal polymorphs(cocrystal 1 and cocrystal 2)exhibit distinct crystal packing styles,which lead to significant variations in their physicochemical properties.Notably,cocrystal 2 has a high density of 1.963 g·cm^(-3)at 170 K,exhibiting high detonation performances(9187 m·s^(-1);38.68 GPa)comparable to HMX(1,3,5,7-tetranitro-1,3,5,7-tetrazocane)meanwhile displaying an improved safety(10 J)relative to RDX(1,3,5-trinitro-1,3,5-triazinane),making it a potential high-energy,low-sensitivity energetic material.This work opens up a new strategy to deeply tune properties of energetic materials by constructing energetic-energetic cocrystal polymorphs.These energetic cocrystal polymorphs represent a new field of energetic materials that has not yet been studied.展开更多
Circularly polarized luminescence(CPL)and two-photon absorption(TPA)materials have garnered considerable attentions due to their minimal energy loss and superior optical penetration[1,2].However,the current challenge ...Circularly polarized luminescence(CPL)and two-photon absorption(TPA)materials have garnered considerable attentions due to their minimal energy loss and superior optical penetration[1,2].However,the current challenge lies in the absence of well-developed strategies for designing materials that combine these two exceptional optical properties.展开更多
The virtual cocrystal screening approach based on molecular electrostatic potential surface(MEPS)maps is a fast and feasible computational method to estimate the probability of cocrystal formation by calculating the d...The virtual cocrystal screening approach based on molecular electrostatic potential surface(MEPS)maps is a fast and feasible computational method to estimate the probability of cocrystal formation by calculating the difference in the interaction site pairing energies of monomers and that of their assemblies prior to experimental screening.In this paper,we report 12 cocrystal forms of temozolomide with mono-,di-,and trihydroxy benzoic acids,namely,3-hydroxy-,2,4-dihydroxy-,2,5-dihydroxy-,2,6-dihydroxy-,3,4-dihydroxy-,and 3,4,5-trihydroxy-benzoic acids,as well as benzoic acid,as pharmaceutical coformers for the first time.10 single crystals out of the 12 cocrystal forms were obtained and unequivocally determined by single-crystal X-ray diffraction,which clarified spatial arrangements,molecular conformations,and supramolecular synthons.MEPS further gains some insights into the sites of hydrogen bonding interactions for exploring combination patterns in these assemblies.Modulated stability of TMZ was successfully achieved by cocrystallization with these acids.展开更多
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...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.展开更多
In this work,we utilize a cocrystallization technique to solve the problem of high hygroscopicity of the high-energy oxidant ammonium dinitramide(ADN).For this purpose,a non-hygroscopic oxidant,triaminoguanidine nitra...In this work,we utilize a cocrystallization technique to solve the problem of high hygroscopicity of the high-energy oxidant ammonium dinitramide(ADN).For this purpose,a non-hygroscopic oxidant,triaminoguanidine nitrate(TAGN),is selected as the cocrystallization ligand.The ADN/TAGN system is simulated by using Material Studio 5.5 software,and the DFT of ADN and TAGN molecules are calculated by Gaussian09 software.The most stable molar ratio of the ADN/TAGN cocrystallization is determined to be 1:1,and the hydrogen bonding between the H atom of ADN and the O atom in the TAGN is the driving force for the formation of cocrystals in this system.Moreover,the electrostatic potential interaction pairing energy difference(ΔEpair)<0 kJ·mol^(-1)(-12.71 kJ·mol^(-1))for nADN:nTAGN=1:1 again indicates cocrystallization at this molar ratio.The crystal structure and crystal morphology is predicted.And the hygroscopicity of ADN/TAGN cocrystal at 20℃and 40%relative humidity is calculated to be only 0.45%.The mechanism of hygroscopicity is investigated by examining the roughness of each crystal surface.Overall,the more hygroscopic it is in terms of surface roughness,with the roughest crystal surface(012)having a hygroscopicity of 1.78,which corresponds to a saturated hygroscopicity of 0.61%.The results show that the(001)crystal surface has the smallest band gap(1.06 eV)and the largest sensitivity.Finally,the oxygen equilibrium value for the ADN/TAGN system is calculated to be-8.2%.展开更多
Currently,cocrystallization is a promising strategy for tailoring the physicochemical properties of active pharmaceutical ingredients.Theophylline,an alkaloid and the most primary metabolite of caffeine,is a readily a...Currently,cocrystallization is a promising strategy for tailoring the physicochemical properties of active pharmaceutical ingredients.Theophylline,an alkaloid and the most primary metabolite of caffeine,is a readily available compound found in tea and coffee.It functions primarily as a bronchodilator and respiratory stimulant,making it a mainstay treatment for lung diseases like asthma.Theophylline’s additional potential benefits,including anti-inflammatory and anticancer properties,and its possible role in neurological disorders,have garnered significant research interest.Cocrystal formation presents a viable approach to improve the physicochemical properties of theophylline and potentially mitigate its toxic effects.This review comprehensively explores several successful studies that utilized cocrystallization to favorably alter the physicochemical properties of theophylline or its CCF.Notably,cocrystals can not only enhance the solubility and bioavailability of theophylline but also exhibit synergistic effects with other APIs.The review further delves into the hydrogen bonding sites within the theophylline structure and the hydrogen bonding networks observed in cocrystal structures.展开更多
In the development of new drugs products,especially the development of traditional Chinese medicine active ingredients,solubility and oral bioavailability are the main factors which are restricting the development of ...In the development of new drugs products,especially the development of traditional Chinese medicine active ingredients,solubility and oral bioavailability are the main factors which are restricting the development of new drugs,whereas the physicochemical properties of active ingredients are the key element to affecting these factors.Pharmaceutical cocrystal provides an excellent opportunity to develop new drugs with excellent physical and chemical properties such as melting point,solubility,stability and bioavailability while retaining the pharmacological properties of individuals active pharmaceutical ingredients among pharmaceutical cocrystal compounds.Traditional Chinese herbal medicine has the characteristics of multiple pathways and multiple targets,mainly because it contains many active ingredients,like cocrystals thereof with many components.The active ingredients extracted from traditional Chinese herbal medicine have a wide range of pharmacological activities,but most of the active ingredients affect the development of traditional Chinese medicine active ingredients due to their physical and chemical properties such as solubility.Traditional Chinese medicine pharmaceutical cocrystals can not only improve the physical and chemical properties of drugs without changing the internal structure of drugs,so as to provide a new scheme for the development of traditional Chinese medicine active ingredients.This paper reviews the research progress of active ingredients of traditional Chinese medicine pharmaceutical cocrystal.The preparation methods of cocrystals are summarized and the advantages of cocrystals are illustrated with examples.展开更多
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...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.展开更多
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 ...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.展开更多
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 impro...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.展开更多
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 ...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.展开更多
A new charge transfer cocrystal of 1,2,4,5-tetracyanobenzene(TCNB)-phenazine(PTC)was prepared by solvent evaporation method.The donor and acceptor molecules of cocrystal are stacked face to face with a mixed-stacking,...A new charge transfer cocrystal of 1,2,4,5-tetracyanobenzene(TCNB)-phenazine(PTC)was prepared by solvent evaporation method.The donor and acceptor molecules of cocrystal are stacked face to face with a mixed-stacking,implying a strong charge transfer(CT)interactions in the cocrystal system.The spectroscopic studies,single-crystal X-ray diffraction structure,density functional theory(DFT)and Hirschfield surfaces calculations are carried out to explore the relationship between structure and properties of cocrystal system,which show that the intermolecular interactions in PTC are stronger than those of single components,leading to the stability and photophysical behaviors of cocrystal different from their constitute units.This study will be helpful for the design and preparation of multifunctional cocrystal materials.展开更多
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 rapidl...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.展开更多
Rhein(Rhe), an anthraquinone derivative, exhibits excellent anti-inflammatory effects and other pharmacological activities, but its clinical application remains limited due to poor solubility. The present work aims at...Rhein(Rhe), an anthraquinone derivative, exhibits excellent anti-inflammatory effects and other pharmacological activities, but its clinical application remains limited due to poor solubility. The present work aims at the improvement of solubility and oral bioavailability of Rhe through cocrystal formation. For this purpose, Rhe and matrine(Mat) were selected as pharmaceutical ingredient(API) and cocrystal former(CCF), respectively, and the Rhe-Mat cocrystal was synthesized and characterized by single crystal X-ray diffraction(SXRD), powder X-ray diffraction(PXRD), thermogravimetric analysis(TGA), differential scanning calorimetry(DSC). The formation mechanism of Rhe-Mat cocrystal was elucidated by molecular surface electrostatic potential(MSEP). It is worth mentioning that the 50-fold increment of dissolution in vitro was observed in pure water in the form of Rhe-Mat cocrystal. Furthermore, the in vivo studies revealed that Rhe-Mat cocrystal indicated the faster absorption rate and the higher peak blood concentration than the pure Rhe. Hence, it can be concluded that current study successfully improved the solubility and oral bioavailability of Rhe.展开更多
Luminescent cocrystals have been received much attention in fluorescence imaging and sensor application. In this work, we report that the high-quality chiral luminescent cocrystal can be obtained through a molecular s...Luminescent cocrystals have been received much attention in fluorescence imaging and sensor application. In this work, we report that the high-quality chiral luminescent cocrystal can be obtained through a molecular self-assembly process of 2,20-binaphthol and 2-（3-pyridyl）-1 H-benzimidazole. The assembly modes and stacking fashions of as-obtained cocrystal were determined by single crystal X-ray diffractometer. The structure and optical properties of the cocrystals were characterized by fluorescence emission, fluorescence decay, Raman and circular dichroism spectra. The results show that both the pristine co-assembled units（R-BINOL and S-BINOL） give rise to the R conformation within the final cocrystal, suggesting that the formation of cocrystal can be an effective way to achieve R/S-isomeric transformation of 2,20-binaphthol. It is also expected that the co-crystallization approach has much flexibility and potential applications for the design and selective formation of chiral luminescent materials.展开更多
Codelivery of drugs by drug carriers is a promising strategy against several diseases such as infections and cancer.However,traditional drug carriers are typically characterized by low drug payload,limiting their trea...Codelivery of drugs by drug carriers is a promising strategy against several diseases such as infections and cancer.However,traditional drug carriers are typically characterized by low drug payload,limiting their treatment efficacy.Using nanocrystals of insoluble drug as carriers,a carrier free platform was developed previously to deliver a second insoluble drug for codelivery.To extend the concept,we hypothesized,herein,that the platform allows for codelivery of hydrophobic and hydrophilic drugs using a cocrystalization-like strategy.To obtain proof-of-concept,paclitaxel(PTX),an insoluble chemotherapeutic agent,and dichloroacetic acid(DCA),a water-soluble inhibitor of pyruvate dehydrogenase kinase,were utilized as model drugs.PTX-DCA hybrid nanocrystals(PTX-DCA NCs)were prepared by antisolvent precipitation and characterized.Their in vitro antitumor activity against cancer cells was evaluated.PTX-DCA NCs prepared from the optimized formulation had a diameter of 160 nm and a rodshape morphology and possessed encapsulated efficacy of approximately 30%for DCA.The use of the hybrid crystals enabled synergy to kill cancer cells,in particular in PTX-resistant cells in a dosedependent pattern.In conclusion,by using a cocrystalization-like strategy,a hydrophilic drug can be formulated into a drug’s nanocrystal for codelivery.展开更多
Co-crystal formation can improve the physicochemical properties of a compound,thus enhancing its druggability.Therefore,artificial intelligence-based co-crystal virtual screening in the early stage of drug development...Co-crystal formation can improve the physicochemical properties of a compound,thus enhancing its druggability.Therefore,artificial intelligence-based co-crystal virtual screening in the early stage of drug development has attracted extensive attention from researchers.However,the complexity of developing and applying algorithms hinders it wide application.This study presents a data-driven co-crystal prediction method based on the XGBoost machine learning model of the scikit-learn package.The simplified molecular input line entry specification(SMILES)information of two compounds is simply inputted to determine whether a co-crystal can be formed.The data set includs the co-crystal records presented in the Cambridge Structural Database(CSD)and the records of no co-crystal formation from extant literature and experiments.RDKit molecular descriptors are adopted as the features of a compound in the data set.The developed model shows excellent performance in the proposed co-crystal training and validation sets with high accuracy,sensitivity,and F1 score.The prediction success rate of the model exceeds 90%.The model therefore provides a simple and feasible scheme for designing and screening co-crystal drugs efficiently and accurately.展开更多
The specific crystalline form of a compound remarkably affects its physicochemical properties.Therefore,a detailed analysis of the structural features and intermolecular interactions of a multi-component crystal is fe...The specific crystalline form of a compound remarkably affects its physicochemical properties.Therefore,a detailed analysis of the structural features and intermolecular interactions of a multi-component crystal is feasible to understand the relationships among the structure,physicochemical properties and the formation mechanism.In the present study,three novel cocrystal salt solvates of rhein and berberine were reported for the first time.Various solid characterizations and theoretical computations based on density functional theory(DFT)were carried out to demonstrate the intermolecular interactions.The theoretical computation shows that the strongest interaction existed between berberine cation and rhein anion,and the electrostatic interaction play a dominant role.However,no salt bond was observed between them.Further intrinsic dissolution rate analysis in water shows that the monohydrate exhibits 17 times enhancement in comparison with rhein.The rhein and berberine combined in ionic state in cocrystal salt is the main reason for the solubility improvement.This paper suggests that the interactions between the different components can be visualized and qualitatively and quantitatively analyzed by theoretical computation,which is helpful to understand the relationship between stereochemical structure and physicochemical properties of multi-component complex.展开更多
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, natur...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.展开更多
基金supported by the Beijing Natural Science Foundation(No.7222261)CAMS Innovation Fund for Medical Sciences(No.2022-I2M-1-015)。
文摘The objective of this study was to predict,screen,synthesize,and investigate cocrystals of poorly soluble flavonoids that are commonly found in dietary supplements with bipolar compound picolinic acid(PA).To improve the efficiency and success rate of experimental screening,two virtual tools based on hydrogen bond propensity(HBP)and modified molecular electrostatic potential(MEP)maps were used.The prediction accuracy of HBP and MEP is 58.82%and 94.11%,respectively,presenting that the MEP model is very powerful in the discovery of pharmaceutical cocrystals.Among the 12 successfully obtained cocrystals,4 single crystals of PA with luteolin(LUT),genistein(GEN),taxifolin(TAX),dihydromyricetin(DHM)were obtained for the first time.Charged-assisted O-H…O and N-H…O hydrogen bonds appear as main hydrogen bonding synthons,and PA adopts a zwitterionic form after cocrystallization.GEN-PA,TAX-PA,and DHM-PA showed higher DPPH'radical-scavenging capacities;LUT-PA and DHM-PA showed higher ABTS^(+)radical-scavenging capacities;GEN-PA and DHM-PA possessed better protective effects on H9c2 cells from hypoxic injury caused by CoCl_(2)than corresponding pure flavonoids.
基金support for this study by the National Natural Science Foundation of China(Grant No.22275175)。
文摘Herein,a first example of energetic-energetic cocrystal polymorphs with a 1:1 M ratio was discovered by cocrystallizing CL-20(2,4,6,8,10,12-hexanitro-2,4,6,8,10,12-hexaazaisowurtzitane)with 1,3-DNP(1,3-dinitropyrazole).These two energetic cocrystal polymorphs(cocrystal 1 and cocrystal 2)exhibit distinct crystal packing styles,which lead to significant variations in their physicochemical properties.Notably,cocrystal 2 has a high density of 1.963 g·cm^(-3)at 170 K,exhibiting high detonation performances(9187 m·s^(-1);38.68 GPa)comparable to HMX(1,3,5,7-tetranitro-1,3,5,7-tetrazocane)meanwhile displaying an improved safety(10 J)relative to RDX(1,3,5-trinitro-1,3,5-triazinane),making it a potential high-energy,low-sensitivity energetic material.This work opens up a new strategy to deeply tune properties of energetic materials by constructing energetic-energetic cocrystal polymorphs.These energetic cocrystal polymorphs represent a new field of energetic materials that has not yet been studied.
基金supported by NSFC(22271282)the Self-deployment Project Research Program of Haixi Institutes,Chinese Academy of Sciences with the grant number of CXZX-2022-JQ04.
文摘Circularly polarized luminescence(CPL)and two-photon absorption(TPA)materials have garnered considerable attentions due to their minimal energy loss and superior optical penetration[1,2].However,the current challenge lies in the absence of well-developed strategies for designing materials that combine these two exceptional optical properties.
基金supported by the Beijing Natural Science Foundation(No.7222261)CAMS Innovation Fund for Medical Sciences(Nos.2022-I2M-01-015 and 2022-I2M-JB-010)+1 种基金Key R&D Program of Shan Dong Province(No.2019JZZY020909)Chinese Pharmacopoeia Commission Drug Standard Promoting Fund(No.2022Y01)。
文摘The virtual cocrystal screening approach based on molecular electrostatic potential surface(MEPS)maps is a fast and feasible computational method to estimate the probability of cocrystal formation by calculating the difference in the interaction site pairing energies of monomers and that of their assemblies prior to experimental screening.In this paper,we report 12 cocrystal forms of temozolomide with mono-,di-,and trihydroxy benzoic acids,namely,3-hydroxy-,2,4-dihydroxy-,2,5-dihydroxy-,2,6-dihydroxy-,3,4-dihydroxy-,and 3,4,5-trihydroxy-benzoic acids,as well as benzoic acid,as pharmaceutical coformers for the first time.10 single crystals out of the 12 cocrystal forms were obtained and unequivocally determined by single-crystal X-ray diffraction,which clarified spatial arrangements,molecular conformations,and supramolecular synthons.MEPS further gains some insights into the sites of hydrogen bonding interactions for exploring combination patterns in these assemblies.Modulated stability of TMZ was successfully achieved by cocrystallization with these acids.
基金supported by the National Natural Science Foundation of China(Nos.22001006,22375002,22273057,22225401)the Anhui Provincial Natural Science Foundation(No.2308085Y10)+4 种基金the Open Project of Key Laboratory of Structure and Functional Regulation of Hybrid Materials of Anhui University,Ministry of EducationThe National Key Research and Development Program of China(Nos.2022YFC_(2)403500,2020YFA0210800)The Universities Joint Laboratory of Guangdong,Hong Kong and Macao(No.130/07422011)the Natural Science Foundation of Guangdong Province(No.2022A1515011661)the China Postdoctoral Science Foundation(Nos.2023M730760,2023M740010)。
文摘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.
基金supported by the National Natural Science Foundation of China(22125802).
文摘In this work,we utilize a cocrystallization technique to solve the problem of high hygroscopicity of the high-energy oxidant ammonium dinitramide(ADN).For this purpose,a non-hygroscopic oxidant,triaminoguanidine nitrate(TAGN),is selected as the cocrystallization ligand.The ADN/TAGN system is simulated by using Material Studio 5.5 software,and the DFT of ADN and TAGN molecules are calculated by Gaussian09 software.The most stable molar ratio of the ADN/TAGN cocrystallization is determined to be 1:1,and the hydrogen bonding between the H atom of ADN and the O atom in the TAGN is the driving force for the formation of cocrystals in this system.Moreover,the electrostatic potential interaction pairing energy difference(ΔEpair)<0 kJ·mol^(-1)(-12.71 kJ·mol^(-1))for nADN:nTAGN=1:1 again indicates cocrystallization at this molar ratio.The crystal structure and crystal morphology is predicted.And the hygroscopicity of ADN/TAGN cocrystal at 20℃and 40%relative humidity is calculated to be only 0.45%.The mechanism of hygroscopicity is investigated by examining the roughness of each crystal surface.Overall,the more hygroscopic it is in terms of surface roughness,with the roughest crystal surface(012)having a hygroscopicity of 1.78,which corresponds to a saturated hygroscopicity of 0.61%.The results show that the(001)crystal surface has the smallest band gap(1.06 eV)and the largest sensitivity.Finally,the oxygen equilibrium value for the ADN/TAGN system is calculated to be-8.2%.
基金Xinjiang Uygur Autonomous Region Innovation Environment Construction Special Fund and Technology Innovation Base Construction Key Laboratory Open Project(Grant No.2022D04016)the Key R&D Program of Shan Dong Province(Grant No.2021ZDSYS26)+3 种基金CAMS Innovation Fund for Medical Sciences(Grant No.2022-I2M-1-015)Chinese Pharmacopoeia Commission Drug Standard Promoting Fund(Grant No.2023Y11)Independent Innovation and Achievement Transformation Plan Project of Zaozhuang City(Grant No.2022GH15)2023 Xinjiang Uygur Autonomous Region Innovation Tianchi Talent Introduction Program for financial support.
文摘Currently,cocrystallization is a promising strategy for tailoring the physicochemical properties of active pharmaceutical ingredients.Theophylline,an alkaloid and the most primary metabolite of caffeine,is a readily available compound found in tea and coffee.It functions primarily as a bronchodilator and respiratory stimulant,making it a mainstay treatment for lung diseases like asthma.Theophylline’s additional potential benefits,including anti-inflammatory and anticancer properties,and its possible role in neurological disorders,have garnered significant research interest.Cocrystal formation presents a viable approach to improve the physicochemical properties of theophylline and potentially mitigate its toxic effects.This review comprehensively explores several successful studies that utilized cocrystallization to favorably alter the physicochemical properties of theophylline or its CCF.Notably,cocrystals can not only enhance the solubility and bioavailability of theophylline but also exhibit synergistic effects with other APIs.The review further delves into the hydrogen bonding sites within the theophylline structure and the hydrogen bonding networks observed in cocrystal structures.
基金The National Natural Science Foundation of China(No.81973977,No.81273872)the Fundamental Research Funds for the Central Universities(2021JCXK02)supported this study.
文摘In the development of new drugs products,especially the development of traditional Chinese medicine active ingredients,solubility and oral bioavailability are the main factors which are restricting the development of new drugs,whereas the physicochemical properties of active ingredients are the key element to affecting these factors.Pharmaceutical cocrystal provides an excellent opportunity to develop new drugs with excellent physical and chemical properties such as melting point,solubility,stability and bioavailability while retaining the pharmacological properties of individuals active pharmaceutical ingredients among pharmaceutical cocrystal compounds.Traditional Chinese herbal medicine has the characteristics of multiple pathways and multiple targets,mainly because it contains many active ingredients,like cocrystals thereof with many components.The active ingredients extracted from traditional Chinese herbal medicine have a wide range of pharmacological activities,but most of the active ingredients affect the development of traditional Chinese medicine active ingredients due to their physical and chemical properties such as solubility.Traditional Chinese medicine pharmaceutical cocrystals can not only improve the physical and chemical properties of drugs without changing the internal structure of drugs,so as to provide a new scheme for the development of traditional Chinese medicine active ingredients.This paper reviews the research progress of active ingredients of traditional Chinese medicine pharmaceutical cocrystal.The preparation methods of cocrystals are summarized and the advantages of cocrystals are illustrated with examples.
文摘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.
文摘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.
文摘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.
基金support by National Key research and development Program of China(Grant No.2016YFC1000900)CAMS Innovation Found for Medical Sciences(Grant No.2017-I2M-1-010)+1 种基金Construction and application of technology integration system for efficient identification of natural/effective active small molecules(Grant No.2018ZX09711001-001)National Science and Technology Major Project of China(Grant No.2018ZX09711001-010).
文摘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.
基金financial support from the National Key R&D Program(No.2017YFA0204503)the National Natural Science Foundation of China(Nos.51733004,21875158,91833306,51633006)。
文摘A new charge transfer cocrystal of 1,2,4,5-tetracyanobenzene(TCNB)-phenazine(PTC)was prepared by solvent evaporation method.The donor and acceptor molecules of cocrystal are stacked face to face with a mixed-stacking,implying a strong charge transfer(CT)interactions in the cocrystal system.The spectroscopic studies,single-crystal X-ray diffraction structure,density functional theory(DFT)and Hirschfield surfaces calculations are carried out to explore the relationship between structure and properties of cocrystal system,which show that the intermolecular interactions in PTC are stronger than those of single components,leading to the stability and photophysical behaviors of cocrystal different from their constitute units.This study will be helpful for the design and preparation of multifunctional cocrystal materials.
基金the support of the National Natural Science Foundation of China(No.22005090)Beijing Institute of Technology Research Fund Program for Young Scholars+2 种基金the National Natural Science Foundation of China(No.11672040 and No.21801016)Open Research Fund Program of Science and Technology on Aerospace Chemical Power Laboratory(STACPL120201B02)the State Key Laboratory of Explosion Science and Technology(No.YB2016-17)。
文摘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.
基金supported by Drug Innovation Major Project (Nos. 2018ZX09711001–001–015, 2018ZX09711001–003– 022)CAMS Innovation Fund for Medical Sciences (No. 2016I2M-3–007)。
文摘Rhein(Rhe), an anthraquinone derivative, exhibits excellent anti-inflammatory effects and other pharmacological activities, but its clinical application remains limited due to poor solubility. The present work aims at the improvement of solubility and oral bioavailability of Rhe through cocrystal formation. For this purpose, Rhe and matrine(Mat) were selected as pharmaceutical ingredient(API) and cocrystal former(CCF), respectively, and the Rhe-Mat cocrystal was synthesized and characterized by single crystal X-ray diffraction(SXRD), powder X-ray diffraction(PXRD), thermogravimetric analysis(TGA), differential scanning calorimetry(DSC). The formation mechanism of Rhe-Mat cocrystal was elucidated by molecular surface electrostatic potential(MSEP). It is worth mentioning that the 50-fold increment of dissolution in vitro was observed in pure water in the form of Rhe-Mat cocrystal. Furthermore, the in vivo studies revealed that Rhe-Mat cocrystal indicated the faster absorption rate and the higher peak blood concentration than the pure Rhe. Hence, it can be concluded that current study successfully improved the solubility and oral bioavailability of Rhe.
基金supported by the National Natural Science Foundation of China(NSFC, Nos. 21771021 and 21473013)the National Basic Research Program of China(973 Program, No. 2014CB932103)Beijing Municipal Natural Science Foundation (No. 2152016)
文摘Luminescent cocrystals have been received much attention in fluorescence imaging and sensor application. In this work, we report that the high-quality chiral luminescent cocrystal can be obtained through a molecular self-assembly process of 2,20-binaphthol and 2-（3-pyridyl）-1 H-benzimidazole. The assembly modes and stacking fashions of as-obtained cocrystal were determined by single crystal X-ray diffractometer. The structure and optical properties of the cocrystals were characterized by fluorescence emission, fluorescence decay, Raman and circular dichroism spectra. The results show that both the pristine co-assembled units（R-BINOL and S-BINOL） give rise to the R conformation within the final cocrystal, suggesting that the formation of cocrystal can be an effective way to achieve R/S-isomeric transformation of 2,20-binaphthol. It is also expected that the co-crystallization approach has much flexibility and potential applications for the design and selective formation of chiral luminescent materials.
基金supported by the National Natural Science Foundation of China(Nos.81872823,81871477 and 82073782)the Double First-Class(CPU2018PZQ13,China)of the China Pharmaceutical University+1 种基金the Shanghai Science and Technology Committee(No.19430741500)the Key Laboratory of Modern Chinese Medicine Preparation of Ministry of Education of Jiangxi University of Traditional Chinese Medicine,China(No.TCM-201905)。
文摘Codelivery of drugs by drug carriers is a promising strategy against several diseases such as infections and cancer.However,traditional drug carriers are typically characterized by low drug payload,limiting their treatment efficacy.Using nanocrystals of insoluble drug as carriers,a carrier free platform was developed previously to deliver a second insoluble drug for codelivery.To extend the concept,we hypothesized,herein,that the platform allows for codelivery of hydrophobic and hydrophilic drugs using a cocrystalization-like strategy.To obtain proof-of-concept,paclitaxel(PTX),an insoluble chemotherapeutic agent,and dichloroacetic acid(DCA),a water-soluble inhibitor of pyruvate dehydrogenase kinase,were utilized as model drugs.PTX-DCA hybrid nanocrystals(PTX-DCA NCs)were prepared by antisolvent precipitation and characterized.Their in vitro antitumor activity against cancer cells was evaluated.PTX-DCA NCs prepared from the optimized formulation had a diameter of 160 nm and a rodshape morphology and possessed encapsulated efficacy of approximately 30%for DCA.The use of the hybrid crystals enabled synergy to kill cancer cells,in particular in PTX-resistant cells in a dosedependent pattern.In conclusion,by using a cocrystalization-like strategy,a hydrophilic drug can be formulated into a drug’s nanocrystal for codelivery.
基金The authors acknowledge the National Natural Science Foundation of China(No.22278443)CAMS Innovation Fund for Medical Sciences(No.2022-I2M-1-015)+1 种基金the Key R&D Program of Shan Dong Province(No.2019JZZY020909)the Xinjiang Uygur Autonomous Region Innovation Environment Construction Special Fund and Technology Innovation Base Construction Key Laboratory Open Project(No.2022D04016)for the financial support.
文摘Co-crystal formation can improve the physicochemical properties of a compound,thus enhancing its druggability.Therefore,artificial intelligence-based co-crystal virtual screening in the early stage of drug development has attracted extensive attention from researchers.However,the complexity of developing and applying algorithms hinders it wide application.This study presents a data-driven co-crystal prediction method based on the XGBoost machine learning model of the scikit-learn package.The simplified molecular input line entry specification(SMILES)information of two compounds is simply inputted to determine whether a co-crystal can be formed.The data set includs the co-crystal records presented in the Cambridge Structural Database(CSD)and the records of no co-crystal formation from extant literature and experiments.RDKit molecular descriptors are adopted as the features of a compound in the data set.The developed model shows excellent performance in the proposed co-crystal training and validation sets with high accuracy,sensitivity,and F1 score.The prediction success rate of the model exceeds 90%.The model therefore provides a simple and feasible scheme for designing and screening co-crystal drugs efficiently and accurately.
基金the Drug Innovation Major Project(No.2018ZX09711001-001-015)the CAMS Innovation Fund for Medical Sciences(No.2020-I2M-1-003)。
文摘The specific crystalline form of a compound remarkably affects its physicochemical properties.Therefore,a detailed analysis of the structural features and intermolecular interactions of a multi-component crystal is feasible to understand the relationships among the structure,physicochemical properties and the formation mechanism.In the present study,three novel cocrystal salt solvates of rhein and berberine were reported for the first time.Various solid characterizations and theoretical computations based on density functional theory(DFT)were carried out to demonstrate the intermolecular interactions.The theoretical computation shows that the strongest interaction existed between berberine cation and rhein anion,and the electrostatic interaction play a dominant role.However,no salt bond was observed between them.Further intrinsic dissolution rate analysis in water shows that the monohydrate exhibits 17 times enhancement in comparison with rhein.The rhein and berberine combined in ionic state in cocrystal salt is the main reason for the solubility improvement.This paper suggests that the interactions between the different components can be visualized and qualitatively and quantitatively analyzed by theoretical computation,which is helpful to understand the relationship between stereochemical structure and physicochemical properties of multi-component complex.
文摘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.
