A review on cocrystal of active ingredients in traditional Chinese medicine

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.

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.

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.

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.

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 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.

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.

Cocrystal Phenomena of DABCO with Phenol Derivatives

It has been reported that 1,4-diazabicyclo[2,2,2] octane(DABCO) can form complexed crystals with lithium alkals. Our experimental results show that DABCO can also form cocrystals with phenol derivatives such as phenol(2), o-cresol(3), m-cresol(4), p-cresol(5), p-chlorophenol(6), and p-nitrophenol(7). The separa-

Crystal Structures and Antibacterial Activities of 1,3-Phenylenebis(oxy)diacetic Acid Dihydrate and 4,4'-Bipyridine Cocrystal

Single crystals of two 1,3-phenylenebis（oxy）diacetic acid（C10H10O8） compounds 1 and 2 were obtained via slow evaporation.The compounds were characterized by elemental analysis,IR and single-crystal X-ray diffraction.Compound 1（C10H14O8） crystallizes in the triclinic system,space group P1 with a = 6.3751（6）,b = 8.5311（8）,c = 11.4510（11）A,α = 93.3650（10）,β = 105.3190（10）,γ = 97.2140（10）°,V = 593.15（10） A^3,Z = 2,Mr = 262.21,Dc = 1.468 g/cm^3,F（000） = 276,GOOF = 1.005,° = 0.129 mm^-1,the final R = 0.0361 and w R = 0.0802 for 1854 observed reflections with I 〉 2σ（I）.Compound 2（C30H28N2O12） crystallizes in the triclinic system,space group P1 with a = 9.7416（13）,b = 11.839（2）,c = 12.9828（13） A,α = 74.191（4）,β = 77.953（2）,γ = 74.726（3）°,V = 1374.5（3） A^3,Z = 2,Mr = 608.54,Dc = 1.470 g/cm^3,F（000） = 636,GOOF = 1.061,° = 0.115 mm^-1,the final R = 0.0500 and w R = 0.1221 for 3966 observed reflections with I 〉 2σ（I）.Both compounds 1 and 2 exhibit 3D supramolecular structures under hydrogen bonding interactions.The results of preliminary antibacterial activity show that the title compounds display moderate antibacterial activities against the tested gram positive bacteria（S.aureus,C.albicans and B.subtilis） and gram negative bacteria（E.coli and P.aeruginosa）.

Crystal Structure and Thermal Behavior of a Novel Cocrystal Consisting of 3,3’-Dinitrimino-5,5’-Bis(1H-1,2,4-triazole),H_(2)O and(CH3)_(2)SO

A typical nitroimine bistriazole（DNABT） was synthesized with high yield（90.4%） by nitration reaction from DABT in HNO3 and NH4NO3. Furthermore, a novel cocrystal（1） consisting of DNABT, H2O and DMSO in a 1：2：2 molar ratio was analysized on the crystal structure. Cocrystal 1 crystallizes in the triclinic system, space group P1 with a = 6.3124（18）, b = 8.233（2）, c = 9.775（3） A, β = 98.326（4）°, V = 481.59（74）A^3, Z = 2, Dc = 1.55 g/cm^3, F（000） = 234, μ = 0.337 mm^-1, S = 1.078, the final R = 0.0609 and w R = 0.2743. Additionally, the crystal structure is built up by four strong and seven weak hydrogen bonds. And the hydrogen bond network contributes to the stability of DNABT molecule. Typical TGA and DSC curves indicate the cocrystal 1 includes one endothermic and one exothermic decomposition processes, and the peak temperature at each process is 164.0 and 245.0 ℃. The nonisothermal decomposition kinetics analysis was performed by means of the Kissinger and Ozawa methods. The apparent activation energy（Ea） and pre-exponential factor（A） of the two decompositions are 96.0 kJ·mol^-1, 108.1 s^-1 and 215.8 kJ·mol^-1, 1018.9 s^-1, respectively.

Solubility and Thermodynamic Properties of Sulfamethazine-Saccharin Cocrystal in Pure and Binary (Acetonitrile + 2-Propanol) Solvents

In this work,a new crystallization method was used to prepare two polymorphs of sulfamethazine-saccharin(SMT-SAC)cocrystal in bulk.The purity and crystal form of both polymorphs were confirmed by optical microscopy,scanning electron microscopy,powder X-ray diff raction,diff erential scanning calorimetry,and thermogravimetric analysis.Moreover,the solubility of the stable form(form Ⅱ)was determined by gravimetric analysis in nine pure solvents and one binary(acetoni-trile+2-propanol)solvent at temperatures ranging from 278.15 to 348.15 K at atmospheric pressure.Experimental data were correlated using the modified Apelblat model,theλh equation,the nonrandom two-liquid(NRTL)model,the Jouyban-Acree model,and the CNIBS/Redlich-Kister model.Finally,the apparent thermodynamic properties,such asΔ_(dis)G,Δ_(dis) H,andΔ_(dis) S,were calculated on the basis of the activity coefficient obtained by the NRTL model.All the models correlate well,and all the experimental and calculated results indicate that the dissolution behavior of SMT-SAC cocrystal form II is a spontaneous,endothermic,and entropy-driven process.

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.

Theoretical study of BTF/TNA cocrystal: Effects of hydrostatic pressure and temperature

Cocrystallization is a promising technique for the design and preparation of new explosives,and the stability of cocrystal is highly concerned by the researchers.In order to make a better understanding of the behavior of cocrystal under the extreme conditions,DFT(density functional theory) calculation is performed to investigate the effect of hydrostatic pressure on geometrical and electronic structures of the cocrystal BTF(benzotrifuroxan)/TNA(2,4,6-trinitroaniline).When the hydrostatic pressure is applied,the lattice constants,volume,density and total energy change gradually except at the pressures of 40 GPa and 79e83 GPa.It is noteworthy that new chemical bonds form when the pressure is up to83 GPa.The band gap of the cocrystal becomes smaller when the pressure is applied,and finally the cocrystal shows a characteristic of metal.The mechanical property of cocrystal is calculated by MD(molecular dynamics) simulation.The results show that the cocrystal has a better ductibility at low temperature,and has the best tenacity at 295 K.

真空冷冻干燥不同升温程序对蓝莓干燥特性及品质影响

不同真空冷冻干燥(FD)程序中的温度设定影响果蔬干制品的感官和营养品质。为获得蓝莓FD较优程序,本研究采用差示扫描量热法探究蓝莓热力学特性及玻璃化转变温度(Tg)的变化,采用低场核磁共振技术测定水分分布及含量变化,以收缩率、花青素含量和质构品质为指标,探究5种FD不同升温程序对蓝莓脆干燥特性和营养品质的影响。结果表明,超声处理后蓝莓共晶点、共熔点和Tg无显著变化;随着蓝莓含水率的降低,其Tg升高,蓝莓中的自由水先转换为不易流动水,随后不易流动水转换为自由水和结合水。FD不同程序设定下,蓝莓脆粒的收缩率、色泽、感官和营养品质变化显著(P<0.05)。程序2干燥后蓝莓脆粒的收缩率最小,程序1干燥后蓝莓脆粒的脆性最大,程序5干燥后蓝莓硬度最大;程序4干燥后蓝莓△E值最大,程序1干燥后蓝莓脆粒的维生素C(Vc)含量最高、抗氧化活性较高。综合考虑,确定较优FD程序为程序2:0℃(2 h)→5℃(2 h)→10℃(2 h)→20℃(2 h)→30℃(2 h)→40℃(2 h)→50℃(12 h)。本研究结果为蓝莓脆产品开发提供了理论基础。

太赫兹光谱学研究CL-20/MTNP共晶振动特性

共晶是一种分子层次调控材料物化性质的高效方法,然而目前共晶复杂体系结构与宏观性质间关系一直难以得到深入理解.本文依据太赫兹光谱可激发晶体内弱作用的优势,以CL-20/MTNP共晶为对象开展了太赫兹振动光谱研究.首先,测量CL-20、MTNP和共晶CL-20/MTNP的太赫兹吸收光谱.其次,分析了基于密度泛函理论的振动计算方法,获得了3种物质太赫兹频段振动特性,对吸收光谱进行振动匹配.最后,采用振动分解方法将晶体分子的整体振动分解为分子间和分子内振动.在此基础上,分析了共晶前后振动变化规律.结果表明:共晶后新形成的弱相互作用由CL-20分子主导,同时MTNP分子主要通过3个硝基与CL-20分子交互作用.本文的研究结论为共晶热性质提供了微观解析.

染料木素-川芎嗪共晶在Caco-2细胞模型中的转运研究

旨在考察染料木素(genistein,GEN)、川芎嗪(tetramethylpyrazine,TMP)、染料木素-川芎嗪共晶(GEN-TMP)及染料木素与川芎嗪的物理混合物(GEN+TMP)在Caco-2细胞模型中的转运特征;建立Caco-2细胞模型,并以细胞跨膜电阻和标志物渗漏检查等指标进行验证,采用高效液相色谱法,考察并计算安全浓度下药物的累积转运量、表观渗透系数和外排率,并探讨P糖蛋白(P-gp)抑制剂维拉帕米、乳腺癌耐药蛋白(breast cancer resistant protein,BCRP)抑制剂KO143和多药耐药相关蛋白2(multidrug resistance-associated protein 2,MRP2)抑制剂MK571对转运的影响。结果显示,Caco-2细胞模型完整性与功能性良好,GEN浓度为40μg/mL时,GEN、TMP、GEN-TMP以及GEN+TMP的细胞存活率分别为90.06%、84.21%、97.60%和89.37%;GEN、TMP、GEN-TMP和GEN+TMP的表观渗透系数(P_(app))大于1.0×10^(-6)cm/s,属于吸收良好药物;GEN-TMP中GEN的累积转运量和P_(app)值分别为(2.78±0.11)μg和(8.61±0.33)×10^(-6)cm/s,比GEN的(1.92±0.15)μg和(5.96±0.47)×10^(-6)cm/s提高了44.79%和44.46%;GEN+TMP中GEN的累积转运量和P_(app)值与GEN无显著性差异。GEN只受BCRP的外排作用,GEN-TMP中的GEN同时受到P-gp和BCRP的外排作用,TMP、GEN-TMP和GEN+TMP中的TMP均受到MRP2的外排作用。结果表明,相同浓度下,GEN-TMP的细胞存活率高于GEN+TMP。GEN-TMP的吸收强于GEN和GEN+TMP中的GEN,共晶受外排蛋白的作用区别于GEN和GEN+TMP中的GEN,研究工作为共晶的转运研究提供了借鉴和参考。

共晶改善黄酮类化合物成药性能的研究进展

黄酮类化合物是一类天然有机化合物,种类和数量众多,因具有广泛的药理活性而备受关注,已经成为国内外天然药物开发和研究的热点。然而,黄酮类化合物本身存在着水溶性差、生物利用度低和在体内不稳定等问题,限制了其临床应用。由于黄酮类化合物中通常缺乏可电离的基团,共晶策略是提高这些化合物的溶解度和生物利用度的有效方法。笔者对近年来成功制备的黄酮类化合物共晶对其原料药物溶解度、溶出速率、渗透性、生物利用度等方面的影响进行综述,并简要介绍其改变机制,以期为黄酮类化合物共晶产品的进一步开发与深入研究提供参考。