Modeling approaches that can be used to predict accurately the solubility of amino acids and peptides are of interest for the design of new pharmaceutical processes and in the development of new peptide-based therapeutics. We investigate the capability of the SAFT-γ Mie group-contribution approach to predict the aqueous and alcohol solubility of glycine, alananine, valine, leucine, and serine and of di- and tripeptides containing these amino acids. New SAFT-γ Mie group interactions are characterized using experimental thermodynamic and phase-equilibrium data of compounds and mixtures that contain groups relevant to the amino acids and peptides, but no solubility data (except for the case of glycine). Once all the group interaction parameters are developed, predictive solid-liquid solubility calculations are carried out. Neutral and charged models are considered to account explicitly for the zwitterionic nature of the molecules in aqueous solution, and the solubility of the solution is presented as a function of pH. A detailed discussion of the molecular models and Helmholtz free-energy expressions used to represent the ionic and zwitterionic forms of the amino acids, together with their speciation in solution is also provided. Overall, very good agreement with available data is shown, with an absolute average deviation (AAD) in mole fraction of 0.0038 over 283 solubility data points for the amino acids studied and an AAD in mole fraction of 0.02128 over 141 peptide-solubility points when the systems are studied at their isoelectric point and neutral models are used. The solubility as a function of pH for a range of temperatures is also predicted accurately when charged models are incorporated. These results confirm the predictive accuracy of the SAFT-γ Mie method and pave the way for future studies involving larger peptides.

Reliable solubility data is crucial for controlling and optimising crystallisation conditions, to provide a costeffective purification method with the potential for scaling up. This study investigated the effect of amino acid sequence on determining peptides solubility behaviours. Four dipeptides with different sequences and combinations of alanine and glycine were selected to study their temperature dependent (283.15 K to 313.15 K) aqueous solubilities and solubility in the presence of ethanol and DMSO as antisolvent at 298.15 K. Aqueous solubility data of dipeptides presents the following order: glycyl-L-alanine (gly-ala) > L-alanyl-L-alanine (alaala) > glycyl glycine (gly-gly) > L-alanyl glycine (ala-gly). This solubility order has been substantiated by solvation free energy calculations using molecular dynamics (MD) simulations, providing insights into the underlying molecular interactions that govern these solubility patterns. The solubility data also demonstrated difference in the temperature dependency that: gly-gly > gly-ala > ala-gly > ala-ala, corresponding to their dissolution enthalpy order. In the presence of antisolvent range from 0 % to 80 % (by mass) concentration, peptide's solubility was more susceptible to DMSO than ethanol. Accurate prediction of the solubilities validated the effectiveness of non-random two-liquid (NRTL) model for peptide studies.

In silico methods for predicting solvate formation can guide and simplify solid form screening and solvent selection in crystallization processes. Solvates involve many complicated nonspecific interactions, making solvate prediction challenging. The applicability of three solvate prediction approaches to spironolactone (SPI) in 29 solvents was assessed, including thermodynamic excess enthalpy (Hex), hydrogen bond propensity (HBP), and a random forest model (RF). In experimental screening, 6 new solvates were identified and crystal structures of 5 solvates were revealed. Structural features, interaction calculations, and thermal analysis provided insights into the formation of SPI solvates. Not only strong hydrogen bonds but also weak interactions contribute significantly to the SPI channel and isolated site solvates. The Hex based on COSMO-RS theory (conductor-like screening model for real solvents) has a 65.5% success rate for SPI solvates prediction. The HBP can only be used for solvents with hydrogen bond donors with an 81% hit rate. The RF model shows a predictive success rate of 76.9% for unreported solvents. This work indicates it is difficult for these models to adequately predict solvate systems where multiple dominant interactions (such as hydrogen bonds, van der Waals forces, etc.) may be involved simultaneously. Using both COSMO-RS and HBP methods followed by the RF model may yield better results.

Objective:To explore the different functional connectivity of right caudate nucleus between adults with high myopia and normal vision controls.Methods:The resting-state functional magnetic resonance imaging(fMRI) data were collected from twenty-five high myopia(HM group) and twenty-seven normal vision subjects(NC group). Right caudate nucleus and their subregions(anterior and posterior subregions included) were used as seeds to perform seed-based functional connectivity (FC)analyses at group level under three different frequency bands: convention (0.010~0.080 Hz), slow-5(0.010~0.027 Hz) and slow-4(0.027~0.073 Hz).Results:(1)Compared with NC group, FC of right caudate nucleus with left middle occipital gyrus(MNI: x=-48, y=-84, z=9), left fusiform gyrus(MNI: x=-30, y=-63, z=-12), and right middle frontal gyrus(MNI: x=39, y=12, z=39) were stronger in HM group(all P<0.05, Alphasim Corrected). (2)In HM group, these changed FC were mainly detected in the anterior subregion of right caudate nucleus.(3)The increased FC of right caudate nucleus and its anterior subregion with left middle occipital in HM group were mainly reflected in the frequency band of slow-4(all P<0.05, Alphasim Corrected). Conclusion:The right caudate nucleus in adults with high myopia may play compensatory roles in visual perception and visual attention by enhancing its functional connectivity with visual and visual attentional brain areas.

目的:基于图论的复杂网络方法,探讨高度近视患者(HM)与视力正常者(NC)之间静息态脑功能连接网络的拓扑结构变化.方法:采集25例高度近视患者及27例视力正常被试的静息态fMRI数据,以BN246脑图谱为模板,分别构建两组样本的脑功能网络,计算和比较两组间脑网络的全局属性:小世界性、脑网络全局效能、脑网络局部效能,并进一步对比各节点属性:节点度、节点效能、节点聚类系数和节点局部效能的组间差异.结果:HM组和NC组的脑功能网络均具有小世界性,两组脑网络的小世界性在各稀疏度下均大于1.与NC组比较,HM组的网络局部效能显著降低(t=2.11,P＜0.05);HM组中部分视觉相关脑区的节点属性发生改变,双侧颞下回和右内侧顶枕沟的节点聚类系数和节点局部效能显著降低(t值分别为4.54、4.56、3.73、3.72、3.79和3.82,P值均＜0.001),右侧额下回岛盖的节点聚类系数降低(t=4.15,P＜0.001),右侧尾状核的节点度、节点效能均提高(t=3.74、t=3.72,P值均＜0.001),左侧杏仁核的节点聚类系数降低(t=3.54,P＜0.001).结论:高度近视人群的静息态脑功能连接网络具有小世界属性,但其视觉响应的注意力调制、视觉注意力及与情感相关的脑区节点属性发生了改变,提示高度近视者局部网络信息传递异常.

以十水碳酸钠和双氧水为原料,通过单滴加方式制备过碳酸钠球形颗粒,考察了碳酸钠反应液中碳酸钠的质量分数、六偏磷酸钠的质量分数、氯化钠的质量分数、滴加速率和搅拌速率对产品形貌的影响.结果表明:当碳酸钠反应液中碳酸钠质量分数为33％、六偏磷酸钠质量分数为0.18％、氯化钠的质量分数为16％、滴加速率为6 mL/min、搅拌速率为450 r/min时,可得到粒度大小均匀、颗粒圆整且致密性好的球形过碳酸钠颗粒.

目的:探索屈光参差性弱视患者静息状态下脑网络内及网络间功能连接的变化,为进一步了解弱视对脑功能的影响提供实验依据.方法:采集14名屈光参差性弱视儿童(AAC)和9名正常视力儿童(NSC)的静息态功能磁共振图像,提取其静息态功能连接(rsFC)作为特征,采用多变量模式分析进行分类,并使用单变量分析进行组间比较.结果:多变量模式分析对弱视儿童和正常视力儿童分类的正确率显著较高;弱视儿童组的默认网络内,默认网络与额顶控制网络及背侧注意网络之间的rsFC减弱.结论:基于rsFC的多变量模式分析可以将弱视儿童识别出来;弱视儿童组减弱的rsFC提示弱视儿童在调节外部和内部目标导向认知之间的动态平衡及相互转换以适应任务需求的能力减弱.

Objective To explore the differences of macrostructural and microstructural and their correlations in brain white matter (WM) between left-and right-handed adults.Methods Structural magnetic resonance imaging (sMRI) and diffusion tensor imaging (DTI) were performed on twenty-three left-handed (LH) and thirty-two right-handed (RH) healthy subjects.The WM volume,fractional anisotropy (FA) and mean diffusivity (MD) were mearsured and compared between the two groups by using the voxel-based morphometry (VBM) and voxel-based analysis (VBA) methods.Results (1) LH adults showed lower WM volume than RH adults in bilateral splenium of corpus callosum (SC) (Left:x=-15,y=-57,z =13.5,t=-5.160;Right:x=18,y=-42,z=12,t=-3.654;P＜0.001).Compared with the RH adults,the FA values in WM of the left postcentral gyrus (PoCG) (x =-24,y =-46,z =54) and the above left insula (INS) (x =-36,y =-12,z =20) increased (P＜ 0.001),as well as the average FA values,the average length and number of streamlines in WM tracts increased (P＜0.05) in LH adults.Compared with the RH adults,the MD values in the right HIP (x=24,y=-34,z=-2) decreased(P＜0.001),as well as the average MD values decreased,and the average length in WM tracts increased (P＜0.05) in LH adults.(2)There was positive correlation between FA and the volume of right splenium of corpus callosum in LH and RH adults (LH:r=0.716,RH:r=0.471,P＜0.05).There was negative correlation between FA and MD in the left PoCG (LH:r=-0.769,RH:r=-0.841),left INS (LH:r=-0.775,RH:r=-0.744) and right HIP (LH:r=-0.842,RH:r=-0.742) in LH and RH adults (all P＜0.05).Conclusion There are differences in both macrostructure and microstructure of white matter in several brain regions and WM tracts between left-handed and right-handed people,and correlations between these measures were also observed.

The thermodynamic properties of metamizol monohydrate in pure solvents(methanol,ethanol,n-propanol and isopropanol) and two binary mixed solvent systems including(methanol+ethanol) and(methanol+isopropanol) were measured from 283.15 K to 313.15 K by gravimetric method under atmospheric pressure thought as 0.1 MPa.The modi fied Apelblat equation,the CNIBS/R-K equation,the Hybrid model and the NRTL model were used to correlate the solubility of metamizol monohydrate,respectively.The results show that the solubility of metamizol monohydrate in all the tested solvents increases with the rising temperature which means that it has temperature dependence.What’s more,the effects of solvent components of the binary solvent mixtures on solubility were discussed,it illustrates that the increasing of the molar fraction of methanol gives the system a greater dissolving power.Furthermore,according to the NRTL model,the enthalpy,the Gibbs energy and the entropy of the mixing process were also obtained and discussed.

The solubility, metastable zone width, and induction time of analgin for unseeded batch cooling crystallization in ethanol–aqueous system were experimentally determined. The solubility data could be well described by the van't Hoff equation model. The metastable zone width at various cooling rates was measured, and some parameters of nucleation kinetic were calculated using the Ny'vlt theory. Furthermore, the induction period of various temperatures and supersaturation ratios was also measured. According to classical nucleation theory, some nucleation parameters and interfacial energy was calculated through the induction time (tind) data. Homogeneous nucleation tended to occur when the supersaturation is high, whereas heterogeneous nucleation was more likely to occur when the supersaturation is low.

The solid-liquid equilibrium data of erythromycin ethylsuccinate in six pure organic solvents including tetrahydrofuran, acetone, acetonitrile, hexane, ethanol and 2-propanol were determined by using the gravimetric method over the temperature range from 288.15K to 323.15K. The experimental solubility data was correlated by modified Apelblat equation, van't Hoff, Wilson, and NRTL model, among which the modified Apelblat model was found to have the best agreement with the experimental results. The mixing Gibbs free energy, mixing enthalpy, and mixing entropy were calculated by Non-random two liquid (NRTL) model. The solubility behavior of EES at given temperature were illustrated by Hansen SPs values.

The polymorphism of glycolide has been investigated. Form 1 and Form 2 of glycolide have been identified and characterized by X-ray powder diffraction (XRPD). Differential scanning calorimetry (DSC) and thermogravimetry (TG) analyses were carried out to study the thermodynamic stability relationships and the transition of the two forms of glycolide. Based on the heat of transition rule, Form 1 and Form 2 were determined as an enantiotropic system. The solubility measurements were done at 310.15 K under atmospheric pressure (0.1 MPa) by using the isothermal gravimetrical method for form 1 in this work. According to the solubility data of glycolide Form 1 and Form 2 in ethyl acetate, 1-propanol, 2-propanol, ethanol and 1-butanol, the transition temperature was then estimated by solubility extrapolation method, heat of transition (Delta H-tr) method and confirmed by isothermal transformation method at (308.35 +/- 0.5) K. Among these three methods, the isothermal transformation method provided the most accurate transition temperature with the help of suspended-transformation experiments monitored by online Raman spectroscopy. (C) 2017 Elsevier Ltd.

Solid-liquid equilibrium data of erythromycin thiocyanate dihydrate in four mono-solvents (methanol, ethanol, propan-1-ol and propan-2-ol) and three organic+water solvent mixtures (acetonitrile+water, acetone+water and ethanol+water) were determined by a gravimetric method under atmospheric pressure. The effects of content of organic solvents and temperature on the solubility were investigated and discussed. It was found that the content of organic solvents can significantly affect the solubility of erythromycin thiocyanate dihydrate. The modified Apelblat equation and NRTL model were applied to correlate the solubility data in mono-solvents. The GSM, two modified Jouyban-Acree models (the Van't-JA equation and the Apel-JA equation) and NRTL model were used to correlate the experimental data in three binary solvents systems. Computational results indicated that the AIC (Akaike's Information Criterion) values of two Jouyban-Acree models and NRTL model were lower than that of GSM in binary solvents mixtures, which means that the former three models are better for correlating the experimental solubility data. In addition, the mixing thermodynamic properties of erythromycin thiocyanate dihydrate in different solvents were also calculated based on the experimental solubility data and the NRTL model.

Co-crystals have advantages in physiochemical properties over their constituent components and are expected to use in product formulation such as enhanced active pharmaceutical ingredients, food components with improved absorbability, and specialty chemicals with better performance. The development of pharmaceutical co-crystals might offer advantages over the active pharmaceutical ingredients and overcome some of the limitations encountered with classical strategy (polymorph, solvate and salt formation). In recent years, co-crystals have recently gained much attention for pharmaceutical development especially because it has great advantages in improving the solubility, dissolution, melt point and oral bioavailability. Since the co-crystals lattice comprises two or more kinds of molecules, compared with the conventional structure of the drug crystal, intermolecular force comprising more types such as hydrogen, halogen bond, van der Waals forces,π-πinteraction, so the structure is more complex. The research on the co-crystals structure can be helpful to understand the formation mechanism. The definition, application, preparation and structure of co-crystals were reviewed, it will provide theoretical guidance for the studies of the following research.

The solubility of calcium D-pantothenate in (water + methanol) mixtures and the effect of beta-alanine on the solubility of calcium D-pantothenate in a constant mole ratio of methanol and water was measured from 263.15 K to 303.15 K by the HPLC analysis method (P = 0.1 MPa). The solubility of calcium D-pantothenate increased with increasing temperature in all the mixtures at constant composition. Besides, it also increased with mole fraction of water in (water + methanol) mixtures at a constant temperature. Additionally, the solubility of calcium h-pantothenate was enhanced by beta-alanine at a given temperature. The experimental solubility in (water + methanol) mixtures was correlated by the modified Apelblat equation, the ternary NRTL equation and Solubility-Polarity Model. The Apelblat equation, the quaternary NRTL equation and the Cohn equation were adopted to correlate the experimental solubility in the (water + methanol + beta-alanine) mixtures. Worthwhile, the quaternary NRTL equation was first applied to correlating the quaternary solid-liquid equilibrium. It turned out that all the selected models give good performance on solubility prediction. (C) 2016 Elsevier Ltd.

The concentration of analgin in ethanol-aqueous system was determined by using laser Raman and ATR-FTIR spectroscopy.Through comparing the spectrogram of the solvent and the analgin solution,the characteristic peak position of analgin was found.A linear relationship between the peak intensity and solution concentration was established.Off-line analysis and online monitoring of the concentration of analgin in the cooling crystallization process were done with Raman and ATR-FTIR spectroscopy.From the results,it was found that the signal of ATR-FTIR has a better response than Raman spectroscopy in the cooling crystallization process of analgin,so ATR-FTIR spectroscopy could be used for in situ monitor-ing of industrial production.

The gel-crystal transition during crystallization of Cefpiramide was systematically investigated for the first time in this letter. The results show that gelation is a metastable state, it comes from the three-dimensional mesh self-assembly structure made by carbonyl group, amide group and carboxyl group through hydrogen bonding interaction. After that, the gelator assembles to the crystals slowly, the equilibrium of gelation is broken up, the gel will return to the crystal finally.

Abnormal visual experience can affect the brain structure and function. Visual functional performances of high myopia (HM) individuals were observed to be abnormal in contrast to emmetropics, even with a corrected visual acuity. Attention deficits and brain morphological changes have been revealed in the HM, but it is unknown whether there are functional connectivity (FC) alterations. The current study combined the resting-state functional connectivity density (FCD) mapping and seed-based correlation analysis to investigate FC alterations in the brain of HM. In our results, the HM exhibited decreased short- and long-range FCD in the posterior cingulate cortex/precuneus and decreased long-range FCD in the inferior temporal gyrus, supramarginal gyrus and rostrolateral prefrontal cortex. Specially, long-range FCD in the rostrolateral prefrontal cortex showed a significant positive correlation with the uncorrected visual acuity in the HM. Moreover, the HM showed significantly decreased FC not only between the supramarginal gyrus and rostrolateral prefrontal cortex, but also between networks they belong to, the ventral attention and frontoparietal control networks. These results provide evidence for the FC changes in the HM and may help to understand the attention deficits in myopes.

Amblyopia is a neurological disorder of vision that follows abnormal binocular interaction or visual deprivation during early life. Previous studies have reported multiple functional or structural cortical alterations. Although white matter was also studied, it still cannot be clarified clearly which fasciculus was affected by amblyopia. In the present study, tract-based spatial statistics analysis was applied to diffusion tensor imaging (DTI) to investigate potential diffusion changes of neural tracts in anisometropic amblyopia. Fractional anisotropy (FA) value was calculated and compared between 20 amblyopic children and 18 healthy age-matched controls. In contrast to the controls, significant decreases in FA values were found in right optic radiation (OR), left inferior longitudinal fasciculus/inferior fronto-occipital fasciculus (ILF/IFO) and right superior longitudinal fasciculus (SLF) in the amblyopia. Furthermore, FA values of these identified tracts showed positive correlation with visual acuity. It can be inferred that abnormal visual input not only hinders OR from well developed, but also impairs fasciculi associated with dorsal and ventral visual pathways, which may be responsible for the amblyopic deficiency in object discrimination and stereopsis. Increased FA was detected in right posterior part of corpus callosum (CC) with a medium effect size, which may be due to compensation effect. DTI with subsequent measurement of FA is a useful tool for investigating neuronal tract involvement in amblyopia.

Amblyopia is a developmental disorder resulting from anomalous binocular visual input in early life. Task-based neuroimaging studies have widely investigated cortical functional impairments in amblyopia, but changes in spontaneous neuronal functional activities in amblyopia remain largely unknown. In the present study, functional connectivity density (FCD) mapping, an ultrafast data-driven method based on fMRI, was applied for the first time to investigate changes in cortical functional connectivities in amblyopia during the resting-state. We quantified and compared both short- and long-range FCD in both the brains of children with anisometropic amblyopia (AAC) and normal sighted children (NSC). In contrast to the NSC, the AAC showed significantly decreased short-range FCD in the inferior temporal/fusiform gyri, parieto-occipital and rostrolateral prefrontal cortices, as well as decreased long-range FCD in the premotor cortex, dorsal inferior parietal lobule, frontal-insular and dorsal prefrontal cortices. Furthermore, most regions with reduced long-range FCD in the AAC showed decreased functional connectivity with occipital and posterior parietal cortices in the AAC. The results suggest that chronically poor visual input in amblyopia not only impairs the brain's short-range functional connections in visual pathways and in the frontal cortex, which is important for cognitive control, but also affects long-range functional connections among the visual areas, posterior parietal and frontal cortices that subserve visuomotor and visual-guided actions, visuospatial attention modulation and the integration of salient information. This study provides evidence for abnormal spontaneous brain activities in amblyopia.