Multivariate Analysis of Solubility Parameters for Drug-Polymer Miscibility Assessment in Preparing Raloxifene Hydrochloride Amorphous Solid Dispersions.

The success of obtaining solid dispersions for solubility improvement invariably depends on the miscibility of the drug and polymeric carriers. This study aimed to categorize and select polymeric carriers via the classical group contribution method using the multivariate analysis of the calculated solubility parameter of RX-HCl. The total, partial, and derivate parameters for RX-HCl were calculated. The data were compared with the results of excipients (N = 36), and a hierarchical clustering analysis was further performed. Solid dispersions of selected polymers in different drug loads were produced using solvent casting and characterized via X-ray diffraction, infrared spectroscopy and scanning electron microscopy. RX-HCl presented a Hansen solubility parameter (HSP) of 23.52 MPa1/2. The exploratory analysis of HSP and relative energy difference (RED) elicited a classification for miscible (n = 11), partially miscible (n = 15), and immiscible (n = 10) combinations. The experimental validation followed by a principal component regression exhibited a significant correlation between the crystallinity reduction and calculated parameters, whereas the spectroscopic evaluation highlighted the hydrogen-bonding contribution towards amorphization. The systematic approach presented a high discrimination ability, contributing to optimal excipient selection for the obtention of solid solutions of RX-HCl.

A rapid solid form risk assessment workflow for ophthalmic drug candidates.

OBJECTIVE: This work introduces a material-sparing process that rapidly screens the solid form landscape for ophthalmic compound candidates. SIGNIFICANCE: Crystalline form of compound candidates generated by a Form Risk Assessment (FRA) can be used to reduce their downstream development risk. METHODS: This workflow evaluated nine model compounds with various molecular and polymorphic profiles by using less than 350 mg of drug substances. Kinetic solubility of the model compounds in a variety of solvents was screened to support the experimental design. The FRA workflow integrated several crystallization methods such as temperature-cycled slurrying (thermocycling), cooling, and evaporation. The FRA was also applied on ten ophthalmic compound candidates for verification. X-ray powder diffractometry (XRPD) was used for form identification. RESULTS: For the nine model compounds studied, multiple crystalline forms were generated. This demonstrates the potential of the FRA workflow to reveal polymorphic tendency. In addition, thermocycling process was found to be the most effective technique to capture the thermodynamically most stable form. Satisfactory results were observed with the discovery compounds intended for ophthalmic formulations. CONCLUSIONS: This work introduces a form risk assessment workflow by using sub-gram level of drug substances. The capability of this material-sparing workflow to discover polymorphs and capture the thermodynamically most stable forms within 2-3 weeks makes it suitable for discovery stage compounds, especially for ophthalmic candidates.

Current Trends in API Co-Processing: Spherical Crystallization and Co-Precipitation Techniques.

Active Pharmaceutical Ingredients (APIs) do not always exhibit processable physical properties, which makes their processing in an industrial setup very demanding. These issues often lead to poor robustness and higher cost of the drug product. The issue can be mitigated by co-processing the APIs using suitable solvent media-based techniques to streamline pharmaceutical manufacturing operations. Some of the co-processing methods are the amalgamation of API purification and granulation steps. These techniques also exhibit adequate robustness for successful adoption by the pharmaceutical industry to manufacture high quality drug products. Spherical crystallization and co-precipitation are solvent media-based co-processing approaches that enhances the micromeritic and dissolution characteristics of problematic APIs. These methods not only improve API characteristics but also enable direct compression into tablets. These methods are economical and time-saving as they have the potential for effectively circumventing the granulation step, which can be a major source of variability in the product. This review highlights the recent advancements pertaining to these techniques to aid researchers in adopting the right co-processing method. Similarly, the possibility of scaling up the production of co-processed APIs by these techniques is discussed. The continuous manufacturability by co-processing is outlined with a short note on Process Analytical Technology (PAT) applicability in monitoring and improving the process.

Selection of cost-effective magnesium sources for fluidized struvite crystallization.

Struvite crystallization has been considered a promising approach to recover phosphorus from wastewater. However, its practical application is limited, probably because of the high cost of magnesium (Mg). In this study, a comprehensive economic analysis was conducted using five Mg sources (MgCl2, MgSO4, MgO, Mg(OH)2, and bittern) during the operation of a pilot-scale fluidized bed reactor (FBR), using swine wastewater as the case matrix. First, the economic operating conditions were investigated, and subsequently, the performance and the costs of the five Mg sources were compared. The results indicated that the FBR could be operated most economically at pH of 8.5 and Mg to phosphorus (Mg/P) molar ratio of 1.5. Under these conditions, no significant differences in phosphorus removal and product quality could be found between the five Mg sources. Selecting the most economical Mg source was thus highly dependent on the prices of the reagents and Mg sources. Low-solubility Mg sources were preferable when NaOH was priced higher, while high-solubility Mg sources proved more economical when HNO3 was expensive. The bittern was the most economical choice only when the distances for total inorganic orthophosphate removal and struvite recovery were shorter than 40 and 270km, respectively. The current study provides an overview of the economic selection of an Mg source, which can help reduce the cost of struvite crystallization.

Milling and comilling Praziquantel at cryogenic and room temperatures: Assessment of the process-induced effects on drug properties.

This study is a comprehensive evaluation of praziquantel (PZQ) behavior upon grinding considering the influence of milling temperature (cryogenic vs room temperature), frequency and time and presence of polymers (milled raw PZQ vs comilled PZQ/povidone and PZQ/crospovidone at 50:50 w/w) on two experimental responses (residual crystallinity and PZQ recovery). To this aim a full factorial design was set up and the responses of the experimental design were statistically assessed. The powder temperature, measured in different milling conditions, was found to increase with increasing milling frequency and time, up to a maximum recorded value of 46.9 °C (after 90 min at R.T.), for all the three powder systems. When PZQ was ground in RT environment, the recovery was 100%, independently from frequency and time of milling. Its residual crystallinity remained pronounced (>70%) upon milling, even if treated at the most severe conditions. Conversely, when the drug was milled in presence of the polymers, it showed a higher tendency to degradation and amorphysation, independently from the choice of the polymer. The use of cryogenic conditions, operating at temperatures lower than PZQ glass transition, permitted to dramatically reduce PZQ residual crystallinity when the drug was ground by itself. In the case of binary mixtures, the switch to a cryogenic environment did not affect significantly the experimental responses, but permitted to obtain a more predictable trend of both drug recovery and residual crystallinity when varying time and frequency of milling.

Comparative Assessment of Miniaturized Screening Approaches for Selection of Polymers for Amorphous Drug Stabilization.

The present work highlights the use of miniaturized approaches to screen and prioritize development of solid dispersions that provide stabilization of the amorphous drug against crystallization and enhanced dissolution over the crystalline form. The approaches evaluated include solvent casting and solvent displacement-based techniques. Four compounds were evaluated with both these screening approaches. A dual-pH dilution method using fasted state simulated gastric fluid and fasted state simulated intestinal fluid as media was used to evaluate solubility enhancement ratio in each well of the screen. The concentration at 15 mins after dilution with fasted state simulated intestinal fluid and super-saturation ratio at the end of the dissolution study is used as 2 descriptors of solubility enhancement. The empirical screening approaches were supplemented with theoretical calculations of solubility enhancement to gauge the best-performing amorphous solid dispersion (ASD). Physical stability of the amorphous systems was also evaluated, where applicable. Lead ASD compositions from the screens were scaled up to verify the predictions. To our knowledge, this is the first report where the 2 most common screening approaches for the development of ASDs are compared head to head. These approaches are rapid, material sparing, and can be adapted to accommodate screening of multiple variables such as polymer type, drug load, and ternary systems simultaneously. The strengths, limitations, and most suitable applications for each of the 2 methods are also discussed.

Gentle, fast and effective crystal soaking by acoustic dispensing.

The steady expansion in the capacity of modern beamlines for high-throughput data collection, enabled by increasing X-ray brightness, capacity of robotics and detector speeds, has pushed the bottleneck upstream towards sample preparation. Even in ligand-binding studies using crystal soaking, the experiment best able to exploit beamline capacity, a primary limitation is the need for gentle and nontrivial soaking regimens such as stepwise concentration increases, even for robust and well characterized crystals. Here, the use of acoustic droplet ejection for the soaking of protein crystals with small molecules is described, and it is shown that it is both gentle on crystals and allows very high throughput, with 1000 unique soaks easily performed in under 10 min. In addition to having very low compound consumption (tens of nanolitres per sample), the positional precision of acoustic droplet ejection enables the targeted placement of the compound/solvent away from crystals and towards drop edges, allowing gradual diffusion of solvent across the drop. This ensures both an improvement in the reproducibility of X-ray diffraction and increased solvent tolerance of the crystals, thus enabling higher effective compound-soaking concentrations. The technique is detailed here with examples from the protein target JMJD2D, a histone lysine demethylase with roles in cancer and the focus of active structure-based drug-design efforts.

Fixed target combined with spectral mapping: approaching 100% hit rates for serial crystallography.

The advent of ultrafast highly brilliant coherent X-ray free-electron laser sources has driven the development of novel structure-determination approaches for proteins, and promises visualization of protein dynamics on sub-picosecond timescales with full atomic resolution. Significant efforts are being applied to the development of sample-delivery systems that allow these unique sources to be most efficiently exploited for high-throughput serial femtosecond crystallography. Here, the next iteration of a fixed-target crystallography chip designed for rapid and reliable delivery of up to 11 259 protein crystals with high spatial precision is presented. An experimental scheme for predetermining the positions of crystals in the chip by means of in situ spectroscopy using a fiducial system for rapid, precise alignment and registration of the crystal positions is presented. This delivers unprecedented performance in serial crystallography experiments at room temperature under atmospheric pressure, giving a raw hit rate approaching 100% with an effective indexing rate of approximately 50%, increasing the efficiency of beam usage and allowing the method to be applied to systems where the number of crystals is limited.

Modelling and shadowgraph imaging of cocrystal dissolution and assessment of in vitro antimicrobial activity for sulfadimidine/4-aminosalicylic acid cocrystals.

PURPOSE: The aim of this work was to evaluate the influence of crystal habit on the dissolution and in vitro antibacterial and anitiprotozoal activity of sulfadimidine:4-aminosalicylic acid cocrystals. METHODS: Cocrystals were produced via milling or solvent mediated processes. In vitro dissolution was carried out in the flow-through apparatus, with shadowgraph imaging and mechanistic mathematical models used to observe and simulate particle dissolution. In vitro activity was tested using agar diffusion assays. RESULTS: Cocrystallisation via milling produced small polyhedral crystals with antimicrobial activity significantly higher than sulfadimidine alone, consistent with a fast dissolution rate which was matched only by cocrystals which were milled following solvent evaporation. Cocrystallisation by solvent evaporation (ethanol, acetone) or spray drying produced flattened, plate-like or quasi-spherical cocrystals, respectively, with more hydrophobic surfaces and greater tendency to form aggregates in aqueous media, limiting both the dissolution rate and in vitro activity. Deviation from predicted dissolution profiles was attributable to aggregation behaviour, supported by observations from shadowgraph imaging. CONCLUSIONS: Aggregation behaviour during dissolution of cocrystals with different habits affected the dissolution rate, consistent with in vitro activity. Combining mechanistic models with shadowgraph imaging is a valuable approach for dissolution process analysis.

Assessment of microcrystal quality by transmission electron microscopy for efficient serial femtosecond crystallography.

Serial femtosecond crystallography (SFX) employing high-intensity X-ray free-electron laser (XFEL) sources has enabled structural studies on microcrystalline protein samples at non-cryogenic temperatures. However, the identification and optimization of conditions that produce well diffracting microcrystals remains an experimental challenge. Here, we report parallel SFX and transmission electron microscopy (TEM) experiments using fragmented microcrystals of wild type (WT) homoprotocatechuate 2,3-dioxygenase (HPCD) and an active site variant (H200Q). Despite identical crystallization conditions and morphology, as well as similar crystal size and density, the indexing efficiency of the diffraction data collected using the H200Q variant sample was over 7-fold higher compared to the diffraction results obtained using the WT sample. TEM analysis revealed an abundance of protein aggregates, crystal conglomerates and a smaller population of highly ordered lattices in the WT sample as compared to the H200Q variant sample. While not reported herein, the 1.75 Å resolution structure of the H200Q variant was determined from ∼16 min of beam time, demonstrating the utility of TEM analysis in evaluating sample monodispersity and lattice quality, parameters critical to the efficiency of SFX experiments.

High-density grids for efficient data collection from multiple crystals.

Higher throughput methods to mount and collect data from multiple small and radiation-sensitive crystals are important to support challenging structural investigations using microfocus synchrotron beamlines. Furthermore, efficient sample-delivery methods are essential to carry out productive femtosecond crystallography experiments at X-ray free-electron laser (XFEL) sources such as the Linac Coherent Light Source (LCLS). To address these needs, a high-density sample grid useful as a scaffold for both crystal growth and diffraction data collection has been developed and utilized for efficient goniometer-based sample delivery at synchrotron and XFEL sources. A single grid contains 75 mounting ports and fits inside an SSRL cassette or uni-puck storage container. The use of grids with an SSRL cassette expands the cassette capacity up to 7200 samples. Grids may also be covered with a polymer film or sleeve for efficient room-temperature data collection from multiple samples. New automated routines have been incorporated into the Blu-Ice/DCSS experimental control system to support grids, including semi-automated grid alignment, fully automated positioning of grid ports, rastering and automated data collection. Specialized tools have been developed to support crystallization experiments on grids, including a universal adaptor, which allows grids to be filled by commercial liquid-handling robots, as well as incubation chambers, which support vapor-diffusion and lipidic cubic phase crystallization experiments. Experiments in which crystals were loaded into grids or grown on grids using liquid-handling robots and incubation chambers are described. Crystals were screened at LCLS-XPP and SSRL BL12-2 at room temperature and cryogenic temperatures.

Enhancement of nucleation of protein crystals on nano-wrinkled surfaces.

The synthesis of high quality protein crystals is essential for determining their structure. Hence the development of strategies to facilitate the nucleation of protein crystals is of prime importance. Recently, Ghatak and Ghatak [Langmuir 2013, 29, 4373] reported heterogeneous nucleation of protein crystals on nano-wrinkled surfaces. Through a series of experiments on different proteins, they were able to obtain high quality protein crystals even at low protein concentrations and sometimes without the addition of a precipitant. In this study, the mechanism of protein crystal nucleation on nano-wrinkled surfaces is studied through Monte Carlo simulations. The wrinkled surface is modeled by a sinusoidal surface. Free-energy barriers for heterogeneous crystal nucleation on flat and wrinkled surfaces are computed and compared. The study reveals that the enhancement of nucleation is closely related to the two step nucleation process seen during protein crystallization. There is an enhancement of protein concentration near the trough of the sinusoidal surface which aids in nucleation. However, the high curvature at the trough acts as a deterrent to crystal nucleus formation. Hence, significant lowering of the free-energy barrier is seen only if the increase in the protein concentration at the trough is very high.

The use of the software JST-XRD for identification of crystalline phases in pharmaceutical raw materials and tablets / Uso do software JST-XRD para identifcação de fases cristalinas em insumos farmacêuticos e medicamentos

Study of polymorphism is of great importance for the pharmaceutical industry once polymorphs may display different physicochemical properties, which, in turn, may result in stability differences that can bring problems for the manufacturing stages and the quality of fnal products. Although research on organic polymorphs has greatly increased in the last decades, it still does not cover all needs for the pharmaceutical market. Techniques such as spectroscopy in the infrared region, nuclear magnetic resonance, thermal analysis, X-ray diffraction, etc., can be used to identify polymorphism. The polymorphism is a property of the crystalline solid state, and can be evaluated by X-ray diffraction once each polymorph exhibits one specifc X-ray diffraction pattern. The JST-XRD program is a tool designed to help the identifcation of crystalline phases (including polymorphs) present in pharmaceutical ingredients and tablets by using X-ray diffraction data obtained from scientifc articles and patents. This paper presents new implementations for the JST-XRD and describes its use in the analysis of active pharmaceutical ingredient and marketed tablets of norfloxacin, mebendazole and atorvastatin calcium. By the means of comparison, JSTXRD allowed identifying the crystalline phases in the diffraction patterns of the analyzed drugs, showing the program suitability for polymorphism research, pre-formulation and quality control in pharmaceutical industries. JST-XRD can also be used for educational purposes in undergraduate and graduate programs in order to show the potentiality of X-ray powder diffraction in polymorphism analysis.(AU)

O estudo do polimorfsmo é de grande importância na indústria farmacêutica porque os polimorfos podem apresentar diferentes propriedades físico-químicas, podendo resultar em diferenças na estabilidade e desse modo causar problemas nas etapas de manufatura e no produto fnal. Embora a pesquisa de moléculas orgânicas que apresentam polimorfsmo tenha aumentado bastante nas últimas décadas, ainda não contempla todas as necessidades do mercado farmacêutico. Para a identifcação de polimorfsmo podem ser utilizadas técnicas como espectroscopia na região do infravermelho, ressonância nuclear magnética, análise térmica (DSC), difração de raios X, etc. O polimorfsmo, por ser uma propriedade do estado sólido e cristalino, pode ser avaliado através da difração de raios X, já que cada polimorfo apresenta um padrão de difração de raios X único. O programa JST-XRD é uma ferramenta projetada para auxiliar a identifcação de fases cristalinas, incluindo polimorfos, presentes em insumos farmacêuticos e comprimidos, usando dados de difração de raios X obtidos em artigos científcos e patentes. Esse trabalho apresenta novas implementações no JST-XRD e descreve seu uso na análise de amostras de princípio ativo e comprimidos comerciais de norfloxacino, mebendazol e atorvastatina cálcica. Através das comparações realizadas, JSTXRD permitiu identifcar todas as fases cristalinas dos difratogramas dos fármacos analisados, mostrando que o programa é adequado para pesquisa em polimorfsmo; na pré-formulação e controle de qualidade em indústrias farmacêuticas, assim como para uso didático em cursos de graduação e pós-graduação a fm de mostrar as potencialidades da difração de raios X na análise de polimorfsmo.(AU)

Solution-Processed Large-Area Nanocrystal Arrays of Metal-Organic Frameworks as Wearable, Ultrasensitive, Electronic Skin for Health Monitoring.

Pressure sensors based on solution-processed metal-organic frameworks nanowire arrays are fabricated with very low cost, flexibility, high sensitivity, and ease of integration into sensor arrays. Furthermore, the pressure sensors are suitable for monitoring and diagnosing biomedical signals such as radial artery pressure waveforms in real time.

Nanoscale control of surface immobilized BMP-2: toward a quantitative assessment of BMP-mediated signaling events.

In this work we determine the impact of surface density of immobilized BMP-2 on intracellular signal transduction. We use block copolymer micellar nanolithography to fabricate substrates with precisely spaced and tunable gold nanoparticle arrays carrying single BMP-2 molecules. We found that the immobilized growth factor triggers prolonged and elevated Smad signaling pathway activation compared to the same amount of soluble protein. This approach is suitable for achieving controlled and sustained local delivery of BMP-2 and other growth factors.

Efficient Mammalian Cell Expression and Single-step Purification of Extracellular Glycoproteins for Crystallization.

Production of secreted mammalian proteins for structural and biophysical studies can be challenging, time intensive, and costly. Here described is a time and cost efficient protocol for secreted protein expression in mammalian cells and one step purification using nickel affinity chromatography. The system is based on large scale transient transfection of mammalian cells in suspension, which greatly decreases the time to produce protein, as it eliminates steps, such as developing expression viruses or generating stable expressing cell lines. This protocol utilizes cheap transfection agents, which can be easily made by simple chemical modification, or moderately priced transfection agents, which increase yield through increased transfection efficiency and decreased cytotoxicity. Careful monitoring and maintaining of media glucose levels increases protein yield. Controlling the maturation of native glycans at the expression step increases the final yield of properly folded and functional mammalian proteins, which are ideal properties to pursue X-ray crystallography. In some cases, single step purification produces protein of sufficient purity for crystallization, which is demonstrated here as an example case.

Fabrication, solid state characterization and bioavailability assessment of stable binary amorphous phases of Ritonavir with Quercetin.

In the current study, Quercetin (QRT) was characterized for thermodynamic and kinetic parameters and found as an excellent glass former. QRT was paired with Ritonavir (RTV) (BCS class-IV antiretroviral) to form stable amorphous form and pharmacologically relevant combination. Binary amorphous forms of RTV and QRT in molar ratios 1:1, 1:2 and 2:1 were prepared by solvent evaporation technique and characterized by XRPD, DSC and FTIR. The prepared binary phases were found to become amorphous after solvent evaporation which was confirmed by disappearance of crystalline peaks from X-ray diffractograms and detecting single Tg in DSC studies. The physical stability studies at 40 °C for 90 days found RTV:QRT 1:2 and RTV:QRT 2:1 phases stable, while trace crystallinity was detected for 1:1M ratio. The temperature stability of RTV:QRT 1:2 and RTV:QRT 2:1 amorphous forms can be attributed to phase solubility of both components where the drug in excess acts as a crystallization inhibitor. Except for RTV:QRT 1:2 ratio, there was no evidence of intermolecular interactions between two components. Almost 5 fold increase in the saturation solubility was achieved for RTV, compared to crystalline counterpart. While for QRT, the solubility advantage was not achieved. In vivo oral bioavailability study was conducted for 1:2 binary amorphous form by using pure RTV as a control. Cmax was improved by 1.26 fold and Tmax was decreased by 2h after comparing with control indicating improved absorption. However no significant enhancement of oral bioavailability (1.12 fold after comparing with control) was found for RTV.

Assessment of crystallinity in processed sucrose by near-infrared spectroscopy and application to lyophiles.

The objective of this study was to investigate the capability of near-infrared spectroscopy (NIRS) to determine crystallinity in processed sucrose using a common set of calibration standards derived from binary physical mixtures. NIRS was applied as a primary method using binary mixtures of amorphous and crystalline standards to predict crystallinity in sucrose that was either rendered partially amorphous by milling, partially recrystallized from the amorphous phase, or amorphous lyophiles annealed to induce recrystallization. Crystallinity prediction in the case of milled crystalline and recrystallized amorphous sucrose was feasible using the two-state binary calibration mixtures applying a univariate model. NIRS results for milled sucrose were comparable to those obtained using X-ray powder diffraction. The changes in crystallinity after milling and recrystallization showed expected trends. However, the same NIRS univariate calibration method could not be successfully applied for directly through the vial. To overcome this complication, NIRS was applied as a secondary method relative to water vapor sorption (WVS) where a set of processed samples were measured using both NIRS and WVS and a partial least-squares model applied. The NIRS secondary method was successfully applied and provided a standard error of calibration of 2.11% and standard error of prediction of 3.76%.

A simplified method to attach antibodies on liposomes by biotin-streptavidin affinity for rapid and economical screening of targeted liposomes.

The biotin-Streptavidin (STREP) technique for attachment of monoclonal antibodies (mAbs) (or other ligand types) on liposome surface offers high attachment yield, however it is time consuming and expensive due to the number of steps used and the consumption of large quantities of STREP. Herein, a simplified, fast and economic technique, by incubating pre-mixed biotin-mAb/STREP with biotin-liposomes, at a 3:1:1 biotin-mAb/STREP/biotin-LIP ratio (mol/mol/mol) was evaluated. The physichochemical properties, final mAb attachment yield and targeting potential of liposomes decorated with an anti-transferrin receptor mAb (TfR-mAb), prepared by the simple method (SM) and the conventional method (CM), were compared. The vesicle uptake by hCMEC/D3 cells (known to overexpress TfR) were considered as a measure of liposome targeting capability. Results show that both targeted liposome types (SM and CM) have small size (mean diameters around 150 nm), low poly-dispersity (approx. 0.20) and similar mAb attachment yield (between 64-88%). However, the uptake of the SM-liposomes is slightly lower compared to CM-LIP (24-30% decrease), suggesting that the modulated conformation of mAbs on the liposome surface (triplets attached to one single STREP molecule) results in decreased targeting capability. Nevertheless, the simpler and faster one-step preparation procedure which has very high lipid recovery (> 95%) compared to the CM (50-60%) and 15-30 times lower consumption of STREP, may be a good alternative for initial screening of various mAbs as ligands for targeted liposomal or other nanotechnologies, during pre-clinical development.

Green and economical synthesis of carbon-coated MoO2 nanocrystallines with highly reversible lithium storage capacity.

Carbon-coated MoO2 nanocrystallines with uniform particle size and carbon-coating morphology have been fabricated by a green and economical hydrothermal route and carbonization process. Glucose here acts as a multifunctional agent, not only as the reducing species to prepare MoO2, but also as the carbonaceous precursor and coating agent to form the carbon-coated and nanoscale MoO2 crystallines. The electrochemical tests demonstrate that the as-synthesized carbon-coated MoO2 nanocrystallines exhibit high capacity and excellent capacity retention as an anode material for lithium-ion batteries. The specific discharge capacity is as high as 790 mA h g(-1) in the first cycle and 730 mA h g(-1) over 50 cycles. The significant enhancement in the electrochemical Li storage performance is attributed to the synergistic effect of the nanocrystallines structure with small particle size and uniform carbon-coating shell, which reduces the diffusion distance for Li-ion and electron, provides high electric conductivity and relieves the volume effect during the cycling.