Residual Solvent Research Articles

ESTIMATION OF RESIDUAL SOLVENTS IN NETUPITANT API BY HEADSPACE GAS CHROMATOGRAPHY

Objective: Residual solvents are undesirable components present in Active Pharmaceutical Ingredients (API), excipients, or drug products. To meet the specific quality-based requirements, the presence of these solvents in pharmaceutical products should be monitored to ensure their safety. The main objective of this work is to develop a new method for the determination of residual solvents in netupitant API by an HS-GC method with an FID detector. Methods: An automated headspace GC method has been developed and validated for the estimation of the residual solvents-N-methyl pyrrolidine, xylene, toluene, and N, N Dimethylacetamide in netupitant API. The samples were dissolved in dimethyl sulfoxide and the equilibrium headspace gas was formed at 80 ᵒC, which was analyzed using a DB-624 column (30m*0.53 mm, 3.00 µm) with an injector and detector temperature set at 160 ᵒC and 230 ᵒC, respectively. The initial oven temperature was set at 60 ᵒC for 5 min and programmed at a rate of 10 ᵒC/min to the final temperature of 150 ᵒC, with a hold time of 5 min by maintaining the flow rate of 4.0 ml/min with a split ratio of 1:10, and total run time of 20 min. Nitrogen was used as carrier gas. The method developed was validated as per International Conference for Harmonization (ICH) guidelines for repeatability, linearity, range, ruggedness, detection limit, quantification limit, and recovery studies. Results: The linearity range selected was 50-350µg/ml and the correlation coefficient(γ2) values for all the solvents were found to be>0.99; recovery studies values were in a range of 90-110% and %RSD values were also found to be not more than 10 for the solvents. Conclusion: A novel, accurate, sensitive, and simple method was described for estimating residual solvents in Netupitant API by Headspace Gas Chromatography (HS-GC) coupled with a Flame Ionization Detector (FID). Excellent results have been observed for all the validated parameters with good peak resolution and lesser retention times.

Development and Validation of Head-space Gas Chromatographic Method in Tandem with Flame ionized detection for the determination of Residual solvents in Simeprevir API Synthesis

Residual solvent testing is an integral part of reference material certification. A gas chromatography/flame ionization detector/headspace method has been developed and validated to detect and quantitate commonly used residual solvents in our production processes: Methanol, Tetrahydrofuran, Toluene, Dichloromethane and Dichloroethane in Simeprevir API. A simple and selective HS-GC method is described for the determination & quantification of Residual Solvents in Simeprevir API. Chromatographic separation was achieved on USP G43 equivalent capillary column Thermo Scientific™ Trace GOLD™ TG-624 SilMS, 30m × 0.32mm × 1.8µm column (P/N 26059-3390) using nitrogen as carrier gas by using different temperature gradient of FID Detectors. Linearity was observed in the range 40-120% of standard concentrations for Methanol, Tetrahydrofuran, Toluene, Dichloromethane and Dichloroethane (r2>0.999) for the amount of solvent estimated by the proposed methods was in good agreement. The proposed methods were validated. The accuracy of the methods was assessed by recovery studies at three different levels. Recovery experiments indicated the absence of interference from commonly encountered diluent and API. The method was found to be precise as indicated by the repeatability analysis, showing %RSD less than 10 for Methanol, Tetrahydrofuran, Toluene, Dichloromethane and Dichloroethane. All statistical data proves validity of the methods and can be used for routine analysis of pharmaceutical active ingredients for estimation of Residual Solvents of Methanol, Tetrahydrofuran, Toluene, Dichloromethane and Dichloroethane in Simeprevir. Baseline separation of all five solvents and Simeprevir API is achieved within 20.5 minutes of analysis time. Method validation comprised the following parameters: limit of detection (LOD), limit of quantitation (LOQ), linearity and range, accuracy, precision (repeatability and intermediate precision), system suitability, specificity, and robustness. Linearity and LOQ (ppm) are listed for each solvent in manuscript. The present method was proven to be robust and accurate for quantitative analysis of residual solvent in neat materials.

European fingerprint study on omeprazole drug substances using a multi analytical approach and chemometrics as a tool for the discrimination of manufacturing sources

Like drug products, Active Pharmaceutical Ingredients (APIs) are subject to substandard and falsification issues, which represent a threat to patient health. In order to monitor the quality of drug substances and prevent the use of non-compliant APIs, Official Medicine Control Laboratories work together in a European network developing coordinated strategies and programmes. The API working group proposed a market surveillance study on omeprazole and omeprazole magnesium with the objectives of controlling the pharmaceutical quality of samples, checking compliance with the monographs of the European Pharmacopoeia, and collecting analytical fingerprints that could be further used to differentiate manufacturing sources for future authenticity investigations.The study described in this article reports the analysis carried out by 7 European laboratories on 28 samples from 11 manufacturers with 5 analytical techniques (related substances with HPLC, residual solvents with GC-MS, near infrared spectroscopy, proton nuclear magnetic resonance spectroscopy and X-ray powder diffractometry). The large amount of resulting analytical data were centralized and treated with two chemometric methods: Principal Component Analysis and Hierarchical Clustering Analysis. Data were analyzed separately and in combination (data fusion), allowing us to conclude that NMR and XRPD were suitable to differentiate samples originating from 9 out of 11 manufacturers. Analytical fingerprints associated with chemometrics were demonstrated to be a valuable methodology to discriminate manufacturers of omeprazole and omeprazole magnesium APIs and detect future substandard and falsified APIs.

Full evaporation headspace gas chromatography with thermal conductivity detection for the direct determination of water in solid pharmaceutical bulk products

Headspace gas chromatography (HS-GC) has the potential to be used for water determination in pharmaceutical products. In this article, its use for the determination of water in solid samples is explored without the need of dissolution by means of the full evaporation technique (FET). This way, water is thermally removed from a small amount of sample which is directly weighed in the vial. This simplifies considerably the method since no diluent has to be searched and HS saturation is avoided. Blank corrections were performed to compensate for atmospheric moisture variation. Moreover, the performance of mass spectrometry (MS) and thermal conductivity detection (TCD) was compared. The method showed excellent figures of merit when working with TCD, such as R2> 0.99 and RSD< 5% for each level of the calibration curve. Eight samples were carefully studied at different equilibration temperatures to find the optimal working conditions for each case and the results were compared to the ones obtained by Karl Fischer titration (KFT). Both methods showed restrictions and proper case by case optimization/validation turned out to be mandatory. Hyphenation with a flame ionization detector (FID) in series with the TCD showed the benefit to be useful for testing residual solvents (RS) simultaneously.

On the relevance of toxicological and hygienic assessment and market regulation of herbal dietary supplements made from Mitragyna speciosa Korth (Rubiaceae family)

Ukraine today does not regulate the sale of products made of Kratom (Mitragyna speciosa Korth. (from the family Rubiaceae) and does not take measures to control the quality and safety of this product, despite its rapid spread throughout the country. Аim of the Work is to summarize the results of scientific research on the toxicity of alternative opioids contained in Mitragyna speciosa and combined products based on them. Material and methods. Reports from the World Health Organization (WHO), the European Monitoring Center for Drugs and Drug Addiction (EMCDDA), the United Nations Office on Drugs and Crime, the results of scientific reviews and individual studies on biochemistry, toxicology, forensic identification of substances contained in products made from Mitragyna speciosa, over the past 10 years (Elsevier, PubMed, ToxNet). Results and Discussion. Recently, kratom has been cultivated on different continents and entered the market under the name "Kратом", in English-language sources - "Kratom". Kratom leaves are dried and sold in the form of green powder, tablets, capsules, extracts and gummies. In Ukraine, kratom is sold under hundreds of commercial names on the Internet as "Kratom", "Kratom product", "Kratom organic tea", "Kratom ethnic tea", "Kratom tea" and others. More than 40 structurally related alkaloids, as well as several flavonoids, terpenoid saponins, polyphenols and various glycosides were found in kratom leaves. The pharmacological and toxic effects of kratom for most of its components have not been studied enough. Like other dietary supplements, kratom products should be standardized for alkaloids, microbial contamination, pesticides, heavy metals, residual solvents, benzo(a)pyrene, aflatoxins, etc., with appropriate labeling requirements. Conclusions. Quality products should enter the Ukrainian market - standardized leaf extract of kratom, or other safe products made on its basis. However, recent studies show that mitraginine contained in kratom has great potential for medical science as a model for developing new approaches in very relevant areas of medicine: to treat pain and get rid of opioid dependence. Key Words: Mitragyna speciosa, alternative opioids, toxicity.

Residual-Solvent-Induced Morphological Transformation by Intense Pulsed Light on Spin-Coated and Inkjet-Printed ZnO NP Films for Quantum-Dot Light-Emitting Diodes.

It was demonstrated through a comparison between the spin-coated and inkjet-printed quantum-dot light-emitting diodes' (QLED) performance analysis outcomes that the annealing temperature of a zinc oxide nanoparticle (ZnO NP) electron transport layer (ETL) optimized for intense pulsed light (IPL) via a post-treatment differs depending on the film-formation method used. For a naturally dried ZnO NP ETL formulated without annealing, different film morphologies were observed according to the film-formation method of spin coating and inkjet printing, and the surface-roughness root mean square (RMS) value was increased in an IPL post-treatment due to unevaporated residual solvent. Based on this phenomenon, we classified and analyzed different film profiles according to the deposition method, the presence or absence of annealing, and the annealing temperature.

A generic gas chromatography method for determination of residual solvents in PET radiopharmaceuticals

A novel gas chromatography (GC) method for quantitation of volatile organic compounds (VOCs) in 18F- and 11C-radiopharmaceuticals listed in the European Pharmacopoeia (Ph. Eur.) was proposed. Optimized chromatographic parameters were used for separation of ethanol, acetone, acetonitrile, tetrahydrofuran (THF), dibromomethane (DBM), 2-dimethylaminoethanol (deanol), N,N-dimethylformamide (DMF) and dimethyl sulfoxide (DMSO) which could be detected in radioactive drug samples. The calculated peak resolutions (RS) were higher than 2.0 at ethanol concentration of up to 11 m/m%. Reproducible results could be obtained using base deactivated fused silica wool as packing material of inlet liner. Validation parameters showed excellent linearity (r2 ≥0.9998) in the range from 10 to at least 120% of concentration limit of solvents. The accuracy was determined as recovery of concentrations which ranged from 99.3% to 103.8%. Additionally, the relative standard deviation (RSD) of each solvent for inter-day and intra-day precision were in the range of 0.5–4.2% and 0.4–4.4%, respectively. The limit of quantitation (LOQ) for ethanol, acetone, acetonitrile, THF, DBM, deanol, DMF and DMSO was 0.48, 0.42, 0.43, 0.46, 4.35, 0.73, 0.68 and 0.50 mg/L, respectively. The developed procedure was successively applied for quantitation of ethanol, acetone, acetonitrile and deanol in radioactive drug samples of [11C]methionine, [11C]choline, 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) and O-(2-[18F]fluoroethyl)-L-tyrosine ([18F]FET). The proposed GC method applying flame ionization detection (FID) could be adapted in routine quality control of most frequently used positron emission tomography (PET) radiopharmaceuticals to perform the determination of residual solvents with analysis time of 12 min

Towards a better understanding of thermally treated polycarbophil matrix tablets for controlled release

Polycarbophil (POL), a polyacrylic acid cross-linked with divinyl glycol, is widely used in semisolid and solid dosage forms. When undergoing a thermal treatment in the range 120–160 °C, POL shows interesting morphological modifications, related to changes in physical properties, such as swelling of the powder granules, or hardening and matrix formation if included in the composition of a tablet. Thermal analysis conducted on POL highlighted a thermal event (Z) that can be correlated both to the shrinking of the powder granules and to the matrix formation in compacted POL powder. Modulated differential scanning calorimetry (MDSC) allowed to distinguish, inside event Z, an irreversible process overlapping with a reversible glass transition, attributable to the volatilization of residual solvents identified, through a complex TGA-FTIR-GC–MS interface, as acetate esters used for the polymer production as very fine powder. A specific interaction between acetates and POL, capable of stabilizing the polymer chains in a given conformation, was highlighted. The molecular rearrangement of the POL chains, following the volatilization of the solvent-stabilizers, is therefore ascribable to a loss of energetic stability of this material, which justifies the shrinking phenomena in the granules of the powder and the matrix formation when POL is compacted.

Detection of Residual Solvents in Commercial Supplements Using Headspace (HS)-GC-MS

In order to understand the actual state of residual solvents contained in commercial supplements, we performed a simultaneous analysis of residual solvents by headspace (HS)-GC-MS with reference to the Japanese Pharmacopoeia's "Residual Solvents", for 29 products selected from among commercial supplements (e.g., revitalizers, weight loss pills) that are deeply colored or contain coating agents and extract powder. As a result, benzene (class 1) was detected in eight black-colored supplements, and hexane (class 2B) was also detected in one of those products. On the other hand, methanol (class 2A) was detected in four products containing coating agents and extract powders, such as citrus peel extract. None of these residual solvents exceeded the concentration limits set by the Japanese Pharmacopoeia. Benzene was detected at 1.7 μg/g, which was near the concentration limit, in some products. As raw materials used for the manufacture of the black-colored supplements from which benzene was detected commonly included activated carbon, we analyzed the residual solvents contained in activated carbon commercially available for use as food additive and in food production and medicine. As a result, benzene was detected at high concentrations in activated carbon made from hemp (approximately 29 μg/g) and bamboo (approximately 140 μg/g).

In-process monitoring of total organic volatiles during packaging film manufacturing using portable sensors

Organic solvents are widely used to facilitate ink and coating applications during the lamination of packaging substrates using adhesives. These solvents may remain sequestered between the laminated layers due to their slow diffusion through the laminate structure. This diffusion increases the potential for subsequent migration into food. The residual solvents (also referred to as volatile organic compounds (VOCs)) in laminated films are a significant concern due to heightened regulatory, consumer, and environmental pressure in domestic and global markets. There is a need to develop in-process detection systems for packaging materials as conventional benchtop laboratory analyses are time-consuming, costly, and do not allow for 100% inspection. This work demonstrates an in-process detection system for monitoring VOCs on a commercial food grade film lamination line. This in-process detection system consists of portable sensors including photoionization detector, semiconducting metal oxide sensor, infrared sensor, and electrochemical sensor. Correlations were found between the sensor signals generated from VOC detection during the lamination process and post-conversion benchtop gas chromatography-flame ionization detector (GC-FID) analyses for several solventless and solvent based adhesives. The correlation coefficients between the readings of the electrochemical sensor and GC data were 0.75 and 0.91 for the solventless and Matte Lacquer Ethyl Acetate based adhesive, respectively. Strong positive correlations were also found among the response signals from most sensors for each type of adhesive. Linear regression modeling was completed to predict GC results from the sensor data measured in-process during the lamination process. Results showed that the sensor readings can predict the total amount of VOCs detected by GC-FID with high coefficients of determination (R 2 > 0.90) for the solventless adhesive, ethyl alcohol based adhesive and ethyl acetate based adhesive formulation two. This study is among the first that utilized portable sensors for the detection of VOCs during the film lamination process in the food packaging industry and compared the sensor readings with the results of laboratory GC-FID. Findings of this study demonstrate potential to decrease cost of laboratory analysis, improve solvent and adhesive application control, and increase traceability with nearly 100% inspection of packaging substrates utilizing in-process monitoring technologies. This study also demonstrated viability of in-process regulatory compliance for laminated packaging. • Use of portable sensors including PID and EC were used to monitor VOCs released during film lamination. • VOCs detected by the sensors correlated with GC-FID concentrations for different adhesive formulations. • Mathematical models built predicted GC values from sensor readings for several adhesives.

Separation of volatile compounds from polymers by physisorption

• A proof-of-principle for polymer purification by physisorption (3P) is reported. • Different model (co)polymers were succesfully isolated by the 3P method. • The chemical and macromolecular properties of the final polymers were unaltered. • The adsorbed polymers could be recovered and used for further experimentations. • The 3P method is cost-effective for separating volatile compounds from polymers. After synthesis, specialty polymers can be difficult to purify from residual volatile monomers and solvents in a precise and reproducible manner using current standard separation techniques, which also generate large amounts of waste. Herein, we report a proof-of-principle study of a cost-effective and versatile method for separating residual volatile compounds from synthetic polymers via physisorption ( i.e. , polymer purification by physisorption (3P)). Model polymers were used to evaluate the capabilities and advantages of the 3P method over standard purification techniques regarding separation of volatile compounds, process solvent to polymer yield, and final properties of the resulting polymers. Compared to dialysis and precipitation, the 3P method could separate up to 99% of the residual monomer from a polymerization reaction using a significantly lower fraction of solvent. Unlike the benchmark methods, the molar mass and dispersity of polymers purified by the 3P process remain practically unaffected; polymers were quantitatively recovered for subsequent applications ( e.g. , precursors for block copolymer synthesis or characterization purposes). The 3P method represents a straightforward technique for polymer purification and is suitable for automation, which will help to overcome the unsolved and labor-intensive task of purifying (co)polymer libraries derived from high-throughput experimentation.

Interfacial localization of CNCs in PLA/PBAT blends and its effect on rheological, thermal, and mechanical properties

In this study the effect of interfacial localization of 1 wt% cellulose nanocrystals (CNCs) was investigated on the morphology, rheology, thermal, and mechanical properties of poly (lactic acid), PLA (semicrystalline (sc) and amorphous (a)) and poly (butylene adipate-co-terephthalate), PBAT, blends (75/25 wt%). Different mixing strategies were adopted using solution casting followed by melt mixing to localize CNCs at the interface of PLA/PBAT blends. Scanning electron microscopy (SEM) and atomic force microscopy (AFM) confirmed this localization. The interfacial localization of CNCs significantly impeded the relaxation of the dispersed PBAT droplets in the PLA/PBAT blends and converted the droplet/matrix morphology of the scPLA/PBAT blend nanocomposites into a co-continuous one resulting in a solid-like rheological behavior. Also, CNCs played the role of nucleating agents in the PLA/PBAT blends and improved the crystallization behavior of scPLA and PBAT. Although Young's modulus and yield strength decreased in the neat PLA/PBAT blends, interfacial localization of CNCs improved these properties (mostly in scPLA/PBAT) to be closer to those values of neat PLAs, accompanied by improved elongation at break from ∼3% (scPLA (+IMM)) to ∼150% (scPLA/PBAT/CNC) and impact strength from ∼20 J/m (scPLA (+IMM)) to ∼95 J/m (scPLA/PBAT/CNC). These improvements were less effective in the aPLA/PBAT/CNC due to less effectiveness of CNC localization at the interface because of more residual solvent in aPLA/PBAT/CNC, better affinity of CNCs with solvent compared to polymers and more spherical PBAT dispersed phase compared to that in scPLA/PBAT/CNC blend nanocomposites.

Optimization and Development of a Scalable Palladium-Catalyzed C–H Activation Process for the Geometry-Selective Preparation of Kilograms of YLF466D, a Potent AMP-Activated Protein Kinase Activator

Adenosine 5′-monophosphate-activated protein kinase (AMPK) activator YLF466D is a promising preclinical drug candidate to treat metabolic diseases and myocardial ischemia-reperfusion injury (MIRI). Herein, we report our efforts on optimization and development of a practical and scalable process for the preparation of YLF466D in kilogram scale. The process features a palladium-catalyzed C–H activation under mild reaction conditions, geometry selectivity, effective impurities purging, and low levels of residual solvents in the final active pharmaceutical ingredient (API). We applied this process successfully to prepare more than 17 kg (3.0–3.6 kg per batch) of YLF466D to support its preclinical study.

Nanoparticle-eluting stents for coronary intervention: formulation, characterization, and in vitro evaluation.

Coronary artery disease (CAD) is currently a leading cause of death worldwide. In the history of percutaneous coronary intervention for the treatment of CAD, a drug-eluting stent (DES) is recognized as a revolutionary technology that has the unique ability to significantly reduce restenosis and provide both mechanical and biological solutions simultaneously to the target lesion. The aim of the research work was to design and fabricate DES coated with a nanoparticulate drug formulation. Sirolimus, an inhibitor of the smooth muscle cell (SMC) proliferation and migration, was encapsulated in polymeric nanoparticles (NPs). The NP formulation was characterized for various physicochemical parameters. Cell viability and cell uptake studies were performed using human coronary artery smooth muscle cells (HCASMCs). The developed NP formulation showed enhanced efficacy compared to plain drug solution and exhibited time-dependent uptake into the HCASMCs. The developed NP formulation was coated on the Flexinnium™ ultra-thin cobalt-chromium alloy coronary stent platform. The NP-coated stents were characterized for morphology and residual solvent analysis. In vitro drug release was also evaluated. Ex vivo arterial permeation was carried out to evaluate the NP uptake from the surface of the stents. The characterization studies together corroborated that the developed NP coated stent can be a promising replacement of the current DESs.

Modular Synthesis of Tetraurea and Octaurea Macrocycles Encoded with Specific Monomer Sequences

Modular Synthesis of Tetraurea and Octaurea Macrocycles Encoded with Specific Monomer Sequences

Sirolimus loaded chitosan functionalized poly (lactic-co-glycolic acid) (PLGA) nanoparticles for potential treatment of age-related macular degeneration

The usefulness of sirolimus (SIR) in the treatment of diseases that involve retinal degeneration like age-related macular degeneration (AMD) has been well documented. However, the problem still remains probably owing to the peculiar environment of the eye and/or unfavourable physiochemical profile of SIR. In the present work, we aimed to fabricate sirolimus loaded PLGA nanoparticles (SIR-PLGA-NP) and chitosan decorated PLGA nanoparticles (SIR-CH-PLGA-NP) to be administered via non-invasive subconjunctival route. Both the nanoparticles were characterized in terms of size, zeta potential, DSC, FTIR and XRD analysis. Quality by Design (QbD) approach was employed during the preparation of nanoparticles and the presence of chitosan coating was confirmed through thermogravimetric analysis and contact angle studies. Cationic polymer modification showed sustained in-vitro SIR release and enhanced ex-vivo scleral permeation and penetration. Further, SIR-CH-PLGA-NP revealed enhanced cellular uptake and thus, reduced lipopolysaccharide (LPS)-induced free-radicals generation by RAW 264.7 cells. The prepared nanoparticles were devoid of residual solvent and were found to be safe in HET-CAM analysis, RBCs damage analysis and histopathology studies. Moreover, high anti-angiogenic potential was observed in SIR-CH-PLGA-NP compared with SIR-PLGA-NP in chorioallantoic membrane (CAM) test. Overall, the current work opens up an avenue for further investigation of CH-PLGA-NP as SIR nanocarrier in the treatment of AMD.

Comparison of Pharmaceutical Characteristics between Brand-Name Meropenem and Its Generics.

This study aimed to provide comparative information of pharmaceutical properties, including particle morphology and distribution uniformity, solubility, presence of residual solvent and insoluble particles, and antimicrobial activities, between brand-name meropenem (Mepem®, BNM) and its six generic products (GPs A-F) marketed in China. Particles of GP-A and -C in dry powder had similar diameters of BNM, while other GPs were larger. Only BNM and GP-A were completely dissolved within 100 s in the lab condition. No insoluble particles >25 μm in diameter were detected in BNM and GP-E. Regarding stability of GPs solutions evaluated by concentration of open-ring metabolites at 6 h and 8 h, BNM showed the lowest open-ringed metabolite concentrates. Residual solvent of acetone detected in one GP showed the maximum value, while ethanol and ethyl acetate were detected both in product E and product F. The concordance rates (%) of minimum inhibitory concentration (MIC) of each generic compared to BNM were 89.5, 85, 87.5, 88, 88.5, and 86.5, respectively, although no significant difference was reached in MIC. Pharmaceutical characteristic differences between the BNM and GPs identified in this study could provide insights into understanding the deviations in the drug manufacturing processes of generic drugs.

Integration of Mass Spectrometry Data for Structural Biology.

Mass spectrometry (MS) is increasingly being used to probe the structure and dynamics of proteins and the complexes they form with other macromolecules. There are now several specialized MS methods, each with unique sample preparation, data acquisition, and data processing protocols. Collectively, these methods are referred to as structural MS and include cross-linking, hydrogen-deuterium exchange, hydroxyl radical footprinting, native, ion mobility, and top-down MS. Each of these provides a unique type of structural information, ranging from composition and stoichiometry through to residue level proximity and solvent accessibility. Structural MS has proved particularly beneficial in studying protein classes for which analysis by classic structural biology techniques proves challenging such as glycosylated or intrinsically disordered proteins. To capture the structural details for a particular system, especially larger multiprotein complexes, more than one structural MS method with other structural and biophysical techniques is often required. Key to integrating these diverse data are computational strategies and software solutions to facilitate this process. We provide a background to the structural MS methods and briefly summarize other structural methods and how these are combined with MS. We then describe current state of the art approaches for the integration of structural MS data for structural biology. We quantify how often these methods are used together and provide examples where such combinations have been fruitful. To illustrate the power of integrative approaches, we discuss progress in solving the structures of the proteasome and the nuclear pore complex. We also discuss how information from structural MS, particularly pertaining to protein dynamics, is not currently utilized in integrative workflows and how such information can provide a more accurate picture of the systems studied. We conclude by discussing new developments in the MS and computational fields that will further enable in-cell structural studies.

Removal of residual compositions by powder engineering for high efficiency formamidinium-based perovskite solar cells with operation lifetime over 2000 h

Defects as a result of structural imperfections and/or extrinsic impurities in the perovskite films have a detrimental effect on efficiency and stability of perovskite solar cells (PSCs). Here, we propose to use pre-synthesized crystalline perovskite with perfect stoichiometry to control and lower the density of defects from precursors by the powder engineering method. Compared with raw materials (i.e., PbI 2 and FAI) based perovskites, the average efficiency of the PSCs fabricated based on these pre-synthesized perovskite precursors increased from 18.62% to 19.85%. Moreover, the unwanted intermediate chemical compositions (i.e., the unreacted phases and residual solvent) in the raw material-based perovskite films were significantly reduced in the pre-synthesized δ-FAPbI 3 and α-FAPbI 3 perovskites according to the secondary ion mass spectroscopy depth profiling results. Finally, we obtained the champion efficiency of 22.76% for α-FAPbI 3 and 23.05% for FAPb(I 0.9 Br 0.1 ) 3 based PSCs. Long-term operational stability measurements of the encapsulated FAPb(I 0.9 Br 0.1 ) 3 based PSCs showed a slow decay and maintained the efficiency about 88% after 1200 h (T 80 > 2000 h). Furthermore, a proof-of-concept integrated perovskite solar module-lithium ion battery-light-emitting diode device was demonstrated. Formamidinium-based perovskite solar cells with a high efficiency over 23% and 2000-h T 80 lifetime were fabricated using pre-synthesized crystalline perovskite powders via powder engineering. • Pre-synthesized crystalline perovskite powder with fewer defects is prepared by the powder engineering method. • Residual compositions are removed, which results in improved efficiency and operational stability. • The highest PCEs of 22.76% for α-FAPbI 3 and 23.05% for FAPb(I 0.9 Br 0.1 ) 3 are achieved by the powder engineering method. • A proof-of-concept perovskite solar module-lithium ion battery-light-emitting diode (PSM-LIB-LED) device is demonstrated.

Optimization of amorphous solid dispersion techniques to enhance solubility of febuxostat.

Febuxostat is a selective inhibitor of xanthine oxidase and belongs to BCS class II drugs having low solubility and high permeability. Solubility is the most important parameter which directly affects dissolution, absorption and bioavailability of the drugs. There are different techniques by which we can improve solubility and dissolution rate of poorly soluble drug. Amorphous solid dispersion is one of the methods which can improve solubility as well as powder characteristics. The aim of the present study was to formulate and optimize various methods of formulating solid dispersion by using various drug-to-polymer ratios and identifying the batch which gives higher solubility as well as amorphous powder of the drug febuxostat. Different techniques like hot melt method, solvent evaporation method and spray drying techniques were selected for optimization. Attempts were made to improve solubility of febuxostat by employing Kolliphor P 188, Kolliphor P 237, Eudragit RLPO in different drug-to-polymer ratios (1:1, 1:1.5, 1:2) as carrier. The prepared solid dispersion was characterized for the saturation solubility, percentage yield, using differential scanning calorimetry (DSC), scanning electron microscopy (SEM), powdered X-ray diffraction studies (PXRD), and residual solvent determination. Solid state characterization indicated that febuxostat was present in the amorphous form after mixing with polymeric carrier. In contrast to the pure form of drug, solid dispersion of the drug showed better solubility and amorphous characteristics which can be attributed to decreased crystallinity due to hydrotrophy. Thus, amorphous solid dispersion approach can be used successfully to enhance solubility, dissolution rate and bioavailability of febuxostat.