Compatibility study between sitagliptin and pharmaceutical excipients used in solid dosage forms

Differential scanning calorimetry (DSC) is a primary technique for measuring the thermal properties of materials, which reflects the physico-chemical properties of drug substances. In the present study, it is used as a screening technique for assessing the compatibility of sitagliptin with some currently employed pharmaceutical excipients. The influence of processing conditions and their effects (simple blending, co-grinding or kneading) on drug stability was evaluated. Sitagliptin showed a sharp endothermic peak at 212.1 °C with an enthalpy change of 131.5 J g^?1 indicating melting of drug. Facile transformation of dehydrated sitagliptin to monohydrate form was observed in some mixtures, disappearance of sharp melting endothermic peak of sitagliptin was observed in some mixtures. On the basis of DSC results, sitagliptin was found to be compatible with micro crystalline cellulose, croscarmellose, and pregelatinized starch. Some excipient interaction was observed with magnesium stearate, ascorbic acid, and citric acid. X-ray diffractometry and FT-IR were used as supportive tools in interpreting the DSC results. Overall, the excipients selected were compatible with the API and the mixtures are stable within the tested conditions. These results would be useful for formulation development of the film coated tablets of sitaglitptin.     

Determination of Rutin by a Graphene-Modified Glassy Carbon Electrode

A reduced graphene oxide-modified glassy carbon electrode for sensitive detection of rutin is reported. The modified electrode was obtained by one-step electrochemical reduction of graphene oxide on the bare glassy carbon electrode. In the presence of graphene, an enhanced electrochemical response for rutin appeared with a pair of well-defined anodic and cathodic peaks in pH 3.0 phosphate buffer. Under the optimized conditions, the anodic peak currents exhibited a linear relationship with rutin concentration from 0.1 to 2.0 µM with a detection limit of 23.2 nM. The modified electrode was employed to the analysis of tablets (with satisfactory recovery of 19.96 mg/per tablet) and Flos Sophorae. The graphene-modified electrode exhibited high sensitivity, good stability, and selectivity for the determination of rutin.     

Preparation and Characterization of Ursodeoxycholic Acid Nanosuspension

In the present research, the high pressure homogenization (HPH) technology was applied to prepare ursodeoxycholic acid (UDCA) nanosuspension. The aim of developing this new UDCA formulation was to enhance its bioavailability. The physicochemical characterization of UDCA nanosuspension was performed through particle size and Zeta potential measurements, differential scaning calorimetry (DSC) analysis, x-ray diffraction (XRD) measurements, and drug solubility and dissolution determinations. The mean particle size of UDCA nanosuspension was 297.5 nm with a polydispersity index of 0.162. Its particle size and Zeta potential did not show essential changes before and after water removal. The DSC curve of bulk UDCA showed a sharp endothermic peak at 207.82°C indicating the melting point. The XRD profile of dried powder of UDCA nanosuspension showed 2 intense peaks at 11.92° and 21.56°, respectively, indicating difference from the crystal characteristics of bulk UDCA. Its highest solubility and dissolution rate were 278.6 µg/mL and 98.77%, respectively. The feasibility of preparing nanosuspension by HPH technology was testified through successful preparation of UDCA nanosuspension.     

Physicochemical characterization and stability of microbeads containing cod-liver oil encircled with natural cyclodextrins

The ability of cyclodextrins (CDs) to solubilize cod-liver oil in aqueous solutions was evaluated. Only the natural α-cyclodextrin (αCD) and γ-cyclodextrin (γCD) were able to fully disperse 10 % (v/v) cod-liver oil in aqueous solutions. Confocal imaging revealed that the oil was located in the center of the CD enveloped microbeads (<20 μm in diameter) where it was enclosed within nanocompartments (<1 μm in diameter). The aqueous microbead suspensions were lyophilized to produce dry powder microbeads with rough surfaces. To assess the stability of the cod-liver oil/γCD (3:1 molar ratio) microbead powder, three groups of samples were incubated over a period of 1, 2, 4, 12 and 84 weeks. Group 1 (G1) and group 2 (G2) were incubated at 25 °C and 60 % humidity. G1 was exposed to O₂ for 10 min before sealing off the glass containers while G2 was kept under nitrogen. Group 3 was stored under accelerated conditions at 40 °C and 75 % humidity under nitrogen. The reference was pure cod-liver oil. Results indicated that encapsulating cod-liver oil with γCD delays oxidative degradation when oxygen is present, but does not significantly decrease or increase the long term stability of cod-liver oil under anaerobic conditions. Cod-liver oil/γCD microbeads could be compressed into tablets without decreasing the integrity of encapsulation. The cod-liver oil/γCD microbead powder might be of interest to the pharmaceutical industry as a carrier for lipophilic drugs.     

Forced Degradation Study to Develop and Validate Stability-Indicating RP-LC for Quantification of Ropinirole Hydrochloride in Its Modified Release Tablets

A forced degradation study on ropinirole hydrochloride in bulk and in its modified release tablets was conducted under the conditions of hydrolysis, oxidation and photolysis in order to develop an isocratic stability-indicating LC-UV method for quantification of the drug in tablets. An impurity peak in standard solution was found to increase under acidic and neutral hydrolytic conditions while another degradation product was formed under alkaline condition. The drug and its degradation products were optimally resolved on a Hypersil C₁₈ column with mobile phase composed of diammonium hydrogen orthophosphate (0.05 M; pH 7.2), tetrahydrofuran and methanol (80:15:5% v/v) at a flow rate of 1.0 mL min^?1 at 30 °C using 250 nm as detection wavelength. The method was linear in the range of 0.05–50 μg mL^?1 drug concentrations. The %RSD of inter- and intra-day precision studies was <1. The system suitability parameters remained unaffected during quantification of the drug on three different LC systems. Excellent recoveries (101.59–102.28%) proved that the method was sufficiently accurate. The LOD and LOQ were found to be 0.012 and 0.040 μg mL^?1, respectively. Degradation behaviour of the drug in both bulk and tablets was similar. The drug was very unstable to hydrolytic conditions but stable to oxidative and photolytic conditions. The method can be used for rapid and accurate quantification of ropinirole hydrochloride in tablets during stability testing. Based on chemical reactivity of ropinirole in different media, the degradation products were suspected to be different from the known impurities of the drug.     

Thermal stability of soil organic matter was affected by 23-yr maize and soybean continuous cultivation in northeast of China

Long-term continuous cropping affects the biochemical quality of soil organic matter (SOM), but whether the effects are relevant with their thermal stability is less clear. In northeast China, long-term continuous cropping occurred frequently owing to higher yield and economic interest requirement. To verify the thermal stability properties of SOM affected by the long-term continuous cropping, the study focused on 23-yr continuous cultivated maize and soybean plots, where the effect of cropping is likely to be detected. Bulk soils sampled in 1991 and 2014 were studied by thermogravimetry and differential scanning calorimetry (DSC). The results showed typical bimodal peaks in DSC curve in bulk Mollisols. A labile fraction peak was observed at 354–366 °C low-temperature zone and recalcitrant fraction one at high temperature of 430–438 °C. Energy density (J mg^?1 OM) was greater in soybean plots compared to maize plots; in contrast, long-term continuous maize cultivation also increased energy density, in reverse in soybean plots after 23-yr cultivation. The DSC-T₅₀, temperature at which half of energy release occurred, typically showed larger responses to long-term cultivation than crop species. Results obtained support the hypothesis of a potential link between long-term continuous cropping and the thermal stability of SOM, and a correlation with crop species.     

Stability studies of capecitabine

Differential scanning calorimetry and thermogravimetry techniques were successfully used for stability studies of capecitabine. Decreasing values of melting temperature, heat of fusion, and peak purity calculated from the Van’t Hoff equation indicated the gradual decomposition of capecitabine stored at 40 °C in 75% of relative humidity. The increase in mass loss connected with the water sorption was observed simultaneously. High performance liquid chromatography proved the results of thermoanalytical studies. Infrared spectroscopy (IR) appeared to have the lower sensitivity for the decomposition products detection.     

Sensitive voltammetric determination of rutin at a carbon nanotubes-ionic liquid composite electrode

A new composite electrode of multiwall carbon nanotubes (MWNTs) and 1-dodecyl-3-methylimidazolium hexafluorophosphate (DDMIMPF₆) was fabricated to determine rutin. This electrode showed very attractive electrochemical performances compared to other kinds of ionic liquid modified electrodes and notably improved sensitivity and stability. Electrochemical behavior of rutin at the composite electrode had been investigated in pH 2.09 Britton–Robinson buffer solution by cyclic voltammetry and square wave voltammetry. The experimental results suggested that the composite electrode exhibited an electrocatalytic activity toward the redox of rutin. The electrochemical parameters of rutin were calculated with the results of the charge transfer coefficient (α) and the standard rate constant (k _s) as 0.48 and 2.09 s^?1. Under the selected conditions, the reduction peak current was linearly dependent on the concentration of rutin in the range of 0.03–1.5 μM, with a detection limit of 0.01 μM (S/N?=?3). The relative standard deviation for six times successive determination of 1 μM rutin was 1.6 %. The method was successfully applied to the determination of rutin in tablets and urine samples without the influence of the coexisting substances. In addition, the MWNTs/DDMIMPF₆ composite electrode exhibits a distinct advantage of simple preparation, surface renewal, good reproducibility, and stability.     

Synthesis and thermal stability of ZnO nanowires

ZnO nanowires (NWs) were synthesized on Au-coated Si (100) substrates by vapor transport method. The effect of high temperature annealing on the structural and chemical composition as well as thermal stability was studied. The as-prepared ZnO NWs was nearly stoichiometric and identified as hexagonal ZnO phase. After annealing at 1,473 K, the atomic ratio of O/Zn, the intensity of the diffraction peaks, and the diameter of nanowires were increased. The ZnO NWs were fragmented into nanocrystals and the fragments coalesced with each other after annealing at 1,673 K. The thermal stability of ZnO NWs was studied by thermo-gravimetric (TG) analysis. A sharp increase in the TG curves was observed and can be attributed to the oxidation of some possibly presented Zn atoms. The activation energy of oxidation of Zn interstitial atoms was found to be 484.81 kJ mol^?1. A mass gain peak was observed after annealing at 1,473 K, but it was completely eliminated after annealing at 1,673 K.     

Comprehensive stability‐indicating high‐performance liquid chromatography coupled with diode array detection method for simultaneous determination of amprolium hydrochloride and ethopabate in powder dosage form for veterinary use

This research deals with the development of a stability‐indicating high‐performance liquid chromatography method for simultaneous determination of amprolium hydrochloride and ethopabate. To the best of our knowledge, no comprehensive stability‐indicating method has been reported for analysis of this mixture. Separation was achieved using Kromasil cyano column with gradient elution of the mobile phase composed of sodium hexane sulfonate solution and methanol. Quantification was based on measuring peak areas at 266 nm. Amprolium and ethopabate peaks eluted at retention times 10.42 and 18.53 min, respectively. The proposed procedure was validated with respect to system suitability, linearity, ranges, precision, accuracy, specificity, robustness, detection, and quantification limits. Linearity ranges for amprolium and ethopabate were 1.5–240 and 1–160 μg/mL, respectively. Analytes were subjected to stress conditions of hydrolysis, oxidation and thermal degradation. The proposed method enabled resolution of drugs from their forced‐degradation products and amprolium related substance (2‐picoline). Moreover, specificity was verified by resolution of the analytes from about 22 drugs used in antimicrobial veterinary products. The validated method was successfully applied to assay of the combined veterinary powder dosage form, additionally it was implemented in the accelerated stability study of the dosage form when stored for six months at 40°C and 75% relative humidity.     

Forced Degradation Study on Gliclazide and Application of Validated Stability-Indicating HPLC-UV Method in Stability Testing of Gliclazide Tablets

Forced degradation study on gliclazide was conducted under the conditions of hydrolysis, oxidation, dry heat and photolysis and an isocratic stability-indicating HPLC-UV method was developed and validated. All the seven degradation products (I–VII) formed under different conditions were optimally resolved on a C₁₈ column with mobile phase composed of 40% acetonitrile and 60% ammonium acetate solution (0.025 M, pH 3.5) at a flow rate of 0.25 mL min^?1 using 235 nm as detection wavelength. The method was linear between 5–500 μg mL^?1 drug concentrations. The %RSD of intra- and inter-day precision studies was <1 and <2% respectively. Excellent recoveries (99.81–100.97%) proved the method sufficiently accurate. Each peak resolved always with a resolution of >1.90 indicating the method to be rugged enough. The method was used to study the drug degradation behaviour under the forced conditions. Four degradation products (I–IV) were formed in 0.1 N HCl and water whereas only I and III were formed in 3% H₂O₂. Two new products V and VI in addition to I, III and IV were formed in 0.1 N NaOH. The drug was stable to thermal and photolytic decomposition. The degradation behaviour in water and 0.1 N NaOH was similar under dark and light conditions but a new product VII was formed in 0.01 N HCl in light. In general, the rate of degradation was accelerated by the light. The method was applied successfully in stability testing of gliclazide tablets.     

Influence of temperature and humidity on the degradation process of ascorbic acid in vitamin C chewable tablets

Ascorbic acid (AA) is the active ingredient of vitamin C chewable tablets. It is unstable even at room temperature, and increased temperature and humidity rapidly increase its degradation. To protect the active substance, we made its coating with polymers ethyl cellulose that provides its thermal protection and protection from moisture. We bet each particle of AA with a layer of polymer by the method of fluidization. Extra protection against thermal effects and penetration of moisture and oxygen provides the packaging. By using four kinds of packaging: polypropylene container for tablets, strips of aluminum and polyvinyl chloride Al/PVC strips, glass bottles, and strips of aluminum and polyethylene (Al.PE/PE.Al) of 3, of 6 months and of 12 months. One of the tablets are stored at room temperature (25 ± 2 °C/60% RH ± 5%), and the rest in terms of accelerated aging or increased temperature and humidity (30 ± 2 °C/65% RH ± 5% and 40 ± 2 °C/75% RH ± 5%). The speed of degradation of unprotected AA usually get doubled when there is increasing of the temperature for every 10 °C. Experimentally the concentration of AA was monitored, its oxidation product-dehydroascorbic acid and its degradation product-diketogulonic acid.     

Stabilization Studies on Bacterially Produced Human Paraoxonase 1 for Improving Its Shelf Life

Human paraoxonase 1 (h-PON1) is a ~40 kDa multi-tasking enzyme that plays a major role in determining individual susceptibility towards various disease conditions. It is a strong candidate for the development of therapeutic intervention for various diseases and other conditions in humans. However, purified h-PON1 is unstable and there is a need to find condition(s) that can increase the shelf life of the enzyme. In this report, we present the results of our investigation on the effect of excipients on the stability of bacterially produced human PON1 when stored under different storage conditions. Our results show that (a) glycine and serine are most effective in stabilizing the enzyme when stored in aqueous buffer at 25 °C for 30 days, and (b) trehalose, maltose, and BSA exerted maximum stabilization effect when the enzyme was stored in freeze-dried form at 25 °C for 60 days. Results of this study can be used to increase the shelf life of purified h-PON1 enzyme.     

Compatibility study of quetiapine fumarate with widely used sustained release excipients

The drug-excipient compatibility study of quetiapine fumarate, with widely used sustained release excipients, was carried out employing differential scanning calorimetry (DSC) and Fourier transform infrared spectroscopy (FT-IR). The selected excipients were HPMC K100M, sodium alginate, xanthan gum, Eudragit RSPO, hydrogenated castor oil, carnauba wax, and PEO WSR 303. Equal proportion of drug and excipients was utilized in the interaction study. FT-IR spectra indicated the absence of interaction between drug and excipients. The DSC curve showed a sharp endothermic melting peak at 173.26 °C for quetiapine fumarate. Post melting interaction was observed for carnauba wax, Eudragit RSPO, and hydrogenated castor oil probably due to solubilization of drug in the melted excipient. No interaction was observed for other excipients. The physical mixtures stored at 30 ± 2 °C/65 ± 5% RH did not show any significant degradation of the drug. The concept of systemically conducted preformulation studies will facilitate dossier submission to the drug control authority.     

Physico-Chemical Stability of Warfarin in Ground Mixtures with β-Cyclodextrin or Microcrystalline Cellulose under Storage Conditions

The effects of grinding and the excipients used on the solid state stability of warfarin in ground mixtures with β-cyclodextrin or microcrystalline cellulose have been investigated by using x-ray powder diffractometry, IR spectrophotometry and differential scanning calorimetry. The grinding process did not result in warfarin-excipient interaction, but caused a crystalline form of warfarin to transfer to an amorphous state in the presence of β-cyclodextrin. The stability of this amorphous state of warfarin in tablets made from the ground mixtures stored at 37°C and 75% RH (relative humidity) was also studied. There was only a small amount of amorphous warfarin in tablets that recrystallized under storage conditions. The recrystallization of amorphous warfarin might be due to moisture adsorption. β-cyclodextrin possesses an ability to prevent the recrystallization of large amounts of amorphous warfarin in tablets stored at 37°C and 75% RH.     

盐酸环丙沙星分子印迹电化学传感器

本文将电化学合成与分子印迹技术相结合,采用循环伏安法在石墨电极表面,形成盐酸环丙沙星(CPX)分子印迹聚吡咯薄膜,制备了CPX分子印迹传感器。实验对传感器的制备条件进行了优化,用铁氰化钾作为活性电子探针,采用方波伏安法研究了传感器性能。结果表明,在1×10~(-8)~1×10~(-4)mol/L范围内,峰电流与CPX浓度负对数呈良好的线性关系,检出限(S/N=3)为3.5×10~(-9)mol/L。传感器对模板分子CPX选择性强,重现性和稳定性好,置于室温下15d峰电流强度无明显变化。     

Liquid Formulations for Long-Term Storage of Monoclonal IgGs

Proteins like immunoglobulin (IgGs) are prone to degradation by a variety of pathways. In this study, a stabilizing formulation for long-term storage of a panel of seven monoclonal IgGs was found using differential scanning calorimetry (DSC). In the chosen formulations, the IgGs were subjected to stress, accelerated and real-time storage, and analyzed by size exclusion chromatography to determine fragment and aggregate content, and fluorescence-activated cell sorting to measure immunoreactivity. All IgGs showed the greatest conformational stability near their isoelectric point which was enhanced by adding sorbitol, sucrose, glycine, and sodium chloride. Optimized formulations, found by DSC, containing 20 % sorbitol and 1 M glycine prevented IgG aggregation and fragmentation and conserved immunoreactivity against shear stress, multiple freeze–thaw cycles, accelerated storage at 37 °C, and 12 months storage at 4 and ?20 °C. Relatively poor thermal stability of the antigen-binding fragment domain was shown to limit storage stability of IgGs. This study confirms the predictive power of DSC to find storage formulations which protect IgGs during stress and long-term storage from aggregation and degradation. Liquid formulations found in this study may have a broad utility for other IgGs.     

Thermal and stability study of tetracene using differential scanning calorimetry

A thermal analysis study was made of tetracene using differential scanning calorimetry (DSC). The effect of different scan speeds was investigated. At scan speeds of 0.625 to 10°C min^?1 two large rounded exothermic peaks were produced. The peaks occurred at an increasingly high temperature as the scan speed increased (for example, the peaks occurred at 128 and 130°C at a scan speed of 0.625°C min^?1 and at 148 and 150°C at a scan speed of 10°C min^?1. When tetracene was heated at a scan speed of 80°C min^?1 only one large sharp exothermic peak was produced. It is believed that the two peaks obtained at scan speeds of 0.625 to 10°C min^?1 represent decomposition of the tetracene in two successive stages, while the one peak obtained at 80°C min^?1 represents an explosion. A stability test for tetracene is proposed that involves heating of the tetracene in aluminum pans from the DSC apparatus in ovens at 100, 75, and 60°C, removing the pans and samples at intervals of 30 min, 24 h, and 7 days, respectively, subjecting the samples to DSC at 1.25°C min^?1, and noting the time interval in the oven that produces a DSC curve that shows obliteration of the second peak. Two lots of tetracene made by different processes showed marked differences in stability characteristics.     

Stability Indicating Reversed-Phase High Performance Liquid Chromatography Method for Determination of Impurities in Ofloxacin Tablet Formulations

A gradient reversed-phase high performance liquid chromatography (RP-HPLC) method was developed for separation and quantitation of impurities in pharmaceutical dosage form of ofloxacin tablets. The developed method was a stability indicating test method for estimation of related impurities generated during synthesis, formulation, and storage of ofloxacin tablets. Forced degradation studies were performed on ofloxacin tablets including acid hydrolysis (5.0 M hydrochloric acid), base hydrolysis (5.0 M sodium hydroxide), oxidation (30% hydrogen peroxide), heat (105°C) humidity degradation 25°C/92% RH/119 b & 40 min, and photolytic degradation (2600 Lux/119 h & 40 min). From the degradation study, the degradation was found between 0–15%. Limit of detection and limit of quantification were established in terms of percentage for all potential impurities. The recovery studies were conducted on finished dosage samples (tablets) for all potential impurities and the average percentage recovery was ranged from 90.8 to 104.2. Placebo interference was verified by taking the placebo (composition of excipients) equivalent to weight in portion of test preparation and no interference was observed. The method was validated and found to be linear, accurate, precise, specific, robust, and reliable. The developed method was established in accordance to ICH guidelines.     

Study of Stability of Sesame Oil-In-Water Emulsions Determined using an Optical Analyzer and Measurement of Particle Size and Distribution

The aim of the study was to determine the optimal conditions, that is, the content of sesame oil and the amount of carboxymethylcellulose, to obtain stable dispersion systems. Emulsions were stored under different temperature conditions. For this purpose, six emulsions were prepared and their stability was examined empirically using techniques including particle size analysis, optical microscopy, and the Turbiscan test. The emulsion containing 40 g of oil and 0.6 g of thickener had the highest stability. No destabilizations in whole the range of stored temperature were observed for the emulsion with that composition. Emulsion was stable as well at cool temperature as at extreme environment (40°C). Nowadays, the use of O/W emulsions based on vegetable oil is continuously increasing. To date, sesame oil has been used mainly for direct consumption. The present work indicates a novel possibility for use of sesame oil as the fat base of an emulsion system. Besides, the study gave information about parameters of long-term stability emulsion what is the key in the quality of the dispersion systems. This knowledge is necessary for the industry in order to avoid destabilizing processes occurring in a new product.