Startseite The Optimization and Production of Ginkgolide B Lipid Microemulsion
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The Optimization and Production of Ginkgolide B Lipid Microemulsion

  • Xiao Wu , Zhenpeng Wang , Zhenwen Zhao , Lei Chen , Fengyun Tao , Qian Zhang , Tuo Zhou , Junpu Cui , Meng Liu und Qing Huo EMAIL logo
Veröffentlicht/Copyright: 7. Juni 2019

Abstract

In this study, we introduce a method to formulate Ginkgolide B lipid microemulsion (GB-LM). We have assessed its general characteristics and pharmacokinetics in animals. Soybean oil (10.0%) and oleic acid (2.4%) were chosen as the oil phase, refined egg yolk lecithin (PC98T) (1.8%) as the surfactant, and glycerol (2.25%) as the co-surfactant. The optimized formulation process resulted in particles with average diameter of 185.9 ± 52.5 nm and the zeta potential of −19.8 ± 1.3 mV. The GB-LM remained steady for three months at room temperature. Giving each dose of 4 mg/kg to rats through the vein, a clearance rate of CL (L/h): 2.594 and C max (ng/mL) was achieved: 353.8 through pharmacokinetic analysis and statistical analysis. The AUC of GB-LM was about 1.57-fold higher than that of the products available in the market. In addition, brain tissue distribution studies show that after 0.5 h administration of GB, the concentration of GB in brain tissue can reach its maximum, and then significantly decrease after 2 hours. Therefore, the improved formulation of GB-LM shows encouraging results compared with present products in several features.

1 Introduction

Parkinson’s disease is a nervous-system disease which frequently occurs among the elderly. Its manifestations include slowness of movement, muscular rigidity, tremor at rest, and difficulty with walking. Non-motor symptoms such as sense of smell constipation, depression, and anxiety are also common [1]. As a typical elderly disease, its rate doubles when age grows; 1%~2% of people over 65 suffer from Parkinson’s disease [PD], and the rate increases to 3%~5% for people over 85 [2, 3]. According to the prediction, because of PD’s low-rate of death and high-rate of disability, it will bring challenge to the societal and medical institutions in China, which is now experiencing aging [4].

Ginkgolides (GG) is the main effective component in Ginkgo biloba. It has a wide range of medical use, mainly fornervous-system and cardiovascular diseases [5, 6]. GG is fat soluble; it includes Ginkgolide A, B, C, and also Bilobalide B (BB), all of which have a small solubility: (259.21±3.39), (69.26±2.63), (512.51±3.83), (1247.50±4.09) mg/L in Soybean Oil at 50-60℃ [7].

As the main chemical component in the extract of Ginkgo biloba, GB can protect nerve cell and prevent it from decaying. Its effectiveness in treating nerve-system diseases has already been recognized [8]. GB is a natural free radical scavenger, it can protect the body from the damage of free radicals, improve brain circulation and neuronal dysfunction. The mechanism of action of GB may be that M1 receptors are upregulated in brain tissue of aged animals and Alzheimer’s disease [9, 10, 11], in addition, GB also promotes learning and memory, promotes the development of the nervous system and differentiation of neural stem cells into neurons, and prevents and treats neurodegenerative diseases such as Alzheimer’s disease [12]. GB’s CAS number is [15291-77-7], C20H24O10 with molecular weight 424.40. It has a high melting point (about 300℃); it is soluble in many organic solvents, such as acetone and ethanol. It hardly dissolves in ether or water (2.5×10-4 mol/L) and is completely soluble in cyclohexane, benzene, chloroform and carbon tetrachloride. GB is relatively stable in mineral acid. The oil-water distribution coefficient is 1.72; the ionic product constants are pKa1 = 7.14, pKa2 = 8.60, pKa3 = 11.889 (13, 14). GB has a wide range of clinical applications. However, due to its low solubility, short half-life and low bioavailability, its application is limited. Therefore, it is necessary to develop a new pharmaceutical preparation of GB with improved pharmaceutical parameters.

Lipid microemulsion (LM) is a vegetable oil based nanosphere covered with phospholipid. It is a stable Oil/Water disperse system consisting of oil phase, emulsifier, water phase, the diameter of particle size is between 100~200 nm, which is also called submicroemulsion. Medicament with high dissolvability in oil can be sealed in oil phase and phospholipid interface membrane. The medicament can rapidly turn into active material after the system carries it to a target site and it seldom leaks in advance [15]. LM has become a popular preparation because of its safety, stability, and biocompatibility [16, 17]. By adjusting the composition of oil phase, the polarity of the oil phase, emulsifier, ionic strength and preparation method to increase drug solubility, this system would be able to transfer medicament more effectively and safer than traditional preparations. The onset time is shortened [18, 19] while the side-effects are also prevented since there is few medicament outside the target site [20]. In this research, we designed a drug delivery system based on LM to transport medicament, and developed an optimized formulation of Ginkgolide B-Lipid microemulsion (GB-LM) using single factor and orthogonal experiment design, the physicochemical properties and pharmacokinetic parameters of GB-LM in rats were also established.

2 Experimental Procedure

2.1 Materials and equipment

Ginkgolide B (GB>98.0%) and bilobalide reference substance were purchased from Sichuan Pharmaceutical Co., Ltd (Sichuan,China). Glycerol was purchased from Beijing Chemical Works. PC98T were purchased from Q.P. Corporation. Soybean oil and oleic acid were purchased from Tieling Beiya Medicinal Oil Co. Ltd. Refined egg yolk lecithin and commercial GB injection (The dosage of GB injection 20 mg/mL) was provided by the general hospital of the people’s liberation army. Methanol (MREDA) and tetrahydrofuran (SIGMA-ALORICH) were chromatographic grade in particular. Distilled water was from Guangzhou Watsons, and pure water was drinking water from Rahaha.

Shimadzu LC-2010A HT high performance liquid chromatograph, Artorius CRA225D2 electronic balance of one in one hundred thousand, SEDERE LT-ELSD SEDEX80 evaporative light scattering detector, Kunshan KQ3200DB ultrasonic cleaner.

2.2 Preparation of Ginkgolide B Lipid Microspheres

According to the prescription, soybean oil was weighed and heated to 50-60℃. Ginkgolide, oleic acid and refined egg yolk lecithin phospholipid (PC98T) were added to soybean oil, stirred about 2 minutes at 6000rpm until phospholipid was completely dissolved, this process was protected by nitrogen during heating, it was used as oil phase, heat preservation; According to the prescription, water phase was heated to 50-60℃, oil phase was added to water phase slowly, stirred about 10 minutes at 3000-10000 rpm high speed to form colostrum. It was homogenized 8 times (1000bar, homogenization temperature 40℃), adjusted pH to 6.8 with hydrochloric acid, then filled and sealed with nitrogen, sterilized for 8 minutes at 121℃. The process of GB-LM preparation is illustrated in Figure 1.

Figure 1 Manufacturing process of GB lipid microemulsion.
Figure 1

Manufacturing process of GB lipid microemulsion.

Formulation and process parameters for GB-LM were selected based on the single-variable analysis and orthogonal experimental showed in Table 1. Through the equations below, an index S for composite grade is computed to evaluate the production.

Table 1

Orthogonal experimental design.

LevelsFactors
ABCD
(Soybean oil, %)(Lecithin, %)(Oleic acid, %)(Glycerin, %)
19.01.40.300.20
210.01.60.320.25
311.01.80.340.30
  1. The % stands for the mass percentage of this substance in the prescription

S=S1+S2+S3+S4+S5S1==D200,S2==D90200,S3==D50100,S4=PDI×100,S5=D400%×1000

Where D is the particle size, PDI is polydispersity index, D90 is the maximum particle size of 90% particles, D50 is the maximum particle diameter of 50% particles, D400 is the (%) particle size≥400 nm.

2.3 Measurement of particle size and zeta potential

The mean particle size, polydispersity index and zeta potential were determined by Zetasizer Nano ZS90 (Malvern Instruments Ltd) dynamic light scattering particle size analyzer at the dispersion medium coefficient

of 1.33 at 25℃ where the refractive indices of soybean oil, oleic acid, refined egg yolk lecithin (PC98T), and glycerol are 1.474, 1.377, 1.405 and 1.474, respectively. All samples were diluted 100 times with glycerine (2.25%) at 25℃. All experiments mentioned above were performed at least three times in order to get creditable values.

2.4 Method for determination of GB in lipids

HPLC-ELSD system was used to determine the concentration of GB in lipid microspheres. First, 200 μL of GB was dissolved in 10 mL methanol for breaking emulsion. They were then filtered by a 0.45 μm membrane filter; 10 μL aliquot of the supernatant fluid of broken GB was injected into HPLC-ELSD system, a Diamonsil C18 column (250 mm×4.6 mm, 5μm) was employed to separate samples, the ratio of mobile phase was methanol: tetrahydrofuran : water = 25 : 10 : 65, with the flow rate 1.0 mL/min. All HPLC analyses were performed at (30±1)℃, the drift tube temperature was 40℃, the carrier gas pressure was 2.5 bar, Gain 7. The retention time was 12. 618 min.

GB (15 mg) was accurately weighed and dissolved in 50 mL methanol as a stock solution (the concentration of GB about 0.3 mg/mL). The mother liquid was diluted 8 mL, 7 mL, 5 mL and 3 mL to 10 mL by methanol. The concentration of GB was 0.24 mg/mL, 0.21 mg/mL, 0.15 mg/mL and 0.09 mg/mL. Based on GB standard solutions, the working calibration curve showed visible linearity within the range of 0.9-2.5 mg. The regression line was approximately Y=1.6677X+1.9786 (R2 = 0.9998, n = 5), where X was the logarithm of concentration and Y was the logarithm of the peak area.

2.5 Pharmacodynamics studies

Sprague–Dawley rats weighing 200±20 g were supplied by Peking Union Medical College Hospital Laboratory Animal Center (Beijing, China). 12 rats, both male and female, were randomly separated into GB-LM group and GB commercial product group. The rats were fasted for 12 h and had free access to water before dosing. The GB-LM and GB commercial product were injected intravenously at a dose of 4 mg/kg. All animal care was directed according to the Guiding Principles in the Use of Animals in Toxicology by the Society of Toxicology. Serial blood samples (0.5mL) were collected from the eye socket vein at seven specified time intervals after dosing, and all were placed into heparinized tubes. Another sample of the rat plasma were centrifuged at 3,000 rpm for 10 min. The plasma supernatant (0.5 mL) was mixed with 50 μL of hydrochloric acid (1 mol/L), and plasma samples were frozen at -20℃ until analysis. Plasma samples (100 μL) were mixed with 10 μL per ml of fluconazole solution as the standard, 1.0 mL of ethyl acetate was added, vortexed for 2 min and centrifuged at 5000 rpm for 5 min. Supernatants (800 μL) were collected, passed through a 0.45 μm membrane filter and evaporated to dryness at 40℃ under nitrogen gas. The residues were reconstituted in 200μL acetonitrile and the concentrations of GB in plasma samples were analyzed by LC-MS.

LC–MS was implemented on a Shimadzu 8050 system attached to a Shimadzu 30AD LC system and an 8050 triple quadrupole mass spectrometer (Shimadzu Corporation UFLC XR, Kyoto, Japan). A Shimadzu LC-30AD series chromatographic system consisted of two LC-30A binary pumps, a SIL-30AC autosampler, a DGU-20A3 degasser, SPD-M30A Diode Array Detector and a CTO-20A column oven.

Chromatographic separation of GB in plasma samples was achieved on a Phenomenex Kinetex® C18 column (100 × 2.1 mm, 2.6 μm). The column temperature was set to 30℃. Mobile phase consists of acetonitrile and 0.2% formic acid at a ratio of 35: 65.

The triple quadrupole mass spectrometer operated under multiple reaction monitoring mode for quantitative and qualitative analysis. The optimized electrospray ionization condition was: gas flow 10 L/min, gas temperature 400℃, sheath gas flow 10 L/min, sheath gas temperature 300℃, capillary voltage 3000 V and nozzle voltage 1800 V.

2.6 Brain tissue distribution studies

Six rats were fasted for 12 hours but had water before the treatment. The GB-LM were injected intravenously at 4 mg/kg via the femoral vein. Rats were euthanized at 0.5 and 2 h after dosing. The brain tissues were separated and washed with saline and then were weighed and homogenized in saline solution (100 mg/mL). The homogenates (100 μL) were mixed with 10 μL of fluconazole (10 μg/mL) solution as an internal standard, 50μL of methanol was added, vortexed for 1 min and centrifuged at 10000 rpm for 5 min. Supernatants (100μL) were collected the tissue homogenates were stored at −20℃.

2.7 Pharmacokinetic data analysis

The analysis used program WinNonlin version 4.1 (Pharsight Co.), which used the WinNonlin method to calculate AUC 0-240 (integral of the time concentration curve between 0 min and 240 min), Mean Residence Time (MRT), half-life (t1/2), steady state volume of distribution (Vss), total clearance (Cl), distribution half-life (t1/2α), elimination half-life (t1/2β), elimination rate constant from central compartment (K10), rate constant for drug transfer from central to peripheral compartment (K12), rate constant for drug transfer from peripheral to central compartment (K21). The above data were presented as the mean ± standard derivation. Analysis of variance was employed to estimate the pharmacokinetic difference between GB-LM and the commercial product.

3 Results

3.1 The effects of homogenization pressure and temperature on the preparation of GB-LM

In order to explore the effects of the preparation method on the physicochemical properties of GB-LM, the GB-LM were prepared with the following composition: soybean oil (10.0%), GB (0.2%), PC98T (1.8%), oleic acid (2.4%) and glycerol (2.25%). The effect of homogeneous pressure on the GB-LM preparation is shown in Table 2 the effect of homogeneous temperature on the GB-LM preparation is shown in Table 3. The results showed that a higher pressure and temperature of homogenization led to a decrease in both particle size and PDI, respectively.

Table 2

Effect of homogeneous pressure on the preparation of GB-LM.

Pressure (bar)Size (nm)PDI
700225.90.147
750220.20.132
800210.70.117
900198.40.102
10001850.091
Table 3

Effect of mixing temperature on preparation of GB-LM.

Temperature (°C)Size (nm)PDI
25197.30.131
30188.20.084
40183.70.079

With the increasing pressure in homogenization, the pressure compresses the structure of the emulsion membrane, making the particle size smaller, and dispersing the grease microemulsions in the solvent, the interfacial tension between oil phase and water phase declines, so do PDI and the diameter of the particles. Considering the feasibility of production and the duration of equipment, homogeneous pressure was set at 1000 bar. The homogeneous temperature study indicates that high temperature can decrease the particle diameter of lipid microemulsion but destroy the stability of GB. Because Ginkgolide B is a diterpene lactone compound, the molecule contains multiple reducing hydroxyl functional groups that are thermally unstable; higher temperature can make the structure of emulsified membrane become looser and looser, resulting in rupture, therefore, the temperature should be between 38-40℃.

3.2 The effect of cycle number of homogenization on the GB-LM preparation

GB-LM was prepared as previously described, we studied the effect of homogenization times on the production of GB-LM (Table 4). As homogenization times increases, PDI and the diameter decreases at 1st-3rd times. The decreasing speed slows down at 3rd-8th times, and the data satisfies the requirement at the 7th time. However, we choose the 8th time, as later experiment shows that it meets the stability requirement.

Table 4

Effect of cycle number of homogenization on the GB-LM preparation.

Homogenization timesSize(nm)PDI
1672.30.437
2321.20.214
3200.90.142
4195.30.129
5190.30.111
6191.20.101
7186.30.087
8185.00.091

3.3 Formulation optimization by orthogonal experiment design

Orthogonal experimental design is used for studying the effect of multiple factors at different levels. It takes representative samples; these samples have evenly distributed discrete factors. Orthogonal experimental design is an effective, fast, economical test design [21,22].

On the basis of univariate analysis, orthogonal experiment design to optimize the formulation and the results were obtained as presented in Table 5. K is calculated, which is the average of one certain level with a certain factor; Range is the extremum, which is the largest K minus the smallest K. The sequence of effects on composite grade to evaluate the preparation was

Table 5

The results of orthogonal experimental design for GB-LM.

LevelFactorsS
ABCD
11111472.8
21222283.5
31333399.4
42123245.6
52231385.1
62312190.2
73132416.2
83213435.8
93321303.6
KK1385.233378.200366.267387.167
K2273.633368.133277.567296.633
K3385.200297.733400.233360.267
Range111.60080.467122.66690.534

A>B>C>D. The optimal composition was A2B3C2D2, which means 10.0% soybean oil, 1.8% lecithin, 0.32% oleic acid and 0.25% glycerol (Table 6).

Table 6

Optimum formulation of GB-LM.

Material nameprescription
Soybean oil100g
GB2g
PC98T18g
Oleic acid3.2g
Glycerol2.5g
HCLappropriate amount
Aquae pro injectione1000ml

Based on the results obtained, the optimal preparation and critical process parameters can be summarized as follows: the oil phase was set by adding GB (2.0%) , PC98T (1.8%) and oleic acid (0.32%) into soybean oil (10.0%) , stirring until dissolved at 50-60℃, nitrogen protection; The aqueous phase was prepared by dissolving glycerol (0.25%) in distilled water. Then the oil phase was poured into aqueous phase at 3000-10000 rpm high-speed mixing for 10 min to form the coarse emulsion. The resultant coarse emulsion passed through a homogenizer for one cycle at 200bar, eight cycles at 1000bar to obtain the final emulsion. The pH was adjusted to 6.8, passed through a 0.45 μm membrane filter and sterilized at 125℃ for 8 min.

As a result, the average particle size, polydispersity index and zeta potential of the final formulation were 185.9±52.5nm, 0.091±0.023 and −19.8±1.3mV, respectively

(Table 7, Figure 2). The optimal preparation parameters mentioned above did not differ significantly even after storage at room temperature for three months, the content of GB was only slightly decreased by 2.9%. These results indicate that GB-LM was stable.

Figure 2 Zeta potential and particle size of optimized GB lipid emulsion. Each value represents the average ±S.D. (n=3) .
Figure 2

Zeta potential and particle size of optimized GB lipid emulsion. Each value represents the average ±S.D. (n=3) .

Table 7

Stability of fat emulsion stored at room temperature for three months.

storage time (months)Size (nm)PDIZeta potential (mV)GB content (%)
0185.9±52.50.091±0.023−19.8 ± 1.393.1±0.5
3191.6±42.10.108±0.006−26.5 ± 4.290.2±1.9

3.4 Study on pharmacokinetics of rats in vivo

The pharmacokinetic parameters of GB were determined by intravenous administration of GB-LM and the in-market products at a dose of 4 mg/kg as GB to rats. Figure 3 and Table 8 showed the mean plasma concentration time profiles and the pharmacokinetic parameters of GB. The total plasma concentrations with the lipid micro emulsion formulations were considerably higher than with the commercial product. In particular, the AUC of GB from the lipid micro emulsion was about 1.57-fold higher than that from the commercial product, which indicates that GB had greater bioavailability compared to the other one. In addition, the T1/2α and T1/2β in the GB group were 0.127±0.036 min and 1.506±0.43 min respectively, which were 69.3% and 93.1% longer than those of the

Figure 3 Plasma concentration-time profiles of GB. GB-LM (○) and the commercial product (●). Each value represents the mean ± S.D. (n = 8).
Figure 3

Plasma concentration-time profiles of GB. GB-LM (○) and the commercial product (●). Each value represents the mean ± S.D. (n = 8).

Table 8

Pharmacokinetic parameters of GB after intravenous administration of GB-LM and the commercial product at a dose of 4 mg/kg as GB in rats.

Pharmacokinetic parameterGB-LMThe commercial product
AUC0-240min (min·μg·ml−1)0.365±0.12*0.232±0.18
MRT(mean residence time) (h)1.384±0.39*0.665±0.43
Cmax (ng·ml-1)353.8489.7
Tmax (h)0.080.08
T1/2α (h)0.127±0.0360.075±0.05
T1/2β (h)1.506±0.43*0.780±0.51
K10 (h−1)1.312±0.81*4.542±2.41
K12 (h−1)3.229±4.586.142±3.59
K21 ( h−1)3.972±5.673.292±1.09
Vss (L)1.977±1.2*2.826±1.46
CL (L·h-1)2.594±0.25*3.885±0.47
  1. Each value represents the mean ± S.D. (n=8). * p<0.05compared with the commercial product

commercial product group, respectively. It was clear that incorporating GB into lipid microemulsion resulted in a significant alteration of the pharmacokinetic parameters such as a marked increase in AUC0-240min, MRT, plasma half-life and elimination rate (2.594 L/h vs 3.885 L/h). Thus, the enhanced bioavailability of drug from such lipid microemulsion could be beneficial to its therapeutic effect.

The result shows that the AUC, MRT, T1/2β, K10, Vss, and CL for GB-LM and commercial products differs statistically. In particular, t-test indicates that the in-equivalence between two samples. AUC has a 90% confidence interval between 143% and 182%. The relative bioavailability of GB-LM is 158%±28%.

3.5 Brain tissue distribution

The GB-LM were injected intravenously at a dose of 4 mg/kg via the femoral vein. The brain tissues were dissected respectively at 0.5 and 2 h after dosing, the concentration of GB in the brain tissues were shown in Figure 4. The concentration of GB reached a peak at 0.5h, which indicated GB-LM could pass through the blood brain barrier; the concentration of GB in the brain tissues decreased significantly after 2 h, the MRT was 1.384, these indicate that the drug will not accumulate in the body. With the extension of time, the concentration of the drug in the tissues and organs rapidly decays, and the drug will be quickly removed from the body.

Figure 4 The concentration of GB in the brain tissues distribution.
Figure 4

The concentration of GB in the brain tissues distribution.

4 Conclusion

In conclusion, the optimized formulation of the lipid microemulsion containing GB was developed using orthogonal experimental design. The average particle size, polydispersity index and zeta potential of the optimized formulation were 185.9 ± 52.5 nm, 0.091 ±0.023, and -19.8 ± 1.3 mv, respectively. The formulation was stable for at least three months at room temperature. In addition, GB-LM can pass through the blood brain barrier and reach brain cell. The pharmacokinetic study indicates that it provided a higher AUC and longer terminal half-life value than did the commercial product, indicating that it improved the bioavailability of GB in rats compared with the commercial product. Taken together, the optimized formulation of this lipid microemulsion was a more effective and stable delivery system for GB compared to the existing commercial products.

Acknowledgements

This research was financially supported by the National Natural Science Foundation of China (Grants No. 11475020 and 8151114029) and Beijing Union University Graduate Program.

  1. Conflict of interest: Authors declare no conflict of interest.

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Received: 2018-07-13
Accepted: 2018-11-11
Published Online: 2019-06-07

© 2019 Xiao Wu et al., published by De Gruyter

This work is licensed under the Creative Commons Attribution 4.0 Public License.

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  18. The Use Of Chemical Composition And Additives To Classify Petrol And Diesel Using Gas Chromatography–Mass Spectrometry And Chemometric Analysis: A Uk Study
  19. Minimal Energy Tree with 4 Branched Vertices
  20. Jatropha seed oil derived poly(esteramide-urethane)/ fumed silica nanocomposite coatings for corrosion protection
  21. Calculating topological indices of certain OTIS interconnection networks
  22. Energy storage analysis of R125 in UIO-66 and MOF-5 nanoparticles: A molecular simulation study
  23. Velvet Antler compounds targeting major cell signaling pathways in osteosarcoma - a new insight into mediating the process of invasion and metastasis in OS
  24. Effects of Azadirachta Indica Leaf Extract, Capping Agents, on the Synthesis of Pure And Cu Doped ZnO-Nanoparticles: A Green Approach and Microbial Activity
  25. Aqueous Micro-hydration of Na+(H2O)n=1-7 Clusters: DFT Study
  26. A proposed image-based detection of methamidophos pesticide using peroxyoxalate chemiluminescence system
  27. Phytochemical screening and estrogenic activity of total glycosides of Cistanche deserticola
  28. Biological evaluation of a series of benzothiazole derivatives as mosquitocidal agents
  29. Chemical pretreatments of Trapa bispinosa's peel (TBP) biosorbent to enhance adsorption capacity for Pb(ll)
  30. Dynamic Changes in MMP1 and TIMP1 in the Antifibrotic Process of Dahuang Zhechong Pill in Rats with Liver Fibrosis
  31. The Optimization and Production of Ginkgolide B Lipid Microemulsion
  32. Photodynamic Therapy Enhanced the Antitumor Effects of Berberine on HeLa Cells
  33. Chiral and Achiral Enantiomeric Separation of (±)-Alprenolol
  34. Correlation of Water Fluoride with Body Fluids, Dental Fluorosis and FT4, FT3 –TSH Disruption among Children in an Endemic Fluorosis area in Pakistan
  35. A one-step incubation ELISA kit for rapid determination of dibutyl phthalate in water, beverage and liquor
  36. Free Radical Scavenging Activity of Essential Oil of Eugenia caryophylata from Amboina Island and Derivatives of Eugenol
  37. Effects of Blue and Red Light On Growth And Nitrate Metabolism In Pakchoi
  38. miRNA-199a-5p functions as a tumor suppressor in prolactinomas
  39. Solar photodegradation of carbamazepine from aqueous solutions using a compound parabolic concentrator equipped with a sun tracking system
  40. Influence of sub-inhibitory concentration of selected plant essential oils on the physical and biochemical properties of Pseudomonas orientalis
  41. Preparation and spectroscopic studies of Fe(II), Ru(II), Pd(II) and Zn(II) complexes of Schiff base containing terephthalaldehyde and their transfer hydrogenation and Suzuki-Miyaura coupling reaction
  42. Complex formation in a liquid-liquid extraction-chromogenic system for vanadium(IV)
  43. Synthesis, characterization (IR, 1H, 13C & 31P NMR), fungicidal, herbicidal and molecular docking evaluation of steroid phosphorus compounds
  44. Analysis and Biological Evaluation of Arisaema Amuremse Maxim Essential Oil
  45. A preliminary assessment of potential ecological risk and soil contamination by heavy metals around a cement factory, western Saudi Arabia
  46. Anti- inflammatory effect of Prunus tomentosa Thunb total flavones in LPS-induced RAW264.7 cells
  47. Collaborative Influence of Elevated CO2 Concentration and High Temperature on Potato Biomass Accumulation and Characteristics
  48. Methods of extraction, physicochemical properties of alginates and their applications in biomedical field – a review
  49. Characteristics of liposomes derived from egg yolk
  50. Preparation of ternary ZnO/Ag/cellulose and its enhanced photocatalytic degradation property on phenol and benzene in VOCs
  51. Influence of Human Serum Albumin Glycation on the Binding Affinities for Natural Flavonoids
  52. Synthesis and antioxidant activity of 2-methylthio-pyrido[3,2-e][1,2,4] triazolo[1,5-a]pyrimidines
  53. Comparative study on the antioxidant activities of ten common flower teas from China
  54. Molecular Properties of Symmetrical Networks Using Topological Polynomials
  55. Synthesis of Co3O4 Nano Aggregates by Co-precipitation Method and its Catalytic and Fuel Additive Applications
  56. Phytochemical analysis, Antioxidant and Antiprotoscolices potential of ethanol extracts of selected plants species against Echinococcus granulosus: In-vitro study
  57. Silver nanoparticles enhanced fluorescence for sensitive determination of fluoroquinolones in water solutions
  58. Simultaneous Quantification of the New Psychoactive Substances 3-FMC, 3-FPM, 4-CEC, and 4-BMC in Human Blood using GC-MS
  59. Biodiesel Production by Lipids From Indonesian strain of Microalgae Chlorella vulgaris
  60. Miscibility studies of polystyrene/polyvinyl chloride blend in presence of organoclay
  61. Antibacterial Activities of Transition Metal complexes of Mesocyclic Amidine 1,4-diazacycloheptane (DACH)
  62. Novel 1,8-Naphthyridine Derivatives: Design, Synthesis and in vitro screening of their cytotoxic activity against MCF7 cell line
  63. Investigation of Stress Corrosion Cracking Behaviour of Mg-Al-Zn Alloys in Different pH Environments by SSRT Method
  64. Various Combinations of Flame Retardants for Poly (vinyl chloride)
  65. Phenolic compounds and biological activities of rye (Secale cereale L.) grains
  66. Oxidative degradation of gentamicin present in water by an electro-Fenton process and biodegradability improvement
  67. Optimizing Suitable Conditions for the Removal of Ammonium Nitrogen by a Microbe Isolated from Chicken Manure
  68. Anti-inflammatory, antipyretic, analgesic, and antioxidant activities of Haloxylon salicornicum aqueous fraction
  69. The anti-corrosion behaviour of Satureja montana L. extract on iron in NaCl solution
  70. Interleukin-4, hemopexin, and lipoprotein-associated phospholipase A2 are significantly increased in patients with unstable carotid plaque
  71. A comparative study of the crystal structures of 2-(4-(2-(4-(3-chlorophenyl)pipera -zinyl)ethyl) benzyl)isoindoline-1,3-dione by synchrotron radiation X-ray powder diffraction and single-crystal X-ray diffraction
  72. Conceptual DFT as a Novel Chemoinformatics Tool for Studying the Chemical Reactivity Properties of the Amatoxin Family of Fungal Peptides
  73. Occurrence of Aflatoxin M1 in Milk-based Mithae samples from Pakistan
  74. Kinetics of Iron Removal From Ti-Extraction Blast Furnace Slag by Chlorination Calcination
  75. Increasing the activity of DNAzyme based on the telomeric sequence: 2’-OMe-RNA and LNA modifications
  76. Exploring the optoelectronic properties of a chromene-appended pyrimidone derivative for photovoltaic applications
  77. Effect of He Qi San on DNA Methylation in Type 2 Diabetes Mellitus Patients with Phlegm-blood Stasis Syndrome
  78. Cyclodextrin potentiometric sensors based on selective recognition sites for procainamide: Comparative and theoretical study
  79. Greener synthesis of dimethyl carbonate from carbon dioxide and methanol using a tunable ionic liquid catalyst
  80. Nonisothermal Cold Crystallization Kinetics of Poly(lactic acid)/Bacterial Poly(hydroxyoctanoate) (PHO)/Talc
  81. Enhanced adsorption of sulfonamide antibiotics in water by modified biochar derived from bagasse
  82. Study on the Mechanism of Shugan Xiaozhi Fang on Cells with Non-alcoholic Fatty Liver Disease
  83. Comparative Effects of Salt and Alkali Stress on Antioxidant System in Cotton (Gossypium Hirsutum L.) Leaves
  84. Optimization of chromatographic systems for analysis of selected psychotropic drugs and their metabolites in serum and saliva by HPLC in order to monitor therapeutic drugs
  85. Electrocatalytic Properties of Ni-Doped BaFe12O19 for Oxygen Evolution in Alkaline Solution
  86. Study on the removal of high contents of ammonium from piggery wastewater by clinoptilolite and the corresponding mechanisms
  87. Phytochemistry and toxicological assessment of Bryonia dioica roots used in north-African alternative medicine
  88. The essential oil composition of selected Hemerocallis cultivars and their biological activity
  89. Mechanical Properties of Carbon Fiber Reinforced Nanocrystalline Nickel Composite Electroforming Deposit
  90. Anti-c-myc efficacy block EGFL7 induced prolactinoma tumorigenesis
  91. Topical Issue on Applications of Mathematics in Chemistry
  92. Zagreb Connection Number Index of Nanotubes and Regular Hexagonal Lattice
  93. The Sanskruti index of trees and unicyclic graphs
  94. Valency-based molecular descriptors of Bakelite network BNmn
  95. Computing Topological Indices for Para-Line Graphs of Anthracene
  96. Zagreb Polynomials and redefined Zagreb indices of Dendrimers and Polyomino Chains
  97. Topological Descriptor of 2-Dimensional Silicon Carbons and Their Applications
  98. Topological invariants for the line graphs of some classes of graphs
  99. Words for maximal Subgroups of Fi24
  100. Generators of Maximal Subgroups of Harada-Norton and some Linear Groups
  101. Special Issue on POKOCHA 2018
  102. Influence of Production Parameters on the Content of Polyphenolic Compounds in Extruded Porridge Enriched with Chokeberry Fruit (Aronia melanocarpa (Michx.) Elliott)
  103. Effects of Supercritical Carbon Dioxide Extraction (SC-CO2) on the content of tiliroside in the extracts from Tilia L. flowers
  104. Impact of xanthan gum addition on phenolic acids composition and selected properties of new gluten-free maize-field bean pasta
  105. Impact of storage temperature and time on Moldavian dragonhead oil – spectroscopic and chemometric analysis
  106. The effect of selected substances on the stability of standard solutions in voltammetric analysis of ascorbic acid in fruit juices
  107. Determination of the content of Pb, Cd, Cu, Zn in dairy products from various regions of Poland
  108. Special Issue on IC3PE 2018 Conference
  109. The Photocatalytic Activity of Zns-TiO2 on a Carbon Fiber Prepared by Chemical Bath Deposition
  110. N-octyl chitosan derivatives as amphiphilic carrier agents for herbicide formulations
  111. Kinetics and Mechanistic Study of Hydrolysis of Adenosine Monophosphate Disodium Salt (AMPNa2) in Acidic and Alkaline Media
  112. Antimalarial Activity of Andrographis Paniculata Ness‘s N-hexane Extract and Its Major Compounds
  113. Special Issue on ABB2018 Conference
  114. Special Issue on ICCESEN 2017
  115. Theoretical Diagnostics of Second and Third-order Hyperpolarizabilities of Several Acid Derivatives
  116. Determination of Gamma Rays Efficiency Against Rhizoctonia solani in Potatoes
  117. Studies On Compatibilization Of Recycled Polyethylene/Thermoplastic Starch Blends By Using Different Compatibilizer
  118. Liquid−Liquid Extraction of Linalool from Methyl Eugenol with 1-Ethyl-3-methylimidazolium Hydrogen Sulfate [EMIM][HSO4] Ionic Liquid
  119. Synthesis of Graphene Oxide Through Ultrasonic Assisted Electrochemical Exfoliation
  120. Special Issue on ISCMP 2018
  121. Synthesis and antiproliferative evaluation of some 1,4-naphthoquinone derivatives against human cervical cancer cells
  122. The influence of the grafted aryl groups on the solvation properties of the graphyne and graphdiyne - a MD study
  123. Electrochemical modification of platinum and glassy carbon surfaces with pyridine layers and their use as complexing agents for copper (II) ions
  124. Effect of Electrospinning Process on Total Antioxidant Activity of Electrospun Nanofibers Containing Grape Seed Extract
  125. Effect Of Thermal Treatment Of Trepel At Temperature Range 800-1200˚C
  126. Topical Issue on Agriculture
  127. The effect of Cladophora glomerata exudates on the amino acid composition of Cladophora fracta and Rhizoclonium sp.
  128. Influence of the Static Magnetic Field and Algal Extract on the Germination of Soybean Seeds
  129. The use of UV-induced fluorescence for the assessment of homogeneity of granular mixtures
  130. The use of microorganisms as bio-fertilizers in the cultivation of white lupine
  131. Lyophilized apples on flax oil and ethyl esters of flax oil - stability and antioxidant evaluation
  132. Production of phosphorus biofertilizer based on the renewable materials in large laboratory scale
  133. Human health risk assessment of potential toxic elements in paddy soil and rice (Oryza sativa) from Ugbawka fields, Enugu, Nigeria
  134. Recovery of phosphates(V) from wastewaters of different chemical composition
  135. Special Issue on the 4th Green Chemistry 2018
  136. Dead zone for hydrogenation of propylene reaction carried out on commercial catalyst pellets
  137. Improved thermally stable oligoetherols from 6-aminouracil, ethylene carbonate and boric acid
  138. The role of a chemical loop in removal of hazardous contaminants from coke oven wastewater during its treatment
  139. Combating paraben pollution in surface waters with a variety of photocatalyzed systems: Looking for the most efficient technology
  140. Special Issue on Chemistry Today for Tomorrow 2019
  141. Applying Discriminant and Cluster Analyses to Separate Allergenic from Non-allergenic Proteins
  142. Chemometric Expertise Of Clinical Monitoring Data Of Prolactinoma Patients
  143. Chemomertic Risk Assessment of Soil Pollution
  144. New composite sorbent for speciation analysis of soluble chromium in textiles
  145. Photocatalytic activity of NiFe2O4 and Zn0.5Ni0.5Fe2O4 modified by Eu(III) and Tb(III) for decomposition of Malachite Green
  146. Photophysical and antibacterial activity of light-activated quaternary eosin Y
  147. Spectral properties and biological activity of La(III) and Nd(III) Monensinates
  148. Special Issue on Monitoring, Risk Assessment and Sustainable Management for the Exposure to Environmental Toxins
  149. Soil organic carbon mineralization in relation to microbial dynamics in subtropical red soils dominated by differently sized aggregates
  150. A potential reusable fluorescent aptasensor based on magnetic nanoparticles for ochratoxin A analysis
  151. Special Issue on 13th JCC 2018
  152. Fluorescence study of 5-nitroisatin Schiff base immobilized on SBA-15 for sensing Fe3+
  153. Thermal and Morphology Properties of Cellulose Nanofiber from TEMPO-oxidized Lower part of Empty Fruit Bunches (LEFB)
  154. Encapsulation of Vitamin C in Sesame Liposomes: Computational and Experimental Studies
  155. A comparative study of the utilization of synthetic foaming agent and aluminum powder as pore-forming agents in lightweight geopolymer synthesis
  156. Synthesis of high surface area mesoporous silica SBA-15 by adjusting hydrothermal treatment time and the amount of polyvinyl alcohol
  157. Review of large-pore mesostructured cellular foam (MCF) silica and its applications
  158. Ion Exchange of Benzoate in Ni-Al-Benzoate Layered Double Hydroxide by Amoxicillin
  159. Synthesis And Characterization Of CoMo/Mordenite Catalyst For Hydrotreatment Of Lignin Compound Models
  160. Production of Biodiesel from Nyamplung (Calophyllum inophyllum L.) using Microwave with CaO Catalyst from Eggshell Waste: Optimization of Transesterification Process Parameters
  161. The Study of the Optical Properties of C60 Fullerene in Different Organic Solvents
  162. Composite Material Consisting of HKUST-1 and Indonesian Activated Natural Zeolite and its Application in CO2 Capture
  163. Topical Issue on Environmental Chemistry
  164. Ionic liquids modified cobalt/ZSM-5 as a highly efficient catalyst for enhancing the selectivity towards KA oil in the aerobic oxidation of cyclohexane
  165. Application of Thermal Resistant Gemini Surfactants in Highly Thixotropic Water-in-oil Drilling Fluid System
  166. Screening Study on Rheological Behavior and Phase Transition Point of Polymer-containing Fluids produced under the Oil Freezing Point Temperature
  167. The Chemical Softening Effect and Mechanism of Low Rank Coal Soaked in Alkaline Solution
  168. The Influence Of NO/O2 On The NOx Storage Properties Over A Pt-Ba-Ce/γ-Al2O3 Catalyst
  169. Special Issue on the International conference CosCI 2018
  170. Design of SiO2/TiO2 that Synergistically Increases The Hydrophobicity of Methyltrimethoxysilane Coated Glass
  171. Antidiabetes and Antioxidant agents from Clausena excavata root as medicinal plant of Myanmar
  172. Development of a Gold Immunochromatographic Assay Method Using Candida Biofilm Antigen as a Bioreceptor for Candidiasis in Rats
  173. Special Issue on Applied Biochemistry and Biotechnology 2019
  174. Adsorption of copper ions on Magnolia officinalis residues after solid-phase fermentation with Phanerochaete chrysosporium
  175. Erratum
  176. Erratum to: Sand Dune Characterization For Preparing Metallurgical Grade Silicon
Heruntergeladen am 21.9.2025 von https://www.degruyterbrill.com/document/doi/10.1515/chem-2019-0042/html
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