chapter-4 rp-hplc method for determination of tapentadol...

Chapter-4

RP-HPLC method for determination of

tapentadol and its related impurities

4.1 Introduction

Tapentadol, 3-[(1R,

hydrochloride is in a group of drugs called

opioid is sometimes called narcotic. Tapentadol is approved in United States

moderate to severe chronic pain. Tapentadol is a centrally acting analgesic with a dual mode of

action as an agonist of the µ –opioid receptor and a nor epinephrine reuptake inhibitor [1

chemical structure of tapentadol shown in the Figure

Figure

Tapentadol is a white to off

simulated intestinal fluid (SIF), soluble in ethanol, sparingly solub

soluble in 2-propanol.The melting range of tapentadol is 209

Tapentadol is a new synthetic compound.

manufactured as a single (R, R) stereoisomer. Tapentadol shares a 3

amino structural fragment with morphine and its analogues.

(3-methoxyphenyl)-1-propanone by a Mannich reaction

obtain the racemic 3-dimethylamino

[(1R, 2R)-3-(dimethylamino)-1-ethyl-2-methyl propyl]

hydrochloride is in a group of drugs called opioid pain relievers. It is similar to morphine.

narcotic. Tapentadol is approved in United States and


opioid receptor and a nor epinephrine reuptake inhibitor [1

chemical structure of tapentadol shown in the Figure-4.1

Figure-4.1 Chemical structure of tapentadol

a white to off-white powder. It is freely soluble in water, 0.1N HCL, and

simulated intestinal fluid (SIF), soluble in ethanol, sparingly soluble in methanol and slightly

propanol.The melting range of tapentadol is 209-210 °C.

Tapentadol is a new synthetic compound. It has two chiral centers and

manufactured as a single (R, R) stereoisomer. Tapentadol shares a 3-(3-hydroxyphenyl) propyl

amino structural fragment with morphine and its analogues. Tapentadol was synthesized from 1

propanone by a Mannich reaction using dimethylamine hydrochloride to

dimethylamino-1-(3-methoxyphenyl)-2-methylpropan-1-one(13)[4

methyl propyl] phenol

opioid pain relievers. It is similar to morphine. An

and used to treat


opioid receptor and a nor epinephrine reuptake inhibitor [1-3].The

is freely soluble in water, 0.1N HCL, and in

le in methanol and slightly

has two chiral centers and can be

hydroxyphenyl) propyl

synthesized from 1-

dimethylamine hydrochloride to

one(13)[4-5]. This

intermediate is then subjected to crystallization-induced diastereomer transformation, a Grignard

reaction, acylation and finally to catalytic hydrogenolysis to give (2R, 3R)-2-methyl-3-(3-

methoxyphenyl)-N, N-dimethylpentanamine. Tapentadol was isolated as the hydrochloride salt.

All polymorphic forms of tapentadol are freely soluble within the physiological pH range.

Tapentadol is designated as Class 1 (high permeability, high solubility) in the biopharmaceutics

classification system. Stability data have demonstrated that tapentadol hydrochloride is a stable

substance. A retest period of 30 months with storage below 25°C has been approved.

Tapentadol has trade names Nucynta and Palexia. In India it is available as TAPAL (by

MSN Labs). It is a centrally acting analgesic with a dual mode of action as an agonist of the µ-

opioid receptor and as a norepinephrine reuptake inhibitor. It is also an agonist of the σ2 receptor,

though the function of this orphan receptor remains controversial. Tapentadol was developed by

Grünenthal in conjunction with Johnson & Johnson Pharmaceutical Research and Development.

It is being marketed as immediate release oral tablets of 50 mg, 75 mg, and 100 mg under the

brand name Nucynta.

Tapentadol is used for the treatment of moderate to severe pain for both acute (following

injury, surgery, etc.) and chronic musculoskeletal pain. It is also specifically indicated for

controlling the pain of diabetic neuropathy when round-the-clock opioid medication is required.

Although tapentadol is not indicated for the treatment of non-diabetic neuropathic pain, it is

often used off-label for this purpose. It also has the potential to treat depression like its close

relative, tramadol, but it is not approved for this purpose [6-15].The chronic musculoskeletal

pain were shown in the Figure-4.2

Figure-4.2: Chronic musculoskeletal pain

Tapentadol is available in the United States in both immediate release and extended

release formulations as NUCYNTA® and NUCYNTA ER® respectively, from Janssen

pharmaceuticals. The immediate release formulation is provided in 50 mg (yellow), 75 mg

(orange), and 100 mg (red/orange) tablets, to be used once every 4–6 hours as needed to control

pain, up to a maximum dose of 600 mg per 24 hour period (700 mg on day one). The extended

release formulation is provided in 50 mg (white), 100 mg (very light blue), 150 mg (light blue),

200 mg (blue), and 250 mg (dark blue) dosage. The different dosage forms of tapentadol shown

in the Figure-4.3. The extended release dosage starts at 50 mg twice a day, and is then slowly

titrated to an effective and tolerable dose in the range 100mg to 250mg twice a day, with a

maximum dose of 500 mg (250 mg twice a day) per 24 hour period. The dosage and preparation

used should be frequently re-evaluated by the prescribing physician, and the dose should be

lowered if possible to the lowest effective dose if pain decreases. All preparations of

NUCYNTA® contain only the R, R stereoisomer, which is the weakest isomer in terms of opioid

activity [16-17].

Figure-4.3 Tapentadol tablets

Tapentadol is not official in any pharmacopoeia. A few reports are available in literature

on drug interaction between tapentadol and N-desmethy tapentadol in urine. Since this drug is

being marketed in domestic and international market, the present investigation by the author

describes a rapid, accurate and precise RP-HPLC method for the determination of related

substances in bulk sample and pharmaceutical dosage form. The detector response was linear in

the concentration range of 5.06 – 40.46µg/ml of drug and its related substances. The method was

validated as per ICH guidelines. Accordingly, the aim of present study was to develop a stability

indicating relative substances method by RP-HPLC.

In the available literature, many analytical procedures have been reported for the

quantitative determination of tapentadol in pure form as well as in pharmaceutical dosage

formulation by different analytical techniques like spectrophotometry [18-23] and high

performance liquid chromatography [24-35].

A variety of spectrophotometric methods were developed for the determination of

tapentadol in various pharmaceutical dosage forms. Adithya et.al proposed spectrophotometric

estimation of tapentadol in bulk and its pharmaceutical formulation [18]. Pranathi S. developed

new analytical methods for the estimation of tapentadol in bulk drug and in pharmaceutical

formulations [19]. A first order derivative spectrophotometric method for simultaneous

estimation of paracetamol and tapentadol hydrochloride in tablet dosage form was reported by

Samil d. Desai et.al [20]. Mokhtar et.al proposed spectrophotometric methods for determination

of tapentadol hydrochloride [21].Some other UV spectroscopy methods were reported by

different authors [22-23].

Different high performance liquid chromatography methods are available for determination

of tapentadol in bulk and formulations. Ramanaiah et.al proposed stability indicating RP-LC

method for simultaneous estimation of tapentadol and paracetamol in bulk and its pharmaceutical

formulations [24]. A simple, rapid and cost effective method for the routine analysis of

tapentadol hydrochloride was developed by Gandhi and et.al [25]. Mayur et.al proposed new

HPLC method for tapentadol hydrochloride in formulations [26]. Some more chromatographic

and spectroscopic methods were also reported in literature for tapentadol [27-35].

Though large number assay methods are available in literature for tapentadol, only very

few of them are standard, sensitive and selective. In view of the importance of tapentadol in drug

formulation in the treatment of various chronic diseases, a more simple, sensitive, selective and

robust method is needed for its validation in bulk drug formulations. We are now reporting a

simple sensitive and selective RP-HPLC method for the validation of tapentadol and its related

impurities which is also robust and rugged method. The method is validated as per the ICH

guidelines [36-38].

4.2 Experimental:

4.2.1 Chemicals, Reagents and samples:

The standard, samples of tapentadol and known related substances of tapentadol, such as

methoxy impurity [(2R, 3R)-3-(3-methoxyphenyl)-N,N,2-tri methyl pentanamine] and alcohol

impurity [(2S)-1- dimethylamino)-3-(3-methoxyphenyl)-2-methylpentan-3-ol hydrochloride

were received from Bio-Leo analytical Labs India (P) Ltd. Prasanth nagar, Hyderabad.HPLC

grade methanol, Acetonitrile was purchased from Merck, Mumbai, India. Analytical reagent

grade potassium hydrogen phosphate and potassium hydroxide were purchased from Merck,

Mumbai, India. High purity water was prepared by using Millipore Milli-Q plus water

purification system. The purity of all samples and impurities used in this study was greater than

99%.

4.2.2 Instrumentation:

For initial method development studies Waters prominence HPLC system was employed.

This was equipped with a quaternary UFLC LC-20AD pump, DGU-20A5 degasser, SPD-M20A

diode array detector, SIL-20AC auto sampler,CTO-20AC column oven and CBM-20A

communications bus module. Agilent 1200 series high pressure liquid chromatographic

instrument provided with Auto sampler and VWD UV detector with thermostatted column

compartment connected with EZ Chrom software was employed for the validation of the drug

and its related impurities. The analysis was carried out on Zodiac C18 250 x 4.6mm, column with

5µm particle size.

4.2.3 Standard and sample solutions:

4.2.3.1. Preparation of standard solution:

Accurately weighed and transferred 29.0 mg of tapentadol working standard into a 25 ml

clean and dry volumetric flask. 5.0ml of diluent were added and sonicate to dissolve the drug.

The solution was finally made up to the Volume with acetonitrile: methanol (1:1v/v) used as

diluent. 2.0ml of this solution was further diluted to 100ml with the diluent.

4.2.3.2 Sample preparation:

100.0 mg of tapentadol sample was sonicated with 5ml of diluent for 15minutes in a 50ml

dry volumetric flask and made up to the Volume with diluent. The resultant solution was filtered

through a 0.45 micron filter and the first 5 ml were discarded.

4.3 Evaluation of system suitability:

The system suitability was evaluated by injecting a known Volume of sample containing a

known amount of tapentadol into chromatograph and calculated the number of theoretical plates

and asymmetry of the chromatogram. When the number of theoretical plates is >3000 and tailing

factor of tapentadol peak is not more than 2.0, column is found suitable for analysis.

4.4 Results and discussion:

4.4.1 Method development and optimization:

The main objective of this work is to develop a simple and rapid method for the

determination tapentadol and its related impurities in tablet formulations by using reverse phase

high performance liquid chromatography. The method development was initiated with solubility

study of tapentadol. Based on these studies, acetonitrile: methanol (1:1v/v) mixture was chosen

as diluent for the preparation of samples solutions. From the molecular formula of tapentadol it

was notice that it is polar in nature due to the presence of one –OH group. Hence, a non polar C18

column containing octadecyl chemically bonded to porous silica stationary phase was selected

for developing reverse phase high performance liquid chromatogram. The tapentadol solution

has pH 9.0. Therefore, a buffer solution of pH about ±2.0 with respect the observed pH 7.0 is

most suitable for validation study. Hence, buffer solution of pH 7.0 was chosen for

chromatographic studies. From the molecular structure, it was observed that, there is

chromophore group (Phenyl group) was present in tapentadol. Hence there is possibility for its

UV–Visible detection. The UV experiment was performed for maximum absorbance of

tapentadol and finally concluded that tapentadol shows maximum absorbance at 220nm.

To arrive at the optimal chromatographic conditions for the determination of tapentadol

and its related substances, various trails were performed with different chromatographic

conditions and the results obtained were analyzed

Trail-1

The first trail method was performed by using gradient mode, buffer solution (pH 7.0) as

mobile phase-A and acetonitrie-methanol mixture (3:7v/v) as mobile phase-B. The injection

Volume was 10µL.

Column : Zodiac C18 250X4.6 mm with 5 µm particle size

Pump mode : Gradient

Flow rate : 1.0 ml/min

Detection wavelength : UV , 220 nm

Injection Volume : 10µL

Column temperature : 450C

Run time : 55 min

Buffer : Dissolved 6.8 mg of potassium dihydrogen ortho phosphate into 1000 ml of

Milli-Q water and the pH is adjusted pH 7± 0.005 with 10% KOH.

Mobile phase A : Buffer (pH-7.0)

Mobile phase B : Acetonitrile and methanol (3:7 v/v)

In this trail there is no elution of tapentadol isomer impurities peaks up to run time of 55 minutes

and asymmetry of tapentadol peak was more than 2.0

Trail-2

To overcome the limitations of the above trail method, the experiment was repeated by

changing the mobile phase-B composition using buffer solution-acetonitrile-methanol mixture in

1:2:7(v/v) ratio and reducing the injection Volume from 10µL to 5µL.The remaining conditions

same as above.







Run time : 55 min

Buffer : Dissolved 6.8 mg of potassium dihydrogen ortho phosphate into 1000 ml of

Milli-Q water and the pH is adjusted pH 7± 0.005 with 10% KOH.


Mobile phase B : Buffer, acetonitrile and methanol (1:2:7 v/v)

In this trail also there was no elution of tapentadol isomer impurity peaks up to run time 55

minutes but other impurities like alcohol and methoxy impurities were well separated from

tapentadol and method given excellent peak shape with tailing of tapentadol peak 1.16.

Trail-3

To achieve the separation of tapentadol impurities, the mobile phase-B composition was

changed by using buffer solution-acetonitrile-methanol mixture in 3:2:5(v/v) ratio and the

experiment was repeated under the optima conditions.







Run time : 55 min

Buffer : Dissolved 6.8 mg of Potassium dihydrogen ortho phosphate into 1000 ml of

Milli-Q water mixes to dissolve adjust pH 7± 0.005 with 10% KOH.


Mobile phase B : Buffer, Acetonitrile and methanol (3:2:5 v/v)

In this trail tapentadol peak was eluted in 14 minutes and the isomer impurity of tapentadol was

well separated from the main tapentadol peak.

Finally, satisfactory separation with better peak shape was achieved within a reasonable

retention time with gradient mode with flow rate 1.0mL/min at temperature 450C.

4.5 Method validation:

In order to determine the related substances of tapentadol, the method was validated as

per the ICH guidelines individually in terms of system suitability, specificity, precision,

accuracy, linearity, robustness, limit of detection and limit of quantification (LOD and LOQ) and

solution stability.

4.5.1 System suitability test:

System suitability was studied by injecting diluent as blank, placebo, standard solution

and tapentadol solution into the HPLC system and good resolution was obtained between

impurities and tapentadol. The system suitability results were given in the Table-4.1.The system

suitability chromatogram of tapentadol in bulk and formulation form shown in the Figure-4.4

Table-4.1. Results of system suitability

System suitability parameters Result Acceptance criteria as per USP

Theoretical plates 18819 NLT 3000

Tailing factor 1.16 NMT 2.0

4.5.2 Specificity of method with related substances:

Specificity is the ability of the method to accurately measure the analyte response in the

presence of all potential sample components. The response of the analyte in test mixtures

containing the analyte and all potential components is compared with the response of a solution

containing only analyte.For specificity determination, solution containing diluent and all related

substances of tapentadol such as methoxy impurity [(2R, 3R)-3-(3-methoxyphenyl)-N, N, 2-tri

methyl pentanamine] and alcohol impurity [(2S)-1-dimethylamino)-3-(3-methoxyphenyl)-2-

methylpentan-3-ol hydrochloride were prepared by mixing in suitable proportions. Then diluent,

standard preparation, sample preparation, sample spiked with impurities were injected with the

chromatograph and the peak homogeneity was verified for tapentadol and its related substances

using EZ Chrom software. The summary of specificity experiment results are shown in the

Table-4.2.The specificity chromatogram is given in the Figure-4.5.

Table-4.2: Results of specificity experiment

S.No.

Name of the

impurity/analyte

Peak purity

RT(Individual)

RT (Spiked sample)

1 Tapentadol 1.00000 13.99 13.99

2 Methoxy impurity 1.00000 39.75 39.76

3 Alcohol impurity 1.00000 30.89 30.85

4 Isomer-1 impurity 0.99290 16.05 15.96

5 Isomer-2 impurity 1.00000 16.98 16.94

4.5.3 Precision:

4.5.3.1 System precision (Repeatability):

Six replicate aliquots of sample solution of tapentadol spiked with impurities were

injected into RP-HPLC system and the chromatograms were recorded for checking the

performance of the system under the chromatographic conditions on the day tested and

calculated the relative standard deviation of the percentage of impurity. The RSD values

obtained were 0.49% and 0.25% for methoxy impurity and alcohol impurity respectively. This

showed the good precision of the system. The system precision results are shown in Table-4.3.

Table-4.3: Precision study of tapentadol

4.5.3.2 Intermediate Precision (Ruggedness):

The intermediate precision also called as ruggedness, is the inter-day variation. It is

defined as the degree of reproducibility obtained by following the same procedure as mentioned

for method precision experiment. The ruggedness of the test method was demonstrated by

carrying out precision study in six preparations of sample, a single batch sample by different

analysts, different columns, on different days and using different instruments and calculated the

percentage of impurities. The percentage of relative standard deviation for impurities from six

spiked sample preparations were found to be 0.16% for methoxy impurity and 0.22% for alcohol

impurity showing high ruggedness of the proposed method. The validated intermediate precision

results are given in the Tables-4.4.

Table-4.4: Statistical data of intermediate precision

S.No. Methoxy impurity(%w/w) Alcohol impurity(%w/w)

1 1.00 1.00

2 1.00 1.00

3 0.99 1.00

4 1.00 1.00

5 0.99 1.00

6 1.00 1.00

Average 1.00 1.00

SD: 0.00 0.00

% RSD 0.49 0.25

4.5.4 Accuracy:

The accuracy of the proposed method was tested by rearing sample solutions with known

quantities of methoxy impurity, alcohol impurity at the level of LOQ, 50%, 100%, 150% and

200% of target concentration (i.e., 1.0 % of test concentration.). The chromatograms were

recorded and the recovery percentages were evaluated from the peak areas. The results are

shown in Tables-4.5-4.6.

Table-4.5: Accuracy results of methoxy impurity

Spike level

Amount Added

Amount Recovered

% Recovery

% of mean

S.No. Methoxy impurity(%w/w) Alcohol impurity(%w/w)

1 1.00 1.00

2 1.00 1.00

3 1.00 1.00

4 1.00 1.00

5 1.00 1.00

6 1.00 1.00

Average 1.00 1.00

SD: 0.00 0.00

% RSD 0.16 0.22

(ppm) (ppm) recovery

LOQ level

0.441 0.433 98.25

98.84 0.441 0.439 99.56

0.441 0.435 98.71

50%

10.03 10.40 103.76

104.32 10.03 10.51 104.88

10.03 10.42 103.96

100%

20.05 20.66 103.04

102.88 20.05 20.60 102.72

20.05 20.52 102.35

150%

30.08 31.12 1003.47

103.05 30.08 30.86 102.62

30.08 31.18 103.67

200%

40.10 39.98 99.71

99.42 40.10 39.76 99.14

40.10 39.70 99.01

Table-4.6: Accuracy results of alcohol impurity

Spike level

Amount Added

Amount Recovered

% Recovery

% of mean

(ppm) (ppm) recovery

LOQ level

0.40 0.402 99.78

99.38 0.40 0.402 99.64

0.40 0.989 98.71

50%

10.08 10.35 102.77

102.68 10.08 10.39 103.08

10.08 10.30 102.19

100%

20.15 20.25 100.49

100.17 20.15 20.263 100.53

20.15 20.04 99.47

150%

30.23 31.26 103.42

103.05 30.23 31.36 103.74

30.23 30.82 101.97

200%

40.30 41.02 101.78

101.01 40.30 40.40 100.25

40.30 41.12 102.03

For methoxy impurity, the recovery percentage was calculated and obtained in the range

98.84 to 104.32%. For alcohol impurity, these values were obtained in the range 99.38-103.05%.

All the recovery values indicate good accuracy of the proposed method.

4.5.5 Linearity:

The concentration ranges in which tapentadol, its methoxy impurity and its alcohol

impurity can be determined with good accuracy were evaluated by preparing calibration plots

between the concentration of the analyte and the peak areas. Six different aliquots of standard

solutions (LOQ, 25, 50,100,150 and 200% of test concentration) were injected into the RP-

HPLC chromatograph and the chromatograms were recorded. Plot of peak areas of the resultant

chromatograms were plotted against the analyte. The experimental data obtained are shown in

Tables-4.7, 4.8, 4.9 and 4.10. The resultant linear plots obtained for these data are given in

Figure-4.6

Table-4.7: Results of linearity experiment of tapentadol

S.No.

Level

Amount of

tapentadol(ppm)

Average peak areas of

tapentadol

1 LOQ 0.20 34013

2 25.0% 5.06 677567

3 50.0% 10.12 1431271

4 100.0% 20.23 2771905

5 150.0% 30.35 4165940

6 200.0% 40.46 5575700

Table-4.8: Results of linearity experiment of methoxy impurity

S.No.

Level

Amount of methoxy

impurity (ppm)


methoxy impurity

1 LOQ 0.44 57863

2 25.0% 5.01 537163

3 50.0% 10.03 1200327

4 100.0% 20.05 2522604

5 150.0% 30.08 3778187

6 200.0% 40.10 4969776

Table-4.9: Results of linearity experiment of alcohol impurity

S.No.

Level

Amount of alcohol

impurity (ppm)


alcohol impurity

1 LOQ 0.40 42499

2 25.0% 5.6 547837

3 50.0% 10.11 1254668

4 100.0% 20.22 2632847

5 150.0% 30.33 3880785

6 200.0% 40.44 5196770

The data was subjected to statistatical analysis and the results of these analyses are

presented in Table-4.10. The values of different statistatical analysis like correlation coeffient,

Y- intercept, residual sum square and relative standard deviation conforms high precision and

accuracy of the proposed method.

Table-4.10: Summarized statistical results of tapentadol and its impurities

Tapentadol Methoxy impurity Alcohol impurity

Correlation coefficient 1.0000 0.9998 0.9998

Slope 137485 125667 129897

% of Y-Intercept 4.9599 4.9816 4.9337

Residual sum square 0.9999 0.9995 0.9996

Residual standard deviation 23251 47583 46133

4.5.6 Robustness:

The robustness of an analytical method is a measure of its capacity to remain unaffected

by small changes but deliberate variations in method parameters and provides an indication of its

reliability during normal usage. The study was carried out with respect to change in flow rate,

column temperature and pH of buffer. The chromatographic conditions were maintained same as

per test method in each case. From the obtained results, it was observed that there was no much

variation in retention time, theoretical plates and asymmetry for tapentadol peak, obtained at

different deliberately varied conditions from the test method. Hence method is robust for all the

varied conditions. The complete robustness results are shown in Table-4.11

Table-4.11: Robustness results of tapentadol

Robust Condition Theoretical plates Asymmetry

As per test method 17421 1.07

Flow changed to 0.9ml/min 18321 1.05

Flow changed to 1.1ml/min 17227 1.04

Column Temperature changed to 40°C 16827 1.04

Column Temperature changed to 50°C 19184 1.04

Buffer pH changed to 6.8 16942 1.08

Buffer pH changed to 7.2 18016 1.04

4.5.7 Solution Stability:

The stability of sample solution was tested by recording the chromatograms of freshly

prepared sample solutions of tapentadol at different time intervals i.e. after 24 hours and 48

hours by keeping the sample temperature at 25°C. The % difference in the % of impurities from

those at different time intervals was found as zero. From this observation, it was concluded that

sample solution was stable for 48 hours at ambient temperature (25°C). The solution stability

results are shown in Table-4.12

Table-4.12: Solution stability results

Impurity name Initial After 24 hours After 48 hours

% of Desfluoro impurity 0.00 0.00 0.00

% of difference - NIL NIL

% of Related compound-A 0.13 0.12 0.14

% of difference - 0.01 0.01

% Benzylated impurity 0.00 0.00 0.00

% of difference - NIL NIL

% of total impurities 0.13 0.12 0.14

% of difference - 0.01 0.01

4.5.8 Limit of detection and limit of quantification:

The detection limit and limit of quantification of tapentadol and related substance were

determined by diluting known concentrations. The simplest method to calculate limit of

detection and limit of quantification is signal to noise ratio method. The quantification limits and

detection limits of tapentadol and its impurities are given in the Tables- 4.13-4.14.

Table-4.13: Limit of quantification results of tapentadol and its impurities

S.No.

Name of the component

S/N ratio

% level of component with respect

to sample concentration

1 Tapentadol 10.10 0.01

2 Methoxy impurity 10.38 0.02

3 Alcohol impurity 10.20 0.02

Table-4.14: Limit of detection results of tapentadol and its impurities

S.No.

Name of the component

S/N ratio

% level of component with respect

to sample concentration

1 Tapentadol 2.91 0.003

2 Methoxy impurity 3.32 0.007

3 Alcohol impurity 3.42 0.0062

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