Chapter-4 Domperidon INTRODUCTION Domperidon (DMPN) is a …shodhganga.inflibnet.ac.in/bitstream/10603/78643/10/10_chapter_4.… · The benzimidazole derivative is a dopamine D 2

Chapter-4 Domperidon

Department of Chemistry, Dr. Hari Singh Gour Central University, Sagar (M.P.) 102

INTRODUCTION

Domperidon (DMPN) is a D2 antagonist, chemically related to

haloperidol, but pharmacologically related to metoclopromide. It has

lower ceiling antiemetic and prokinetic actions. Unlike metoclopromide its

prokinetic action is not blocked by atropine and is based only on D2

receptor blockade in upper GI tract. DMPN crosses blood brain barrier

less readily and rarely causes the extra pyramidal side effects [1-5].

Structure

N

NH

NN

NHO

O

Cl

DMPN, [5–chloro-1-{1-[3-(2-oxobenzenimidazolin–1–yl)-propyl]-4

piperidyl} benzimidazolin-2-one] is a white, or almost white powder. It

is used as an anti-emetic and to control gastrointestinal effects of

dopaminergic drugs in the management of Parkinsonism [6-8].

Formula - C22H24ClN5O2

Solubility - Practically insoluble in water, slightly soluble in

alcohol. It is soluble in dimethylformamide [9]

Mol. Wt. - 425.11 g/mol

Brand name - DMP (D1), Dompet (D2), Domestol (D3)

Identification - Identification of pure drug is performed by

FT-IR (Shimadzu 8400s) and compared

with standard one available in Indian

pharmacopeia.



Fig. 4.1: Reference IR spectrum of DMPN

Table 4.1: Characteristics absorption frequencies for identification of

pure DMPN

S. No. Types of Vibrations Frequency (cm-1)

1. Ar. C – H Stretching 3072.71

2. C – Cl 732.97

3. N – H Bending 1489.1

4. C = O Stretching 1716.7

5. C – N Stretching 1332.21

6. C = C Stretching 1624.12



Fig

. 4.2

: IR

spectr

um

of

pure

DM

PN



Bioavailability - DMPN after oral dosing undergoes extensive gastric

and hepatic first pass metabolism resulting in low bioavailability

(15%) which therefore may not minimize the rate of vomiting [10].

Protein binding - 91-93%

Metabolism - DMPN undergoes first-pass and gut wall metabolism.

Through hydroxylation and oxidative N-dealkylation, DMPN is

metabolized to hydroxyl DMPN and 2, 3-dihydro-2-oxo-1-H-benzimidazole

-1-propionic acid, respectively [11-12].

Excretion - Breast Milk, renal

History - Janssen Pharmaceutical has brought DMPN before the FDA

several times in the last two decades, with the most recent effort in

the 1990s. Numerous U.S. clinical drug trials have demonstrated its

safety and efficacy in dealing with gastro paresis symptoms, but the

FDA turned down Janssen’s application for DMPN, even though the

FDA’s division of gastrointestinal drugs had approved DMPN.

Adverse effect - Some of the side effects associated with DMPN are an

extensive of its dopamine antagonist properties. A majority of these

side effects resolve spontaneously during continued therapy or are

tolerated. However, more serious of troublesome side effects (e.g.

galactorrhea, gynecomastia, or menstrual irregularities) can be dose-

related and will respond to lowering the dose or discontinuing therapy [13].

The benzimidazole derivative is a dopamine D2 receptor

antagonist that has been marketed in Europe and other countries as a

prokinetic and antiemetic since 1978 [14]. Its localization outside the

blood – brain barrier and antiemetic properties has made it is a useful

adjunct in therapy for Parkinson’s disease. There has been

rehabilitated curiosity in antidopaminergic prokinetic agents since the

abandonment of cisapride, a 5-HT4 agonist, from the market. DMPN is

also as a prokinetic negotiator for treatment of upper gastrointestinal

motility disorders. It continues to be an attractive alternative to

metoclopramide because it has fewer neurological side effects [15].



Patients receiving DMPN or other prokinetic agents for diabetic

gastropathy or gastroparesis should also be managing diet, lifestyle,

and other medications to optimize gastric motility.

Bio–Analytical methods -

Several methods have been reported for DMPN determination,

including spectrophotometric [16-18], and High Performance Liquid

Chromatography [19-26].

Sadana et al., have given a HPLC method for estimation of

DMPN in pharmaceutical preparations [27].

Zarapkar et al., have determined DMPN by high performance

thin layer chromatography in pharmaceutical preparations [28].

Mohan et al., have described an extractive spectrophotometric

determination of DMPN in its pharmaceutical dosage forms [29].

Mohemend et al., have described first derivative UV-visible

spectrophotometric assay of DMPN [30].

Rao et al., have described a spectrophotometric method for the

estimation of DMPN and omeprazole [31].

Abdelal et al., have reported method development and validation

for the simultaneous determination of cinnarizine and DMPN in

pharmaceutical preparations by capillary electrophoresis [32].

Sivakumar et al., have developed a validated reverse-phase

HPLC method for simultaneous determination of DMPN and

pantaprazole in pharmaceutical dosage forms [33].

Kakde et al., have reported a spectrophotometric method for

simultaneous estimation of DMPN in pharmaceutical formulations

[34].

Amin et al., have reported spectrophotometric methods for the

determination of anti-emetic drug in bulk and pharmaceutical

preparations [35].



Nema et al., have described a spectrophotometric method for the

determination of DMPN on the basis of redox reaction [36].

The BP 1998 reported a titrimetric method [37]. This titrimetric

procedure requires about 0.25 g to provide accurate results, yet, no

work has been performed to use a redox reaction for the determination

of DMPN. The purpose of the present study was to apply redox

reaction in presence of polymeric micellar media to develop simple,

accurate, sensitive and reproducible methods that can be used in

laboratories where modern and expensive apparatus, such as that

required for GLC, HPLC is not available.



The therapeutic efficacy of a drug product intended to be

administered by oral route mainly depends on its absorption by the

gastrointestinal tract. However for a drug substance to be absorbed, it

needs to be solubilized. Numerous works have been carried out in

order to modify the dissolution kinetics of poorly water-soluble drugs

to improve their bioavailability. DMPN is a D2 antagonist used as anti-

emetic has poor aqueous solubility (0.986 mg/mL) [38]. Dissolution

rate test forms an essential tool in pharmaceutical product

development as well as in quality control. Dissolution characteristics

of a dosage form have a direct bearing on its efficacy especially when

the medication is poorly soluble or insoluble in aqueous fluids such as

DMPN. The use of hydrophilic polymers as carriers for the dissolution

enhancement of poorly water soluble drug is increasing [39-40]

various hydrophilic carriers such as polyethylene glycol [41]

polyvinylpyrrolidone [42-43] and sugars [44] have been investigated

for improvement of dissolution characteristics and bioavailability of

poorly aqueous soluble drugs.

Determination of λmax of pure DMPN drug:

10 g/mL of pure DMPN in methanol was prepared. The

prepared solution was scanned in UV region (200-400 nm) to get

absorbance maxima (Fig. 4.3).

Fig. 4.3: Determination of λmax of DMPN



Verification of Beer’s Lambert law:

Stock solution was prepared by dissolving accurate 100 mg of

substance (DMPN) in 10 mL of methanol in 100 mL calibrated flask.

Then made up to the mark with distilled water then above stock

solution was further diluted to get solution containing 0.1 µg/mL

to 50 µg/mL and measure the absorbance at its max 285 nm

against water as blank. A plot of Beer’s law (Absorbance vs

concentration) gave a highly precise, reproducible straight line that

passed through the origin with satisfactory statistical parameters.

Beer’s law obeyed in the concentration range of 1–50µg/mL (Fig.4.4).

Fig. 4.4: Verification of Beer’s Lambert law

Solubility measurements:

100 mg DMPN was added to 50 mL of each solvent such as

0.5% PEG 400, CTAB, SLS, PEG 4000 and PVP 44000 taken in flask

and the mixture were shaken at 37ºC ± 0.5ºC in a magnetic stirrer.

5mL aliquot was withdrawn at 1 hour interval and filtered immediately

by using a 0.45 m syringe filter. The filtered sample were diluted

suitably and assayed for DMPN by UV-visible spectrophotometer at 285nm.

Shaking continued until two consecutive estimations were the same.



Table 4.2: Solubility of DMPN in different media

S.

No. Sample

Wt. of

drug

(mg)

Overall

volume

(mL)

Abs.

Solubility

increase

in fold

1. DMPN + Distilled water 100 50 0.156 1.00

2. DMPN + 0.5 % CTAB 100 50 0.926 5.93

3. DMPN + 0.5 % PEG 400 100 50 0.630 4.08

4. DMPN + 0.5 % PEG 4000 100 50 0.304 1.95

5. DMPN + 0.5 % SLS 100 50 0.310 1.99

6. DMPN + 0.5 % PVP 44000 100 50 1.553 9.96

Fig. 4.5: Solubility determination of DMPN in different fluids



Polymeric surfactants (PVP 44000) form nanoscopic core-shell

structures above the critical micellar concentrations. In the

hydrophobic drugs while the hydrophobic part serves as reservoirs for

hydrophobic drugs, the hydrophilic part serves as interface between

the bulk aqueous phase and the hydrophobic domain. This unique

architecture enables polymeric micelles to serve as nanoscopic depots

or stabilizers for poorly water-soluble compounds.

Fig. 4.6: Solubilization of drugs in surfactant micelles, depending on

the drug hydrophobicity. The black bold lines (▬) represent the drug

at different sites in the micelle. The black circles represent the

surfactant heads, the black bold curve lines represent surfactant

heads consisting of PVP and the light black curved lines represent the

surfactant tails.

In Vitro dissolution study:

The three different brands of DMPN have been purchased from

local market. For the sake of convenience these are abbreviated as -

1. DMP (D1)

2. Dompet (D2)

3. Domestol (D3)

Dissolution study is particularly important for insoluble or low

solubility drugs, where absorption is dissolution-rate limited. At the

same time, development of a dissolution method for this group of drug



is very challenging. In continuation of our earlier work on dissolution

study [45-46], this work describes dissolution quality assessments, in

the evaluation of the rate of dissolution for a water insoluble drug

DMPN.

1. Apparatus : Electrolab TDT - 08L USP

2. Dissolution medium: 0.5 % PVP 44000 in water

3. Rotation speed: 75 rpm

4. Preparation of DMPN standard solution: 1.12 mg DMPN was

weighed precisely and transferred in 100 mL volumetric flask

and diluted up to the mark with dissolution media. 5 mL of the

above solution is further diluted up to 50 mL with dissolution

media i.e. 0.5 % aqueous PVP.

5. Test preparation: The dissolution of DMPN from commercial

formulations (10 mg) was studied in 900 mL of dissolution

medium using a (Basket method) USP-29 at Electro lab TDT-

08L dissolution rate test apparatus. Dissolution medium (900

mL) was maintain at 37°± 0.5°C and agitated at a speed of 75

rpm under sink condition, withdrawal the 5 mL of sample at

each time interval from the dissolution apparatus and

withdrawal volume replaced by fresh dissolution media to

maintain the sink condition, filtered the withdrawn sample and

prepared appropriate dilution. The sample solution was

analyzed at 285 nm by UV-Vis. spectrophotometer.

6. Time point: Dissolution amount was measured separately at

60, 120, 180, 240, 360, 480 and 600 minutes.

claim Lable

100

100

potency

dilution Test

dilution Std.

Std. of Absorbance

Sample of Absorbance



Table 4.3: Sample absorbance at different time intervals

S.

No. Time (min)

Absorbance

D1 D2 D3

1. 60 0.054 0.045 0.039

2. 120 0.072 0.057 0.096

3. 180 0.090 0.123 0.132

4. 240 0.118 0.135 0.144

5. 360 0.156 0.147 0.156

6. 480 0.183 0.216 0.210

7. 600 0.286 0.285 0.287

Standard Abs. 0.291

Table 4.4: % drug release of various formulations in polyvinylpyrrolidone at different time

S.

No. Time (min)

% drug release

D1 D2 D3

1. 60 18 15 13

2. 120 24 19 32

3. 180 30 41 44

4. 240 40 45 48

5. 360 50 49 52

6. 480 61 72 70

7. 600 95 94 95



Table 4.5: log time, square root of time and log % of drug release

S.

No.

Time

(min) log time

Square

root of

time

log % drug release

D1 D2 D3

1. 60 1.77 7.74 1.25 1.17 1.11

2. 120 2.079 10.95 1.38 1.27 1.36

3. 180 2.25 13.41 1.47 1.61 1.64

4. 240 2.38 15.49 1.59 1.65 1.68

5. 360 2.55 18.97 1.71 1.69 1.71

6. 480 2.68 21.90 1.78 1.85 1.84

7. 600 2.77 24.49 1.97 1.97 1.98



Fig. 4.7: Dissolution profile (n=3) of three commercial products of

DMPN in polymeric micellar media (Zero order plot)

Fig. 4.8: Regression plot for zero order



Fig. 4.9: First order plot

Fig. 4.10: Regression plot for first order



Fig. 4.11: Korsmeyer Plot

Fig. 4.12: Regression plot for Korsmeyer model



Fig. 4.13: Higuchi plot

Fig. 4.14: Regression plot for Higuchi model



Table 4.6: Kinetic parameters for D1

S. No. Time

(min)

Rate Constant (k)

First order Korsmeyer Higuchi Zero order

1. 60 3.92 × 10-2 1.13 × 10-2 1.03 0.133

2. 120 1.99 × 10-2 9.41 × 10-3 1.27 0.116

3. 180 1.36 × 10-2 8.91 × 10-3 1.49 0.111

4. 240 1.06 × 10-2 9.75 × 10-3 1.93 0.125

5. 360 7.53 × 10-3 9.60 × 10-3 2.21 0.116

6. 480 6.01 × 10-3 9.25 × 10-3 2.32 0.106

7. 600 - 1.25 × 10-2 3.51 0.143

r2 0.9721 0.9545 0.9048 0.9564

Slope (n) 0.67


S. No. Time

(min)

Rate Constant (k)

First

order Korsmeyer Higuchi Zero order

1. 60 3.90 × 10-2 6.04 × 10-3 0.77 0.10

2. 120 1.97 × 10-2 4.40 × 10-3 0.91 0.08

3. 180 1.42 × 10-2 6.88 × 10-3 2.38 0.17

4. 240 1.09 × 10-2 6.00 × 10-3 2.3 0.15

5. 360 7.44 × 10-3 4.73 × 10-3 2.10 0.11

6. 480 6.80 × 10-3 5.52 × 10-3 2.87 0.13

7. 600 - 6.10 × 10-3 3.51 0.14

r2 0.8698 0.970 0.9351 0.9559

Slope (n) 0.79




S. No. Time

(min)

Rate Constant (k)

First order Korsmeyer Higuchi Zero order

1. 60 3.80 × 10-2 4.85 × 10-3 0.64 0.08

2. 120 2.00 × 10-2 4.88 × 10-3 1.93 0.12

3. 180 1.40 × 10-2 6.72 × 10-3 3.28 0.20

4. 240 1.10 × 10-2 5.80 × 10-3 2.98 0.16

5. 360 8.00 × 10-3 4.52 × 10-3 2.84 0.12

6. 480 7.00 × 10-3 4.95 × 10-3 3.37 0.13

7. 600 - 5.51 × 10-3 4.01 0.14

r2 0.8262 0.9579 0.9355 0.9392

Slope (n) 0.81

RESULTS AND DISCUSSION

The solubility of DMPN was determined at 37ºC ± 0.5ºC in

different fluids is listed in Table 4.2. Surfactant greatly increases the

solubility of DMPN. The surprising increase in solubility of DMPN by

9.96 fold is found in 0.5% PVP (Fig. 4.5).

Mechanism and kinetics of drug release - To know the mechanism

of drug release from these formulations, the data were treated

according to zero-order (cumulative amount of % drug release vs. time

and its regression plots are shown in Fig. 4.7 and 4.8), first order (log

cumulative % of drug release vs time and its regression plots in Fig.

4.9 and 4.10) Korsmeyer plot (log cumulative % of drug release vs log

time and its regression plots in Fig.4.11 and 4.12) and Higuchi’s



(cumulative % of drug release vs. square root of time and its

regression plots in Fig. 4.13 and 4.14) equations. As can be revealed

from Fig.4.7, neither of the tablets followed a complete zero order

release nor first order pattern. Diffusion is related to transport of

drug from the dosage matrix in to the in vitro study fluids depending

on the concentration. As gradient varies, the drug is released, and the

distance for diffusion increases, which is referred as Korsmeyer

kinetics. In our experiment, the in vitro release profile of DMPN from

all the brands could be best expressed by Korsmeyer equation, as the

plot showed high linearity (r2 > 0.95). The slope of the regression line

from Korsmeyer plot indicates the rate of drug release. The

comparative Korsmeyer release rates for different brands are

presented in Fig. 4.11. Table 4.6, 4.7 and 4.8 reveal that the k

obtained from Korsmeyer-Peppas model shows better result with high

correlation coefficient (r2 = 0.954-0.970).

The Korsmeyer-Peppas model is used to analyze drug release

from pharmaceutical dosage forms when the release mechanism is not

well known or when more than one type of release phenomena is

involved. The exponent, termed the release exponent n, was studied by

Peppas and coworkers to characterize different drug release

mechanisms from thin films. They noted that profile with n = 0.5

exhibited a drug release mechanisms controlled by Fickian diffusion,

while drug release rate was independent of time and controlled by a

swelling mechanism when n = 1. In the current study, the value of

release rate exponent (n), ranged between 0.67 – 0.81. Values of n

between 0.5 and 1.0 were regarded as an indicator for the

superposition of both phenomena, and the drug release mechanism

was termed anomalous (non-Fickian) transport.



Preparation of stock solution of pure DMPN drug:

Stock solution of DMPN was prepared by dissolving 425 mg in

1:1 acetic acid and water and made up to the mark in 100 mL

volumetric flask. The above stock solution was further diluted to get a

working standard solution.

Preparation of different solutions for calibration curve in

presence of V(V):

It was difficult to select the suitable concentration of DMPN

because at CMC of PVP, below the drug concentration (4×10-5)

reaction did not occur. Similarly at higher concentration of drug

(1×10-2) reaction mixture precipitated.

Different volumes of the drug solutions (in range 0.04 – 4.0 mL)

prepared above were accurately measured into different 10 mL

volumetric flask. After the addition of 0.1 mL of V(V), 0.3 mL of PVP (to

get the solution of 3 × 10-6 M) and 1.5 mL (18 M) were successively

added and diluted up to the mark with water. The contents of each

flask were mixed well. Initially yellow color of reaction mixture slightly

changes to pink then finally turns to purple. The absorbance of light

pink colored species formed. Absorbance of each solution was then

measured after 15 min. at 355 nm. A calibration graph was

constructed by plotting the absorbance against the concentration of

the drug (Fig.4.16).



Fig. 4.15: Absorption maxima of V(V) and V(IV)

Table 4.9: Reaction mixture

Sample

Concentration (M)

Stock solution (M) Required (M)

[DMPN] 0.01 0.00002-0.004

[V(V)] 0.01 0.0001

[H+] 18 1.5

[PVP 44000] 0.0001 3 × 10-6

Overall volume 10 mL



Table 4.10: Absorbance of standard solution of pure drug at different concentrations in presence of V(V)

S. No. Concentration (M) Absorbance (at 355 nm)

1. 0.00004 0.552

2. 0.00006 0.554

3. 0.00008 0.555

4. 0.0002 0.560

5. 0.0004 0.568

6. 0.0005 0.574

7. 0.0008 0.583

8. 0.001 0.589

9. 0.002 0.589

10. 0.003 0.587

11. 0.004 0.584

y = 0.0001x + 0.5509

R2 = 0.9943

0.55

0.555

0.56

0.565

0.57

0.575

0.58

0 50 100 150 200 250

Concentration ( g/mL)

Absorb

an

ce

Fig. 4.16: Calibration curve of pure drug in presence of V(V)



Preparation of sample solutions:

For the determination of DMPN in tablets, the above method

was used with no modification. About ten tablets were grinded into

finely divide powder. An accurately amount equivalent to 425 mg was

weighed and dissolved in 1:1 acetic acid and water. The solution was

shaken well for 30 min. to ensure a homogenous solution. The residue

was removed through 0.45 m syringe filter and washings were taken

into a 100 mL standard flask and diluted with 1:1 acetic acid and

water. Then three concentrations of DMPN within the linearity range

were selected i.e. 0.00008, 0.0002 and 0.0004.

Table 4.11: Absorbance of sample solutions of different marketed

brands at three concentrations

S.

No.

Concentration

(M)

Absorbance (355 nm)

Pure drug D1 D2 D3

1. 0.00008 0.555 0.551 0.561 0.559

2. 0.0002 0.56 0.556 0.571 0.555

3. 0.0004 0.568 0.567 0.573 0.565

Table 4.12: Recovery Study

S. No. Label claim in mg Amount of drug found (%)

D1 D2 D3

1. 10 99.27 101.08 100.72

2. 10 99.28 101.96 99.10

3. 10 99.82 100.88 99.47

Average Recovery (%) 99.47 101.31 99.77

Standard Deviation 0.312 0.576 0.846



RESULTS AND DISCUSSION

Spectral studies:

The spectrum of reference pure drug of DMPN in organic solvent

shows an absorption band at 285 nm. The addition of acidic solution

of V(V) to the drug solution causes change in the absorption spectrum

with new characteristic band peaking at 355 nm. The equilibrium is

attained in 10 minute. Therefore, a kinetically based spectrophotometric

method was developed for the quantitative determination of DMPN by

measuring the increase in absorbance at 355 nm as a function of

time.

Linearity:

Beer’s law obeyed in the concentration range of 17–212 g/mL.

Application of the method to tablets:

The accuracy of the proposed method was checked by

performing recovery experiments. For this, a known amount of the

pure drug was added to pre-analysed dosage forms and then

determined by the recommended procedure. The result obtained in

table 4.12 showed that the mean recovery and standard deviation

were in the range of 99.77 ± 0.312 to 101.31 ± 0.576 respectively.

These results also suggested that there is no interference from the

common excipients present in dosage forms.

Optical characteristics such as Beer’s law limits, molar

absorbitivity and Sandell’s sensitivity for DMPN, are given in table

4.13.



Table 4.13: Quality Control Parameters

S. No. Parameters DMPN

1. max (nm) 355

2. Beer’s Range ( g/mL) 17 - 212

3. Molar Absorbtivity (L mol-1 cm-1) 1.28 × 105

4. Sandell’s Sensitivity (µg cm-2) 0.0033

5. Regression equation 0.994

6. Intercept 0.5509

7. Slope 0.0001

8. Limit of Detection (µg/mL) 2.62 ×102

9. Limit of Quantization (µg/mL) 8.75 × 102

10. Standard Deviation of calibration line 0.008

PROPOSED MECHANISM

The proposed method is based on the formation of an

intermediate complex. The reaction proceeds through the reduction of

V(V) to V(IV) and the subsequent formation of intensive pink-brownish

color complex.

The absorption spectrum of the colored species in the proposed

method at suitable conditions recovered in the general procedure

show a characteristic max at 355 nm (Fig. 4.15).

In conclusion, I have found that DMPN is mainly N-Dealkylated

by V(V) which is confirmed by LC-MS (Fig. 4.17).



Fig. 4.17: Mass Spectrum of DMPN + V(V)



VO2+ + H3O V(OH)32+

V(OH)32+ + HSO4 [V(OH)3HSO4]

+-

[A]

N

NH

O

Cl

N

N

O

N

H

+ [A]

Cl

N

N

O

NN

NH

OHHOSO3OH V OH

OH

+

DMPN

Cl

N

N

O

NN

NH

OH

HOSO3OH V OH

OH

+

[B] Intermediate complex

[B] + Dn

Dn

[C] Adduct

Fast step N- dealkylation

N

NH

O

COOH

Cl

N

N

O

NH

H

+

2,3- dihydro, 2- oxo 1H- benzimidazole-1-

propionic acid (m/z - 193)

5- chloro 4-Piperidinyl 1,3-

dihyrobenzimidazol-2-one

(m/z - 252)



CONCLUSION

The proposed method was successfully applied to determine

DMPN in their pharmaceutical preparation. Importantly, no any

method is available yet today for its determination.

The proposed method is simpler, less time consuming and more

sensitive than official method [47] (based on titrimetry and

potentiometry).

Although the color development at room temperature required

1h for completion, this can be shortened to 20 min. by

introducing polymeric surfactant.

The proposed method advantageous over other reported UV-

visible spectrophotometric method with respect to their higher

sensitivity with permits of the determination of up to 17 g/mL.

Simplicity, reproducibility, precision, accuracy and stability of

colored species for a week noted advantages.

No interference from associated excipients, additives and

degraded products were observed.



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