920-927 Hanif LAJP 3659:Hanif

Latin American Journal of Pharmacy (formerly Acta Farmacéutica Bonaerense)

Regular article Received: March 17, 2014 Revised version: April 12, 2014 Accepted: April 18, 2014

Lat. Am. J. Pharm. 33 (6): 920-7 (2014)

Formulation Development and Optimization of Flurbiprufen and Ranitidine Bilayer Tablet Designed by Central Composite Rotatable Design (CCRD) and Their In Vitro Kinetic Studies Muhammad HANIF 1,2 *, Usman ZIA 1, Akhtar RASUL 1, Shahid SHAH 2, Nida NAZER 1, Vesh CHAURASIYA 2 & Shahnila SATTAR 3 1

2

College of Pharmacy, GC University Faisalabad,Pakistan Department of Pharmacy, Bahauddin Zakariya University,Multan ,Pakistan 3 Department of organic chemistry, Institute of Chemical Sciences, Bahauddin Zakariya University, Multan, Pakistan.

SUMMARY. Bilayer tablets of flurbiprofen SR and ranitidine IR was developed by using HPMC K4-M and colloidal silicon dioxide. Twenty formulations were planned by using design expert and micromeritic properties were analyzed for selection of six suitable formulations. Single punch machine was used for compression of bilayer tablets and physicochemical and quality control evaluation was performed successfully. Weight variation, hardness, friability and disintegration time were evaluated by pharmacopeial procedures. Release of ranitidine IR was studied for 60 min, while flurbiprofen SR was analysed for 24 h. In vitro kinetic studies like zero order, first order, Hixson-Crowell, and Weibull were applied to ranitidine IR formulation and flurbiprofen SR formulation was evaluated by zero order, first order, Higuchi, Korsmeyer-Peppas, Hixson-Crowell and Weibull. Regression values of a first order in IR and zero order in SR were found to more than 0.97 and Weibull model was used to explain the shape factor formulation. S1 formulation was considered as the best one and was selected for further in vivo studies. RESUMEN. Se desarrollaron comprimidos bicapa de flurbiprofeno SR y ranitidina IR mediante el uso de HPMC K4-M y dióxido de silicio coloidal. Veinte formulaciones fueron planeadas usando diseño experto y se analizaron las propiedades micromeríticas para la selección de seis formulaciones. Se utilizó una compresora simple para la obtención de los comprimidos bicapa y la evaluación de las propiedades físico-químicas y de control de calidad fueron exitosas. La variación de peso, dureza, friabilidad y tiempo de desintegración fueron evaluados por procedimietnos farmacopeicos. La liberación de ranitidina IR se estudió durante 60 min y flurbiprofeno SR durante 24 h. Estudios cinéticos in vitro de orden cero, primer orden, Hixson-Crowell y Weibull fueron aplicados a la formulación de ranitidina IR., en tanto que la formulación de flurbiprofeno SR fue evaluada mediante estudios de orden cero, primer orden, Higuchi, Korsmeyer-Peppas, Hixson-Crowell y Weibull. Los valores de la regresión de primer orden en IR y de orden cero en SR resultaron superiores a 0.97 y el modelo de Weibull se usó para explicar la formulación del factor de forma. La formulación S1 se consideró la mejor y fue seleccionada para posteriores estudios in vivo.

INTRODUCTION World health economists are mainly concerned about the cost effectiveness of the medicines by seeking the strategies to change the world of medicines of proven clinical effectiveness as well as cost effectiveness 1. NSAIDs are the most widely prescribed drugs for the management of pain and inflammation. The prevalence of gastro duodenal ulcer is 15 to 30% in regular users of NSAIDs and it may develop in a week to months. H2 receptor antago-

nists are very effective in reducing the risk of NSAID induce ulcer and also used when necessary to relieve NSAIDs related dyspepsia 2. Flurbiprofen belongs to non-steroidal anti-inflammatory drugs. It is a white or slightly yellowish crystalline powder slightly soluble in water at pH 7.0. The chemical name is 2-fluoro-αmethyl-1,1-biphenyl-4-acetic acid (Fig. 1). Ranitidine reversibly blocks the H2 receptors and used in heart burn, peptic ulcer, and dyspepsia. It is soluble in water having empirical

KEY WORDS: Hydroxypropylmethylcellulose, Immediate release, In vitro kineticand slow release. *

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Author to whom correspondence should be addressed. E-mail: [email protected]

ISSN 0326 2383 (printed ed.) ISSN 2362-3853 (on line ed.)

Latin American Journal of Pharmacy - 33 (6) - 2014

Optimization of formulation Flurbiprofen containing layer was used as SR and dose was calculated by using Eq. [1]. Ranitidine HCl

[1]

Flurbiprufen

Figure 1. Chemical structure of ranitidine HCl and

Flurbiprofen.

formula C 13H 22N 4O 3S.HCl. Ranitidine can be used with NSAIDs to control their ulcerative nature by increasing pH of stomach. It is suggested that the formulations which reduces the ulcer also found analgesic combination with H2-receptor blockers for concominent therapy 3. Central Composite Rotatable Design (CCRD) was used for the development of bilayer tablets. CCRD with four variables and five levels were used for optimization of flurbiprofen SR and ranitidine IR formulations. Micromeritic properties allows to select the best formulations for compression and their physicochemical properties were analyzed. Ranitidine and flurbiprofen release studies were performed in different dissolution mediums of pH 4.5 and 7.2. In vitro kinetic like first order, zero order and Higuchi represent the model dependent approaches and similarity and dissimilarity factors were created for the comparison of selected compressed formulations 4-9. MATERIALS AND METHODS Flurbiprofen and ranitidine both were gifted from Axis Pharmaceuticals Faisalabad and Irza Pharmaceuticals Lahore, respectively. Hydroxypropyl methyl cellulose (HPMC) K-4M and microcrystalline cellulose (Avicel PH-102) were purchased from Merck, Germany, and were used as sustained release and immediate release agents, respectively. Aerocil from Fumed silica, FGF, USA and magnesium stearate was from Parchem, USA, Starch was purchased from Merck, Germany and used as binder. Instruments were single punch tableting machine (Single punch, Rimec, Minipress-1), friabilator (Roche, EF-1W,USP 24), hardness tester (Pfizer hardness tester) disintegration apparatus and dissolution apparatus DTR,270, China (USPII, Peddle apparatus), and spectrophotometre UV visible 3000, ORI, Germany, were used. Softwares used were Design-Expert® version 8 Stat-Ease Inc. for optimization of formulations and DD solver for model dependent and model independent dissolution kinetic models.

where Dt is the dose for sustained release, td is the time required for sustained release which is 2 h, t1/2 is the half-life which is 6 h and Dn is the normal dose i.e., 238 mg/O.D. Experimental Design Central composite design with four variables and five levels were used for twenty formulation. Maximum and minimum concentrations were expressed as +β and –β, while the values of +1 and -1 were calculated by using simple formulae shown in Table 1 for both SR and IR formulation. Calculate amounts of all excipients having SR or IR nature are shown in Table 2 . Code

Actual value of variable

-β

xmin

-1

[(xmax + xmin)/2] – [(xmax - xmin)/2α]

0

[(xmax + xmin)/2]

+1

[(xmax + xmin)/2] + [(xmax - xmin)/2α]

+β

xmax

Table 1. Relationship between coded and actual values of a variable. -β

-1

0

+1

+β

Optimized formulation for flurbiprofen granules (SR)

HPMC MCC Starch Mag. Stearate

20 10 5 1

25 20 15 2

30 30 25 3

35 40 35 4

40 50 50 5

Optimized formulation for ranitidine powder blend (IR)

Aerocil MCC Starch Mag. Stearate

15 10 5 1

19 20 6 2

23 30 7 3

26 40 8 4

30 50 10 5

Table 2. Optimized formulation for flurbiprofen gran-

ules (SR) and ranitidine power blend (IR).

Micromeretic Properties of Powder and granules Bulk and tapped densities of the powder blends of ranitidine (IR) and granules of Flurbiprofen (SR) were calculated by Eqs. [2-4]:

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HANIF M., ZIA U., RASUL A., SHAH S., NAZER N., CHAURASIYA V. & SATTAR S.

[2]

[3] where ρb and ρt bulk and tapped densities of the powder and granules whilem is the mass and v is the volume powder and granules. [4] where H is the height of the heap and D is the diameter heap. Compression of flurbiprofen (SR)and ranitidine (IR) bilayer tablets Starch paste was prepared by adding starch in suficient amount of water. Polymer, drug (flurbiprofen) and other excipients like colouring agent, filler and binder were geometrically mixed in tumbler mixer for 9 min with prepared starch paste and mixed in pestle and mortar. Solid mass was passed through a sieve 20 and obtained granules were dried under room temperature for 24 h and then in the oven at 40 °C for 4 h. Ranitidine powder excipients listed in Table 4 were accurately weighed and geometrical mixed for 9 min. Magnesium stearate was added as lubricant. Single punch compression machine was used for compression of bilayer tablets having supposed weight 900 ± 60 mg and was packed in tight, closed light resistant container.

and dissolution studies of randomly selected formulations were performed in USP-II dissolution apparatus having 900 mL buffer pf pH 4.5 and 7.2. Five mL aliquot was withdrawn and replaced with fresh medium after 5, 10, 15, 30, 45, and 60 min for IR and 2, 4, 6, 8, 10, 12, and 24 h for SR release. Withdrawn samples were filtered through 0.45 µL syringe filter and percentage of drug was measured by spectrophotometer at 314 nm for ranitidine and 247 nm for furbiprofen, respectively. Model dependent approaches Model dependent approaches were used for the in vitro kinetic evaluations of IR and SR formulation. Zero order equation [6], first order equation [7], Higuchi release mode equation [8], Hickson Crowel equation [9] and Weibull models equation [10] were used to analyse the mathematical expression of drug release. [6] where Qt is the drug dissolved in time t, Q0 is the initial amount of drug and k0 is zero order release constant. [7] where Qt is the drug is dissolved in time t, Q0 is the initial amount of drug and k1 is the first order release constant. [8]

Weight variation and hardness Twenty tablets were randomly selected and accurately weighed. Standard deviation of each formulation was obtained by using Microsft Excel 2007. The Monsento Hardness tester was used for calculation of hardness in kg after selecting twenty tablets randomly.

where Qt is the drug dissolved at time t, C is the initial drug concentration, Cs is solubility of drug in the matrix media and D the diffusivity of the drug. [9]

Friability Sample of 10 tablets were randomly selected and placed in Roche friabilator after dedusting The drum was rotated for 100 times with the speed of 25 rpm. Loose dust from the tablets was removed and accurately weighed the tablets. The % of friability was calculated by Eq. [5].

where W 0 is the initial amount of drug in dosage form, Wt is the remaining amount of drug in pharmaceutical dosage form at time t, and Ks is the surface-volume relation constant.

[5]

α defines the time scale of the process, the location parameter, Ti is the lag time before the onset of release and in most cases it is zero and the shape parameter (b) characterizes the curve behavior as dissolution phenomenon. The value

Disintegration and dissolution rate Six tablets were selected and disintegration time was measured in distilled water at 37 °C 922

[10]


of b is the most important, i.e., b = 1 (case 1, sigmoid shaped curve), b > 1 (case II, parabolic shaped curve), and b < 1 (case III, consistent to exponent). A simple, power equation model (Eq. [11]) was developed to explain the drug release behaviour with the elapsed time t [11] where α is the constant and showed structural and geometrical characteristics of the dosage form, Mt/Mα is the fraction release of drug, Mt is the release of drug at time t, and Mα is the time after which drug is completely released and n is the release rate constant indicating the drug release mechanism: n = 0.5 explains diffusion mechanism, n = 0.5-0.9 showed mixed phenomenon, n = 1 have chain relaxation phenomenon, n >1 explained super case II, unknown mechanism. Model independent approaches To analyze the drug release kinetics, model independent approaches were also used which include difference factor f 1 (Eq. [12]) and similarity factor f 2 (Eq. [13]). [12]

[13] where R is for reference formulation and T is for sample formulations, and n is the number of dissolution points.

RESULTS Formulation development and optimization of bilayer tablets were successfully performed after optimizing 20 best formulations. Central composite rotatable design (CCRD) was used to select formulation. Average weight of selected formulations (S1, S2, S3, S4, S5, and S6) having excellent flow properties were within the desired range of 900-960 mg as shown in Table 3. Fig. 2 shows the increased compressibility index by increasing the HPMC and starch in the granules while decreased in angle of repose with same concentrations. By increasing the concentration of Avicel, Aerocil and starch in the powder blend of ranitidine, the compressibility index, Hausner’s ratio and angle of repose decreased, as shown in Fig. 3 and Table 4. Physicochemical evaluation Results of weight variation was quite up to mark and with the range of ± 5 according to British Pharmacopiea. Hardness of compressed

Figure 2. RSM graphs showed effect of different SR Excipients on flow properties of granules.

Figure 3. RSM graphs showed the effect of excipients on micromeritic properties of powders blend.

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Concentration of API and Excipients for 238mg Flurbiprofen (SR) Formulation HPMC (mg)

MCC (mg)

Starch (mg)

150 200 200 175 150 217

150 75 75 112 75 112

150 75 75 112 75 112

S1 S2 S3 S4 S5 S6

Concentration of API and Excipients for 150mg Ranitidine (IR)

Magnesium SR layer stearate weight (mg)

1.25 1.25 10.00 5.63 10.00 5.63

690 590 600 645 550 685

Avicel (mg)

Aerosil (mg)

Starch (mg)

90 135 90 135 180 45

15.00 10.50 15.00 10.50 15.00 10.50

15.00 37.50 60.00 7.50 15.00 37.50

Magnesium Total IR layer stearate weight (mg) (mg) (mg)

0.75 1.88 0.75 3.38 0.75 3.38

270 330 315 290 360 245

960 920 915 935 910 930

Table 3. Concentration of API and Excipients for 238 mg Flurbiprofen SR and 150 mg Ranitidine IR.

Hausner Ratio

Formulations

Bulk Densiy

Tapped Density

Compressibility Index

Angle of Repose

Result

26.59 32.54 26.67 32.45 33.46 27.65

Excellent Good Excellent Good Good Excellent

28.45 26.9 34.76 31.68 26.66 28.45

Excellent Excellent Good Good Excellent Excellent

Ranitidine IR Layer

S1 S2 S3 S4 S5 S6

1.10 1.14 1.05 1.16 1.12 1.09

0.29 0.30 0.28 0.30 0.28 0.29

0.32 0.34 0.29 0.34 0.31 0.32

9.09 12.14 5.18 13.81 10.46 8.57

Flurbiprofen SR granule layer

S1 S2 S3 S4 S5 S6

1.02 1.03 1.15 1.13 1.04 1.02

0.87 0.86 0.9 0.8 0.84 0.87

0.89 0.89 1.03 0.9 0.88 0.89

1.97 2.78 12.67 11.14 3.69 1.97

Table 4. Micromeritics results of ranitidine IR powder and flurbiprofen granule.

Hardness

Weight variation (mg)

Friability (%)

Disintegration time

Limits

3-10 kg

± 5%

≤1

Ranitidine (min)

Flurbiprofen (h)

S1 S2 S3 S4 S5 S6

6.04 6.23 5.98 6.29 6.06 6.44

950 ± 0.5 910 ± 0.5 920 ± 0.35 935 ± 0.1 910 ± 0.4 930 ± 0.1

0.75 0.53 0.5 0.37 0.63 0.33

17 23 15 25 19 16

4.6 3.9 4.2 No disintegrate 3.5 No disintegrate

Table 5. Physicochemical parameters of Bilayer tablets

bilayer tablets was found to be 6.04-6.44 kg/cm3 having direct effect of Avicel and HPMC.The IR portion of the bilayer tablet was disintegrated within 15-30 min while the SR portion of flurbiprofen disintegrated not less than 4 h for formulations S1,S3, S4, S6 but formulation S2 and S5 disintegrated the SR layer after 3.9 and 3.5 h, respectively. Friability were less than 1% in all formulation and in quite according to the Pharmacopial limits as shown in Table 5. 924

Drug Release Percentage release of ranitidine (IR) and flurbiprofen (SR) are shown in Fig. 4. All formulations showed the sudden release of ranitidine and slow release of Flurbiprofen. Formulation S1 was considered as best due to the presence of 72% HPMC in SR layer. Ratio of ranitidine IR and Flurbiprofen SR layer was (72:28) in S1 formulation while other formulations ratio were 64:36, 66:34, 69:31, 60:40, and 74:26 for S2, S3, S4, and S5, respectively.


Figure 4. Percentage release of ranitidne (IR) and flurbiprofen (SR) of comporessed formulations.

Model dependent approaches Model dependent approaches in all six formulations for IR portion of bilayer tablet applied after 45 min release which followed first order release. SR formulations results were evaluated for 24 h which followed zero order release and Higuchi model. Value of n determines the Fickian and non-Fickian rate of diffusion as shown in Table 6 for SR and IR, respectively. Formulations S5 and S6 had the n value closer to 1 showed more tendencies to follow the Peppas

Zero order

First order

Higuchi

model. Weibul model for SR and IR portion were applied and value of β determined. Flurbiprofen SR formulation showed the β values greater than 1 and had parabolic shaped curve but ranitidine IR had β values less than 1 which showed consistent to exponent. Model independent approaches Difference factor (ƒ 1) of formulation was identical and increase proportionality of dissimilarity between two dissolution profiles as we in-

Korsmeyer-Peppas

Weibull

Hixon-Crowel

Flurbiprofen SR layer

S1 S2 S3 S4 S5 S6

R2

K (h–1)

R2

K (h–1)

R2

K (h–1)

R2

K (h–1)

n

R2

β

R2

K (h–1)

0.9716 0.9796 0.9855 0.963 0.991 0.9816

7.633 11.034 7.876 10.003 9.166 9.032

0.9418 0.9799 0.9626 0.9931 0.9753 0.9536

0.128 0.265 0.132 0.225 0.180 0.174

0.9539 0.9953 0.9707 0.9880 0.9872 0.9709

22.112 31.978 22.487 29.077 26.505 26.104

0.973 0.995 0.985 0.988 0.993 0.981

3.364 43.419 6.175 50.323 13.538 8.771

1.247 0.485 1.064 0.416 0.801 0.952

0.9687 0.9781 0.9759 0.9997 0.9931 0.9780

4.907 1.714 4.150 2.013 4.736 5.396

0.9513 0.9836 0.9700 0.9969 0.9842 0.9640

0.036 0.069 0.037 0.061 0.049 0.048

N/A N/A N/A N/A N/A N/A


0.9804 0.9965 0.9936 0.9951 0.9859 0.9973

0.661 0.663 0.076 0.795 0.830 0.985

0.959 0.991 0.991 0.992 0.982 0.992

0.012 0.007 0.008 0.004 0.008 0.009

Ranitidine IR layer

S1 S2 S3 S4 S5 S6

0.7912 0.9117 0.8741 0.9547 0.8932 0.8976

1.170 0.932 1.045 0.788 1.112 1.146

0.9717 0.9944 0.9920 0.9957 0.9776 0.9868

0.050 0.024 0.029 0.016 0.027 0.031

0.8908 0.9749 0.9503 0.9909 0.9524 0.9601

11.166 8.633 9.565 7.178 9.864 10.344


Table 6. Model dependent dissolution approximation of SR Flurbiprofen and IR Ranitidine tablets.

Formulations

Ranitidine (ƒ1)

Flurbiprofen (ƒ1)

Ranitidine (ƒ2)

Flurbiprofen (ƒ2)

S2 S3 S4 S5 S6

13.16 4.71 18.69 7.30 4.31

16.15 8.31 19.15 8.50 3.40

55.30 68.08 56.99 43.25 68.41

59.99 66.87 53.47 44.64 66.96

Table 7. Similarity and Diffential factors of compressed formulations taking S1 as standard.

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crease the concentration of HPMC. The differential factor of ranitidine and flurbiprofen was found to be less than 15 and Similarity value (f 2) was calculated and was found more than 50 as shown in Table 7. Similarity factor is to evaluate false negative and false positive rates of decisions for approval drug products based on f 2. Table 7 is suggested after taking S1 as standard, S3 and S6 are more similar than S2, S4, and S5 for both Ranitidine and Flurbiprofen formulations.

DISCUSSION Microcrystalline cellulose widely used for tableting both in wet granulation and direct compression because of its wide usage like diluent/lubricant, binder and disintegrant 10. Bolhuis et al. investigated that the formulations containing microcrystalline cellulose (Avicel PH-102) showed low compressibility index and high value of angle of repose 11. Lahdenpaa et al. reported that by using high concentration of microcrystalline cellulose PH-102, flow properties and cushing strength of powders are increased 12 . Verhoeven et al. reported that in early rheumatoid arthritis, combination therapy as cost effective 13. Flurbiprofen is an ideal drug for arthritis and other painful inflammatory conditions. Ulcerogenic effects of NSAIDs can be reduced by combination of NSAIDs with antiulcer drug 14. Other parameters like oral controlled release matrix formulation of NSAIDs was also used to avoid the gastric effects of drug 10,11,15-17. Weight variation studies were carried out from batch to batch and uniform weight of all formulations was obtained between the pharmacopoeial specifications. Results were within the range of ± 5% that is in acceptable limits. Similar results were found by Zade et al. for fast dissolving tablets of tizanidine 18. Shoaib et al. used the HPMC as a polymer in the matrix tablet of ibuprofen and found that similar weight variation results having average weight of the tablet more than 800 mg 19. The formulations contained more concentration of HPMC and starch have more tendency to hard. Dabbagh & Beitmashal reported that by increasing the concentration of HPMC in the sustained release formulation, the tablet get the hardness more than 6 kg. Avicel PH 102 and starch have inverse proportion to hardness of formulations. Avicel PH 102 has hygroscopic na-

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ture and weak hydrogen bonding while HPMC has direct effect on hardness of tablet. Lahdenpaa et al. found that the increasing concentration of avicel PH 102, decreasing the strength of formulation 11. The formulations showed better hardness also have suitable friability results. Formulation has high concentration of HPMC showed better friability values Sheskey & Cabelka suggested that by increasing the concentration of HPMC, the value of friability decreased 21. Granular compaction and compression force in direct compression affects the friability values. Liquid within the granules and lump and porosity are involved in more friable of granules 22. The results were within the range of 0.33-0.75% that are in acceptable limits. S6 formulation has least friability value in all six formulations. Multiple point dissolution studies of Ranitidine (IR) showed the excellent release of S1 formulation due to presence of less quantity of starch which acted as disintegrator. Remaining formulations like S2 to S5 showed more than 85% drug release of Ranitidine (IR) within 60 minutes due to less quantityof starch. S1 formulation showed little bit late ranitidine (IR) release due to combine effect of starch, avicel and aerosol. Flurbiprofen (SR) layer was depended on concentration of HPMC. Formulations S1 showed slowest release behavior of Flurbiprofen due to highest concentration of MCC and starch while HPMC concentration provided the agonistic approaches with these excipients. S2 to S6 had the faster release formulation pattern as compare to S1. Model dependent approaches in six formulations were applied successfuly. Different formulations of IR (ranitidine) followed the first order release while the SR (Flurbiprofen) was followed the zero order release. Hadgraft 23 reported the diffusion controlled release of sustained release formulations. Similar studies were also reported by Shah et al. 24. Model independent approaches like similarity and difference factors of six formulations were applied. f 2 is the similarity factor and its value were found to be closed to 100 or more than 50. Similar findings were previously suggested by Dressman et al. 25 while the difference factor f 1 is the difference factor and its value was found to be zero or less than 15. Costa & Sousa reviewed the modeling comparison of dissolution profiles and summarized the similarity and dissimilarity factors 5.


CONCLUSION Bilayer tablets of Flurbiprofen and ranitidine was prepared successfully. Formulations parameters were applied and considered within the acceptable ranges. In vitro release studies of six formulations were calculated and different kinetic models were applied. The most suitable formulation was S1 on the basis of their disintegration and release behavior. The proposed formulation of Flurbiprofen and Ranitidine in the same dosage form (bilayer tablet) could be used for future in vivo studies. Acknowledgements. We acknowledge Irza pharma Lahore and Axis pharma Faisalabad for providing samples of ranitidine and flurbiprofen. We also thankful to Department of Pharmaceutics, Govt. College University Faisalabad for providing us an opportunity to perform a series of experimental work in the labs. REFERENCES

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