Table of Contents  
ORIGINAL ARTICLE
Year : 2013  |  Volume : 4  |  Issue : 1  |  Page : 24-31  

A validated stability-indicating high performance liquid chromatographic method for moxifloxacin hydrochloride and ketorolac tromethamine eye drops and its application in pH dependent degradation kinetics


Department of Quality Assurance, Shri Sarvajanik Pharmacy College, Mehsana, Gujarat, India

Date of Web Publication18-Mar-2013

Correspondence Address:
Jayant B Dave
Shri Sarvajanik Pharmacy College, Near Arvind Baugh,Mehsana, Gujarat
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2229-5186.108802

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   Abstract 

Background and Aim: A fixed dose combination of moxifloxacin hydrochloride and ketorolac tromethamine is used in ratio of 1:1 as eye drops for the treatment of the reduction of post operative inflammatory conditions of the eye. A simple, precise, and accurate High Performance Liquid Chromatographic (HPLC) method was developed and validated for determination of moxifloxacin hydrochloride and ketorolac tromethamine in eye drops. Materials and Methods: Isocratic HPLC separation was achieved on a ACE C 18 column (C 18 (5 μm, 150 mm×4.6 mm, i.d.)) using the mobile phase 10 mM potassium di-hydrogen phosphate buffer pH 4.6-Acetonitrile (75:25 v/v) at a flow rate of 1.0 mL/min. The detection was performed at 307 nm. Drugs were subjected to acid, alkali and neutral hydrolysis, oxidation and photo degradation. Moreover, the proposed HPLC method was utilized to investigate the pH dependent degradation kinetics of moxifloxacin hydrochloride and ketorolac tromethamine in buffer solutions at different pH values like 2.0, 6.8 and 9.0. Results and Conclusion: The retention time (t R ) of moxifloxacin hydrochloride and ketorolac tromethamine were 3.81±0.01 and 8.82±0.02 min, respectively. The method was linear in the concentration range of 2-20 μ/mL each for moxifloxacin hydrochloride and ketorolac tromethamine with a correlation coefficient of 0.9996 and 0.9999, respectively. The method was validated for linearity, precision, accuracy, robustness, specificity, limit of detection and limit of quantitation. The drugs could be effectively separated from different degradation products and hence the method can be used for stability analysis. Different kinetics parameters like apparent first-order rate constant, half-life and t 90 (time for 90% potency left) were calculated.

Keywords: High performance liquid chromatography, ketorolac tromethamine, method validation, moxifloxacin hydrochloride, pH dependent degradation kinetics, stability-indicating method


How to cite this article:
Dave JB, Vyas PJ, Patel CN. A validated stability-indicating high performance liquid chromatographic method for moxifloxacin hydrochloride and ketorolac tromethamine eye drops and its application in pH dependent degradation kinetics. Chron Young Sci 2013;4:24-31

How to cite this URL:
Dave JB, Vyas PJ, Patel CN. A validated stability-indicating high performance liquid chromatographic method for moxifloxacin hydrochloride and ketorolac tromethamine eye drops and its application in pH dependent degradation kinetics. Chron Young Sci [serial online] 2013 [cited 2019 Oct 16];4:24-31. Available from: http://www.cysonline.org/text.asp?2013/4/1/24/108802


   Introduction Top


Moxifloxacin hydrochloride is 1-Cyclopropyl-6-fluoro-8-methoxy-7-[(4aS, 7aS)-octahydro-6H-pyrrolo [3, 4b]pyridin-6-yl]-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid hydrochloride [1] [Figure 1]. It is a newer fluoroquinolone drug indicated for the treatment of bacterial infections. Moxifloxacin hydrochloride is a broad-spectrum antibiotic that is active against both Gram-positive and Gram-negative bacteria. It functions by inhibiting DNA gyrase, a type II topoisomerase, and topoisomerase IV, enzymes necessary to separate bacterial DNA, thereby inhibiting cell replication. [2,]3[,[4] Ketorolac tromethamine is 2-Amino-2-(hydroxymethyl) propane-1, 3-diol (1RS)-5-benzoyl-2, 3-dihydro-1H-pyrrolizine-1-carboxylate. [1] [Figure 2] It acts by blocking prostaglandin synthesis by inhibiting cyclooxygenase 1 and 2. Prostaglandins have been shown to be mediators of certain kinds of intraocular inflammation and also produce disruption of the blood-aqueous humour barrier, vasodilation, increased vascular permeability, leukocytosis, and increased intraocular pressure. [5],[6] A detailed survey of analytical literature for moxifloxacin hydrochloride revealed several methods based on varied techniques, viz, HPLC, [7],[8],[9],[10] Spectrophotometry, [11],[12] High-Performance Thin-Layer Chromatography (HPTLC). [13],[14] Similarly, a survey of the analytical literature for ketorolac tromethamine revealed several methods like HPLC, [15],[16] HPTLC, [17],[18] LC/MS/MS (Liquid Chromatography-Mass Spectrometry-Tandem Mass Spectrometry), [19] capillary electro chromatography. [20] The published literature revealed spectrophotometric determination of moxifloxacin hydrochloride and ketorolac tromethamine in combination. [21],[22] According to detailed survey of analytical literature none of the reported analytical procedures describes a simple and satisfactory HPLC method for simultaneous determination of moxifloxacin hydrochloride and ketorolac tromethamine in their combined dosage forms. Hence, the objective of this work was to develop simple, precise, and rapid HPLC method for combination drug products containing moxifloxacin and ketorolac tromethamine.
Figure 1: Moxifloxacin hydrochloride

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Figure 2: Ketorolac tromethamine

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   Materials and Methods Top


Instrumentation

Liquid chromatographic Shimadzu (LC-2010C HT ) system manufactured by Shimadzu, Kyoto, Japan, equipped with auto-sampler, UV and Photodiode Array (PDA) detector and Rheodyne injector and ACE C 18 column (150 × 4.6 mm 2 i.d., 5 μm particle size) was used. An analytical balance (Acculab ALC-210.4, Huntingdon Valley, PA); pH meter (Thermo Electron Corp., Pune India); and sonicator (EN 30 US Enertech Fast Clean, Mumbai, India) were used.

Materials

Moxifloxacin hydrochloride and ketorolac tromethamine bulk powder were gifted by cadila health Care. Ltd. (Ahmadabad, India) and torrent pharma. Ltd. (Gandhinagar, India), respectively. The commercial Eye drops (MOXICIP-KT, 0.5 w/v% of moxifloxacin hydrochloride and 0.5 w/v% of ketorolac tromethamine) was procured from the local market. Acetonitrile (HPLC grade, Finar Chemicals Ltd., Ahmadabad, India); Water (HPLC grade, Finar Chemicals Pvt. Ltd, Ahmadabad, India); and nylon filter (Millipore Ltd., Bangalore, India) were used.

Preparation of standard stock solution

Accurately weighed quantity of 10 mg of moxifloxacin hydrochloride and ketorolac tromethamine were transferred into a 100 mL volumetric flask and dissolved in water to obtain the standard stock solution 100 μg/mL each of moxifloxacin hydrochloride and ketorolac tromethamine.

Preparation of sample solution

An aliquot of Ophthalmic formulation (MOXICIP-KT, 0.5 w/v% moxifloxacin hydrochloride and 0.5 w/v% ketorolac tromethamine) 0.2 mL was taken in 100 mL volumetric flask and diluted to mark with water to yield 10 μg/mL each of moxifloxacin hydrochloride and ketorolac tromethamine.

Chromatographic condition

The mobile phase was chosen after several trials with methanol, acetonitrile, water, and buffer solutions in various proportions and at different pH values. A mobile phase consisting of acetonitrile: Phosphate buffer pH 4.6 (25:75 v/v) was selected to achieve good separation and resolution. A flow rate of 1 mL/min gave an optimal signal-to-noise ratio with a reasonable separation time and run time was 13 min. Using a reversed-phase C 18 column, the retention times for moxifloxacin hydrochloride and ketorolac tromethamine were observed to be 3.81±0.01 and 8.82±0.02 min, respectively. The wavelength was fixed at isosbetic point of 307 nm which gave good absorbance both for moxifloxacin hydrochloride and ketorolac tromethamine.

Method validation

This optimized HPLC method was validated for the parameters listed in the International Conference on Harmonization (ICH Q2 (R1)) guidelines. [23]

Linearity

Aliquots of 0.2, 0.4, 0.6, 0.8, 1.0, 1.2, 1.4, 1.6, 1.8, and 2.0 mL of the stock solution of moxifloxacin hydrochloride and ketorolac tromethamine were transferred into a series of 10 mL volumetric flasks and diluted to the mark with water to yield 2, 4, 6, 8, 10, 12, 14, 16, 18, and 20 μg/mL each of moxifloxacin hydrochloride and ketorolac tromethamine. The calibration curve was constructed by plotting peak areas versus concentrations, and the regression equation was calculated. Each response was an average of five determinations.

Precision

Intraday and interday precision were evaluated by determining the corresponding responses of standard solutions in triplicate on the same day (repeatability) and on different days (intermediate precision) at three concentrations of 2, 10, and 20 μg/mL each of moxifloxacin hydrochloride and ketorolac tromethamine. The results were reported in terms of % RSD (Relative standard deviation).

Accuracy

Accuracy was determined by calculating recovery of moxifloxacin hydrochloride and ketorolac tromethamine by the standard addition method. Known amounts of standard solutions of moxifloxacin hydrochloride (2.5, 5, 7.5 μg/mL) and ketorolac tromethamine (2.5, 5, 7.5 μg/mL) were added to a prequantified test solutions 10 μg/mL each of moxifloxacin hydrochloride and ketorolac tromethamine. Each solution was injected in triplicate, and the recovery was calculated by measuring peak areas and fitting these values into the regression equation of the calibration curve.

Limit of detection and limit of quantitation

LOD and LOQ were obtained by calculating using the Standard formula as per the ICH guidelines,

LOD=3.3 × (σ/S), LOQ=10 × (σ/S).

Robustness

The robustness study was performed to evaluate the influence of small but deliberate variations in the chromatographic conditions. The robustness was checked by changing the mobile phase flow rate (±0.1 mL/min); composition (±5% in organic phase); pH (±0.2 units); and temperature (±5°C).

System suitability test parameters

System suitability parameters were verified with respect to number of theoretical plates, asymmetric factor, resolution, capacity factor, and % RSD of six replicate of injection of moxifloxacin hydrochloride (10 μg/ml) and ketorolac tromethamine (10 μg/ml).

Specificity

The specificity of the method was established through the study of resolution factor of the drug peak from the nearest peak and peak purity data of the analyte peaks in forced degradation samples.

Forced degradation studies

Acid hydrolysis


Ten milliliter of a mixture of solution containing 1 mg/mL each of moxifloxacin hydrochloride and ketorolac tromethamine in 1 M HCl was heated at 80°C for 6 h, then neutralized with 1 N NaOH after cooling and diluted with water to give 100 μg/mL each of moxifloxacin hydrochloride and ketorolac tromethamine. This acid degradation sample was analyzed under the optimized chromatographic conditions.

Alkali hydrolysis

Ten milliliter of a mixture of solution containing 1 mg/mL each of moxifloxacin hydrochloride and ketorolac tromethamine in 2 N NaOH was heated at 80°C for 4 h and then neutralized with 2 N HCL after cooling and diluted with water to 100 mL to give 100 μg/mL each of moxifloxacin hydrochloride and ketorolac tromethamine. This alkali degradation sample was analyzed under the optimized chromatographic conditions.

Oxidative degradation

Ten milliliter of a mixture of solution containing 1 mg/mL each of moxifloxacin hydrochloride and ketorolac tromethamine in 30% H 2 O 2 was stored at room temperature for 6 h and diluted with water to 100 mL to give 100 μg/mL each of moxifloxacin hydrochloride and ketorolac tromethamine. This oxidative degradation sample was analyzed under the optimized chromatographic conditions.

Neutral hydrolysis

Ten milliliter of a mixture of solution containing 1 mg/mL each of moxifloxacin hydrochloride and ketorolac tromethamine in water was heated at 80°C for 12 h and diluted with water to 100 mL to give 100 μg/mL each of moxifloxacin hydrochloride and ketorolac tromethamine. This thermal and aqueous degradation sample was analyzed under the optimized chromatographic conditions.

Photo degradation

Ten milliliter of a mixture of solution containing 1 mg/mL each of moxifloxacin hydrochloride and ketorolac tromethamine in water was placed in photo-stability chamber (UV-light) for 12 h and diluted with water to 100 mL to give 100 μg/mL each of moxifloxacin hydrochloride and ketorolac tromethamine. This photo degradation sample was analyzed under the optimized chromatographic conditions.

pH dependent degradation kinetics

The pH of 2.0, 6.8, and 9.0 were used for measurement of pH degradation profile of moxifloxacin hydrochloride and ketorolac tromethamine. Accurately weighed 100 mg each of moxifloxacin hydrochloride and ketorolac tromethamine were transferred into 100 mL volumetric flask and diluted to volume with respective buffer solutions prepared as per Indian Pharmacopoeia [24] to give 1 mg/mL each of moxifloxacin hydrochloride and ketorolac tromethamine. These solutions were kept for the reflux at 60°C for different time intervals (up to 48 h). From the different pH containing stock solution (1000 μg/mL) transfer 1 mL into 10 mL volumetric flask at the specified time interval and dilute up to mark with water (100 μg/mL) and store these solutions into refrigerator (2-8°C). Inject the stored solutions under the optimized chromatographic conditions. The concentration of remaining moxifloxacin hydrochloride and ketorolac tromethamine were calculated at each pH value and time interval.


   Results and Discussion Top


Optimized chromatographic conditions

Different mobile phases were tried to separate moxifloxacin hydrochloride and ketorolac tromethamine. The optimum results were obtained with mobile phase consisting of acetonitrile: Phosphate buffer pH 4.6 (25:75 v/v). The t R values of moxifloxacin hydrochloride and ketorolac tromethamine were observed at 3.81±0.01 and 8.82±0.02 min, respectively. The representive chromatogram is given in [Figure 3].
Figure 3: HPLC chromatogram of moxifloxacin (10 μg/mL) and ketorolac (10 μg/mL): Peak of moxifloxacin (tR= 3.8) and ketorolac (tR=8.8)

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Linearity

The response for the drugs was found to be linear in the concentration range of 2-20 μg/mL each for moxifloxacin hydrochloride and ketorolac tromethamine with correlation coefficient of 0.9996 and 0.9999, respectively. The linear regression equation obtained were y=29412x-17621 and y=25806x+293.8 for moxifloxacin hydrochloride and ketorolac tromethamine, respectively [Table 1].
Table 1: Linearity data for moxifloxacin hydrochloride and ketorolac tromethamine

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Precision

The % RSD values for intraday precision study were found to be not more than 0.20% and 0.22% for moxifloxacin hydrochloride and ketorolac tromethamine, respectively, whereas % RSD values for interday precision were found to be not more than 0.25% and 0.29% for moxifloxacin hydrochloride and ketorolac tromethamine, respectively, thus confirming precision of the method [Table 2].
Table 2: Precision data for moxifloxacin hydrochloride and ketorolac tromethamine

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Accuracy

Excellent recoveries were obtained at each level of added concentrations of 25%, 50%, 75% (n=3). The result obtained indicated the mean recovery of 98.79-101.22% for moxifloxacin hydrochloride and 99.60-101.01% for ketorolac tromethamine [Table 3].
Table 3: Accuracy data for analysis of moxifloxacin hydrochloride and ketorolac tromethamine

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Limit of detection

The LOD was found to be 0.014 μg/mL and 0.021 μg/mL for moxifloxacin hydrochloride and ketorolac tromethamine, respectively [Table 4].
Table 4: Summary of validation parameters of moxifloxacin hydrochloride and ketorolac tromethamine

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Limit of quantitation

The LOQ was found to be 0.042 μg/mL and 0.065 μg/mL for moxifloxacin hydrochloride and ketorolac tromethamine, respectively [Table 4].

Robustness

There were no significant differences between results obtained by applying the analytical method under established and varied conditions proving the robustness of the method [Table 5].
Table 5: Robustness data of moxifloxacin hydrochloride and ketorolac tromethamine

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System suitability test parameters

The system suitability test parameters like number of theoretical plates, asymmetric factor, resolution, and capacity factor are listed in [Table 6].
Table 6: System suitability parameters of moxifloxacin hydrochloride and ketorolac tromethamine

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Specificity

The specificity of the method was proved by checking the peak purity of both analyte peaks in forced degradation samples which were close to 1.0 [Figure 4].
Figure 4: Peak purity spectra of moxifloxacin (a) and ketorolac (b)

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Formulation analysis

In the sample of moxifloxacin hydrochloride and ketorolac tromethamine eye drops (0.5% W/V of moxifloxacin hydrochloride and 0.5% of ketorolac tromethamine) content of moxifloxacin hydrochloride was found to be 98.46±0.39% and that of ketorolac tromethamine was found to be 101.11±0.28% [Table 7].
Table 7: Analysis of market formulation of moxifloxacin hydrochloride and ketorolac tromethamine

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Forced degradation study

Acid hydrolysis


In the acid degradation study, moxifloxacin hydrochloride showed one additional peak (t R=2.9) and ketorolac tromethamine showed one additional peak (t R=6.9) [Figure 5].
Figure 5: Chromatogram for acid hydrolysis of moxifloxacin, ketorolac and its degradants: degrade 1 (tR= 2.9), degrade 2 (tR= 6.9)

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Alkali hydrolysis

In the alkali degradation study, moxifloxacin hydrochloride showed one additional peak (t R=2.7). However, ketorolac tromethamine showed two additional peaks (t R=5.3 and 6.3) [Figure 6].
Figure 6: Chromatogram for alkali hydrolysis of moxifloxacin, ketorolac and its degradants: degrade 1 (tR= 2.7), degrade 2 (tR= 5.3), degrade 3 (tR= 6.3)

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Oxidative degradation

In the oxidative degradation study, moxifloxacin hydrochloride showed one additional peak (t R=2.9) and ketorolac tromethamine showed one additional peak (t R=6.9) [Figure 7].
Figure 7: Chromatogram for oxidative degradation of moxifloxacin, ketorolac and its degradants: degrade 1 (tR= 2.9), degrade 2 (tR= 6.9)

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Neutral hydrolysis

The thermal and aqueous degradation sample showed no additional peaks [Figure 8].
Figure 8: Chromatogram for neutral hydrolysis of moxifloxacin and ketorolac

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Photo degradation

In the photo degradation study, moxifloxacin hydrochloride showed no additional peaks. However, ketorolac tromethamine show one additional peak (t R=13.0) [Figure 9].
Figure 9: Chromatogram for photo degradation of moxifloxacin, ketorolac and its degradants: degrade 1 (tR= 13.0)

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Discussion of degradation studies of moxifloxacin hydrochloride and ketorolac tromethamine

Forced degradation studies of moxifloxacin hydrochloride and ketorolac tromethamine mixture were carried out under various stress conditions. Percentage degradation of moxifloxacin hydrochloride and ketorolac tromethamine under various stress conditions was calculated and listed in [Table 8]. Degradation results indicated that moxifloxacin hydrochloride degraded significantly under acidic and oxidative conditions and marginally in alkaline condition whereas ketorolac tromethamine degraded significantly under alkaline and oxidative conditions and marginally in photolytic condition.
Table 8: Result of degradation of moxifloxacin hydrochloride and ketorolac tromethamine

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pH dependent degradation kinetics

The pH-rate profile of degradation of moxifloxacin hydrochloride and ketorolac tromethamine in buffer solutions was studied at 60°C using the HPLC method. [Figure 10] and [Figure 11] First-order kinetics plots for the degradation of moxifloxacin hydrochloride and ketorolac tromethamine for each pH value are shown in [Figure 12] and [Figure 13], respectively. The apparent first-order degradation rate constant, t1/2 and t90 were calculated at all three pH values of 2.0, 6.8, and 9.0 for moxifloxacin hydrochloride and ketorolac tromethamine. [Table 9] From the degradation kinetics data, it can be concluded that the moxifloxacin hydrochloride is susceptible to acidic whereas ketorolac tromethamine is susceptible to alkaline degradation. The pH-rate profile study showed that the moxifloxacin hydrochloride and ketorolac tromethamine are most stable at pH 6.8. The results are not in full agreement with data published by S. K. Motwani et al. at 40°C. [14] Our result showed very high stability at pH 6.8 and much less degradation at pH 9.0 compared to published data.
Figure 10: pH-rate profile for the decomposition of moxifloxacin at 60ªC

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Figure 11: pH-rate profile for the decomposition of ketorolac at 60ªC

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Figure 12:

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Figure 13:

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Table 9: Degradation rate constant (K), half‑life (t1/2) and t90 for moxifloxacin hydrochloride and ketorolac tromethamine

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   Conclusion Top


The new HPLC method was found to be simple, precise, accurate, robust, and stability indicating for the estimation of moxifloxacin hydrochloride and ketorolac tromethamine in combined ophthalmic dosage form. Forced degradation study revealed that moxifloxacin hydrochloride degraded significantly under acidic and oxidative conditions and marginally in alkaline condition whereas ketorolac tromethamine degraded significantly under alkaline and oxidative conditions and marginally in Photolytic condition. The developed HPLC method adequately separated the drug from the degradation products proving the specificity of method and can be used for stability analysis. From the degradation kinetics data, it can be concluded that the moxifloxacin hydrochloride is susceptible to acidic pH whereas ketorolac tromethamine is susceptible to alkaline pH. The pH-rate profile study showed that the moxifloxacin hydrochloride and ketorolac tromethamine are most stable at pH 6.8.


   Acknowledgment Top


The authors are thankful to Cadila Health Care Ltd., Ahmedabad, India and Torrent Pharma Ltd., Gandhinagar, India for providing gift sample of moxifloxacin and ketorolac for research. The authors are highly thankful to Shri Sarvajanik Pharmacy College, Mehsana, Gujarat, India for providing all the facilities to carry out the work.

 
   References Top

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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8], [Figure 9], [Figure 10], [Figure 11], [Figure 12], [Figure 13]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8], [Table 9]


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