Generic Ion ChromatographyâConductivity Detection Method for

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Generic ion chromatography-conductivity detection method for analysis of palladium scavengers in new drug substances Lanfang Zou, Raffeal Bennett, Imad A. Haidar Ahmad, Brandon M. Jocher, Li Zhang, Xiaodong Bu, Ian Mangion, and Erik L Regalado Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.9b00101 • Publication Date (Web): 19 Apr 2019 Downloaded from http://pubs.acs.org on April 19, 2019

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Organic Process Research & Development

Generic ion chromatography-conductivity detection method for analysis of palladium scavengers in new drug substances Lanfang Zou±, Raffeal Bennett±, Imad A. Haidar Ahmad*, Brandon M. Jocher, Li Zhang, Xiaodong Bu*, Ian Mangion, Erik L. Regalado* Process Research and Development, MRL, Merck & Co., Inc., Rahway, USA Corresponding author. Tel.: +1 732 594 5452 (E.L.R) *E-mail address: [email protected] ±

Both authors (L. Zou and R. Bennett) have contributed equally to this work and should be considered first authors.

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ABSTRACT: The revolution of palladium-catalyzed reactions in the synthesis of new molecules has created an unprecedented need for highly efficient palladium (Pd) removal processes. Metal scavengers with very selective and efficient removal properties are being extensively applied across process research & development (PR&D) to meet very tight specifications for residual Pd levels. Analytical procedures for the determination of residual Pd are wellestablished; however, developing methodologies to detect a variety of Pd-scavengers in multicomponent reaction mixtures is currently considered an emerging challenge in pharmaceutical analysis. Herein, a simple and efficient generic ion chromatographyconductivity detection (IC-CD) method on a Dionex IonPac AS19 column in conjunction with a fully aqueous eluent profile (potassium hydroxide-based) capable of chromatographically resolving over 10 Pd-scavenger species commonly used in PR&D workflows is described. Computer-assisted separation modeling using ACD Labs/LC Simulator served to generate 3D resolution maps with excellent separation conditions that matched the outcome of subsequent experimental data. Method validation experiments showed excellent analytical performance in linearity, recovery, repeatability, and LOQ/LOD. In addition, these same chromatographic conditions can separate multiple anionic species and active pharmaceutical (API) counterions along with Pd scavengers in the same experimental run. We also provide strategic examples where API counterion interferences (e.g. sulfate) can be minimized by treating the API sulfate form with barium acetate to enhance recovery of the Pd-scavenger analyte.

Keywords: ion chromatography-conductivity detection; method development; palladium removal; metal scavenger; pharmaceutical chemistry; generic method



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1. INTRODUCTION The use of organometallic reactions has grown exponentially in recent decades1, 2. Among them, palladium catalyzed cross-coupling methods have become a workhorse for the construction of C-C, C-N, and C-O bonds in the synthesis of new active pharmaceutical ingredients (APIs) and synthetic intermediates3-6 including some of the top selling drugs7, 8

. To further emphasize the importance of these reactions, the Nobel Prize in Chemistry

2010 was awarded jointly to Richard F. Heck, Eiichi Negishi9 and Akira Suzuki10 for palladium-catalyzed cross couplings in organic synthesis11, 12. The increased use of Pd in the synthesis of pharmaceuticals has been accompanied by an evolution of tools and technologies for enabling synthetic and analytical chemistry13-19; however, many challenges still remain. One of these challenges, and perhaps the most important, is the adequate removal of the metal species from the reaction mixture20. Traditionally, metal scavengers have been widely applied to remove Pd and other metals in a selective and efficient manner21-28. A general illustration of this process is presented in Figure 1a. After the process is complete, residual Pd and scavenger levels in the final API must be tested, and in some cases depending on target dosage, a specification for residual levels of Pd must be met in accordance with ICH Q3D guidelines (maximum 100µg / day Pd for oral applications) 29. This tight control requires the availability of sensitive analytical methods to ensure that these toxic species are removed below the specification threshold. Analytical methods for the determination of Pd have been extensively investigated and implemented across many scientific disciplines, with a variety of sensitive and straightforward procedures currently available17, 18, 30-35. As anyone could imagine, most of the leading chemistry groups in developing efficient methodologies for Pd treatment focus the analysis on residual Pd levels. However, the development and implementation of analytical procedures targeting the scavengers has been largely ignored, with only a few isolated references on methods used for natural products and environmental applications 36, 37

. In pharmaceutical chemistry, it is mandatory to demonstrate that both Pd and

scavenger species are removed from the synthetic intermediates and final APIs. In this regard, the lack of a simple and straightforward analytical assay capable of reaching low 4 ACS Paragon Plus Environment

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quantitation levels of the scavenger in multicomponent reaction mixtures becomes a serious problem during pharmaceutical development and manufacturing. The development of sensitive analytical methods for the determination of residual levels of Pd scavengers can be very problematic. Several illustrations of the problems that can arise with the analysis of these species are presented in Figure 1b. Method development using conventional direct GC or LC approaches is not viable in several cases due to: 1) high boiling point, 2) degradation at low pH38, 3) lack of chromophore for LC-UV analysis, and 4) poor chromatographic performance at neutral or high pH for analysis using LC coupled to charged aerosol or mass spectrometry detectors. Optimization of a synthetic route in the development of new drug substances involves the screening of multiple reaction variables 14, 39-41 including Pd scavengers. Consequently, the time spent developing new analytical procedures for quantitation of these species can result in delaying an entire pipeline program.

Figure 1. a) General mechanism of Pd removal using scavengers. b) Examples of Pd-scavenger structures and challenges for analytical method development.

The development and validation of generic or more universal chromatographic methods has proliferated in both academia and industry

42-51

. Such generic chromatographic



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methodologies can be successfully applied to minimize the time spent developing new analytical assays prior to each analysis session, while streamlining method transfer to manufacturing facilities. In this study, a new systematic approach for the analysis of over 10 of the most commonly used Pd scavengers in a single chromatographic run is reported. The use of this simple and efficient generic IC-CD method for the analysis of residual Pd scavenger content in pharmaceuticals is demonstrated with full validation data provided to enable its application in a regulatory setting. 2. EXPERIMENTAL 2.1. Instrumentation Residual Pd-scavenger analyses were performed on an Thermo ScientificTM DionexTM ICS-5000+ Reagent-Free HPICTM system (Thermo Scientific, Rockford, IL, USA) with an Thermo Scientific Dionex AS-AP autosampler, Dionex dual pump (DP) module with eluent generator cartridge (EGC 500 KOH) and Dionex continuously regenerated anion trap column (CR-ATC 500) and high pressure EG degasser using a conductivity detector (CD) equipped with a Dionex Anion Electrolytically Regenerated Suppressor (AERS 500 2 mm) in recycle mode. The system was controlled by Thermo Scientific Dionex Chromeleon 7 Chromatography Data System (CDS), version 7.2 Chromatographic System (Thermo Scientific). 2.2. Chemicals and reagents Potassium 2-isocyanoacetate (85%), ammonium pyrrolidinedithiocarbamate (99%), NAcetyl-L-cysteine (98%), succinic acid (99%), glutaric acid (99%), and 1,3propanedisulfonic acid (70% in H2O) were obtained from Sigma-Aldrich, Inc. (St Louis, MO, USA). Potassium ethylxanthate (97%) was obtained from Acros Organics (Fair Lawn, NJ, USA). Potassium isopropylxanthate (PIX) was purchased from Enamine (Monmouth, NJ, USA). Sodium dimethyldithiocarbamate dihydrate (98%) and cis-cyclohexane-1,2dicarboxylic acid (98%) were purchased from TCI America (Portland, OR, USA). Sodium diethyldithiocarbamate (97%) was obtained from Combi-Blocks (San Francisco, CA, USA). De-ionized water was obtained from a Milli-Q Gradient A10 from Millipore (Bedford, MA, USA). 0.1 N sodium hydroxide solution was obtained from Honeywell 6 ACS Paragon Plus Environment

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(Mexico City, Mexico). HPLC grade acetonitrile was obtained from Fisher Scientific (Hampton, NJ, USA). 2.3. Stationary Phases Nine hydroxide-selective anion exchange stationary phases from the Dionex IonPac line were screened for their ability to separate Pd scavengers, all of which were purchased from Thermo Scientific (Rockford, IL, USA). These stationary phases include the AS16, AS19, and AS11-HC columns in 4 µm, 2 x 250 mm format; another AS19 column in 10 µm 4 x 250mm format; the AS28 column in 4 µm, 2 x 150 mm format; the AS18, AS25, and AS26 columns in 7.5 µm, 2 x 250 mm format; the Fast Anion IIIA in 7.5 µm, 3 x 250 mm format; and the AS15 column in 9 µm, 2 x 250 mm format. 2.4. Experimental conditions used for LC-Simulator modeling From the afore-listed screening study, the following column and chromatographic conditions were selected for continued IEC method development for separation of 11 Pd scavengers (Figure 2) and chromatographic modeling(Figure 3): IC resin: IonPac AS19 Column (2 mm x 250 mm, 4 µm particles) column and IonPac AG19 guard column (2 mm x 50 mm, 11 µm particles, same phase as the main column). High purity hydroxide ions are produced using reagent-free system with EGC 500 KOH eluent generator using DI water as carrier. Flow rate: 0.5 mL/min. Three gradients, 10-55 mM [OH-] in 10, 20, and 30 min, and holding the [OH-] at 55 mM for 5 min and then re-equilibrium for 5 min, were executed at three temperatures (25, 30, and 40 °C) in order to build a 3D resolution map. It is important to point out that we scouted a narrow temperature range, because of instrument limitations on instrument control (25-41oC). The resultant experimental data was input and processed using ACD/LC Simulator 2015 Release (Version L10R41), Advanced Chemistry Development, Inc. (ACD), Toronto, Ontario, Canada, further referred to as LC Simulator. 2.5 Validation experiments The IC-CD experiments were designed to satisfy the minimal validation requirements for quantitative analysis. For method simplicity a pure aqueous diluent was used, which can 7 ACS Paragon Plus Environment


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allow transferability to other aqueous diluents. Repeatability was evaluated for 3 injections of each Pd scavenger. The linear (dynamic) range for each analyte was established by a minimum of 4 data points, specific to each scavenger, ranging from the LOQ to 0.5 mg/mL of the dry salt. Acceptable linearity was determined based on a correlation coefficient (R) ≥ 0.998. LOQ: the Limit of Quantitation (LOQ) was determined as (a) the concentration that had a minimum signal to noise ratio (S/N) of 10:1. Specificity: The resolution of all analytes was established with respect to each other. The authors note that interactions between Pd scavengers may occur during the sampling and analysis and therefore impact the specificity of the method. 2.6. Optimized Anion-Exchange Chromatography method The 3D resolution map was built based on the conditions listed-above, which allowed us to develop the following optimized method for separation of all 11 scavengers using the same IC column and mobile phase. Isocratic: 24 mM [OH-] for 37 min. Flow rate: 0.5 mL/min. Column temperature: 41°C. Injection volume: 5 μL. UV detection: 254 nm. Experimental chromatogram is shown in Figure 3b. It is important to point out that we do not typically advise the use of simulated conditions that are extrapolated outside of the originally tested range of conditions. However, 41°C is only one degree outside of the tested range. Furthermore, the simulated method showed a good correlation with the corresponding experimental result. 2.7 Preparation of standards and samples Stock standard and diluted solutions were prepared following GMP procedures in 100 mL volumetric flasks using Grade A glass pipettes. From the stock standard preparation, serial dilutions were performed to prepare the linearity standards. Standards used for quantitative analysis are prepared at similar concentration to that of the target concentration in the sample. For sample analysis, solids are weighed and diluted at a concentration necessary to obtain the desired LOQ 2.7. Procedure to removed SO42- ion to improve recovery of PIX The removal of sulfate from the ceftolozane sulfate drug substance was performed via a precipitation (double displacement) reaction with barium acetate. In this work, 10 mg 8 ACS Paragon Plus Environment

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of drug substance were dissolved in 1 mL of a 90/10 v/v 0.1 N NaOH/ACN diluent. Five mg of barium acetate was dissolved into the sample solution and centrifuged for 5 minutes. The supernatant, containing PIX and the drug substance, was then collected for further analysis, and the remaining barium sulfate precipitate was discarded. 3. RESULTS AND DISCUSSION The development and optimization of a generic chromatographic method for the separation of multiple Pd scavenger species in a single experimental run is crucial for a fast and reliable turnaround of analytical results during process chemistry optimization. All of the 11 compounds selected in this investigation form part of a comprehensive list of the most effective Pd scavengers utilized by synthetic and process chemists in our laboratories. The list includes xanthates (compounds 2-4, 9 and 10) and other structurally diverse scavengers, e.g. a cyanoacetate (1), aliphatic dicarboxylic acids (5, 6 and 8), N-acetyl-L-cysteine (7) and propanedisulfonic acid (11) as depicted in Figure 2. Figure 2. Structures of Pd scavengers investigated in this study.

We examined the separation of this mixture on several columns packed with different anion-exchange resins using readily available ion chromatography coupled to conductivity detector instrumentation (IC-CD). A complete listing of the columns and best outcomes are shown in Table 1, with all screening conditions described in the Experimental section. The selection of the best screening hits for method development is based on chromatographic peak shape, retention and resolution. In this regard, the IonPac AS19 resin proved to be an excellent stationary phase candidate for method development and optimization. All analytes eluted within the screening time window and the most analytes (8) were resolved from this unoptimized method. This column is packed with a novel hyperbranched anion-exchange condensation polymer, electrostatically attached to the 9 ACS Paragon Plus Environment


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surface of a wide-pore polymeric substrate. The substrate is surface-sulfonated like other Dionex latex-coated anion-exchange materials; however, in this anion exchange resin, alternating treatments of epoxy monomer and amines produce a coating that grows directly off the surface of the substrate.52 Good chromatographic performance for the separation of several Pd scavengers was achieved when combined with a fully aqueous potassium hydroxide-based eluent (generated in situ via a KOH generator). A very convenient feature of this setup is that the user only has to add water into the mobile phase feed. The use of organic eluents in the mobile phase is not required when using this approach, allowing us to reduce cost and environmental impact, something of vital importance in the implementation of generic chromatographic methodologies. Table 1. List of stationary phase resins used for screening of Pd scavengers.

Stationary phase

AS19 AS16 AS26 AS25 AS18 Fast Anion IIIA AS28 AS11-HC AS15

Analytes eluted a 11 11 11 11 11 10 9 9 5

Analytes separated b 8 2 5 3 5 2 2 3 3

a

number of compounds eluted out of a total of 11 analytes. b number of analytes that were individually resolved from all other compounds

The aforementioned screening results were subsequently optimized in order to develop generic chromatographic conditions that separates all of the scavengers in a single experimental run. Such generic methods could be effectively applied to the separation and analysis of metal scavenger species beyond the scope of this list, where reduction in method development efforts can lead to significant time savings when multiplied across the many samples submitted for quantitative analysis. Modern chromatographic screening technologies, in conjunction with computer-assisted separation modeling are quickly becoming a very effective approach to generate robust chromatographic methods44, 53. The experimental data acquired from varying column temperature (25, 30, and 40 °C) and gradient elution time (10, 20, and 30 min) was input and processed using ACD/LC 10 ACS Paragon Plus Environment

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Simulator software. The 3D resolution map that was subsequently used for the prediction of chromatographic conditions and elution profiles is depicted in Figure 3.

Figure 3. IC-CD method development for separation of 11 scavengers from modeling to experimental conditions. (a) 3D resolution map (b) final optimized method. All chromatographic conditions applied to build the modeling and 3D resolution map are described in the Experimental section, as well as the final optimized conditions.

The 3D resolution map illustrates the area (orange) of robust conditions allowing for the efficient and convenient resolution of all 11 Pd scavengers using isocratic elution, in particular, all of the critical pairs that are very difficult to separate (e.g. scavengers 6, 7, and 8) using the initial gradient and column temperature. Figure 3 also shows the overlaid chromatographic profiles from injection of multiple standard mixtures illustrating the power of modern chromatography simulation and modeling software when applied for method development. These experimental chromatographic data were compared to simulated outcomes. The comparisons shown in Table 2 indicate an excellent match, with overall ∆tR differences below 2 % between predicted and experimental data, except for analyte peak 9 and 10 (2.3 and 2.8% respectively).



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Table 2. Summary of predicted and experimental retention time values along with the absolute percentage difference between them for all Pd scavengers.

Peak #

tR, predicted

tR, exp

tR (%)

1 2 3 4 5 6 7 8 9 10 11

5.01 9.17 10.43 11.11 15.83 15.93 16.74 17.14 21.36 22.59 33.99

5.07 9.13 10.37 10.9 15.69 15.61 16.67 17.42 20.88 21.97 34.41

1.2 0.4 0.6 1.9 0.9 2.0 0.4 1.6 2.3 2.8 1.2

From this optimized isocratic method, validation experiments were conducted for quantitative analysis of Pd scavengers. Table 3 summarizes the linear range, the calibration parameters determined by linear regression (response factor [m] and y-intercept [b]), linearity (R), and the S/N of the LOQ. Response factors of standards were determined to be linear within the range studied, having a correlation coefficient (R) ≥ 0.998. The % RSD of retention times for all tested standard solutions was ≤ 0.20%. These validation experiments serve as the basis for the method used in the initial stages of drug development, prior to expanded validation of the method for the specific product. The quantitation ranges (0.0483 – 613 µg/mL of Pd scavenger anion) are also listed in Table 3. However, the detection range for a particular Pd scavenger is usually dependent upon the solubility of the drug substance in the diluent. For example, the quantitation limit of residual Pd scavenger in a drug substance that is soluble at 5 mg/mL is 5 times lower than the quantitation limit of Pd scavenger in a drug substance that is soluble at only 1 mg/mL. It is important to mention that this validation data is preliminary, but satisfies the needs of early stage validation for quantitative R&D assays. Table 3. Summary of validation results for the generic Pd scavenger method

Analyte 1 2

RT (min) ± %RSD

Linear range (µg/mL)

Linear Equation (mx+b)

Linearity (R)

LOQ (S/N)

5.06 ± 0.08 8.97 ± 0.03

299 – 0.292 339 – 1.32

65.88x + 0.08 11.37x + 0.03

0.9998 0.9999

179 103.3 12

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3 4 5 6 7 8 9 10 11

10.18 ± 0.04 10.66 ± 0.03 15.56 ± 0.04 15.66 ± 0.01 16.37 ± 0.03 17.30 ± 0.07 20.64 ± 0.03 21.73 ± 0.00 34.15 ± 0.20

27.2 – 0.424 443 – 0.432 121 – 0.474 124 – 0.485 502 – 7.85 49.5 – 0.0483 378 – 0.369 92.6 – 0.362 613 – 0.598

22.48x + 0.00 23.50x + 0.10 42.47x + 0.12 42.23x + 0.10 47.25x + -0.29 52.88x + 0.01 28.37x + 0.03 21.12x + 0.03 109.15x + -0.21

0.9998 0.9996 0.9985 0.9991 0.9997 1.0000 0.9998 0.9984 1.0000

41.2 109.2 138.2 177.4 636.6 6.3 19.6 25 21.6

This method covers a diverse set of the most used Pd scavengers by medicinal and process chemists in the synthesis of new drug substances. In addition, our IC-CD conditions can also serve as starting point for method development in order to analyze other challenging salt anions not represented in Table 3, e.g. API counterions among other anionic species. Figure 4 shows the overlaid chromatograms from injections of multiple Pd scavengers and a seven anion standard mixture composed by: F-, Cl-, NO2-, Br-, NO3-, PO43-, and SO42-. This example serves to illustrate the value of this chromatographic procedure, in which, all the species investigated are baseline resolved within 37 min.

Figure 4. IC-CD overlays of all 11 Pd scavengers together with seven anions typically used as API counterions. All chromatographic conditions are the same as described in Figure 3 and experimental section.

It is important to highlight that the separation of Pd scavengers from salt counterions is extremely valuable since most of the API products are manufactured as salts to improve bioavailability, stability and purity. In this regard, quantitation of residual Pd scavenger levels in API salts can be problematic in certain cases where the scavenger analyte target elutes close to the API counterion. Figure 5a shows a recently developed Pd removal process applied to the ceftolozane manufacturing route from extensive optimization of metal scavenging20. Process chemists removed Pd to levels below 0.2 ppm using a novel 13 ACS Paragon Plus Environment


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procedure with Potassium isopropylxanthate (PIX, compound 9), and consequently, residual levels of the PIX scavenger had to be determined. The procedure depicted in Figure 5b employs barium acetate in order to reduce sulfate anion interference from all samples. BaSO4 is formed from this reaction, which is insoluble in 0.1 N NaOH / ACN (90/10, v/v). PIX becomes part of the supernatant that is analyzed by IC-CD analysis after centrifugation of the reaction mixture. Although our procedure was validated from outcomes using state-of-the-art IC instrumentation and column technologies (4 μm IonPac AS19 resin, 2 x 250 mm), other readily available IC equipment with a larger particle stationary phase and wider column (10 μm IonPac AS19 resin, 4 x 250 mm) can deliver acceptable results as shown in Figure 5b. In this case, a modified gradient elution and column using a similar KOH (Aq.)-based eluent profile was successfully applied to the separation of all seven anionic species from the target PIX analyte. In addition, optimized treatment of 10 mg samples with 5 mg Ba(OAc)2 in 1 mL 0.1 N NaOH (aq.) / CH3CN (90/10, v/v) was very effective at improving initially unacceptable recoveries from 50% all the way up to 96%, as demonstrated in the chromatogram traces in Figure 5b. It is important to point out that having both API counterion and Pd scavenger analytes within such a close retention time window is very unlikely. Nevertheless, this new procedure can offer a viable solution to remove salt interferences such as SO42- from samples containing Pd scavengers that might coelute.


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a) Pd removal using metal scavenger (PIX highlighted)

Potassium isopropyl xanthate (PIX)

b) Procedure to remove SO42- and increase PIX recovery prior to IC-CD analysis

API (sulfate salt)

Ba(OAc)2 treatment

Reaction Mixture

Centrifuge

Supernatant (PIX) precipitate (BaSO4)

Residual PIX

IC-CD analysis pix 7 Anions

1mL buffer pH 8.5

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


0.045 mg pix 0.009 mg pix

Recovery = 50% 10 mg API + 0.009 mg pix

10 mg API + 0.009 mg pix + 1mg Ba(OAc)2

10 mg API + 0.009 mg pix + 2.5mg Ba(OAc)2

Recovery = 96%

***** 0

10 mg API + 0.009 mg pix + 5mg Ba(OAc)2 5

10

15

20

25

min

30

Figure 5. a) Zerbaxa ceftolozane palladium removal with PIX scavenger (reproduced from reference20). b) Procedure to remove sulfate interference and increase PIX recovery from 50 to 96% consisting on sample treatment with barium acetate followed by centrifugation and IC-CD analysis of supernatant. Analysis was performed on a Dionex IonPac AS19 (4 x 250 mm) column with flow rate at 1.0 mL/min and 30 °C column temperature. A KOH eluent gradient was employed with 10 mM from 0-1 min, 10-15 mM from 1-10 min, 15-58 mM from 10-40 min, and 58 mM from 40-45 min. The ASRS 300 4mm Self-Regenerating Suppressor, recycle mode at 38 mA, a conductivity detector with cell temperature at 35 °C, and an autosampler at 5 °C.

4. CONCLUSIONS A simple and efficient generic IC-CD method for separation and analysis of over 10 Pdscavengers, API counterions amongst other ionic species commonly used in PR&D workflows was developed and implemented. Our method combines the use of a Dionex IonPac AS19 resin in conjunction with a fully aqueous (potassium hydroxide-based) eluent 15 ACS Paragon Plus Environment


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using readily available technology. Chromatographic conditions were optimized using ACD Labs chromatography simulation software showing an excellent match between modeling and experimental data. The use of this IC-CD approach to the detection of residual Pd scavengers in new drug substances is demonstrated with validation data provided to enable this method to be applied in quantitative analyses. In addition, a strategic example where API counterion interference (SO42-) can be removed using Ba(OAc)2 to enhance recovery (from 50 to 96%) of the Pd-scavenger target in the supernatant was provided. AUTHOR INFORMATION *Corresponding Authors Phone: +1 732 594 1226. E-mail: [email protected] Phone: +1 732 594 0369. E-mail: [email protected] Phone: +1 732 594 5452. E-mail: [email protected] ORCID Lanfang Zou: 0000-0002-5384-8553 Raffeal Bennett: 0000-0002-0628-0774 Imad A. Haidar Ahmad: 0000-0003-2240-4754 Xiaodong Bu: 0000-0001-6868-0282 Erik L. Regalado: 0000-0002-7352-6391 Notes The authors declare no competing interests ACKNOWLEDGMENTS We thank Dr. Frank Bernardoni and Daniel Zewge for their valuable suggestions. REFERENCES (1) Magano, J.; Dunetz, J. R., Large-Scale Applications of Transition Metal-Catalyzed Couplings for the Synthesis of Pharmaceuticals. Chemical Reviews 2015, 111, 2177-2250. (2) Friedfeld, M. R.; Zhong, H.; Ruck, R. T.; Shevlin, M.; Chirik, P. J., Cobalt-catalyzed asymmetric hydrogenation of enamides enabled by single-electron reduction. Science 2018, 360, 888-893. (3) Wang, D.; Weinstein, A. B.; White, P. B.; Stahl, S. S., Ligand-Promoted PalladiumCatalyzed Aerobic Oxidation Reactions. Chemical Reviews 2018, 118, 2636-2679. 16 ACS Paragon Plus Environment

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