Effective Method To Remove Metal Elements from Pharmaceutical

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Organic Process Research & Development

Effective Method to Remove Metal Elements from Pharmaceutical Intermediates with Poly-chelated Resin Scavenger Hidetoshi Miyamoto,* Chihiro Sakumoto, Eriko Takekoshi, Yukiko Maeda, Narumi Hiramoto, Takahiro Itoh and Yoshiaki Kato Pharmaceutical Production & Technology Department, Teijin Pharma Limited, Iwakuni 7408511, Japan

* Corresponding Author [email protected]

ACS Paragon Plus Environment

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Table of Contents Graphic


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ABSTRACT: A catalytic reaction is an important methodology for the production of pharmaceuticals from the viewpoint of green and sustainable chemistry. Since elemental impurity levels should be controlled within acceptable limits in API, the development of removal of element is also important as well. The technology for removal of elements was developed using cost-effective poly-chelated resin scavenger. The precious elements were removed efficiently by passing through the packed cartridge filled with appropriate scavenger. The feasibility of the scavenger was evaluated and the application for actual manufacturing process is described. In contrast to another type of immobilized scavengers, poly-chelated resin scavenger provides an inexpensive method to scavenge several elements. Key words : scavenger, catalytic reaction, metal elements, palladium, copper


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INTRODUCTION The synthesis of drug substances involves the use of transition-metal catalysts and the residual elemental impurities would consequently reside in the drug substances. While ICH Q3D provides guideline for qualification and control of the elemental impurities, limited guidance is provided for these impurities. 1 Elemental impurity levels in the drug substance should be controlled within acceptable limits that are quite strict with the establishment of a Permitted Daily Exposure (PDE) for each element of toxicological concern. According to the Q3D, palladium, rhodium and ruthenium catalyst that are widely used for C–C and C–hetero atom bond formation are placed into Class 2B. These elemental impurities require risk assessment across potential elemental impurity sources to evaluate comparing predicted levels with PDE only if they are intentionally added to the processes. Considering the preparation of the drug substances, there are some possibilities of the contamination of elemental impurities. Among them, an intentional addition of element affects the profile of the drug substance considerably. Versatile approaches such as extraction 2 , precipitation, crystallization and absorption 3 can be applied for the removal of elements. Single methodology is not quite appropriate for removal of all kind of elements and the choice of scavenger for a particular process depends on several factors. For example, the performance of methodology would strongly depend on an differentiation of oxidation states (e.g., Pd(0) or Pd(II)) resulting a lack of generality and reproducibility. And these factors include the nature of the solvent system (aqueous or organic), the prevention of a potential loss of product, the presence of byproducts or unreacted reagents in solution and whether the scavenger will be applied in a batch process or continuous flow system. Consequently, it is extremely important to consider every possibility in an appropriate manner without ruling any option for removal technology.


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If the residual element level is not enough to fit an acceptable limit under treatment of extraction and/or crystallization, the crude product could be treated with solid-phase adsorbent to remove element. Cost-effective and scalable methods to remove elements have been developed.4 Merck group has reported a binary system of chelating agents combined with carbon or silica gel adsorbents. 5 Astra Zeneca group has conducted the operations for pharmaceutical pilot plant manufactures to remove a variety of metals including palladium, rhodium and iridium using silica based adsorbent. 6 Notable advantage of these methodologies is that the separation of scavenger is a straightforward by filtration or can be used in the fixed-bed adsorbent. These scavenging operations are more efficient in a volumetric productivity and can avoid the product loss as low as possible in comparison with the recrystallization. Our work focused on the development of more facile and cost-effective method to remove the residual elements using chelating agent. As the ability of forming a complex with metal elements varies depending on the structure of functional groups such as an iminodiasetic acid (IDA) group, a low-molecular polyamine group, aminophosphoric acid group, an isothionium group are commercially available. Among them, chelating resins introducing an IDA group are mainly used, but chelating resins introducing a low-molecular polyamine group are used for removing metals from a solution containing a large amount of alkali metals. These chelating resins form a complex with many metals, but the stability constant of a complex formed in significantly low as compared to ethylenediamine tetraacetic acid (EDTA), a typical chelating agent, and there arises a disadvantage that metal removal and collection rates are subject to variation due to interference by contaminant ions if the concentration of those contaminant ions in a treated solution in high. Nippon Filcon Co., Ltd.7 has developed a polymer bounded poly-chelated resin scavenger to remove elements and there are several types of scavenger. 8 These scavengers can be usually


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applied to removal of elements in water with tolerance for any pH and we can adopt an appropriate type of scavenger to suit a kind of element. The scavengers have been widely used at a low cost on an industrial scale for preparation of drinking water, treatment of waste water from factory and recovery of non-environmentally friendly elements from salt/flesh water. The polychelated resin scavenger can be used in various cartridge formats suitable for the recirculation flow system to afford a bespoke flow solution or scaled up to industrial size cartridges for large volume treatments. It is noteworthy that the residual elements can be removed from salt water or high salt content waste water at pH below 7 without adsorption of alkaline metal and alkaline earth metal such as Na, K, Ca, Ba, Mg, etc. This suggests that this type of adsorbent would have an excellent affinity for a particular ion in the presence of interfering ions. We infer that the residual elements would be removed selectively from the crude mixture of transition metal catalyzed reaction including inorganic base (e.g. Na2CO3 and K2CO3). Furthermore, these adsorbent can be customized to adsorb specific elements by optimization of the component ratio, the particle and pore size and allowed the use of this particular type of modified adsorbent over a wide range of elemental attenuation requirements. Moreover, when the metal adsorbent to which heavy metals have been adsorbed is treated with as acidic aqueous solution such as nitric acid or hydrochloric acid, heavy metals adsorbed by formation of chelates are quickly detached, and therefore adsorbed heavy metals can be collected with high efficiency and the metal adsorbent can be regenerated. Among other variation in our hand, we investigated a specific type of scavenger to evaluate the efficiency of removal of elements. This report described the application of poly-chelated resin for scavenging of precious elements residues to get high purity products.


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RESULTS AND DISCUSSION Initial Screening. The preparation for kg scale of API was required for the clinical study. In this project, the key reaction was the C–C bond formation via palladium catalyzed coupling reaction and the residual palladium level should be controlled to below 10 ppm at the end game. However, it was not so easy to remove the residual palladium by the extraction, treatment with activated charcoal and crystallization. Due to the achievement to find an effective scavenger, the initial screening was conducted to examine their ability to remove palladium from the solution in organic solvent. The solution of Pd(PPh3)4 in i-PrOH/DMF (183 ppm relative to the solution) was passed through the scavenger with the recirculation manner via a metering tube pump (Table 1). The silica bound equivalent of 2,4,6-trimercaptotriazine, Isolute® Si-TMT (molecular loading: typically 0.3 mmol/g) from Biotage, was examined to evaluate the ability of scavenging palladium from a solution and palladium in the solution was removed by 46.6% (entry 1). Smopex® 234 FG (molecular loading: typically 3 mmol/g) that is a fibrous material with a polypropylene or viscose backbone grafted with functional groups gave an only 20.7% reduction of palladium (entry 2). With functionalized spherical mesoporous silica based scavenger, QuadraSil™ TA (molecular loading: typically 0.5~1.5 mmol/g) from Johnson Matthey, more than 80% of the palladium was removed from the solution (entry 3). Activated charcoal affording quite simple and inexpensive system provided moderate palladium removal (entry 4). We could not find an efficient scavenger to remove palladium at this point. Among tested, we were finally aware that cost-affordable polychelated resin scavengers developed by Nippon Filcon Co., Ltd. have been applied for removal of elements from the aqueous solution on an industrial scale. Especially, PCR series that is one of poly-chelated resin scavengers have a high affinity for the metal compared to the other


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compounds. Therefore, we have investigated for removal of palladium using PCR series that has a polyethyleneimine skeleton being introduced into the polymer carrier. PCR-PA, PCR-A (Na) and PCR-B were treated with the solution of Pd(PPh3)4 in i-PrOH/DMF via column absorption and the residual palladium level was reduced by 72.0%, 79.0% and 91.7%, respectively (entries 5, 6 and 7). The scavenging using PCR-B2 that is a key commodity scavenger was conducted as well and highly efficient removal was observed in our tested (entry 8).

Table 1. Initial screening

entry

Pdresidual

Pdremoved

(ppm)

(%)

Agent

1

Isolute® Si-TMT

97.8

46.6

2

Smopex® 234 FG

145.1

20.7

3

QuadraSil™ TA

25.1

86.3

4

Activated charcoal

71.8

60.8

5

PCR-PA

51.2

72.0

6

PCR-A (Na)

38.5

79.0

7

PCR-B

15.1

91.7

8

PCR-B2

9.7

94.7

i-PrOH/DMF (5:1, 60 mL) solution of Pd(PPh3)4 (120 mg, Pd 11 mg) with 183 ppm of palladium (relative to the solution) was passed through the packed cartridge (13 mm diameter, 6 mL) with agent (300 mg) for 6 hr at rt. The flow rate was 6 mL/min. The resulting scavenged mixture was filtered through a PTFE 0.2 µm filter into a clean vial for palladium testing by ICP analysis.

Technological Information. PCR series is a polyamine polymer which has repeating units of ethyleneimine and N-carboxy-methylated ethyleneimine represented by the following chemical


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formula 1 (Figure 1) in the polymer chain and in which the average molecular weight of polyethyleneimine forming a chain frame is 600 to 150,000 is immobilized or held on an appropriate support as a metal adsorbent functional group.9 The basic chain frame of PCR-B is polyethyleneimine. Polyethyleneimine produced by a well-known method such as ring-opening polymerization ethyleneimine and polycondensation of ethylene chloride and ethylenediamine can be used. Normally, polyethyleneimine has intermixed structures of primary, secondary and tertiary amines as shown in the following chemical formula 2 (Figure 1) in addition to a linear structure. The average of a polyamine polymer having a chain frame of polyethyleneimine having a high molecular weight is that not only the stability constant of a formed complex increases with increase in the chain length of polyethyleneimine, but also a large number of metals are adsorbed in the molecular chain of the polyamine polymer. Furthermore, it is estimated that the adsorption rate is enhanced as the polymer chain of the polyamine polymer extends in a treated solution to increase a degree of freedom. On the other hand, a metal adsorbent comprising a polyamine polymer having a chain frame of low-molecular polyamine is not an adsorbent with good adsorption efficiency and a high metal adsorption capacity.

Figure 1. Chemical formula 1 and 2


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The carboxymethyl group is not introduced into all the nitrogen of polyethyleneimine and the polyamine polymer has a structure in which secondary amino group (imino groups) and tertiary amino group remains as shown in the following chemical formula 3 that is a basic chain frame of PCR-PA and PCR-A (Na) in its sodium salt form (Figure 2). The polyamine polymer may be introduced on various supports using remaining secondary amino groups. Furthermore, since secondary amino groups remain, the polyamine polymer shows a behavior similar to that of a low-molecular polyamine type chelating resin and is unsusceptible to interference by alkali metals and alkali earth metals.

Figure 2. Chemical formula 3

The degree of partial carboxy-methylation of polyethyleneimine is adjusted by adjustment of conditions for carboxy-methylation. If the degree of carboxy-methylation increases, heavy metals can be adsorbed in a wide range of pH, but absorptivity for alkali metals and alkali earth metals also increases. Therefore, when metals in a solution in which those metals coexists in a large amount are to be removed and collected, the collection rate of intended heavy metals decreases due to interference by these metals. PCR-PA is much more efficient to adsorb many type of metal in stable condition. On the other hand, PCR-B is charged positively in acidic solution so that it is more preferable for adsorbent metals such as palladium that may be charged


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negatively in aqueous solution. As suggested in the results (Table 1), PCR-B is much better to remove palladium from organic solution as same as the investigation in aqueous solution. When a polyamine polymer having a large number of chelating functional groups in the molecules is immobilized on a porous support by introduction to form a porous metal adsorbent, the porous support having a functional group reactive with an imino group may be either an organic polymer or an inorganic material (Figure 3). PCR-PA and PCR-B have a copolymer of poly(glycidyl methacrylate) and ethylene glycol dimethacrylate as a base polymer in which a polyamine polymer is chemically bounded and affixed to a porous support. A base polymer of PCR-B2 is a copolymer of poly(glycidyl methacrylate) and divinylbenzene that is nonhydrophilic polymer having a functional group to a high degree. Therefore, the saturated adsorption amount of metals is much bigger than other type of polymer. Actually, working capacity for removal of palladium increased from PCR-PA and PCR-B to PCR-B2 in order. We examined a compatibility with a range of organic solvents for performing organic synthesis in organic solvent. PCR series were prepared in organic solvents such as toluene, ethyl acetate, iso-propanol and methanol. To determine the compatibility of PCR with an organic solvent, the dissolution of PCR in an organic solvent (ethyl acetate and iso-propanol) was investigated by analysis so that monomers, oligomers and functional groups of the scavenger “PCR series” did not dissolve into an organic solvent. These data encouraged us to use the scavenger to remove metal element contamination from an organic solution because the scavenger should be a compatible with organic solvents that are usually used for the organic reaction to prepare the drug candidates.


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Figure 3. Immobilized poly-chelated resin scavenger

Metals Attenuation in Recirculation Mode. Collection of data from monitoring points was assessed to evaluate the effectiveness of attenuation processes (Figure 4). Palladium was removed via recirculation of the solution in i-PrOH/DMF through poly-chelated resin (PCR-B2) with periodic monitoring of the palladium content by ICP analysis. As indicated in Figure 4, rapid increase in uptake of element was observed in the first hour and initially the rate of adsorption is fast which might be due to the presence of more active sites on the surface of the scavenger. After treatment for 2 hr, palladium was attenuated predominantly by immobilization in the poly-chelated resin and quickly reduced by 81.4%. The recirculation was allowed to continue for 16 hr and the palladium was almost completely removed by >99%. As time goes on, active sites usually deceased so that the rate of adsorption decreased as well. In that case, the ratio of palladium removal depended on the operation time.


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Figure 4. Palladium attenuation versus time

i-PrOH/DMF (5:1, 60 mL) solution of Pd(PPh3)4 (120 mg, Pd 11 mg) with 183 ppm of palladium (relative to the solution) was passed through the packed cartridge (13 mm diameter, 6 mL) with agent (300 mg) for 6 hr at rt. The flow rate was 6 mL/min. The resulting scavenged mixture was filtered through a PTFE 0.2 µm filter into a clean vial for palladium testing by ICP analysis.

The correlation of the amount of scavenger with palladium (the ratio of scavenger versus palladium catalyst, wt/wt) was investigated to make sure that an adequate amount of scavenger and residence time for the scavenging process were optimized (Figure 5). The palladium solution was recirculated with 300 mg and 200 mg of the scavenger. The ratio of scavenger versus palladium was about 27 (wt/wt) and 18 (wt/wt), respectively. Using 300 mg of the scavenger, palladium was reduced mostly after 6 hr (94.7% removal) and removed completely after 16 hr by >99%. On the other hand, when the ratio was reduced to 18 (wt/wt), the removal ratio went down to 85.6% compared to 94.7% and the palladium was removed by >95% during the prolonged treatment. Consequently, appropriate ratio of scavenger versus palladium requires about 25 (wt/wt) in terms of adequate operational time (e.g. overnight).


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Figure 5. Correlation of amount of scavenger with palladium removal

i-PrOH/DMF (5:1, 60 mL) solution of Pd(PPh3)4 (120 mg, Pd 11 mg) with 183 ppm of palladium (relative to the solution) was passed through the packed cartridge (13 mm diameter, 6 mL) with agent (300 mg or 200 mg) for 6 hr at rt. The flow rate was 6 mL/min. The resulting scavenged mixture was filtered through a PTFE 0.2 µm filter into a clean vial for palladium testing by ICP analysis.

Screenings of various solvents for the removal of palladium were carried out and Table 2 lists the solvents that are typically used for our current project. When the product is isolated as a solid by crystallization under aqueous conditions, MeCN, i-PrOH and DMF were usually used as a poor solvent. The removals of palladium from the solution in these solvents were not efficient (entries 1, 2 and 3). On the other hand, palladium in the mixture of i-PrOH/DMF was almost completely removed by 94.7% (entry 4). It might suggest that the performance of scavenging would depend on a differentiation of oxidation states in each solvent. The scavenger in THF or toluene which is used for the crystallization under conditions in organic solvent system provided sufficient palladium removal (entries 5 and 6). Interestingly, PCR-A (Na) which is sodium salt of PCR-PA adsorbing many type of metal in stable condition removed the residual palladium efficiently in comparison with PCR-B2 (entry 7). These results suggest that it is important to select an appropriate scavenger for the conditions.


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Table 2. Solvent effect

entry

Pdresidual

Pdremoved

(ppm)

(%)

Solvent

1

MeCN

123.3

32.6

2

i-PrOH

151.5

17.2

3

DMF

143.8

21.4

4

i-PrOH/DMF (5:1)

9.7

94.7

5

THF

17.3

90.5

6

Toluene

99

7

i-PrOH*

32

82.5

Solution of Pd(PPh3)4 (120 mg, Pd 11 mg) in solvent (60 mL) with 183 ppm of palladium (relative to the solution) was passed through the packed cartridge (13 mm diameter, 6 mL) with PCR-B2 (300 mg) for 6 hr at rt. The flow rate was 6 mL/min. The resulting scavenged mixture was filtered through a PTFE 0.2 µm filter into a clean vial for palladium testing by ICP analysis. * using PCR-A (Na) instead of PCR-B2

The poly-chelated resin scavenger “PCR-B2” was applied to the recirculation scavenging of various palladium and copper reagents (Table 3). Several type of palladium complex was removed by ca. 80% and more (entries 1 to 4). Copper (II) salt such as CuBr2 and Cu(OAc)2 were efficiently removed by more than 90% (entries 5 and 6). In contrast, Copper (I) salt “CuBr” was removed in moderate by 72.7% (entry 7). But the residual of copper (I) salt “CuOAc” was almost completely removed (entry 8). These results suggested that metal could be removed regardless of a differentiation of oxidation states. On the other hand, an affinity of metal between phosphine or counter ion and scavenger might have an affect on the removal of metal.


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Table 3. Removal of various elements

entry

Metaloriginal

Metalresidual

Metalremoved

(ppm)*

(ppm)

(%)

Metal reagent

1

Pd(PPh3)4

183

9.7

94.7

2

Pd(OAc)2

237

0.3

99.9

3

PdCl2(dppf)2▪CH2Cl2

283

60

78.8

4

Pd2(dba)3

183

3

98.4

5

CuBr2

237

14.7

93.8

6

Cu(OAc)2

183

17

90.7

7

CuBr

183

50

72.7

8

CuOAc

183

1

99.5

i-PrOH/DMF (5:1, 60 mL) solution of metal reagent was passed through the packed cartridge (13 mm diameter, 6 mL) with PCR-B2 (300 mg) for 6 hr at rt. The flow rate was 6 mL/min. The resulting scavenged mixture was filtered through a PTFE 0.2 µm filter into a clean vial for palladium and copper testing by ICP analysis. * relative to the solution

Applications in Synthesis. Several methods have been developed to remove residual elements from reaction products for the preparation of the active pharmaceutical ingredients and its intermediates.10 Residual elements are removed efficiently by crystallization in most cases, but the removal effect depends on the structure of the product. Especially, the substrate contained heteroatoms which might act as a metal ligand is awkward to remove metal elements by crystallization. Furthermore, the chelating resin is easily hampered by alkaline earth metal that is usually used for metal-catalyzed reactions and efficient removal of metal is prevented. Therefore, we investigated to apply the poly-chelated resin to removal of elements from the reaction mixture.


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In scheme 1, scavenging of palladium from the reaction solution of the compound 1 was conducted. According to the reported procedure, the Suzuki-Miyaura coupling reaction was carried out and the organic layer was separated after addition of THF to afford the solution.11 The resulting organic layer contained about 306 ppm of palladium (relative to solution, 5000 ppm relative to compound 1) was treated with poly-chelated resin scavenger “PCR-B2” (60 wt% relative to compound 1) via recirculation method at ambient temperature for 10 hr. The solution after treatment was analyzed by ICP and palladium was removed by 95.4% without formation of a new impurity. This result suggested that the chelating resin is not easily hampered by alkaline metal, potassium salt.

Scheme 1. Synthesis of 2-amino-5-phenylpyrazine using Suzuki-Miyaura reaction

In another program, heterocyclic compound 2 was prepared via Negishi C–C bond formation reaction catalyzed by palladium (Scheme 2). The residual content of palladium was not in consistency with each batch. If the residual level is higher than the specification of the compound 2, it is hard to remove the palladium efficiently at the downstream steps. The solution in THF and anisole contained 328 ppm of palladium (relative to solution, 8000 ppm relative to compound 2) was treated with poly-chelated resin scavenger “PCR-B2” (40 wt% relative to


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compound 2) in a recirculation mode and palladium in a solution was reduced by 98.8% down to 4 ppm.

Scheme 2. Synthesis of intermediate using a Negishi reaction

The palladium removal from another type of heterocyclic compound 3 was investigated (Scheme 3). Suzuki-Miyaura coupling reaction of imidazole intermediate was conducted in toluene, EtOH and water with K2CO3 and then the aqueous layer was separated. The organic layer was diluted with EtOH and the reaction stream contained about 500 ppm of the residual palladium (relative to solution, 12600 ppm relative to compound 3). The solution containing palladium was treated with PCR-B2 (60 wt% relative to compound 3) and the palladium contamination was reduced by 93.4%.


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Scheme 3. Synthesis of imidazole intermediate using a Suzuki-Miyaura reaction N

ArB(OH)2

+

R2

X N R1

Het

Pd cat.

N

R2

N R1

Het

Ar

3 Pd content Before treatment: 500 ppm After treatment: 33 ppm (93.4% removed)

Febuxostat (Uloric®, TMX-67) is a class of medications called xanthine oxidase inhibitors and works by decreasing the amount of uric acid that is made in the body.12 Febuxostat has been approved by the U.S. Food and Drug Administration to treat gout, a painful condition characterized by elevated levels of uric acid that can build up in the blood, joints and soft tissue. The penultimate of Febuxostat was prepared via palladium catalyzed C–H coupling reaction (Scheme 4).13 After the reaction, the mixture was treated with a subsequent work-up conditions but the residual copper was not consistent in each batch. Furthermore, downstream steps including extractions, adsorption and crystallization did not promote sufficient copper removal with acceptable level. The reaction mixture contained 310 ppm of palladium and 1845 ppm of copper (relative to compound 4, Pd 29.3 ppm and Cu 70.9 ppm relative to the solution) was treated with PCR-B2 (10 wt% of loading relative to compound 4) for 10 hr in a circulation mode providing an efficient cupper removal by 97.2% without formation of any new impurities and any product loss. On the other hand, palladium was removed by only 30.4% and the removal of palladium was not improved by using more amount of PCR-B2 (20 wt% relative to compound 4), even though contamination of copper was completely removed by >99%. These results suggested that PCR-B2 would be hampered by copper. Once equilibrium is achieved the increase in contact time had no effect on removal efficiency which may be due to saturation of the


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adsorbent bed with copper followed by adsorption-desorption process that might occur after saturation. Using PCR-PA instead of PCR-B2 gave a better result for removal of palladium.

Scheme 4. Synthesis of penultimate of Febuxostat

Appearance. The existence of palladium on the surface of poly-chelated resin was carried out with an energy-dispersive X-ray (EDX) analysis equipped with the SEM (Figure 6). As shown Figure 6, SEM image shows that the particles have been formed on the surface of resin in the entire observed surface, while, for the resin, the clusters are observed (Figure 6, (a) and (b)). The morphology of resin after treatment shows obvious difference except that the agglomerates become more compact. Scanning electron microscopy with energy dispersive X-ray spectroscopy (SEM-EDX) is the best known and most widely used to determine the elemental composition of a sample. The SEM-EDX analysis of resin confirmed the immobilization of palladium onto the surface of resin and palladium is adsorbed at each circled area in yellow (Figure 6, (c)). Higher magnification (x 100,000) of SEM mapping photograph shows that the


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palladium is adsorbed into loosely packed structure with lots of cavities, cracks and pores (Figure 6, (d) and (e) at each circled are in yellow).

Figure 6. FE-SEM image of (a) naked of resin (b) and (c) resin after treatment, EDX image of (d) and (e) resin after treatment

(a)

(b)

(c)

(d)

(e)


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CONCLUTIONS Environmentally friendly and sustainable reactions with catalyst have come to occupy an increasingly important position in the pharmaceutical industry. Accordingly, several methodologies have been developed to find a more concise and cost-effective ways to remove elements of catalyst and precious elements can be retrieved from the adsorbent after treatment. In this manuscript, we describe that poly-chelated resin can be applied for scavenging of elements. This type of poly-chelated resin is an affordable price and has already used for the water industry to remove precious elements in an extremely large quantities. Therefore, we expect to perform in conformity to GMP guideline in the pharmaceutical industry as well and the poly-chelated resin scavenger would be one of options to remove metal elements for particular process.

Experimental Section Palladium concentrations of samples were tested using either the compact iCAP 7400 ICPOES DUO Analyzer (ICP: inductively coupled plasma mass spectroscopy, Thermo Scientific). Samples were either diluted directly in concentrated nitric acid or rotavap-evaporated first and then redissolved in concentrated nitric for ICP-MS analysis. HPLC analysis was carried out using as Agilent 1200 system with diode array UV-visible detection, reverse phase HPLC column, and water/MeCN as mobile phases. Scanning electron microscopy (SEM) images of the samples were acquired on JEOL-JSM7500 (JEOL) scanning electron microscope (x 1,000). Higher magnificent (x 100,000) SEM and EDX mapping of the sample was acquired on S-4800 (Hitachi Technologies) and X-MAX-80 (Horiba).


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ACKNOWLEDGMENT We thank Drs. Kanazawa, Suzuki and Mr. Iwamoto for providing materials for studies, and Mr. Kato (Nippon Filcon Co., Ltd.) for helpful discussions. We also thank Nippon Filcon Co., Ltd. for the generous gift of several poly-chelated resin scavengers.

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Effective Method To Remove Metal Elements from Pharmaceutical

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