Process and product for removing contaminants in liquid compositions - Patents.com

Abstract

A functionalized polymeric sorbent for removing impurities from a feedstream containing an active pharmaceutical ingredient (API), the sorbent comprising particles functionalized with at least one functional group capable of binding one or more contaminants, the polymer comprising Macro It is a reticular polymer. The functionalized polymeric adsorbent also has a thickness of at least 0.65 cm 3 The adsorbent has a pore volume of 10 ... body , 2,4,6-trimercaptotriazine-ethylenedithiol (TMT-EDT) adduct body or a combination thereof, the polymer being Macro They can be composed of either reticular or swellable polymers. The sorbents can be used in continuous or batch processes for removing contaminants from drug substance-containing feed streams, including elemental impurities, particularly palladium.

Description

[Technical Field]

[0001] Priority claims This patent application claims priority under U.S. Provisional Patent Application No. 63 / 223,418, filed July 19, 2021.

[0002] FIELD OF THE INVENTION The present invention relates to functional polymeric absorbents generally used for removing contaminants from liquid compositions and methods of using the same. to More specifically, functionalized polymeric absorbents and methods of use for removing contaminants such as elemental impurities in the processing of active pharmaceutical ingredients (APIs) to Related 。 [Background technology]

[0003] Background of the Invention In March 2019, the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use published the Q3D(R1) guideline for elemental impurities in pharmaceuticals. This guideline specifies the levels of elemental impurities permitted in pharmaceuticals. Elements are divided into three classes based on their permissible daily exposure (PDE). Class 1 lists the metals As, Cd, Hg, and Pb. These are toxic to humans and are present in pharmaceuticals as impurities in chemicals used in the manufacture of pharmaceuticals or drug substances. Class 2 is divided into Class 2A and Class 2B. Class 2A includes Co, V, and Ni, while Class 2B includes Ag, Au, Ir, Os, Pd, Pt, Rh, Ru, Se, and Tl. These elements are commonly present in drug substances because they are used in their manufacture. Class 2A elements are more likely to be present in drug substances than Class 2B elements. Class 3 elements include Ba, Cr, Cu, Li, Mo, Sb, and Sn. Class 3 elements are considered to be less toxic than Class 1 or 2 elements.

[0004] Most Class 2 elements are used as catalysts in the manufacture of drug substances, and the elements must be removed during the drug substance manufacturing process so that their concentrations are below the PDE after drug substance production. The sorbents used in industry to remove elemental impurities are based on silica, polymers, or polymer fibers and contain functional groups that bind to the elements. These functional groups include sulfur- or nitrogen-containing groups such as mercaptans and amines (both alkyl and aryl). The amount of sorbent required to remove a particular impurity can be significant, and the drug substance solution may need to be passed through multiple columns to achieve the desired reduction in elemental impurity concentration.

[0005] It is also often necessary or desirable to remove elemental impurities and other contaminants from liquid compositions outside of the manufacturing process of the active pharmaceutical ingredient (API). Summary of the Invention

[0006] Summary of the Invention To meet this need, in one embodiment, a polymeric polymer functionalized with at least one functional group capable of binding one or more contaminants is provided. Macroreticular polymer particles We are developing an adsorbent containing Particle pore volume is at least 0.65 cm 3 / g.

[0007] In one embodiment, Functionalized Macroreticular Polymers Adsorbent particle The pores must be at least 0.65 cm 3 / g and an average particle size of less than 150 microns.

[0008] In another embodiment, the adsorbent particle The pores have a particle size distribution D90 in the range of about 50 to 150 microns.

[0009] In some embodiments, the adsorbent particle The pores must be at least 0.65 cm 3 / g volume and 300m2 / g.

[0010] In some embodiments, the pores of the adsorbent are at least 0.65 cm 3 / g volume and D50 is 200 Å has a pore size distribution that is less than

[0011] In certain embodiments, the at least one functional group moiety comprises cysteamine, 2,4,6-trimercaptotriazine (TMT), 2,4,6-dimercaptotriazine (DMT), 2,4,6-dimercaptotriazine-ethanedithiol (DMT-EDT) adduct, 2,4,6-trimercaptotriazine-ethanedithiol (TMT-EDT) adduct, thioglycolic acid (TGA), thiourea, 4-mercaptopyridine, 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), ethylenediaminetetraacetic acid (EDTA), thiosulfate (TS), mercaptomethylphosphonic acid (MPA), trimercaptotriazine-methyl-phosphonic acid (TMT-PA), and mixtures of any of the foregoing.

[0012] In some embodiments, the at least one functional group moiety includes cysteamine, 2,4,6-trimercaptotriazine (TMT), 2,4,6-dimercaptotriazine (DMT), 2,4,6-dimercaptotriazine-ethanedithiol (DMT-EDT) adduct, 2,4,6-trimercaptotriazine-ethanedithiol (TMT-EDT) adduct, and mixtures of any of the foregoing.

[0013] In one embodiment, at least one functional group site is a 2,4,6-dimercaptotriazine-ethanedithiol (DMT-EDT) adduct. body , 2,4,6-trimercaptotriazine-ethanedithiol (TMT-EDT) adduct body , and mixtures of any of the foregoing may be used.

[0014] In one embodiment, 2,4,6-dimercaptotriazine-ethanedithiol (DMT-EDT) adduct body , 2,4,6-trimercaptotriazine-ethanedithiol (TMT-EDT) adduct body , and mixtures of any of the foregoing Selected At least one functional group The polymer particles are functionalized with In one embodiment, the polymer is a swellable polymer. 、 Polymers are Macro In another embodiment, the polymer is a reticular polymer. Macroreticular Polymer-based, 2,4,6-dimercaptotriazine-ethanedithiol (DMT-EDT) adduct body , 2,4,6-trimercaptotriazine-ethanedithiol (TMT-EDT) adduct body and mixtures of any of the foregoing, the pores of the adsorbent having at least one functional group moiety selected from the group consisting of at least 0.65 cm 3 In some embodiments, the pores have a volume of at least 0.65 cm 3 / g and an average particle size in the range of about 50 to 300 microns, or in the range of 125 to 250 microns, or in the range of less than 150 microns.

[0015] Also described herein is a polymer functionalized with an alkene group. transformation The following synthesis method is disclosed: Steps Includes. a.) reacting the polymer with a first reactant comprising a thiol group and a linking group, whereby the thiol group of the first reactant reacts with an alkene group of the polymer to form a first intermediate having a thioether bond between the polymer and the linking group; Steps . b.) The aforementioned 1st The intermediate is reacted with an aryl or heteroaryl group a second reactant comprisingwherein the aryl group or heteroaryl group is substituted or unsubstituted, and the substituted or unsubstituted aryl group or heteroaryl group is directly or indirectly bound to a linking group. Second intermediate Form Steps . c.) The aforementioned Second intermediate of Third reactant to convert the attached substituted or unsubstituted aryl or heteroaryl groups into functional group sites, thereby functionalizing the polymer at the functional group sites. transformation Steps to do this.

[0016] In some embodiments, functional groups in the manufacturing process are capable of binding one or more contaminants.

[0017] In certain embodiments, the functional group moiety in the manufacturing process comprises at least one thiol group, at least one thio group, or a combination thereof.

[0018] In another embodiment, the second reaction thing is a heteroaryl group Contains .

[0019] In another embodiment, the second reaction thing contains a heteroaryl group that is a substituted triazine group.

[0020] Also disclosed herein is a process for reducing the concentration of at least one contaminant in a liquid composition, the process comprising contacting the liquid composition with an adsorbent under purification conditions to adsorb at least a portion of the at least one contaminant, wherein the adsorbent comprises pores of a functionalized polymer having at least one functional site capable of binding one or more contaminants. Macro Reticular polymer, at least 0.65 cm 3 / g pore volume.

[0021] Also disclosed herein is a process for reducing the concentration of at least one contaminant in a liquid composition, the process comprising contacting the liquid composition with an adsorbent under purification conditions to adsorb at least a portion of the at least one contaminant, wherein the adsorbent is a 2,4,6-dimercaptotriazine-ethanedithiol (DMT-EDT) adduct. body , 2,4,6-trimercaptotriazine-ethanedithiol (TMT-EDT) adduct body and mixtures of any of the foregoing. transformation In one embodiment of this process, the polymer is a swellable polymer. In one embodiment, the polymer is Macro In another embodiment, the polymer is a reticular polymer. Macro The functionalized polymer adsorbent is a reticular polymer with a surface area of ​​at least 0.65 cm 3 In another embodiment, the pores of the adsorbent are formed of 2,4,6-dimercaptotriazine-ethanedithiol (DMT-EDT) adduct. body , 2,4,6-trimercaptotriazine-ethanedithiol (TMT-EDT) adduct body and wherein the mixture has an average particle size in the range of about 100-300 microns, or in the range of 125-250 microns. In one embodiment of the process, the adsorbent particles are 2,4,6-dimercaptotriazine-ethanedithiol (DMT-EDT) adducts. body , 2,4,6-trimercaptotriazine-ethanedithiol (TMT-EDT) adduct body and has an average particle size of less than 150 microns.

[0022] The process of reducing the concentration of contaminants is accomplished in various embodiments using any of the adsorbents disclosed herein.

[0023] As described herein, contacting the liquid composition with the adsorbent can be either a batch process or a continuous process.

[0024] In certain embodiments, the liquid composition comprises a drug substance or a precursor thereof.

[0025] In some embodiments, the liquid composition is a composition in the manufacturing process of a drug substance.

[0026] In certain embodiments, the liquid composition is a composition in a manufacturing process for a drug substance, and the composition further comprises a drug substance or a precursor thereof.

[0027] In one embodiment, the at least one contaminant is an elemental impurity selected from at least one element of Class 1, Class 2A, Class 2B, and Class 3 of the ICH Q3D(R1) guideline.

[0028] In one embodiment, the sorbent binds a quantity of the elemental impurity in the liquid composition, providing a liquid composition with a concentration calculated to ensure that the concentration of the elemental impurity in the recovered drug substance is at or below the Permitted Daily Exposure (PDE).

[0029] Other embodiments and configurations will be better understood with reference to the following detailed description. [Brief explanation of the drawings]

[0030] Brief description of the diagram [Figure 1] 1 shows isothermal data for the two adsorbents of Example 1 after desired pore sizing, compared to two commercially available adsorbents. [Figure 2]Figure 2A shows the incremental pore size distributions of the three adsorbents of Example 1 compared to two commercially available adsorbents, measured as incremental pore volume as a function of pore width, before pore size sizing. Figure 2B shows the incremental pore size distributions of the three adsorbents of Example 1 compared to the as-prepared polymer, measured as incremental pore volume as a function of pore width, before pore size sizing. Figure 2C shows the cumulative pore size distributions of the three adsorbents of Example 1 compared to two commercially available adsorbents, measured as cumulative pore volume as a function of pore width, before pore size sizing. Figure 2D shows the cumulative pore size distributions of the three adsorbents of Example 1 compared to the as-prepared polymer, measured as cumulative pore volume as a function of pore width. [Figure 3] 1 is a graph showing the Pd affinity of the adsorbent of Example 1 after sizing to a desired particle size compared to two commercially available adsorbents. [Figure 4] 1 is a graph showing the Pd affinity of the adsorbent of Example 1 after sizing to the desired particle size using 80 mg of adsorbent and 20 mg of adsorbent. [Figure 5] 1 is a graph showing the Pd capacity of the adsorbent of Example 1 compared to two commercially available adsorbents after sizing to a desired particle size. [Figure 6] 1 is a graph showing the adsorption rate of the adsorbent of Example 1 after sizing to a desired particle size compared to a commercially available silicon-based adsorbent. [Figure 7] 1 is a graph showing the Pd affinity of the adsorbent of Example 1 after sizing to a desired particle size in a polar solvent compared to two commercially available adsorbents. [Figure 8] 1 is a graph showing the Pd affinity of the adsorbent of Example 1 after sizing to the desired particle size compared to two commercially available adsorbents in the presence of the active pharmaceutical ingredient ibuprofen. [Figure 9] 1 is a graph showing the Pd affinity of the adsorbent of Example 1 after sizing to the desired particle size compared to two commercially available adsorbents in the presence of the active pharmaceutical ingredient quinine. [Figure 10]1 is a graph showing the Cu affinity of the adsorbent of Example 1 after sizing to a desired particle size compared to two commercially available adsorbents. [Figure 11] 1 is a graph showing the Pd capacity of the adsorbents of Examples 1D, 1E, and 9B after sizing to the desired particle size compared to a commercially available adsorbent. [Figure 12] 1 is a graph showing the particle size distribution of the adsorbent product of Example 11. DETAILED DESCRIPTION OF THE INVENTION

[0031] Details of the invention Disclosed herein are functionalized polymeric adsorbents and processes for using the adsorbents to remove contaminants from liquid compositions. The adsorbents and processes are particularly useful when the liquid composition is a solution or stream containing an active pharmaceutical ingredient (API) and the contaminant is an elemental impurity, although the adsorbents and processes are not limited to such solutions or streams or to such elemental impurities. Also disclosed are methods for producing the adsorbents.

[0032] As used herein, the terms "removal" and "removing" mean that the concentration of a contaminant in a composition is reduced compared to the initial concentration in the composition, but do not necessarily mean that the concentration of the contaminant is reduced to 0%.

[0033] The term C1-C6 alkyl, as used herein, means a saturated alkyl group having from 1 to 6 carbon atoms, which group may be straight, branched, or cyclic.

[0034] Terms such as "pore size," "pore diameter," and "pore width" are used interchangeably herein. Average pore size is determined by the formula 4V / A, where V is the measured pore volume and A is the measured BET gravimetric surface area, where V and A are both measured by nitrogen isotherms. The nitrogen isotherms reported herein were measured at 77 K using a Micromeritics Tristar 3020 porosimeter.

[0035] As used herein, the term "pore size distribution DX of Y" means that X% of the pores in the sample are smaller than Y. For example, "pore size distribution D50=90 Å " indicates that 50% of the pores in the sample are 90 Å It means that the pore size is less than

[0036] The term "particle size distribution D90 of [number]" means that X% of the particles fall into that range. For example, "particle size distribution D90 of 50 to 150 microns" means that 90% of the particles in a sample have a size between 50 and 150 microns.

[0037] Adsorbent The sorbents disclosed herein are based on particles of polymers functionalized via a linker group with at least one functional moiety capable of binding one or more contaminants, wherein the polymer is Macro Reticular polymer, at least 0.65 cm 3 / g pore volume. In one embodiment, the adsorbent particles have an average particle size of less than 150 microns. In another embodiment, the adsorbent particles have a particle size distribution D90 in the range of about 50 to 150 microns.

[0038] As used herein Macroreticular The polymers are generally crosslinked and are tough, rigid, sponge-like materials with large, discrete pores that are not soluble in water or organic solvents. Macroreticular The polymer has olefinic groups that can be attached to or contained within the polymer backbone. Macroreticular There are also polymers. Macroreticular One class of polymers is based on copolymers of ethylvinylbenzene and divinylbenzene. Macroreticular The polymer is Amberlite manufactured by DuPont. (registered trademark) Suitable polymers for the adsorbents disclosed herein include Amberlite (registered trademark) XAD4 and Amberlite (registered trademark) XAD16 is one example, but Amberlite (registered trademark) In some embodiments, the polymer used prior to functionalization may be a Macro The reticular polymers exhibited a 10-300 .ANG. kinetic energy distribution as measured by nitrogen uptake isotherms coupled with DFT transformations. Å and has an average pore diameter in the range of 100 to 250 Å It has a peak in the range of

[0039] Nitrogen isotherms can be used to measure the Brunauer-Emmett-Teller (BET) surface area and pore volume of the starting polymer or the polymer functionalized to form the adsorbent. Macroreticular The polymer particles are 300m 2 In some embodiments, the functionalized Macroreticular The polymer particles are 350m 2 / g or greater than 400m 2 / g or greater than 450m 2 / g, the BET surface area depends on the degree of functionalization, the size of the linker group, and the size of the functional moiety.

[0040] After functionalization to form the adsorbent Macroreticular The polymer particles have a diameter of 0.65 cm as measured by nitrogen isotherm. 3 / g or greater than 0.7cm 3 / g or greater than 0.8cm 3 / g or greater than 0.9cm 3 / g or greater than 1.0 cm 3 / g or more.

[0041] After functionalization Macroreticular The polymer particles are 20 to 200 Å , or 50 to 150 Å , or 60-100 ÅIn one embodiment, the functionalized porous particles have an average pore size in the range of D50 of 200 Å Less than or equal to 150 Å Less than or equal to 125 Å In another embodiment, the D50 pore size is between 60 and 140. Å , or 70 to 130 Å , or 80-120 Å , or 90-110 Å In another embodiment, the functionalized porous particles have a D90 in the range of 400 Å Less than or equal to 350 Å Less than or equal to 325 Å Less than or 300 Å In one embodiment, the D90 pore size distribution is less than 100 to 500 Å , or 125 to 400 Å , or 150-300 Å , or 150-250 Å In one embodiment, the functionalized porous particles have a D10 in the range of 100 Å Less than or equal to 80 Å Less than or equal to 60 Å Less than or equal to 40 Å In another embodiment, the D10 pore size distribution is less than 10 to 50 Å , or 15 to 40 Å , or 15 to 30 Å The range is.

[0042] The functionalization disclosed herein MacroThe average particle size of the reticular polymer is less than 150 microns, or less than 100 microns, or less than 50 microns. In some embodiments, the average particle size is in the range of 50-150 microns. In other embodiments, the average particle size is in the range of 50-100 microns. In some embodiments, the average particle size is in the range of 100-150 microns. In other embodiments, the average particle size is less than 50 microns. This particle size reduction can be achieved by directly functionalizing particles of the desired size or by techniques such as crushing larger particles. Following particle size reduction, the polymer product can be sieved to obtain particles within the desired size range. The particle size reduction step can be performed before or after functionalizing the polymer with functional moieties, although it is preferable to perform the particle size reduction, if desired, before the functionalization step.

[0043] In some embodiments, functionalization Macro The reticular polymer adsorbent particles have a particle size distribution D90 in the range of about 50 to 150 microns. Reticular The polymer has a particle size distribution D90 in the range of about 70 to 130 microns. Macro The reticular polymer has a particle size distribution D90 in the range of about 80 to 120 microns. Reticular The polymer has a particle size distribution D90 in the range of about 85-100 microns. Reticular The polymer has a particle size distribution D50 in the range of about 20 to 70 microns. Macro The reticular polymer has a particle size distribution D50 in the range of about 30-60 microns. MacroThe reticular polymer has a particle size distribution, D50, in the range of about 40-50 microns. To limit excess fines in the adsorbent product, which can cause pressure drop buildup and filter clogging, in some embodiments the ratio of D50 / D10 is less than 150, in some embodiments the ratio of D50 / D10 is less than 120, and in some embodiments the ratio of D50 / D10 is less than 100. To limit the number of large particles in the adsorbent product, which can reduce adsorption efficiency, in some embodiments the ratio of D90 / D50 is less than 10, in some embodiments the ratio of D90 / D50 is less than 7, and in some embodiments the ratio of D90 / D50 is less than 5.

[0044] In another embodiment, the functionalized Macro The average particle size of the reticular polymer can be in the range of about 50 to 300 microns, or in the range of 125 to 250 microns.

[0045] The adsorbent polymer particles are functionalized with at least one functional group capable of binding one or more contaminants. basisIn some embodiments, at least one functional group is linked to the polymer by a thioether bond, where the at least one functional group comprises one or more thiol groups, one or more thio groups, a combination of thiol and amino groups, or a combination of thio and amino groups. Suitable functional groups include, but are not limited to, cysteamine, dimercaptotriazine, trimercaptotriazine, 2,4,6-dimercaptotriazine-ethylenedithiol (DMT-EDT) adduct, 2,4,6-trimercaptotriazine-ethylenedithiol (TMT-EDT) adduct, thioglycolic acid (TGA), thiourea, 4-mercaptopyridine, 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), ethylenediaminetetraacetic acid (EDTA), thiosulfuric acid (TS), mercaptomethylphosphonic acid (MPA), trimercaptotriazine-methylphosphonic acid (TMT-PA), and mixtures of any of the foregoing. These functional groups are preferred when the elemental impurity is a metal impurity, particularly palladium. In certain embodiments, the functional group is cysteamine, dimercaptotriazine, trimercaptotriazine, 2,4,6-dimercaptotriazine-ethylenedithiol (DMT-EDT) adduct. body , 2,4,6-trimercaptotriazine-ethylenedithiol (TMT-EDT) adduct body In another embodiment, the functional group is a 2,4,6-dimercaptotriazine-ethylenedithiol (DMT-EDT) adduct. body , 2,4,6-trimercaptotriazine-ethylenedithiol (TMT-EDT) adduct body and mixtures of any of the foregoing.

[0046] In one embodiment, the present applicants have developed a 2,4,6-dimercaptotriazine-ethanedithiol (DMT-EDT) adduct. body , 2,4,6-trimercaptotriazine-ethanedithiol (TMT-EDT) adduct bodyand a mixture of any of the foregoing, wherein the polymer is Macro In one embodiment, the polymer is a 2,4,6-dimercaptotriazine-ethanedithiol (DMT-EDT) adduct. body , 2,4,6-trimercaptotriazine-ethanedithiol (TMT-EDT) adduct body The adsorbent particles having at least one functional group selected from the group consisting of 2,4,6-dimercaptotriazine-ethanedithiol (DMT-EDT) adducts have an average particle size ranging from about 100 to 300 microns, or from 125 to 250 microns. body , 2,4,6-trimercaptotriazine-ethanedithiol (TMT-EDT) adduct body and mixtures of any of the foregoing, the adsorbent particles having at least one functional group selected from the group consisting of: a) a hydroxybenzoate; b) a hydroxybenzoate; c) a hydroxybenzoate; d) a hydroxybenzoate;

[0047] Surprisingly, the polymeric adsorbents disclosed herein have been found to have significantly improved properties compared to both commercially available polymeric adsorbents and commercially available silica-based adsorbents. In particular, the reaction rate of the disclosed adsorbents with impurities is up to an order of magnitude faster than that of the commercially available adsorbents, the affinity of the disclosed adsorbents for the impurities to be removed is superior to that of the commercially available adsorbents, and the capacity of the adsorbents for the impurities to be removed is significantly superior to that of the commercially available adsorbents.

[0048] Adsorbent synthesis (manufacturing) This specification discloses methods for making functionalized polymeric adsorbents. The adsorbents disclosed herein and methods for using the adsorbents to reduce the concentration of contaminants in liquid compositions are not necessarily limited to adsorbents made by the methods disclosed below.

[0049] The method for synthesizing the adsorbent disclosed herein comprises the following steps. a.)A polymer containing an alkene group is reacted with a first reactant containing a thiol group and a linking group, whereby the thiol group of the first reactant reacts with the alkene group of the polymer in a thiol-ene reaction to form a first intermediate having a thioether bond between the polymer and the linking group. b.) The aforementioned 1st The intermediate may be a compound containing an aryl or heteroaryl group. Second The aryl or heteroaryl group is substituted or unsubstituted, and the aryl or heteroaryl group is directly or indirectly bonded to a linking group. Second An intermediate is formed. c.) The second intermediate is reacted with a third reactant to functionalize the attached substituted or unsubstituted aryl or heteroaryl group. basis thereby functionalizing the polymer. The aforementioned The functional groups allow for binding of one or more contaminants.

[0050] First reactant reacting with a polymer, optionally in the presence of an initiator, First reactant promotes a thiol-ene reaction between the thiol groups of the polymer and the alkene groups of the polymer; 1st In one embodiment, an intermediate is formed. 1st reaction thing can be a thiol compound of the formula HS-C1-C6 alkyl-R, where the moiety R is a saturated or unsaturated alkyl 、 The functional group R further comprises an alkyl or aryl bridge between the thiol group and the linking group. In certain embodiments, the linking group is -NH and the functional group R is -C-C alkyl. In certain embodiments, the linking group is -NH and the functional group R is -C-C alkyl. In certain embodiments, the functional group R is -NH and the linking group is -C-C alkyl. 1st reaction thingis HSC2H4NH2. In another embodiment, the first reaction thing is a thiol compound of formula HS-Ar-R, where Ar is an optionally substituted aryl or heteroaryl group which may be monocyclic, bicyclic, or polycyclic, and R is defined as above.

[0051] Second reaction thing is a substituted or unsubstituted aryl or heteroaryl group Includes , reacting with the linking group of the first intermediate to form a second intermediate. The aryl or heteroaryl group can be monocyclic, bicyclic, or polycyclic. Optionally, the substituent can include a halide, preferably chloride. In some embodiments, the second reaction thing is a heteroaryl group Contains In one embodiment, the heteroaryl group is a triazine. In another embodiment, the second reaction thing is chloride Cyanuric chloride is.

[0052] Third Reaction thing reacts with the second intermediate to form a functional group basis Forming a sense of basis Preferably, the third reaction thing can contain one or more thiol groups. thing is a sulfide salt or an alkyl thiol or alkyl polythiol Possible In one embodiment, the third reaction thing can be NaSH. In some embodiments, the third reaction thing can be selected from HS-C1-C6 alkyl-SH, with HS-C2H4-SH being preferred.

[0053] An example of a method for synthesizing the adsorbent disclosed herein is shown in Method 1 below. [ka] Method 1 where AIBN is the initiator azobisisobutyronitrile and DIPEA is the base N,N-diisopropylethylamine. The starting material (I) is a polymer having alkene groups exemplified as pendant olefin groups. Macro Reticular polystyrene and ethylvinylbenzene and divinylbenzene Macro The starting material (I) is reacted with a thioalkylamine or a reticular copolymer. the First reaction with a salt, such as cysteamine or cysteamine chloride thing and optionally in the presence of an initiator such as AIBN to produce a first intermediate thioalkylamine-functionalized polymer (II) having pendant amino groups. The thioalkylamine-functionalized polymer (II) itself functions as a suitable adsorbent for certain impurities. Therefore, the reaction can be considered complete after the first functionalization step. If other functional groups are desired, the reaction can be continued to the next step. If further functionalization is desired, the thioalkylamine-functionalized polymer (II) can be added to the first intermediate thioalkylamine-functionalized polymer (II). transformation Polymer (II) is reacted with a second reactant, such as a halogenated triazine, such as cyanuric chloride, to form a second intermediate, which is polymer (III) having pendant halogenated triazine groups. Polymer (III) is reacted with a third reactant, which is a sulfide salt. thing to form a polymer (IV) functionalized with thioalkylaminodimercaptotriazine groups, or thing with a dithioalkyl such as ethanedithiol to form the thioalkylaminodimercaptotriazine-ethylenedithiol adduct body It is also possible to form a functionalized polymer (V) with

[0054] The process of reducing pollutant concentrations A process for reducing the concentration of at least one contaminant in a liquid composition includes contacting the liquid composition with an adsorbent under purification conditions as disclosed herein to adsorb at least a portion of the at least one contaminant. In some embodiments, the liquid composition is a composition in a manufacturing process for an active pharmaceutical ingredient. In some embodiments, the composition includes an active pharmaceutical ingredient or a precursor thereof, which may be interchangeably referred to as an active pharmaceutical ingredient (API).

[0055] In June 2013, the International Council for Harmonization for Pharmaceuticals for Human Use (ICH) established guidelines for the levels of elemental impurities in pharmaceuticals. The latest guideline, Q3D(R1), was adopted in March 2019. Elemental impurities are present in pharmaceuticals as residual amounts of impurities or catalytic metals. Because these impurities do not provide any therapeutic benefit to patients, they must be controlled within narrow limits. The ICH established a permissible daily exposure (PDE) for each elemental impurity based on toxicity data. The PDE for each elemental impurity was calculated based on the route of administration (oral, parenteral, or inhalation) and the daily drug intake. The ICH further classified elemental impurities into several classes. Class 1 consists of As, Cd, Hg, and Pb, which are toxic to humans and are rarely used in pharmaceutical manufacturing. Class 2 is further divided into Class 2A and Class 2B. Class 2 elements are substances whose toxicity to the human body is route-dependent (administration method). Class 2A elements are more likely to be present in pharmaceuticals. Class 2A elements are Co, Ni, and V, while Class 2B elements are Ag, Au, Ir, Os, Pd, Pt, Rh, Ru, Se, and Tl, which are unlikely to be present. Class 3 elements are Ba, Cr, Cu, Li, Mo, Sb, and Sn, which have low oral toxicity. The PDEs for various elemental impurities and routes of administration are shown in Table A.2.1 of the guideline and are reproduced below.

[0056] Table A.2.1: Permissible Daily Exposures for Elemental Impurities 1 [Table 1] 1 Table A.2.1 is reproduced with permission from the ICH guideline Q3D(R1) https: / / www.ema.europa.eu / en / documents / scientific-guideline / international-conference-harmonisation-technical-requirements-registration-pharmaceuticals-human-use_en-32.pdf.

[0057] The feed stream or feed solution (the terms are used interchangeably) contains the drug substance and one or more contaminants, such as the elemental impurities listed above. The feed stream or feed solution may be in an organic or aqueous solvent. Contains any of the following: The solvent may be the solvent used in the synthesis of the drug substance, or if the synthesis of the drug substance requires multiple steps, the solvent may be the solvent used in the final reaction step, or the solvent used in the purification of the drug substance. Examples of solvents include water, methanol, ethanol, isopropanol, butanol, t-butyl alcohol, acetone, dimethyl sulfoxide, dimethylformamide, ethyl acetate, isopropyl acetate, methyl tert-butyl ether, diethyl ether, dichloromethane, chloroform, benzene, toluene, xylene, hexane, dichlorobenzene, acetonitrile, N-methyl-2-pyrrolidone, 4-dimethylaminopyridine, hexamethylphosphoramide, tetrahydrofuran, ethylene glycol, and mixtures thereof.

[0058] The feed stream also contains contaminants, including but not limited to additives, by-products, unreacted starting materials, and catalyst decomposition products. The process described below can be used to remove elemental impurities and / or other contaminants, but it should be understood that while the process is described using elemental impurities, it is not limited to removing only elemental impurities.

[0059] FunctionalizedThe polymeric sorbent is contacted with the feed stream under purification conditions such that the sorbent adsorbs and removes unwanted elemental impurities from the feed stream to provide a purified active pharmaceutical ingredient (API) stream. ) The feed stream can be contacted in a batch system by combining the feed stream with the adsorbent in a suitable vessel to provide a purified active pharmaceutical ingredient (API) stream. The purification step can be carried out at temperatures ranging from about -50°C to about 120°C, or from about -20°C to about 100°C, or from about 0°C to about 80°C, or from about 10°C to about 70°C, or from about 20°C to about 60°C. Advantageously, the functionalized polymers of the present disclosure function well at room temperature and do not require special temperature control. Other temperatures may be used depending on the manufacturing process of the active pharmaceutical ingredient.

[0060] Other purification conditions include the time required to achieve the desired removal of elemental impurities. Advantages of the functionalized polymers disclosed herein include improved reaction rates and shorter contact times than prior art adsorbents. Contact times vary considerably and depend on the contact temperature, pH, and pressure of the feed stream. Generally, contact times range from a few seconds to several days, more specifically from about 5 seconds to about 3 days, or from about 1 minute to about 1 day, or from about 10 minutes to about 18 hours, or from about 20 minutes to about 12 hours, or from about 40 minutes to about 8 hours, or from about 1 hour to about 6 hours. Optionally, to shorten the time required to achieve the desired final concentration of metal impurities, the mixture can be agitated or stirred to increase contact between the adsorbent and the feed stream. Agitation can be achieved using a vibrating table, orbital shaker, or other suitable device. This can be achieved using a mechanical stirrer. The agitation rate is adjusted to about 0.2 revolutions per minute to about 15 revolutions per minute, or from about 0.5 revolutions per minute to about 10 revolutions per minute, or from about 1 revolution per minute to about 8 revolutions per minute. If, after a predetermined time, the concentration plateaus but it is determined that the elemental impurity concentration still exceeds the required limit, the drug substance stream can be separated from the adsorbent and contacted with a fresh amount of adsorbent. The w / w% (weight percent concentration), i.e., weight of adsorbent / weight of fluid, between the two purification steps need not be the same. That is, the amount of adsorbent used in the first step can be greater or less than the amount used in the second step. For example, the w / w% in the first step can be about 0.1 w / w% to about 70 w / w%, or about 0.5 w / w% to about 60 w / w%, or about 1 w / w% to about 50 w / w%, or about 2 w / w% to about 40 w / w%, or about 5 w / w% to about 30 w / w%, or about 1 w / w% to about 30 w / w%, or about 0.5 w / w% to about 60 w / w%, or about 1 w / w% to about 50 w / w%, or about 2 w / w% to about 40 w / w%, or about 5 w / w% to about 30 w / w%. In the second step, the w / w% can vary from about 0.1 w / w% to about 70 w / w%, or from about 0.5 w / w% to about 60 w / w%, or from about 1 w / w% to about 50 w / w%, or from about 2 w / w% to about 40 w / w%, or from about 5 w / w% to about 30 w / w%.

[0061] Another parameter that can be adjusted is the pH of the feed stream. pH can affect the affinity of functional moieties for the particular elemental impurity being removed. The optimum pH or range may be different for each functional site, and this optimum pH or range can be determined experimentally.

[0062] The adsorbents used in the batch process described above can be a mixture of two or more adsorbents to optimize the removal of multiple elemental impurities. At least one of the adsorbents is a functionalized polymer as disclosed herein, and at least one of the other adsorbents is another adsorbent, such as another functionalized polymer as disclosed herein, activated carbon, a silica-based adsorbent, or a metal-organic framework (MOF)-based adsorbent. It is possible to experimentally determine which adsorbent better adsorbs a given elemental impurity, thereby obtaining an optimal adsorbent mixture for purifying any active pharmaceutical ingredient (API) feed stream based on the composition of elemental impurities in the feed stream. Two or more adsorbents can also be mixed. Instead of using a mixture of adsorbents in a single vessel, a process is also possible in which the active pharmaceutical ingredient (API) feed stream is mixed with a first adsorbent in a single vessel, the adsorbent is separated from the partially purified stream (using known means), and the partially purified stream is mixed with the second adsorbent in a second vessel under similar or different purification conditions to provide a purified active pharmaceutical ingredient (API) stream.

[0063] The amounts of the two sorbents can be the same or different. The relative amount of each sorbent can be varied based on the affinity of the sorbent for a particular elemental impurity or the total capacity of the sorbent for the elemental impurity. The purification conditions used for each sorbent (if used in different vessels) can also be adjusted to optimize elemental impurity removal. The maximum concentration of elemental impurity to be achieved in the purified drug substance stream depends on the PDE of the elemental impurity, the elemental impurity concentration in the drug substance feed stream, and the final concentration of the elemental impurity in the drug substance (Table A.2.1).

[0064] In another embodiment, the methods presented herein are carried out as a continuous process. In this case, the adsorbent is placed in a bed through which a feed stream containing the active pharmaceutical ingredient and one or more contaminants flows. In some embodiments, the bed is in the form of a rigid structure such as a column. The column can have any type of shape, such as square, rectangular, or circular. A circular column is the most common type of column. The feed stream is introduced through one or more inlet ports, and the feed stream flows downward or upward through the column. In other embodiments, two or more inlet ports are provided to ensure uniform radial distribution of the feed stream across the column. One or more inlet ports are spaced around the circumference of the column. For downflow feed streams, a shower-type configuration is used, located at the top or cap of the column, to allow a shower of feed stream to contact the adsorbent with the most uniform radial distribution across the column.

[0065] The intake port can have any shape known in the art, such as an opening that covers the diameter and shape of the outlet, which determines the area and flow pattern. API Stream The mixture is removed through an outlet and sent to another vessel or reactor to separate the active pharmaceutical ingredient (API).

[0066] Columns are sized according to the volume of feed stream to be purified. The height-to-diameter ratio of a column can vary considerably. Factors to consider include the amount of backpressure generated, the flow rate of the feed stream, i.e., contact time, the amount of drug to be purified, the level of purification required, and the effectiveness of the column media. For example, a high height:diameter ratio can result in high backpressure and increase the time required to pass the feed stream through the column. A low height:diameter ratio reduces backpressure but decreases contact time and may result in less uniform radial flow distribution. Computational fluid dynamics (CFD) can be used to model various configurations and identify optimal configurations.

[0067] To ensure that the elemental impurity concentration of the purified stream meets the ICH guidelines for that particular elemental impurity, the flow rate must be controlled to ensure sufficient contact time between the feed stream and the adsorbent. This is because the contact time depends on the flow rate of the feed stream and the reactor size, i.e., the cross-sectional area of ​​the reactor. The linear velocity is an excellent parameter to use because it takes into account the size of the reactor. The linear velocity is in the range of about 0.02 to about 300 cm / min, or about 0.05 to about 200 cm / min, or about 0.1 to about 100 cm / min, or about 0.2 to about 50 cm / min.

[0068] The column can be operated over a wide temperature range. The lower end of the range depends on the temperature at which the active pharmaceutical ingredient (API) begins to precipitate out of solution. Temperatures vary from about -50°C to about 120°C, or from about -20°C to about 100°C, or from about 0°C to about 80°C, or from about 10°C to about 70°C, or from about 20°C to about 60°C. The column can be operated at atmospheric pressure, but can also be operated over a wide range of pressures, from subatmospheric to superatmospheric. Generally, the pressure range can be from about 0.01 kPa to about 1000 kPa, or from about 5 kPa to about 500 kPa, or from about 10 kPa to about 200 kPa, or from about 20 kPa to about 100 kPa.

[0069] Although a column can use only one adsorbent material, it may be advantageous to use two or more adsorbents if the feed stream contains one or more elemental impurities. Here, at least one of the adsorbents can be a functionalized polymer as disclosed herein, and at least one of the other adsorbents can be another functionalized polymer as disclosed herein, or another adsorbent, such as activated carbon, silica-based adsorbents, or MOF-based adsorbents. In this case, a mixture of different adsorbents can be used to pack the column. Alternatively, two or more adsorbents can be layered in alternating layers. The layers do not need to be of equal size; they can be sized according to the affinity of the adsorbent for a particular elemental impurity, the adsorption capacity of the adsorbent(s) for the elemental impurity, or the concentration of the elemental impurity in the feed stream. The order of the adsorbents within the column is also determined by the affinity and adsorption capacity of each adsorbent for various elemental impurities. Multiple columns can also be used, and the adsorbents in each column can be the same or different.

[0070] If the stream exiting a purification column has a concentration of one or more elemental impurities above the PDE, the outlet stream can be passed through the same column a second or multiple times. This can be accomplished by removing the outlet stream from the outlet port through a loop adjacent to the outlet port and passing the stream through a loop on a column or reactor adjacent to the inlet port to the inlet port. Alternatively, the outlet stream can be passed through a second column containing fresh adsorbent. The second column can contain the same adsorbent as the first column, or a different adsorbent, or a different axial arrangement of the adsorbent. In some embodiments, the feed stream has been passed through the purification column once, and the outlet stream is a purified stream that meets ICH guidelines for elemental impurities.

[0071] In the foregoing embodiments of the method, whether in batch or continuous mode, when more than one adsorbent is used, at least one of the adsorbents is a functionalized adsorbent having an average particle size of less than 150 microns as described herein. Macro and one or more additional adsorbents are other functionalized polymers with an average particle size of less than 150 microns. Macro It may be a reticular polymer or such adsorbent of different particle size or other types of adsorbent such as activated carbon, silica-based adsorbents or MOF-based adsorbents.

[0072] The use of the adsorbents and methods disclosed herein has been shown to provide improved performance in the areas of adsorbent affinity for the impurities to be removed, reaction kinetics, and adsorbent capacity. In certain embodiments, the process reduces the concentration of elemental impurities to less than 5 ppm in an active pharmaceutical ingredient (API) product stream. In certain embodiments, the process reduces the concentration of elemental impurities to less than 2 ppm in an active pharmaceutical ingredient (API) product stream. In certain embodiments, the process reduces the concentration of elemental impurities to less than 1 ppm in an active pharmaceutical ingredient (API) product stream.

[0073] In the examples below, the following abbreviations are used: CA - Cysteamine DCT-Dichlorotriazine DIPEA-N,N-diisopropylethylamine DMF - Dimethylformamide DMT - Dimercaptotriazine EDT - Ethanedithiol MeOH - methanol THF - tetrahydrofuran

[0074] Example

[0075] Example 1 Macro Preparation of reticular polymer adsorbents Amberlite® XAD4-based adsorbents

[0076] A. Polymer particle size reduction. Amberlite (registered trademark) XAD4 (obtained from Sigma-Aldrich) Macro The reticular polymer (300 g) was dried overnight in an oven at 100 °C to remove water. This dried polymer (136 g) was then run in batches through a coffee blade grinder until all of the polymer passed through a 250 μm sieve. The sieved polymer was then moistened with MeOH and rinsed with 2 L of water. The polymer was then passed through 125 μm and 53 μm sieves under a stream of water to refine the particle size. Once the water flowing through the sieves was clear, the 125-53 μm fraction was dried overnight in an oven at 100 °C. The final yield was 31 g of 125-53 μm polymer.

[0077] B. Cysteamine functionalization and full-size polymer particles. 1 L Pyrex (registered trademark) In a jar, cysteamine hydrochloride (51.1 g, 450 mmol), PEG-400 (6.6 ml), and AIBN initiator (1.27 g, 1.7 wt% of polymer) were dissolved in DMF (470 ml). Amberlite was received from a supplier. (registered trademark)XAD4 (75 g) was added. The reaction was heated in an oven at 80 °C overnight. The resulting CA-functionalized polymer product was washed with approximately 400 ml of DMF 2x, MeOH 1x, 1 M NaOH (4 h), water 3x, MeOH 2x, and MeOH (overnight soak) before being dried by rotary evaporation to give 84 g of product. Elemental analysis of the product showed N=1.46 mmol / g and S=1.00 mmol / g.

[0078] C. Dichlorotriazine functionalized, full-size polymer particles. 250 mL Pyrex (registered trademark) In a jar, cyanuric chloride (22.1 g, 120 mmol) was dissolved in THF (120 ml). The solution was cooled to 5°C in an ice bath, and DIPEA (20.9 ml, 120 mmol) was added. 40 g of the CA-functionalized polymer from Example 1B was added in 5 g increments, with approximately 10 minutes between each addition. The reaction was strongly exothermic, but the temperature remained below 12°C. A ninhydrin test showed that the polymer product was pale blue, and the ninhydrin solution was clear. After approximately 4 hours, the resulting DCT-functionalized polymer product was washed twice with acetone, soaked in acetone overnight, and dried by rotary evaporation to yield 46 g of product. Elemental analysis indicated that the product had 3.11 mmol / g N and 2.00 mmol / g Cl.

[0079] D. Functionalized DCT converted to dimercaptotriazine, full-size polymer particles. 100 mL Pyrex (registered trademark) In a jar, NaSH (1.12 g, 20 mmol) was dissolved in water (40 mL). 5 g of the DCT-functional polymer from Example 1C was dissolved in acetone (10 mL) and added to the NaSH solution. The reaction was allowed to proceed overnight at room temperature. The resulting DMT-functional polymer was then dissolved in water. 3x , MeOH 3x , THF 3x The product was washed with HCl and soaked overnight. The final material was dried by rotary evaporation. Elemental analysis showed the product to have 3.30 mmol / g N and 2.21 mmol / g S.

[0080] E. Functionalized DCT converted to DMT-ethanedithiol, full-sized polymer particles. 100 mL Pyrex (registered trademark) Ethanedithiol (2.11 ml, 25.2 mmol) was dissolved in DMF (63 ml) in a bottle. The solution was cooled in an ice bath. A 60% suspension of NaH in mineral oil (1.01 g, 25.2 mmol) was added in four portions. The thiolate solution was allowed to warm to room temperature, after which the DMT-EDT functional polymer from Step C (6.3 g) was added. The reaction was placed in a 100 °C oven overnight. The resulting DMT-EDT functional polymer was filtered while still warm and washed with 2x DMF, 1M HCl, 2x DMF, 2x water, 2x THF, THF (overnight soak), and 3x THF. Drying by rotary evaporation gave 6.36 g of product. Elemental analysis of the product indicated a N content of 2.55 mmol / g and a S content of 2.39 mmol / g.

[0081] Amberlite® XAD16-based adsorbents

[0082] Amberlite (registered trademark) XAD16 was prepared by the procedure of Example 1A to a particle size of 125-53 μm. After activation at 100°C, nitrogen uptake at 731 torr was 1101 cm 3 This process was repeated until the desired size of Amberlite was obtained. Amberlite with this reduced particle size (registered trademark) XAD16 particles were used in Examples 1F-1H.

[0083] F. Functionalization with Cysteamine. In a 250 mL round-bottom flask, cysteamine hydrochloride (10.2 g, 90 mmol), PEG-400 (1.3 mL), and AIBN (255 mg, 1.7 wt% of polymer) were dissolved in DMF (94 mL). 125-53 μm Amberlite XAD16 (15 g) was added. The reaction was heated at 70 °C overnight without stirring. The functionalized polymer was washed with DMF, 1 M aq. NaOH, water, and MeOH (overnight). After each wash, the polymer was rinsed once with the wash solvent on the filter and allowed to soak in the solvent for at least 1 hour. The polymer was air-dried in a fume hood. Elemental analysis showed the product to have 0.92 mmol / g N and 1.27 mmol / g S. After activation at 100 °C, the nitrogen uptake at 735 torr was 896 cm 3 / g.

[0084] G. Functionalization with Dichlorotriazine. A 200 mL round-bottom flask equipped with a stir bar was charged with THF (60 mL) and cyanuric chloride (5.53 g, 30 mmol). The solution was cooled to 5°C. The product from Example 1F (10 g) was slowly added, followed by the slow addition of DIPEA (5.2 ml, 30 mmol). The reaction was maintained below 10°C. After the addition of cyanuric chloride, the polymer was allowed to react for an additional hour. A ninhydrin test showed that the polymer product was pale blue, and the ninhydrin solution was clear. The functionalized polymer was then washed with THF and acetone (overnight). After each wash, the polymer was rinsed once with the wash solvent on a filter and allowed to soak in the solvent for at least 1 hour. The polymer was air-dried in a fume hood. Elemental analysis indicated that the product had 3.00 mmol / g N, 1.67 mmol / g Cl, and 0.96 mmol / g S. After activation at 100 °C, the nitrogen uptake at 735 torr was 787 cm 3 / g.

[0085] H. Conversion of functionalized DCT to captotriazine. (registered trademark)NaSH (1.79 g, 32 mmol) was dissolved in water (30 ml) in a Pyrex bottle. The polymer from Example 1G (8 g) was dissolved in THF (16 ml) and added to the NaSH solution. The reaction was allowed to proceed overnight at room temperature. The functionalized polymer was washed with water, MeOH, and THF (overnight). After each wash, the polymer was rinsed twice with the wash solvent on the filter and allowed to soak in the solvent for at least 1 hour. The resin was air-dried in a fume hood. Elemental analysis of the product showed N = 3.08 mmol / g, S = 2.09 mmol / g, and Cl = below the detection limit. After activation at 100 °C, the nitrogen uptake at 723 torr was 645 cm 3 / g.

[0086] Presized polymer-based adsorbents

[0087] I. Polymer Particle Size Reduction. Amberlite XAD4 (300 g) was dried overnight in an oven at 100 °C to remove moisture. This dried polymer (136 g) was run in batches through a coffee blade grinder until all polymer particles passed through a 250 μm sieve. This is the smallest sieve the polymer can pass through (ground polymers tend to clog smaller sieves due to static electricity). MeOH was added to the polymer below 250 μm (enough to wet it), followed by 2 L of water. The polymer was then sized through 125 μm and 53 μm sieves under a stream of water. Once the water was clear, the 125-53 μm fraction was dried overnight in an oven at 100 °C. The final yield was 31 g of 125-53 μm Amberlite. After activation at 100 °C, the nitrogen uptake at 735 torr was 810 cm 3 This process was repeated until the desired size of polymer was obtained.

[0088] J. Functionalization with Cysteamine. In a 1 L round-bottom flask, cysteamine hydrochloride (40.9 g, 260 mmol), PEG-400 (5.3 ml), and AIBN (1.02 g, 1.7 wt % of Amberlite) were dissolved in DMF (375 ml) with mechanical stirring. Amberlite XAD4 (125-53 μm, from Example 1I) (60 g) was added. The reaction was heated at 70 °C overnight. The functionalized polymer was washed with DMF, 1 M aq. NaOH, water, and MeOH. For each wash, the polymer was washed once on the filter with approximately 150 ml of wash solvent and soaked in approximately 500 ml of solvent for at least 1 hour. The polymer was air-dried in a fume hood. Elemental analysis indicated the product had 0.99 mmol / g N and 1.01 mmol / g S. After activation at 100 °C, the nitrogen uptake at 735 torr was 647 cm 3 / g.

[0089] K. Functionalization with Dichlorotriazine. To a 1 L round-bottom flask was added THF (200 ml), the polymer product from Example 1J (45 g), and DIPEA (24 ml, 135 mmol) with mechanical stirring. The solution was cooled to 5°C. A solution of cyanuric chloride (24.9 g, 135 mmol) in THF (100 ml) was added dropwise. The reaction was maintained below 10°C. After the addition of cyanuric chloride, the polymer was allowed to react for an additional hour. A ninhydrin test showed that the polymer product was pale blue, and the ninhydrin solution was clear. The functionalized polymer was washed with THF and acetone. After each wash, the resin was rinsed once with the wash solvent on the filter and allowed to soak in the solvent for at least 1 hour. The final acetone soak was overnight. The polymer was air-dried in a fume hood. Elemental analysis revealed that the product had a nitrogen concentration of 2.69 mmol / g, a chloride concentration of 1.27 mmol / g, and a sulfur concentration of 1.09 mmol / g. After activation at 100°C, the nitrogen absorption at 735 torr was 542 cm 3 / g.

[0090] L. Conversion of Functionalized DCT to Dimercaptotriazine. 250 mL Pyrex (registered trademark)NaSH (6.73 g, 120 mmol) was dissolved in water (120 ml) in a jar. The product from Example 1K (30 g) was dissolved in THF (60 ml) and added to the NaSH solution. The reaction was allowed to proceed overnight at room temperature. The functionalized polymer was then washed with water, MeOH, and THF (overnight). After each wash, the polymer was rinsed twice with the wash solvent on the filter and allowed to soak in the solvent for at least 1 hour. The polymer was air-dried in a fume hood. Elemental analysis of the product revealed N of 2.73 mmol / g, S of 1.93 mmol / g, and Cl of 0.4%, below the detection limit. After activation at 100°C, the nitrogen uptake at 735 torr was 544 cm 3 / g.

[0091] Samples of the functionalized porous polymers of Examples 1B, 1D, and 1E were activated at 100°C and nitrogen isotherms were used to determine the BET surface area, pore volume, N2 uptake, and pore size distribution (see Tables I and II and Figures 4, 5A-D). Control A was a commercially available silica-dimercaptotriazine adsorbent with particle sizes between 50 and 100 μm and an average pore diameter of 63 μm. Å , pore volume 0.34 cm 3 / g, N2 uptake 221cm 3 / g range. Control B is Macroreticular Trimercaptotriazine on polymeric support Contains The commercially available adsorbent has a measured average particle size of 150-355 μm and an average pore diameter of 93 Å , pore volume 0.57 cm 3 / g, N2 uptake 377cm 3 / g. For comparison, Functionalization The average pore diameters of porous polymers 1B, 1D, and 1E are 69 Å , 75 Å , 84 Å , and pore volumes of 1.06 cm 3 / g, 0.78cm 3 / g, 0.89cm 3 / g, and N2 uptake was 691 cm 3 / g, 505cm 3 / g, 529cm 3 / g.

[0092] Pore ​​characteristics [Table 2] a. Single-point adsorption and total pore volume

[0093] Pore ​​size distribution [Table 3] a. Average adsorption pore diameter (4V / A by BET) b. The percentage of pores with diameters smaller than this value is 10%. c. The percentage of pores with diameters smaller than this value is 50% (median pore diameter). d. The percentage of pores with diameters smaller than this value is 90%.

[0094] Figure 1 shows the isotherm data for the products of Examples 1D and 1E relative to that of Control A and Control B. The products of Examples 1D and 1E had higher nitrogen uptake than either of the control samples, indicating that these examples have higher pore volume and surface area than the control samples. This parameter is believed to lead to improved performance in both adsorption kinetics and adsorbent capacity.

[0095] FIG. 2A illustrates the incremental pore size distributions of Examples 1B, 1D, and 1E compared to Control A and Control B. FIG. 2B illustrates the incremental pore size distributions of Examples 1B, 1D, and 1E compared to the as-prepared Amberlite XAD4 polymer. FIG. 2C illustrates the cumulative pore size distributions of Examples 1B, 1D, and 1E compared to Control A and Control B. FIG. 2D illustrates the cumulative pore size distributions of Examples 1B, 1D, and 1E compared to the as-prepared Amberlite XAD4 polymer. It can be seen that each of the adsorbents of Examples 1B, 1D, and 1E has a higher pore volume than either of the two controls, measured on either an incremental or cumulative basis. This also suggests that the adsorbents of the present disclosure have both improved kinetics and adsorption capacity.

[0096] Approximately 5g samples of each of the products of Examples 1B, 1D, and 1E were ground and sized according to the procedure of Example 1A for use in Examples 2-7 below.

[0097] In the following Examples 2 to 7, inductively coupled plasma measurements were performed using a Thermo iCap7600 ICP-OES with a detection limit of 0.001 ppm to 100 ppm Pd. Measurements using a UV-visible spectrophotometer were performed using a MetraSpec Pro with a wavelength scan of 300 nm to 450 nm with a detection limit of 1 ppm to 300 ppm Pd.

[0098] Example 2 – Measurement of the affinity of adsorbents for Pd Samples were prepared by adding 80 mg of each adsorbent to a 10 ml aliquot of a 50:50 mixture of dimethylformamide and tetrahydrofuran spiked with 85 ppm Pd as PdCl2(P(phenyl)3)2 (Sigma). Samples were mixed on an orbital shaker at 50 rpm for 24 hours and then filtered through a 0.22 micrometer PTFE syringe filter. Each sample was 3 times The residual Pd in ​​the solution was measured by inductively coupled plasma. The results are shown in Figure 3. All of the adsorbents in Example 1 had less than 5 ppm of residual Pd in ​​the samples, and Examples 1D, 1F, and 1L had less than 1 ppm of residual Pd in ​​the samples, indicating that the adsorbents in Example 1 each performed significantly better than Control B. This example was repeated using 25 mg of each of the adsorbents from Example ID and Example IE instead of 80 mg. As shown in Figure 4, at this level the adsorbents of Examples 1D and 1E outperformed Control A in Pd adsorption.

[0099] Example 3 – Measurement of Pd adsorption capacity Samples were prepared by adding 40 mg of each adsorbent to a 20 ml aliquot of a solution of PdCl2(P(phenyl)3)2 (Sigma) in 50:50 dimethylformamide:tetrahydrofuran spiked with 300 ppm Pd. Samples were mixed on an orbital shaker at 50 rpm for 24 hours and then filtered through a 0.22 micrometer PTFE syringe filter. Each sample was 3 timesThe residual Pd in ​​the solution was measured using a UV-visible spectrophotometer. The adsorbents evaluated were the adsorbents prepared in Example 1, DMT on a silica carrier, and the like. Contains Commercially available adsorbents (Control A), and reported mean particle sizes between 150 and 350 μm Macro TMT on reticular polymer supports Contains The commercial adsorbent (Control B) was used. The results are shown in Figure 5. It can be seen that the adsorbent of Example 1 has a higher palladium capacity than Control A and significantly higher than Control B. This allows for the use of less adsorbent by weight to achieve the same amount of purification as the control.

[0100] The improved Pd capacity of the adsorbents disclosed herein compared to the commercial adsorbent is consistent with the isothermal data for these samples shown in Figure 1, which shows that the adsorbents disclosed herein adsorb more N than the commercial adsorbent at all pressures from zero to 760 torr.

[0101] Example 4 – Kinetic adsorption measurements Samples were prepared by adding 80 mg of each adsorbent to be evaluated to a 10 ml aliquot of a 100 ppm Pd solution of PdCl2(P(phenyl)3)2 (Sigma) in 50:50 dimethylformamide:tetrahydrofuran. Both the adsorbent from Example 1E and the adsorbent from Control A had average particle sizes ranging from 50 to 100 μm. The samples were mixed on an orbital shaker at 50 rpm, and samples were taken every 5 minutes and returned to the orbital shaker. The amount of Pd remaining in solution was measured using a UV-Vis spectrophotometer. Kinetic data are shown in Figure 6, and demonstrate that the adsorbent from Example 1 removed Pd from solution below the instrument's detection level within 5 minutes. In comparison, the silica-based adsorbent from Control A still had 60 ppm Pd remaining in solution after 5 minutes, and 35 ppm Pd remaining in solution after 50 minutes. This is a major advantage of the adsorbent disclosed herein compared to prior art silica-based adsorbents, and it can be said that it can significantly shorten the time of the purification step in the production of drug substances and speed up the production cycle of drug substances.

[0102] Example 5 – Determination of the affinity of adsorbents for Pd in ​​polar solvents Samples were prepared by adding 80 mg of each adsorbent to be evaluated to a 10 ml aliquot of a solution containing 100 ppm Pd as Pd(OAc)2 (Sigma) in isopropyl alcohol. Isopropyl alcohol is a polar solvent and a non-swelling solvent for polystyrene. Pd(OAc)2 was chosen as the Pd salt because it dissolves in isopropyl alcohol, whereas PdCl2 (P(phenyl)3)2 does not. Samples were mixed on an orbital shaker at 50 rpm for 24 hours and then filtered through a 0.22 micrometer PTFE syringe filter. Each sample was 30 ml. times Residual Pd in ​​the solution was measured by inductively coupled plasma. The results are shown in Figure 7. It can be seen that the adsorbent of Example 1 is comparable to or better than Control A and Control B.

[0103] Example 6 – Determination of the affinity of adsorbents for Pd in ​​the presence of the active pharmaceutical ingredient (API) ibuprofen Samples were prepared by adding 80 mg of each adsorbent to be evaluated in 10 ml aliquots to a solution of 80 ppm Pd in ​​PdCl2(P(phenyl)3)2 (Sigma) in 50:50 dimethylformamide:tetrahydrofuran, with ibuprofen added at a concentration of 20 mg / ml. Samples were mixed on an orbital shaker at 50 rpm for 24 hours and then filtered through a 0.22 micrometer PTFE syringe filter. Each sample was 3 times Residual Pd in ​​the solution was measured by inductively coupled plasma. The results are shown in Figure 8. It can be seen that the adsorbents of Examples 1B, 1D, and 1E are comparable to Control A and significantly superior to Control B.

[0104] Example 7 - Determination of the affinity of adsorbents for Pd in ​​the presence of the active pharmaceutical ingredient (API) quinine. Samples were prepared by adding 80 mg of each sorbent to be evaluated to a 10 ml aliquot of an 80 ppm Pd solution in PdCl2(P(phenyl)3)2 (Sigma) in 50:50 dimethylformamide:tetrahydrofuran, followed by the addition of quinine at a concentration of 20 mg / ml. Samples were mixed on an orbital shaker at 50 rpm for 24 hours and filtered through a 0.22 micrometer PTFE syringe filter. Each sample consisted of two times Residual Pd in ​​the solution was measured by inductively coupled plasma. The results are shown in Figure 9. Adsorbents 1B, 1D, and 1E of Example 1 are found to be comparable to Controls A and B.

[0105] implementation Example 8 - Determination of the affinity of adsorbents for copper. Samples were prepared by adding 80 mg of each adsorbent to be evaluated to a 10 ml aliquot of a 100 ppm Cu-spiked solution of CuI (Sigma) in acetonitrile. The samples were mixed on an orbital shaker at 50 rpm for 24 hours and then filtered through a 0.22 micrometer PTFE syringe filter. Each sample was 3 times Residual Cu in the solution was measured by inductively coupled plasma. The results are shown in Figure 10. Adsorbents 1B, 1D, and 1E of Example 1 are found to be comparable to or better than Control A and Control B.

[0106] In another embodiment of the present disclosure, 2,4,6-dimercaptotriazine-ethanedithiol (DMT-EDT) adduct body , 2,4,6-trimercaptotriazine-ethanedithiol (TMT-EDT) adduct body and mixtures of any of the foregoing, wherein the polymer is a swellable polymer. In another embodiment, the swellable polymer can be based on polystyrene, optionally containing other monomers. In one embodiment, a 2,4,6-dimercaptotriazine-ethanedithiol (DMT-EDT) adduct is used. body , 2,4,6-trimercaptotriazine-ethanedithiol (TMT-EDT) adduct body The adsorbent particles having at least one functional group selected from the group consisting of 2,4,6-dimercaptotriazine-ethanedithiol (DMT-EDT) adducts, and mixtures of any of the foregoing, have an average particle size measured on an undissolved basis in the range of about 100 to 300 microns, or in the range of 125 to 250 microns. body , 2,4,6-trimercaptotriazine-ethanedithiol (TMT-EDT) adduct body and mixtures of any of the foregoing, the adsorbent particles having at least one functional group selected from have an average particle size measured on an undissolved basis of less than 150 microns.

[0107] Furthermore, unexpectedly, swellable polystyrene polymers functionalized with 2,4,6-trimercaptotriazine-ethylenedithiol (TMT-EDT) adducts or 2,4,6-dimercaptotriazine-ethylenedithiol (DMT-EDT) adducts were synthesized. Contains It was found that the adsorbent had excellent adsorption capacity.

[0108] Example 9 - Functionalization of polystyrene with dimercaptotriazineethanediol A. Functionalization of polystyrene with DCT. 1 L Pyrex (registered trademark) In a bottle, cyanuric chloride (46.8 g, 254 mmol) was dissolved in THF (500 mL). The solution was cooled to 5 °C in an ice bath, and DIPEA (27.7 mL, 159 mmol) was added. PS-NH2 (65.0 g, 1% crosslinked, ~127 mmol -CH2NH2) was added in approximately 10 g portions. The reaction was highly exothermic and monitored by the ninhydrin test. After approximately 4 h, the resulting functionalized polystyrene product was washed twice with THF, soaked in THF overnight, and dried by rotary evaporation to yield 102 g of product. Elemental analysis revealed that the product had 5.02 mmol / g N and 2.61 mmol / g Cl.

[0109] B. Conversion of functionalized DCT to DMT-EDT. (registered trademark)In a vial, ethanedithiol (6.7 ml, 80 mmol) was dissolved in DMF (200 ml). The solution was cooled in an ice bath. Next, a 60% suspension of NaH in mineral oil (3.20 g, 80 mmol) was added in approximately four portions. The thiolate solution was allowed to warm to room temperature, and then the PS-DMT-EDT product from Step A (20 g) was added. The reaction was placed in a 100 °C oven overnight. The resulting PS-DMT-EDT product was filtered while still warm and washed with 2x DMF, 1 M HCl, 2x DMF, 2x water, 2x THF, THF (overnight soak), 3x THF, and MeOH (this shrinks the polymer and makes drying much easier), followed by rotary evaporation to give 18.2 g of product. Elemental analysis revealed that the product had a N content of 4.27 mmol / g and a S content of 2.91 mmol / g.

[0110] Example 10 – Measurement of Pd adsorption capacity Samples were prepared by adding 40 mg of each adsorbent to be evaluated to a 20 ml aliquot of a 170 ppm Pd solution of PdCl2(P(phenyl)3)2(Oakwood) in 50:50 dimethylformamide:tetrahydrofuran. The samples were mixed on an orbital shaker at 50 rpm for 24 hours and then filtered through a 0.22 micrometer PTFE syringe filter. Each sample was 3 times Residual Pd in ​​the solution was measured by ICP spectrophotometry. The adsorbents evaluated were those prepared in Examples 9B, 1D, and 1E, and DMT on a silica support. Contains The commercial adsorbent (Control A) is shown in Figure 11. It can be seen that the adsorbent of Example 9B has a higher palladium capacity than Control A.

[0111] Example 11 – Large-scale preparation of adsorbent V and particle size measurement The adsorbent shown in Structure V of Method 1 was prepared on a 10-liter scale using essentially the same process as steps A, B, C, and E of Example 1. The resulting particles were analyzed by scanning electron microscopy (SEM) and found to have an average particle size of 95.2 ± 31 microns. To measure the particle size distribution, a small sample of the adsorbent was attached to black double-sided tape attached to an SEM sample plate. The sample was then placed in the SEM under vacuum and examined at 37x magnification. The length of each particle was measured manually using the ruler tool provided with the SEM software. The number of particles was tallied in 25-μm size intervals, from 0 μm to 200 μm. The results are shown in Figure 12.

Claims

1. 1. A method for reducing a concentration of at least one contaminant in a liquid composition comprising at least one contaminant, comprising: contacting the liquid composition with an adsorbent under purification conditions to adsorb at least a portion of the at least one contaminant; the sorbent comprises particles of a macroreticular polymer functionalized with at least one functional group capable of binding one or more contaminants; The method of claim 1, wherein the adsorbent has a pore volume of at least 0.65 cm3 / g.

2. The method of claim 1 , wherein the liquid composition is a composition in a manufacturing process for a pharmaceutical active ingredient.

3. The method of claim 1 , wherein the liquid composition comprises a pharmaceutical active ingredient or a precursor thereof.

4. 2. The method of claim 1, wherein the at least one contaminant is an elemental impurity selected from at least one element of Class 1, Class 2A, Class 2B, and Class 3 of the ICH Q3D(R1) guideline.

5. 5. The method of claim 4, wherein the sorbent binds the amount of elemental impurity in the liquid composition to provide a liquid composition having a concentration of the elemental impurity such that the concentration of the elemental impurity in the recovered drug substance is at or below a Permitted Daily Exposure (PDE).

6. 2. The method of claim 1, wherein the at least one functional group is selected from cysteamine, 2,4,6,-trimercaptotriazine (TMT), 2,4,6,-dimercaptotriazine (DMT), 2,4,6,-dimercaptotriazine-ethanedithiol (DMT-EDT) adduct, 2,4,6,-trimercaptotriazine-ethanedithiol (TMT-EDT) adduct, thioglycolic acid (TGA), thiourea, 4-mercaptopyridine, 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), ethylenediaminetetraacetic acid (EDTA), thiosulfate (TS), mercaptomethylphosphonic acid (MPA), trimercaptotriazine-methyl-phosphonic acid (TMT-PA), and mixtures of any of the foregoing.

7. 10. The method of claim 1, wherein the functionalized macroreticular polymer adsorbent particles have a particle size distribution D90 in the range of 50 to 150 microns.

8. 10. The method of claim 1, wherein the particles of the adsorbent have an average particle size of less than 150 microns.

9. An adsorbent comprising particles of a macroreticular polymer functionalized with at least one functional group capable of binding one or more contaminants, said particles of the adsorbent having a pore volume of at least 0.65 cm3 / g.

10. The adsorbent of claim 9, wherein the macroreticular polymer has an average pore diameter of 69 Å to 110 Å.

11. The adsorbent of claim 9, wherein the particles of the adsorbent have a pore size distribution with D50 less than 200 Å.

12. The adsorbent of claim 9, wherein the at least one functional group is selected from cysteamine, 2,4,6-trimercaptotriazine (TMT), 2,4,6-dimercaptotriazine (DMT), 2,4,6-dimercaptotriazine-ethanedithiol (DMT-EDT) adduct, 2,4,6-trimercaptotriazine-ethanedithiol (TMT-EDT) adduct, thioglycolic acid (TGA), thiourea, 4-mercaptopyridine, 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), ethylenediaminetetraacetic acid (EDTA), thiosulfate (TS), mercaptomethylphosphonic acid (MPA), trimercaptotriazine-methyl-phosphonic acid (TMT-PA), and mixtures of any of the foregoing.

13. 10. The adsorbent of claim 9, wherein the functionalized macroreticular polymer adsorbent particles have a particle size distribution D90 in the range of 50 to 150 microns.

14. 1. A method for functionalizing a polymer containing alkene groups, comprising: a.) reacting the polymer with a first reactant comprising a thiol group and a linking group, wherein the thiol group of the first reactant reacts with an alkene group of the polymer in a thiol-ene reaction to form a thioether bond between the polymer and the linking group; b.) reacting the product of step a. with a second reactant comprising an aryl or heteroaryl group, said aryl or heteroaryl group being substituted or unsubstituted, and attaching said second reactant to a linking group; and c.) reacting the product of step b. with a third reactant having a functional group, said third reactant binding to said second reactant linking said functional groups, thereby functionalizing said polymer with said functional groups. A method comprising:

15. 15. The method of claim 14, wherein the functional group linked to the triazine group by reaction in step c. comprises a thiol group.

16. 15. The method of claim 14, wherein the third reactant is selected from a sulfide salt and a polythiolated alkane.

17. 1. An adsorbent comprising particles of a polymer functionalized with at least one functional group selected from a 2,4,6-dimercaptotriazine-ethanedithiol (DMT-EDT) adduct, a 2,4,6-trimercaptotriazine-ethanedithiol (TMT-EDT) adduct, or a combination thereof, wherein the polymer is selected from a swellable polymer and a macroreticular polymer.

18. The adsorbent of claim 17, wherein the polymer is a macroreticular polymer.

19. 20. The adsorbent of claim 17, wherein the polymer is a swellable polymer.

20. 1. A method for reducing a concentration of at least one contaminant in a liquid composition comprising at least one contaminant, comprising: contacting the liquid composition with an adsorbent under purification conditions to adsorb at least a portion of the at least one contaminant; The method of claim 1, wherein the adsorbent comprises particles of a polymer functionalized with at least one functional group selected from 2,4,6-dimercaptotriazine-ethanedithiol (DMT-EDT) adducts, 2,4,6-trimercaptotriazine-ethanedithiol (TMT-EDT) adducts, and mixtures of any of the foregoing, and the polymer is selected from swellable polymers and macroreticular polymers.

21. The method of claim 20, wherein the polymer is a macroreticular polymer.

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