WO2023025406A1 - Separation of volatile compounds from polymers by physisorption for high throughput applications - Google Patents

Abstract

The present invention relates to a method for the purification of polymers which can be automated, parallelized and used in high-throughput, high-output or combinatorial experimental workflows to prepare libraries of purified polymeric materials. In each embodiment of the invention disclosed herein, a porous substrate of large surface area is contacted with an organic or aqueous solution that contains a polymer to be purified. Hence, the polymeric material is physisorbed as a thin film on the substrate and volatile impurities and solvents, such as residual monomers and process solvents, are removed from the substrate with the aid of a gas stream or vacuum at different temperatures; thereby, the content of volatile impurities and solvents in the polymeric material is significantly reduced. The method of this invention can be particularly applied to the synthesis, purification, characterization, screening, and testing of libraries of (co)polymers by means of commercially available automated parallel platforms commonly utilized in high-throughput, high-output or combinatorial experimental approaches.

Description

Description

SEPARATION OF VOLATILE COMPOUNDS FROM POLYMERS BY PHYSISORPTION FOR HIGH THROUGHPUT APPLICATIONS

Background of Invention

1 . Field of Invention / Technical Field

The present invention relates to a method for the purification of polymers.

2. Background

The research and development of polymers involves not only the identification and selection of suitable candidates from a practically unlimited universe of materials but also the development and optimization of synthetic and purification methods to enable access to such universe of materials, and, eventually, scale up preparation for more promising candidates.

Optimization of synthetic routes and purification methods, particularly for polymers, is a tedious and resource-intensive process. For instance, only a limited amount of a starting polymeric material is often available, but many preparative studies are necessary to optimize the purification of such polymer (or polymer libraries). Thus, sequential investigations such as characterizations, further chemical transformations, screenings, or assays are difficult to perform in a long turnaround using current methods. The screening of polymer libraries for highly specific applications can be time consuming, labor and resource intensive. For instance, after synthesis, a crude polymer reaction mixture usually contains unreacted monomers, residual solvents, and/or other impurities. Such substances represent a problem in further synthetic steps, characterization methods, processing, or applications including the manufacture of functionalized (co)polymers [1], food packing items, drug delivery systems for biomedical usages, etc. A variety of methods for purifying polymers, e.g., precipitation [2], dialysis[3], chromatography [4-6], steam or gas stripping [7], and use of supercritical fluids [8-10], are currently utilized in academia and industry depending on the subsequent utilization or characterization of such materials. However, most of these methods can be laborious, time-consuming, expensive, poorly reproducible, and produce significant amounts of waste [1]; furthermore, well- trained and experienced chemists, along with additional set-ups, and/or large amounts of solvents might be required [11]. Although such methods can remove most of residual monomers and other impurities, in many cases, the solvents utilized in these processes also become additional pollutants that require proper disposal. Moreover, oftentimes, purification of polymer libraries is performed manually, which results in a great amount of preparation time. Additionally, in many instances, the manual purification of the polymers results in waste or modification of some properties of the polymeric product.

Thus, there is a need in the art to develop fully automated, parallel, accurate, reproducible, and efficient methods for synthesizing and purifying polymers and polymer libraries for high-throughput, high-output or combinatorial experimental approaches for R&D purposes. The invention disclosed herein offers a straightforward, automated and reproducible polymer purification method, which can bridge the existing gap between high-throughput, high-output or combinatorial polymer synthesis and characterization / property screening. 3. Summary of the Invention

In one aspect, this disclosure provides a method to separate residual volatile compounds (i.e., monomers, solvents, additives, etc.) from synthetic (co)polymers. For example, this disclosure provides a method where the physisorption of a polymeric material to be purified takes place on a solid, porous and inert substrate (preferable with a high surface area and good wettability by a wide arrange of solvents) to form polymer adsorbed films that are subsequently dried with the aid of a gas stream or vacuum at different temperatures. Thereby, volatile impurities, monomers, solvents, or additives, are carried away by evaporation (or sublimation) from the polymer film adsorbed on the substrate, yielding a polymeric material with a significantly reduced amount of volatile compounds and supported on a substrate. The disclosed method is effective, inexpensive, and versatile as it can separate a broad range of volatile monomers and solvents commonly used in polymer manufacturing.

In another aspect, this disclosure provides a purification method that significantly reduces solvent waste as compared to other methods in the art, while producing polymers with a similar or lower content of residual volatile compounds and unaltered macromolecular characteristics (/.e., molar mass distribution). In certain embodiments, the residual monomer content is less than 1% after applying the purification method disclosed herein. In certain embodiments the physisorption process is carried out by dropping the polymer solution onto the substrate to impregnate it. In some such embodiments a gas stream (e.g., air, argon, nitrogen, carbon dioxide, etc.) or vacuum is applied on the polymer-physisorbed substrate at different temperature to remove volatile impurities by evaporation or sublimation. In certain embodiments, the adsorbed polymer films can be retrieved from the substrate in a quantitatively way for subsequent synthetic procedures, characterizations, screenings, and/or assays. In various aspects, this disclosure provides a cost-effective and efficient purification method to remove volatile compounds from polymer libraries. In most embodiments, the proof of concept of the disclosed method minimizes the alteration of the macromolecular properties (i.e., molar mass distribution) of the purified polymers.

In yet another aspect, this disclosure provides a multi-step synthetic procedure to prepare statistical, gradient, asymmetric, block, grafted, brush, star, or the like copolymers of high purity via the use of combinations of the herein disclosed substrates impregnated with suitable polymeric precursor materials, with well-known in the art reversible deactivation radical polymerization (RDRP) techniques. In certain embodiments, the method includes the immersion of polymer-physisorbed substrates into a suitable solvent to retrieve the purified polymer and the subsequent or simultaneous addition of a second, third or more monomers and radical initiators, catalysts, or ligands to perform chain extension polymerization or functionalization reactions. The polymer-physisorbed substrate can be weighted to estimate a certain amount of polymeric material (down to the micro scale) necessary for a subsequent tasks or operations, for example, by conveniently cutting the necessary amount of polymer-physisorbed substrate or extracting the polymeric material with the aid of a suitable solvent.

In still another aspect, the purification method disclosed herein is automatized and embedded into existing high-throughput I high-output experimental workflows and/or commercially-available robotized parallel synthesizers [12], In some embodiments the method comprises dispensing reactants into a reaction vessel in a commercially- available robotized parallel synthesizer to perform the polymerization or functionalization reactions. When the desired reaction time elapses, with the aid of a commercially-available robotized platform, the “crude” polymeric reaction mixture is diluted with a suitable solvent and dispensed onto a suitable substrate. The substrate is supported on a suitable container with a mechanism that can control temperature and can supply a gas stream or vacuum to the impregnated substrate via suitable ducts or via an adapted ventilation mechanism. The purification step is completed by applying the gas stream for the necessary period and at various temperatures to obtain a purified polymeric material impregnated on the substrate. In certain embodiments the synthesis procedure is automatized, and the purification is completed manually. In certain embodiments the full method or experimental workflow is automatized. The method disclosed herein may be useful to fill up one of the missing links (/.e., unattended polymer purification) in the operation of self-driving laboratories for polymer research and development.

The methods of the present invention represent a convenient option for the synthesis, purification, and characterization of functional (co)polymers of complex macromolecular architecture. Based on the mentioned advantages, the methods disclosed herein can be regarded as an automated and cost-effective alternative for separating residual volatile compounds from polymeric materials for further use in high-end value applications, for example, but not limited, advanced characterization, screening or testing methods, or synthesis of statistical, gradient, asymmetric, block, grafted, brush, star or the like copolymers of higher purity and reproducibility.

These and other objects of the invention are described in more detail in the following paragraphs. These objects should not be deemed to narrow the scope of the invention.

4. Detailed Description of the Invention

Definition of terms

As used herein, (co)polymer refers to a macromolecular compound within the molar mass range from 500 to 10,000,000 g mol’¹. The (co)polymer is synthesized by polymerization methods well-known in the art such as, but not limited to, Reversible Addition-Fragmentation chain transfer (RAFT) polymerization technique. The (co)polymers can be statistical, gradient, asymmetric, block, grafted, brush, star or the like (co)polymers, and/or hydrophilic, hydrophobic, or of amphiphilic nature. The solubility of the (co)polymers in solvents of different nature is the range from 0.01 to 75 wt. % or from 0.1 g L^-1 to 750 g L^-1, preferably in the range from 0.01 to 20 wt. % or from 0.1 g L"¹ to 200 g L^-1, and more preferably in the range from 0.01 to 10 wt. % or from 0.1 g L ¹ to 100 g L ¹, and even more preferably in the range from 0.01 to 5 wt. % or from 0.1 g L^-1 to 50 g L^-1

As used herein, a “substrate” refers to a porous material with a large surface area (e.g., cellulose, silica, zeolite, polymeric monolith, metal-organic framework, activated charcoal, graphene, carbon nanotubes, etc.) used to form polymer thin films to remove volatile compounds that are not adsorbed onto the substrate, and thereby, yielding a purified polymeric material while improving the purification process and handling.

As used herein, adsorbed, physisorbed or impregnated polymer refers to a polymer thin film physically attached (not chemically, i.e., not covalently-bonded) to the substrate, where the polymer thin film partially, substantially, or completely covers the surface area of the substrate.

As used herein, a gas stream refers to the application of a flux of air or inert gases to remove volatile impurities from the polymer thin film adsorbed onto the substrate. The application of gas stream is provided via suitable gas ducts, or ventilator installations, or a closed laboratory fume hood provided with air extraction or vacuum.

As used herein, a “liquid dispensing unit” refers to a device that is capable of dispensing liquids (e.g., polymeric solutions, solvents, monomers or reagent solutions) into a container or containers (for example, but not limited, vials, reaction vessels or substrates). Examples of liquid dispensing units include commercially available (and known in the art) automated liquid dispensing parallel platforms (e.g., an ASW-2000, Accelerator, or SWAVE dispensing units manufactured by Chemspeed Technologies®; other manufacturers of this equipment include Tecan, Hamilton, Gilson, Mettler Toledo, Unchained Labs, etc.). The foregoing and other features of the invention are hereinafter more described and particularly pointed out in the claims. It is to be understood that the aspects described herein are not limited to specific processes, compounds, synthetic methods, articles, devices, or uses as such can, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing aspects only, and, unless specifically defined herein, is not intended to be limiting.

Fig. 1 is a schematic representation for a typical embodiment of the disclosed method of the invention. In a first embodiment, a polymeric material to be purified is dissolved in an organic solvent to form a polymer solution in the concentration range from 0.1 to 50 wt. % or from 1 g L^-1 to 500 g L^-1, and preferably in the concentration range from 5 to 20 wt. % or from 50 g L^-1 to 200 g L^-1. Subsequently, the polymer solution is deposited onto a porous substrate to achieve its impregnation with polymer solution. This adsorption process can be adjusted to yield a specific amount of impregnated polymer onto the porous substrate by depositing several layers of polymer thin films and/or by varying the polymer concentration of the impregnation solution. The amount of impregnated polymer will correspond to the final amount of purified polymeric material.

Volatile solvents and impurities in the polymer solution (e.g., volatile residual solvents, unreacted monomers, and other impurities) are removed from the substrate by applying a gas stream which carries away volatile compounds yielding a polymer- physisorbed substrate, which is impregnated with a thin film of purified polymer.

In common embodiments, but not limited to, a commercially available cellulose filter paper was used as a porous substrate. The method disclosed herein is not limited to a specific substrate. Other materials fulfilling similar characteristics (high porosity (/.e., surface area), good wettability by aqueous and most common organic solvents, and avoidance of de-wettability with time) could also be used for this purpose. The present methods can be used to purify virtually any polymer contaminated with volatile impurities regardless of the polar or non-polar nature of the polymeric material. In all embodiments of the invention, all impurities, including residual solvents and unreacted monomers, are substantially removed in one step. In addition, intensive human intervention or specialized experience in the art are not commonly required.

In certain embodiments, if a large library of (co)polymers is to be purified, the disclosed method can be automatized and run in parallel in automated parallel platforms with suitable containers and robotized liquid dispensing capabilities. a. Purification of polymers by physisorption

In at least one aspect, this disclosure provides a method of adsorbing a polymeric material to be purified and a porous substrate for the purification of such polymeric material. In certain embodiments, the method comprises of combining a polymer solution and a porous substrate to impregnate the substrate. In certain embodiments the impregnation process is performed manually. In certain embodiments the physisorption process is performed by dispensing the polymer solution with the aid of a robotized liquid dispensing unit.

In most embodiments the amount of physisorbed polymer film is adjusted by applying several impregnation cycles (/.e., several layers) or by using impregnation solutions of different polymer concentration. In certain embodiments, the efficiency of the removal of volatile impurities is optimized by using three or more impregnation cycles, more preferably two or one impregnation cycles. In certain embodiments the efficiency of the removal of volatile impurities is optimized by using impregnation solutions within the polymer concentration range from 0.01 to 75 wt. % or from 0.1 g L^-1 to 750 g L^-1, preferably in the range from 0.01 to 20 wt. % or from 0.1 g L^-1 to 200 g L~¹, and more preferably in the range from 0.01 to 10 wt. % or from 0.1 g L^-1 to 100 g L^-1, and even more preferably in the range from 0.01 to 5 wt. % or from 0.1 g L ¹ to 50 g L ¹. In certain embodiments, the yield of purified polymer is in the range from 10 to 50 wt. % correlated to the amount of porous substrate used.

In common embodiments, a gas stream is provided by suitable gas ducts or by ventilator installations, or by a closed laboratory fume hood, or vacuum is provided by suitable installations (e.g., commercially available vacuum pumps). In some such embodiments, controller devices control the operation of the gas stream, vacuum, or extraction (in case of using a fume hood). In most embodiments, the gas stream or vacuum are evenly distributed on the impregnated porous substrate without dropping or expelling the substrate from its container during the drying process. In certain embodiments, the application of a gas stream or vacuum is in the time range from 0.1 to 1000 h, and preferably in the time range from 1 to 100 h. The time of applied gas stream, vacuum, or extraction may be pre-established by the amount of remnant impurities on the adsorbed substrate, which can be monitored by suitable analytical techniques such as, but not limited to, proton nuclear magnetic resonance (¹H NMR), gas chromatography, mass spectroscopy, high-pressure liquid chromatography, etc. In common embodiments, different temperature conditions of physisorbed substrate are provided by suitable heating or cooling devices with control systems. The application of temperature to physisorbed substrates during removal of volatile substances or impurities from polymeric materials are in the temperature range from -110 to 400 °C, preferably from -10 to 200 °C, and even more preferably from 30 to 180 °C. For example, the removal of certain chemical substances, such as solvents and/or monomers with a relatively high-boiling point value (as determined at normal atmospheric conditions), benefit from drying periods longer than 24 h, such about, 48 h or about 80 h. In certain embodiments, the removal of remnant monomers was benefited for monomers with boiling point (as determined at normal atmospheric conditions) in the range from -110 to 250 °C, preferably from -10 to 200 °C, and even more preferably from 30 to 180 °C.

In at least one aspect, this disclosure provides a polymer-physisorbed substrate. The polymer-physisorbed substrate may be for subsequent use in characterization, screening, testing, formulations or chemical reactions. In certain embodiments, a plurality of polymer-physisorbed substrates may be for use in a plurality of chemical reactions and/or physicochemical characterizations, such as high throughput screening of large (co)polymer libraries. For example, in certain embodiments, a polymer-physisorbed substrate, solvents, initiators and monomers are combined in a mixing vessel and mechanical stirring is applied to redissolve the polymer. In some such embodiments, the reaction vessel can contain the reagents in the corresponding solvent during mechanical or magnetic stirring. In such embodiments, the polymer-physisorbed substrate is manually added to the reaction vessel. The researcher may calculate the amount of required polymer from the polymer yield estimated during the purification process. In some such embodiments, the polymer- physisorbed substrate is manually cut to yield the desired amount of purified polymer. In some such embodiments, the amount of polymer retrieved, from the polymer-physisorbed substrate, can be estimated by spectroscopy techniques, such as ultraviolet-visible spectroscopy (UV-Vis). In some such embodiments, a polymer chain extension or functionalization reaction is performed by first removing the substrate from the reaction mixture, then degassing the reaction mixture with an inert gas, and increasing the temperature to initiate the reaction. In certain embodiments, the chain extension or functionalization reaction is performed by leaving the substrate immersed in the reaction mixture. In some such embodiments, the obtained copolymer or functionalized (co)polymer is purified by impregnating a copolymer solution derived from the reaction mixture, at a suitable (co)polymer concentration, on a porous substrate of large surface area. In such embodiments, the method comprises combining the (co)polymer solution and the porous substrate to impregnate partially, substantially or completely the substrate. In some such embodiments, the impregnation process is automatized or performed manually. As another example, the polymer-physisorbed substrates may be used for the rapid characterization, screening and/or testing of (co)polymer libraries.

In at least one aspect, the disclosure provides a method for preparing a library of (co)polymer-physisorbed substrates. In certain embodiments, a parallel procedure, with a robotized liquid dispensing unit, is used to first perform the synthesis of (co)polymers by different procedures [13-15], and then the purification method disclosed herein is applied manually or with the aid of a robotized liquid dispensing unit. Fig. 2 is a schematic representation of the automatized synthesis and purification of (co)polymer libraries. In some such embodiments, polymerization reactions are performed in the automatized parallel platform; thereafter, polymer- physisorbed substrates are obtained by a manual or automatized impregnation on the corresponding porous substrates. In some such embodiments the polymer- physisorbed substrates are dried by applying vacuum or a gas stream via a vacuum or ventilator system adapted to the automated platform at different temperatures. In certain embodiments, the application of a gas stream or vacuum is in the time range from 0.1 to 1000 h, and preferably in the time range from 1 to 100 h. The time of applied gas stream, vacuum, or extraction may be pre-established by the amount of remnant impurities on the adsorbed substrate, which can be monitored by suitable analytical techniques such as, but not limited to, proton nuclear magnetic resonance (¹H NMR), gas chromatography, mass spectroscopy, high-pressure liquid chromatography, etc. In common embodiments, different temperature conditions of physisorbed substrate are provided by suitable heating or cooling devices with control systems. The application of temperature to physisorbed substrates during removal of volatile substances or impurities from polymeric materials are in the temperature range from -110 to 400 °C, preferably from -10 to 200 °C, and even more preferably from 30 to 180 °C. The obtained polymer-physisorbed substrates may be used for plurality of chemical reactions or plurality of physicochemical characterizations, screening and/or assays. In some such embodiments, for example, the polymer-physisorbed substrates are directly used for characterizations via suitable techniques for the analysis of solids, such as, but not limited to, Differential Scanning Calorimetry (DSC), Thermogravimetric analysis (TGA), Fourier- transform infrared spectroscopy (FITR), Raman spectroscopy, among others. In certain embodiments, as another example, the polymer characterizations are performed by mixing the polymer-physisorbed substrates with a suitable solvent to redissolve the (co)polymer, and therefore, use the resulting polymer solution to perform the corresponding characterization technique; such as, but not limited to, Size Exclusion Chromatography (SEC), UV-Vis, high pressure liquid chromatography (HPLC), matrix-assisted laser desorption/ionization spectroscopy (MALDI), ¹H NMR, (cito)toxicity studies, turbidimetry analysis, dynamic light scattering (DLS), rheology, viscosimetry, analytical ultracentrifugation, among others. In such embodiments, after dissolving the (co)polymer, the polymer-free substrate is removed prior to characterization. In certain embodiments, the redissolved polymers and porous substrate are incubated for a certain period of time and under suitable temperature and pressure or ultrasonic conditions to achieve the full dissolution of the polymer. For example, the corresponding vessels with the mixture of polymer- physisorbed substrate and solvent may be placed on a heater/shaker or in an ultrasonic bath and heated to a certain temperature (depending on the (co)polymer and solvent type) for a pre-determined period of time (e.g., 2, 24, and 48 h).

5. Examples

The following examples are provided to illustrate the purification process of the invention disclosed herein. They are intended solely as possible methods described by way of examples without limiting the invention to their contents or specific application.

Example 1 : Synthesis and purification of a hydrophilic polymer

100.0 parts by weight of monomer 2-(dimethylamino) ethyl methacrylate (DMAEMA) (TCI Chemicals), 0.3 parts by weight of initiator 4,4'-Azobis(4-cyanovaleric acid) (ACVA) (Sigma-Aldrich), 1 .8 parts by weight of 4-cyano-4-(thiobenzoylthio)pentanoic acid (Strem Chemicals) and 2.5 parts by weight of 1 ,3,5-trioxane (used as internal reference, Sigma-Aldrich) were combined with 166.4 parts by weight of ethanol in a reaction vessel. The reaction vessel was septum-sealed to provide a mixture with a DMAEMA concentration of 2M. The reaction vessel was treated with nitrogen gas (N₂) to remove oxygen (O₂) from the reaction mixture. The reaction vessel was placed in a previously heated oil bath at 65 °C for 8.5 h. Once the polymerization time elapsed, the resulting poly(2-(dimethylamino)ethyl methacrylate (Sample A, PDMAEMA) was characterized and yielded a number average molecular weight (A _n) of 6.2 KDa, and dispersity (£) = M M_n) of 1.24 by SEC (determined in a chloroform (CHCI3), triethyl amine (EtaN), and 2-propanol solvent mixture (refractive index (Rl) detection, poly(methyl methacrylate) (PMMA) calibration) and a residual DMAEMA content of 41 .7 % (as determined by ¹H NMR).

5-mL aliquots of the reaction mixture were combined with ethanol to provide diluted solutions with ca. 10 and 20 wt.% of polymer concentration. Cellulose filter paper (porous substrate) was impregnated with the corresponding polymer solution to adsorb a polymer film. The impregnation process was performed using two solutions with a polymer concentration of 10 and 20 wt.%, respectively, and 1 to 3 layers (L) to yield polymer-physisorbed substrates. The polymer-physisorbed substrates were subjected to an airstream in a fume hood for 80 h; thereafter, different amounts of residual monomer, physisorbed solution (per pristine substrate), and yield of purified polymer (per pristine substrate) were obtained for the substrates shown in Table 1 .

The purified polymers were characterized, via ¹H NMR, by combining the corresponding PDMAEMA-physisorbed substrates with the characterization solvent deuterated chloroform (CDCI3) to redissolve the physisorbed polymer. As shown in Table 1 , Entries A_x.nL represent the PDMAEMA solution with concentration (x) and number of layers applied to the substrate (y). Table 1 demonstrates that the content of DMAEMA monomer is less than 1 % in the final PDMAEMA-physisorbed substrates. Entries A₁₀-IL. AIO-2L> A₁₀-3L, and A₂O-IL, A₂O-2L, A_20-3L, respectively demonstrated that the yield of purified polymer depends on the polymer concentration of the solution used for impregnation and on the number of impregnation layers.

Example 2: Synthesis and purification of a hydrophobic low-molar-mass polymer 100.0 parts by weight of monomer methyl methacrylate (MMA) (TCI Chemicals), 0.23 parts by weight of initiator Azobisisobutyronitrile (AIBN) (Sigma-Aldrich), 3.9 parts by weight of 4-cyano-4-[(dodecylsulfanylthiocarbonyl)sulfanyl]pentanoic acid, (Strem Chemicals) and 2.0 parts by weight of 1 ,3,5-trioxane (used as internal reference, Sigma-Aldrich) were combined with 124.6 parts by weight of toluene in a reaction vessel. The reaction vessel was septum-sealed to provide a mixture with a MMA concentration of 4M. The reaction vessel was treated with N₂ to remove O₂ from the reaction mixture. The reaction vessel was placed in a previously heated oil bath at 65 °C for 8.5 h. Once the polymerization time elapsed, the resulting poly(methyl methacrylate (Sample B, PMMA) was characterized and yielded a M_n of 5.5 KDa, and £) of 1 .16 as estimated by SEC (determined in CHCI₃, Et₃N, and 2- propanol (Rl detection, PMMA calibration)) and a residual MMA content of 26.3% (as determined by ¹H NMR). 5-mL aliquots of the reaction mixture were combined with acetone to provide diluted solutions with ca. 10 and 20 wt.% of polymer concentration. Cellulose filter paper (substrate) was impregnated with the corresponding polymer solution to adsorb a polymer film. The impregnation process was performed using two solutions with a polymer concentration of 10 and 20 wt.%, respectively, and 1 to 3 layers (L) to yield polymer-physisorbed substrates. The polymer-physisorbed substrates were subjected to an airstream in a fume hood for 80 h; thereafter, different amounts of residual monomer, physisorbed solution (per pristine substrate) and yield of purified polymer (per pristine substrate) were obtained for the substrates shown in Table 2.

All in all, the purification goal to remove up to 99% of residual monomer is achieved by decreasing polymer concentration of the impregnating solution and number of impregnated layers. Lower residual amounts of MMA were achieved by decreasing the number of impregnated layers and polymer concentration of the impregnating solution, as shown in Table 2, entry B₁₀-IL- Nonetheless, when using two or more layers and a polymer concentration of 20 wt.% in the impregnating solution, the use of a high-boiling point solvent was detrimental for the removal of residual. Importantly, as shown in entries B10.3i. and B20-3L, the yield of polymer adsorbed on the substrate increased with increasing the polymer concentration of the impregnating solution.

Example 3: Synthesis and purification of a hydrophobic high-molar-mass polymer

100.0 parts by weight of monomer methyl methacrylate (MMA) (TCI Chemicals), 0.09 parts by weight of initiator Azobisisobutyronitrile (AIBN) (Sigma-Aldrich), 1 .58 parts by weight of 4-cyano-4-[(dodecylsulfanylthiocarbonyl)sulfanyl]pentanoic acid, (Strem Chemicals) and 2.0 parts by weight of 1 ,3,5-trioxane (used as internal reference, Sigma-Aldrich) were combined with 124.6 parts by weight of toluene in a reaction vessel. The vessel was septum-sealed to provide a mixture with a MMA concentration of 4M. The vessel was treated with N₂ to remove O₂ from the reaction mixture. The vessel was placed in a previously heated oil bath at 65 °C for 8.5 h. Once the polymerization time elapsed, the resulting poly(methyl methacrylate (Sample C, PMMA) was characterized and yielded a M_n of 15.84 KDa, and £> of 1 .16 as estimated by SEC (determined in CHCI3, Et₃N, and 2-propanol (Rl detection, PMMA calibration)) and a residual MMA content of 32.8% (as determined by ¹H NMR). 5-mL aliquots of the reaction mixture were combined with acetone to provide diluted solutions with ca. 10 and 20 wt.% of polymer concentration. Cellulose filter paper (substrate) was impregnated with the corresponding polymer solution to adsorb a polymer film. The impregnation process was performed using two solutions with a polymer concentration of 10 and 20 wt.%, respectively, and 1 to 3 layers (L) to yield polymer-physisorbed substrates. The polymer-physisorbed substrates were subjected to an airstream in a fume hood for 80 h; thereafter, different amounts of residual monomer, physisorbed solution (per pristine substrate) and yield of purified polymer (per pristine substrate) were obtained for the substrates shown in Table 3.

As shown in Table 3, Sample C (PMMA of higher molar mass) was efficiently purified to obtain polymer-physisorbed substrates with a monomer content < 1 % in most cases. Thus, the purification method disclosed herein benefited from a limited diffusion shown by polymers with a higher molar mass.

Example 4

Reproducibility and homogeneity of the physisorption process in the purification method disclosed herein are important aspects for subsequent characterization or chemical transformations. The homogeneity of the physisorbed PMMA on the corresponding substrates (Sample B, Example 2) was examined by means of UV-Vis spectroscopy. Different zones of a PMMA-physisorbed substrate were carefully cut off and used to prepare solutions with a theoretically identical polymer concentration (0.1 wt. %). For instance, PMMA-physisorbed substrates with two layers of polymer solution, derived from solutions of different polymer concentration (B10-2L and 620-21). were used to prepare the corresponding samples for quantifying the intensity of the UV-Vis absorption band at 310 nm (ascribed to the end-group of the polymer chains) [16], Additionally, a control solution, with a polymer concentration of 0.1 wt. %, was prepared from the same crude polymeric solution (Sample B; see Example 2) and purified by a method well-known in the art (/'.e., precipitation, Sample B₂O-P)-

Fig. 3A shows that the intensity of the absorbance signal was similar for the three different solutions prepared from sample B^^L (using different zones of the corresponding substrate) at the same concentration (SD = 0.021 ). Moreover, the intensity of these signals is also similar to that recorded for the control solution (dotted line). Analogous experiments, using solutions prepared from the respective precipitated polymers, yielded a standard deviation (SD = 0.020, Fig. 3B) comparable to samples subjected to the purification method disclosed herein. Thus, polymer solutions could be prepared from polymer-physisorbed substrates in a quantitative manner. Consequently, the purification method disclosed herein can be regarded as a homogeneous, reproducible, and readily accurate method of polymer purification.

Example 5: Comparative study of the purification method disclosed herein with other polymer purification techniques.

The effectiveness of the purification method disclosed herein was compared to that of other conventional polymer purification techniques well-known in the art (/.e., precipitation and dialysis). For this purpose, the assessed variables were removal of unreacted monomer, effect of the purification method on the M_n and £) of the polymer, and amount of required solvent for the entire purification process. Table 4 exemplifies the final properties of PDMAEMA (Sample A; see Example 1 for details of the polymer synthesis) subjected to three purification methods.

Table 4. Measured properties of PDMAEMA (Sample A, Example 1 (20 wt. %)) after separating residual monomer by three different purification techniques.

Method Residual monomer M_n [kg mol'¹] ^c) D SD [kg mol'¹] Solvent to polymer ratio [wt. content [%] ^b) %] ^d)

Crude Polymer 41.7 6.2 1.25

Physisorption ^a) 0.29 6.8 1.27 0.3 24:1

Precipitation 0.71 7.5 1.24 0.5 900:1

Dialysis 0.22 7.4 1.77 0.6 13400:1 a⁾ Performed with a substrate adsorbed with sample A₂O-2L; ^b> Estimated by ¹H NMR (ratio of monomer to polymer signal); ^c) Estimated by Size Exclusion Chromatography (SEC) in CHCI₃, Et₃N, and 2-propanol (Rl detection, PMMA calibration); ^d) Ratio in weight of solvent used to purify one unit of polymer.

As observed in Table 4, the “crude” polymer mixture (sample obtained directly after the polymerization reaction; see Example 1 for details of the polymer synthesis) revealed a high residual monomer content. After purification, the residual monomer content was < 1 wt. % by all three surveyed methods. The purification by the purification method disclosed herein decreased the amount of residual monomer by ca. 40% respect to that obtained by the precipitation method (which was performed in hexane, three cycles). In comparison with the dialysis method, the purification method of physisorption disclosed herein revealed a similar final monomer content, which validates the effectiveness of the purification method disclosed herein.

Moreover, it is known that some polymer properties such as molar mass distribution and £> can be altered when a polymer sample is subjected to different purification procedures. For instance, M_n and £> values, and SEC traces displayed in Table 4 and Fig. 4, respectively, show that the molar mass distribution of the polymers purified by precipitation (up to three cycles) shifts towards a higher A _n range in relation to the “crude” polymer sample (dotted line). After three precipitation cycles, SD values of 0.5 and 0.3 and 0.6 kg mol'¹ were estimated for M_n of samples A, B and C (see Examples 1 to 3 for details of the polymer synthesis), respectively. These deviations are ascribed to the removal of low molar mass polymer chains, which remain dissolved or dispersed in the solvent/non-solvent mixture, and their subsequent elimination during consecutive filtration steps of a precipitation procedure [17,18]. Thereafter, as multiple variables can affect the final molar mass and the corresponding distribution of a purified polymer material during a precipitation process, well-examined and customized protocols for different polymer samples must be pre-established to obtain precise and reproducible results utilizing this technique. As shown in Table 4 and Fig. 4 and taking as a reference the “crude” polymeric solution (dotted lines), SEC traces of polymers purified by the physisorption purification methods disclosed herein revealed that their M_n and £) were significantly less affected than those of samples subjected to the other purification procedures. Moreover, the obtained SD values were the lowest for the physisorption purification method disclosed herein when a solution of 20 wt. % polymer was used (Fig. 4: Samples A, SD = 0.3 kg mol'¹; B, SD = 0.05 kg mol'¹). An additional analysis of the measured £) revealed that polymers purified by the physisorption purification method disclosed herein remained nearly unmodified, while the values derived from precipitated polymers decreased after each precipitation cycle (Table 4). Regarding the dialysis method, a somewhat similar effect on the molar mass distribution of the obtained polymers was observed (Fig. 4, dialysis). Thus, the selection of appropriate dialysis conditions is critical as multiple factors impact the effectiveness of a dialysis system (e.g., solvent, polymer concentration, molecular weight cut-off (MWCO) and chemical compatibility of the utilized dialysis membrane, stirring, temperature, among others) [19] [20,21].

Another important parameter is the amount of purification solvents used in each evaluated purification technique. As shown in Table 4, the removal of residual monomer from a given sample of polymer (e.g., PDMAEMA, Sample A, see Example 1 for details of the polymer synthesis), the techniques of precipitation and dialysis required considerably larger equivalents (in weight) of solvent per equivalent (in weight) of purified polymer (compare solvent to polymer ratio in Table 4) than the purification method based on physisorption and disclosed herein. This fact, added to the necessity of specialized set-ups to perform dialysis or precipitations (e.g., dialysis membranes of different MWCO, large precipitation vessels, or stirring systems), lead to an increase in the costs for separating residual monomer (or other volatile substances) from polymer samples. The purification method disclosed herein demonstrated better efficiency as only a minimum amount of purification solvent was necessary to yield polymers with a residual monomer content comparable to that obtained in conventional purification methods.

To further exemplify the effectivity of the physisorption purification method disclosed herein, cytotoxicity assays of different aqueous polymeric solutions, prepared from Sample A (Example 1 ) after purification by the method disclosed herein and the benchmark methods (/.e., precipitation and dialysis), was investigated on L929 cells after incubation for 24 h and using polymeric solutions of different concentration (up to 1 mg mL'¹) (Fig. 5). As a negative control and for comparison purposes, a solution of Sample A (Example 1 ), which was only rota evaporated directly after the synthesis of the polymer, was included in this analysis. Fig. 5 shows that the polymeric solutions prepared from polymer-physisorbed samples revealed similar cell viability to that obtained from dialyzed samples. Such tendency continued up to 50 pg mL’¹ of polymer concentration; after this concentration value the cell viability decreased for all tested samples. It should be noted that DMAEMA monomer and its respective PDMAEMA homopolymer (Sample A; Example 1 ) are known to be cytotoxic substances, which can be ascribed to the potential formation of cationic charges generated at their pendant amino groups in aqueous solutions [22]. On the other hand, the methods of precipitation and rota evaporation revealed a more pronounced cytotoxicological effect on the evaluated cells from 10 pg ml_’¹ of polymer concentration onwards, and a sharp decrease of cell viability after 50 pg mL’¹ of polymer concentration, which clearly denotes the lower efficiency of the these methods to remove cytotoxic monomers. Hence, the efficiency of the physisorption purification method disclosed herein for the removal of toxic monomers was further validated.

Example 6: Chain extension reactions of RAFT homopolymers subjected to the purification method disclosed herein.

In at least one aspect, this disclosure provides a method to obtain physisorbed- polymer substrates which can be used for subsequent chemical transformations. In certain embodiments, the method is performed in a micro scale. In certain embodiments, for example physisorbed-PMMA substrates (Sample B, see Example 2 for details of the polymer synthesis and preparation of the physisorbed-PMMA substrates) were used as macro chain transfer agents (macroCTA) to perform a copolymerization reaction with a second hydrophilic monomer (DMAEMA) and produce amphiphilic block copolymers. Five micro-scale tests were performed by measuring sub-milligram scale reactants and polymer-physisorbed substrates. As noted above, the substrate was conveniently cut into small pieces to obtain the desired amount of polymer (according to the yield of physisorbed polymer on the substrate, as determined by gravimetry (see Table 2)). Thereafter, the respective pieces of substrate were transferred into a reaction vessel with reaction solvent (/.©-, 1 ,4-dioxane). The substrate was incubated and magnetically stirred for 20 minutes to redissolve the physisorbed polymer. Next, DMAEMA, AIBN initiator, and 1 ,3,5- trioxane were added into the reaction vessel. The total reaction volume was 1.6 mL with an initial DMAEMA monomer concentration of 0.25M (see Table 5). Thereafter, the reaction vessel was septum sealed, and subsequently degassed by sparging N₂ gas for 20 minutes.

The reaction mixture was placed into pre-heated oil bath at 65 °C for 12 h. Aliquots were withdrawn at 0 and 12 h to estimate monomer conversion and molar mass of the obtained block copolymers. Once the reaction time elapsed, the “crude” mixtures were purified by the method disclosed herein, as described before. In a similar embodiment, a PMMA-physisorbed substrate containing the desired amount of the respective PMMA were immersed in 1 ,4-dioxane for 1 h prior to polymerization (note that in the previous embodiment the substrate remained inside the polymerization mixture during the entire chain extension reaction). Thereafter, the respective pieces of substrate were removed from the reaction mixture. Such mixture of re-dissolved polymer (/.e., macroCTA) was used to perform a second chain extension reaction as described above. For comparison purposes, a third set of chain extension reactions were carried out in a conventional procedure. To this end, the respective amount of PMMA purified by precipitation was used and copolymerized by the procedure described above (see Table 5, entries I and III).

As summarized in Table 6, the results obtained from the conventional procedure (i.e., macroCTA purified by precipitation) yielded comparable results (molar mass and monomer conversion) to the results obtained from macroCTA’s derived from polymer-physisorbed substrates. Furthermore, the experimental results of molar mass were similar to the theoretical values, and the £) value was as low as 1.17 for the macroCTA’s obtained from physisorbed substrates (see Table 6, entry II). As shown for entries II and IV, the incubation period and subsequent removal of the substrate, prior the reactions, improved the control over the chain extension to yield block copolymers with relatively low values of

In sum, the micro-scale (e.g., from 1 to 100 mg) block copolymerization provided predictive outcome results using polymer-physisorbed substrates as source of macroCTAs; similar to the benchmark polymerization using a polymer purified by precipitation (compare entries I with II, and III with IV and V in Table 6, respectively). As shown in entries II and IV (Table 6), the removal of the substrate could be optional as the polymerization with the substrate inside the reaction mixtures yielded similar values to those obtained by the conventional method. The final block copolymers were purified by the physisorption purification method disclosed herein, yielding purified materials with a low content of residual monomer (see Table 7). Thus, a purified library of block copolymers for further studies and/or characterization was obtained by the purification method disclosed herein. The purification of amphiphilic (block, statistical, gradient or asymmetric) copolymers is known as a challenging, time-consuming, and poorly reproducible procedure by means of conventional techniques; such procedures may require exhaustive preparative studies to find adequate solvent mixtures to perform an effective precipitation or dialysis [23,24],

Table 7. Amount of residual monomer, determined by ¹H NMR, for the synthesized block copolymers (P(MMA-b-DMAEMA)) after treatment with the purification method disclosed herein.

^a) Estimated by ¹H NMR (ratio of monomer to polymer signal).

The method for polymer purification disclosed herein allowed for the preparation of a library of copolymers in a micro scale, avoiding the use of large amounts of solvents and preventing the use of intensive preparative or sophisticated purification procedures.

Example 7: Automated synthesis and purification methods for the screening of polymer libraries

14 polymerization reactions were performed in parallel to produce purified statistical copolymers via high throughput schemes (see Table 8). In this example, a (co)polymer library of poly[2-(dimethylamino) ethyl methacrylate-stat-hydroxyethyl methacrylate] (P(DMAEMA-stat-HEMA) was synthesized using an automated parallel synthesizer and procedures well-known in the art. In this scheme, solutions of monomers, initiator, chain transfer agent, solvent, and internal reference were transferred into the reaction vessels with the aid of a robotized liquid dispensing unit. The reactions were degassed with N₂ for 20 minutes and subsequently carried out at 80 °C for 5 h. Different conditions in each of the 14 reactions are summarized in Table 8. After the polymerization time elapsed, each “crude” polymer mixture was diluted to ca. 20 wt.% with the aid of the robotized liquid dispensing unit. Thereafter, each of the obtained polymer solutions were purified by manually performing the purification method of physisorption disclosed herein.

The results from this set of polymerizations are shown in Table 9. As shown, the exemplified libraries of copolymers were purified to yield (co)polymers with residual monomer content as low as 2%. Regardless of the copolymer composition, the purification procedure was performed in the same way. As shown, the final properties of the polymers purified by physisorption (determined by ¹H NMR) are quite comparable to the theoretical values of molar mass and copolymer composition. Thus, a library of statistical copolymers was prepared and successfully purified with the purification method disclosed herein. After applying an airstream to the polymer-physisorbed substrates in a fume hood, the final amount of physisorbed polymer was calculated to be in the range from 18 to 37 wt.%.

The purification method disclosed herein was also tested in an automated fashion using a robotized liquid dispensing unit and an adapted ventilator installation (to directly apply an airstream to the physisorbed substrates). Such procedure was implemented by adding the “crude” polymer solution to the corresponding substrate (cellulose filter paper). The robotized liquid dispensing unit was used to dispense the polymer solution dropwise and homogeneously over the entire surface of the corresponding substrate. The addition of the solution was performed using, but not limited to, a zig-zag scheme to avoid any zones with an excess (or lack) of polymer solution. For this comparison, selected samples of (co)polymers were purified by both the manual and the automated physisorption purification procedure disclosed herein.

The results shown in Table 10 revealed that, for the different (co)polymer compositions tested, the amount of residual monomer was similar for both methods of physisorption: manual and fume hood extraction (Samples 8 to 10, Table 9) or robotized liquid dispensing and ventilator installation (Samples 8A to 10A, Table 10). Moreover, the obtained composition and M_n of the (co)polymers was found to have comparable results between both utilized methods of physisorption. Thus, the automated procedure was validated as a method to yield similar results to those obtained with the manual procedure. Therefore, the physisorption purification method disclosed herein was successfully adapted to an automated parallel platform for the synthesis and purification of (co)polymer libraries. Thus, the high-throughput workflow disclosed herein for the synthesis and characterization of (co)polymers can be performed in an automated fashion.

A screening of other physicochemical properties of the obtained (co)polymer libraries can also be performed using polymer-physisorbed substrates to prepare polymer solutions for further characterizations. For instance, after purification time elapsed, the polymer-physisorbed substrates were cut and re-dissolved in water to prepare aqueous polymer solutions. Thereafter, the thermo-responsive behavior of aqueous solutions derived from the synthesized and purified polymers was analyzed by light transmittance measurements. As shown, in Fig. 6A, aqueous polymeric solutions of Samples 8 to 13 (Table 9), revealed the thermo-responsive effect of PDMAEMA- based polymers well-known in the art. A cloud point temperature was registered at ca. 36 °C for the PDMAEMA homopolymer sample (entry 8, Table 9). The cloud point temperature increased with decreasing the comonomer composition ratio of DMAEMA/HEMA. Thus, the addition of hydrophilic HEMA monomer units, increased the solubility of these copolymers to the point where the thermoresponsive behavior was practically removed for a sample with a comonomer composition ratio of DMAEMA/HEMA = 80/20 (entry 13, Table 9).

A second example of characterization of the obtained copolymers was performed by evaluating the cytotoxicity of these materials in aqueous solutions (Fig. 6B). The cytotoxicity assay results confirmed that copolymers with a high content of PDMAEMA (entries 1 and 2, Table 9) are toxic materials for L929 cells after 24 h of incubation and from 100 pg mL’¹ of polymer concentration onwards. Resulting copolymers with a content of PHEMA greater than 48% (entries 3 to 7, Table 9) showed a negligible cytotoxicological effect (up to 1000 pg mL’¹ of polymer concentration). Hence, the process of synthesis and purification disclosed herein allowed for the rapid and straightforward identification of optimal compositions to produce non-cytotoxic P(DMAEMA-stat-HEMA) copolymers.

In another set of characterization examples, the obtained library of P(DMAEMA-sfat- HEMA)-physisorbed substrates was directly utilized as solid samples. To such end, as described above, the polymer-physisorbed substrates were conveniently cut into pieces. In this example, the substrates were cut in circular shapes (ca. 5 mm) to fit into commercially available DSC and/or TGA holders, for the direct testing of the thermal behavior of the physisorbed polymers. For instance, as shown in Fig. 6C, the glass transition temperature (T_g) of the library of copolymers (Samples 1 to 7, Table 9) systematically increased (from 9.8 to 89.4 °C) by the incorporation of HEMA monomeric units into the copolymer chains. Such behavior was confirmed by other researchers for a similar P(DMAEMA-stat-HEMA) library synthesized and purified by conventional procedures [25].

The automated synthesis and purification method disclosed herein allowed the fast and straightforward obtention, characterization, and screening of a library of copolymers; therefore, the exemplified library of copolymers corroborated experimental results observed in a previous report [25], without the need of complex, intensive, and/or time-consuming purification procedures. Hence, the library of copolymers was rapidly screened to find the most suitable composition to optimize a given property and/or application, such as thermo-responsive or thermal behavior, cytotoxicity, among others. Moreover, the examination of copolymer libraries, could be easily extended to include more compositions and/or other variables (e.g., molar mass, structure, monomers, chain transfer agents, etc.) to perform highly systematic investigations with automated synthesis procedures along with the easy-to- implement purification method disclosed in this invention.

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Claims

46 Claims

1. A method of reducing amount of residual volatile substances in polymers containing impurities, the method comprising: a. Dissolving the polymer containing impurities in a solvent to produce a polymer solution; b. Impregnating the polymer solution onto a substrate and the subsequent removal of volatile substances; wherein said method results in the formation of a purified polymer.

2. The method of claim 1 , further comprising: c. Quantitatively recovering the purified polymer by contacting the impregnated substrate with a solvent for the re-dissolution of purified polymers for chemical transformations and/or characterization methods.

3. The method of claim 1 or 2, wherein the solvent is selected from the group consisting of hydrocarbons, ketones, alcohols or water.

4. The method of claims 1 to 3, wherein the impurities to be removed are volatile substances from the group consisting of hydrocarbons, monomers, ketones, alcohols or water. 47

5. The method of claims 1 to 4, wherein the substrate is a porous material with large surface area, high wettability and chemically inert to the solvents and impurities in use.

6. The method of claims 1 to 5, where in the purification procedure a polymer is physisorbed onto a substrate, which is supported in a suitable container, and a gas stream or vacuum are used to remove volatile substances from said substrate.

7. The method of claims 1 to 6, where different temperature conditions are provided by suitable heating or cooling devices with control systems.

8. The method of claims 1 to 7, wherein the purification procedure is one of at least two procedures carried out in parallel and/or in robotized platforms.

9. The method of claims 1 to 8, wherein a polymer is physisorbed into a substrate using a robotized liquid dispensing unit; wherein the substrate is supported in a suitable container of the robotized platform.