Ultra-Pure Methyl Vinyl Ether-Co-Maleic Anhydride Copolymers and Methods for Preparing Same

Abstract

Ultra-pure methyl vinyl ether-co-maleic anhydride (PMVE/MA) copolymers and the process to produce such ultra-pure polymers by removing trace impurities are provided. A process to provide an ultra-pure methyl vinyl ether-co-maleic anhydride material by solvent washing PMVE/MA copolymer with a solvent, comprises the steps of: (1) providing a solvent system in which impurities in the copolymer matrix are soluble and in which the PMVE/MA copolymer is not soluble, and wherein the solvent system does not react with the copolymer; (2) washing a dry powder or wet filter cake of PMVE/MA copolymer with the solvent system to efficiently and effectively extract trace impurities from the matrix; (3) filtering said copolymer from the solvent system; and (4) drying the subsequent wet filter cake of said copolymer to obtain an ultra-pure methyl vinyl ether-co-maleic anhydride copolymer.

Claims

1. A process to provide an ultra-pure methyl vinyl ether-co-maleic anhydride material by solvent washing a methyl vinyl ether-co-maleic anhydride (PMVE/MA) copolymer with a solvent, comprising the steps of: (1) providing a solvent system in which one or more impurities in the copolymer matrix are soluble and in which the PMVE/MA copolymer is not soluble, and wherein the solvent system does not react with the copolymer; (2) washing a dry powder or wet filter cake of PMVE/MA copolymer with the solvent system to efficiently and effectively extract trace impurities from the copolymer matrix; (3) filtering said copolymer from the solvent system; and (4) drying the subsequent wet filter cake of said copolymer to obtain an ultra-pure methyl vinyl ether-co-maleic anhydride copolymer.

2. The process according to claim 1, wherein the one or more impurities comprise one or more of dimethoxy ethane (DME), trimethoxy butane (TMB), acetaldehyde and methanol.

3. The process of claim 1, wherein the solvent system is selected from the group consisting of chlorinated solvents, hydrocarbon, acetates, nonreactive alcohols, aromatics, ethers and any mixture thereof.

4. The process of claim 3, wherein the solvent system comprises methylene chloride, isopropyl acetate, ethyl acetate, isopropyl acetate, cyclohexane, pentane, hexane, cyclohexane, heptane, t-butanol, toluene, or methyl vinyl ether or mixtures thereof.

5. The process according to claim 1, wherein the weight ratio of wash solvent to PMVE/MA copolymer in step (2) is in the range of 1:1 to 20:1 wt/wt.

6. The process according to claim 1, wherein the wash temperature during step (2) is in the temperature range of 20-140° C.

7. The process according to claim 1, wherein step (2) is performed in a continuous manner or individual batch wash cycles.

8. The process according to claim 1, wherein the total extraction time of step (2) is in the range of 5 minutes to 48 hours.

9. An ultra-pure methyl vinyl ether-co-maleic anhydride copolymer or a derivative thereof having individual impurity levels, except for solvent, of less than 5000 ppm.

10. The ultra-pure methyl vinyl ether-co-maleic anhydride copolymer or a derivative thereof according to claim 9, having individual impurity levels of one or more of methoxy ethane (DME), trimethoxy butane (TMB) levels, acetaldehyde and methanol, of less than 5000 ppm.

11. The ultra-pure methyl vinyl ether-co-maleic anhydride copolymer derivative of claim 9, being ultra-pure methyl vinyl ether-co-maleic anhydride copolymer reacted with water, alcohol and/or metal salts.

12. The ultra-pure methyl vinyl ether-co-maleic anhydride copolymer derivative of claim 11, being a methyl vinyl ether-co-maleic acid copolymer, methyl vinyl ether-co-maleic half ester copolymer, methyl vinyl ether-co-maleic acid sodium/calcium mixed salt or methyl vinyl ether-co-maleic acid calcium/zinc mixed salt.

13. A composition or device comprising an ultra-pure methyl vinyl ether-co-maleic anhydride copolymer or a derivative thereof according to claim 9.

14. The composition or device of claim 13, being a pharmaceutical composition, a medical device, a personal care composition, an oral care composition or a wound care composition.

Description

LEGEND TO THE FIGURES

[0035] FIG. 1: GC chromatograph of impurity concentrate from untreated commercial PMVE/MA copolymer.

[0036] FIG. 2: GC chromatograph of an impurity concentrate from washed commercial PMVE/MA copolymer using a process of the invention.

[0037] FIG. 3: GC chromatograph of the impurity concentrate of the original PMVE/MA copolymer before dichloromethane wash from Example 4.

[0038] FIG. 4: GC chromatograph of the impurity concentrate of the PMVE/MA copolymer after being washed twice with dichloromethane from Example 4.

[0039] FIG. 5: Expanded GC chromatograms showing the TMB impurity peak reduction with solvent reference for the toluene wash sequence conducted at 75° C. (for details see Example 6 and Table 5). Panel A: original PMVE/MA copolymer sample comprising 321 ppm TMB. Panel B: after 1st wash, comprising 102 ppm TMB. Panel C: after 2nd wash, comprising 63 ppm TMB.

EXPERIMENTAL SECTION

Impurity Analysis Method:

[0040] Five grams of dry PMVE/MA copolymer powder is placed in a Soxhlet extractor and extracted with 300 ml of analytical grade methylene chloride for 24 hrs. The methylene chloride is concentrated to approximately 5 ml and the concentrate analyzed by direct GC injection. Standard curve analysis is used to determine exact amounts of dimethoxy ethane (DME) and trimethoxy butane (TMB) in the extracted samples.

[0041] Though all impurities showed significant reduction after the wash process, determining all impurity compositions and concentrations was unrealistic. Instead, the impurities DME and TMB were followed to show the decrease in impurity levels. Both DME and TMB are due to acetaldehyde side reactions and represent the type of impurities expected during the polymerization process to make PMVE/MA copolymers.

Example 1: Comparison of GC Chromatograms of PMVE/MA Before and After Wash Process Using Dichloromethane Solvent

[0042] Commercial PMVE/MA batch AN075 was washed with a 5-fold excess of dichloromethane. The temperature for the extraction was 40° C. and a total of 2 batch extractions were conducted for a period of 3 hr each. The GC chromatograms for the resultant impurity concentrate for the normal and washed batches are shown in FIGS. 1 and 2, respectively.

[0043] As can be seen from the GC chromatograms, all impurities are significantly reduced as a result of the wash process. DME and TMB levels for the unwashed AN075 were 208 and 313 ppm, respectively. The DME and TMB levels after undergoing the wash process were 12 and 60 ppm, respectively.

Example 2: Wash Experiment of PMVE/MA Copolymer Using Ethyl Acetate/Cyclohexane Solvent Mix

[0044] PMVE/MA batch AN088 was washed multiple times with a 4-fold excess of ethyl acetate/cyclohexane solvent mix (weight ratio 54:46). Each wash cycle was conducted at 70° C. for 3 hr, the product filtered, a sample taken for impurity testing and then underwent the subsequent wash cycles. In total, four wash cycles were conducted on the PMVE/MA copolymer. Table 1 shows the reduction of TMB after each wash cycle.

TABLE-US-00001 TABLE 1 Sample Wash cycle TMB (ppm) AN088 original 0 49 AN088-1 wash 1 5 AN088-2 wash 2 2 AN088-3 wash 3 1 AN088-4 wash 4 0.6
As can be observed in Table 1, the ethyl acetate/cyclohexane 54/46 by wt mixture is an excellent solvent system for the removal of trace impurities in the PMVE/MA copolymer. The exact number of washes is developed depending on the product requirement with respect to allowable trace impurities.

Example 3: Effect of Wash Time on the Removal of Trace Impurities in PMVE/MA Copolymers

[0045] A batch of PMVE/MA copolymer was washed with ethyl acetate/cyclohexane 54/46 wt solvent mix for varying wash durations. The wash temperature was 73° C. and the amount of solvent used was 3-fold excess of copolymer. The effect of wash duration on impurity removal is summarized in Table 2 below.

TABLE-US-00002 TABLE 2 Sample Wash Duration TMB (ppm) PMVE/MA original 0 90 PMVE/MA-W 15 min 67 PMVE/MA-W1 1 hr 26 PMVE/MA-W2 2 hr 18 PMVE/MA-W3 3 hr 16 PMVE/MA-W4 6 hr 8
As can be seen in the table, the duration of washing step (2) in a method of the invention is an important factor in removing trace impurities from the PMVE/MA matrix. This is not surprising, because impurities are expected to be both on the powder surface and entrapped in the polymer powder matrix and thus the polymer must have time to swell so the impurities can be released and washed away. The final number and duration of individual wash cycles will typically depend on balancing economic factors and required degree of impurity removal.

Example 4: Wash Experiment of PMVE/MA Copolymer Using Dichloromethane Solvent

[0046] PMVE/MA batch OAS160501002 underwent multiple dichloromethane wash cycles and DME and TMB impurity levels monitored after each wash cycle. The temperature for each solvent wash cycle was conducted at 50° C. for 3 hr and the amount of solvent used was 4-fold excess of copolymer based on weight. The following Table 4 shows a summary of the impurity results.

TABLE-US-00003 TABLE 4 Sample DME (ppm) TMB (ppm) PMVE/MA original 52 66 (see FIG. 3) PMVE/MA-1.sup.st wash 9 20 PMVE/MA-2.sup.nd wash 0.8 2 (see FIG. 4) PMVE/MA-3.sup.rd wash 0.6 0.7 PMVE/MA-4.sup.th wash 0.3 0.3
The GC chromatograph representing the impurity profile for the original PMVE/MA sample is shown in FIG. 3 with both DME and TMB impurities identified. FIG. 4 shows the resultant GC chromatograph of the extracted impuities from the PMVE/MA powder after being washed twice with dichloromethane.

Example 5: Wash Experiments of PMVE/MA Copolymer Using a Methyl Vinyl Ether Solvent System

[0047] PMVE/MA material OAS170308014 underwent 3 wash cycles, with each wash cycle using a 3-fold weight excess of methyl vinyl ether at 35° C. for 3 hr. The TMB level for the initial PMVE/MA copolymer before wash was 59 ppm and the TMB level after the 3 wash cycles was 5.2 ppm.

Example 6: Wash Experiments of PMVE/MA Copolymer Using a Toluene Solvent System

[0048] PMVE/MA material OAS170108002 was washed with a 4-fold excess of toluene by weight. Both the wash temperature and number of wash cycles were varied to see the effect on impurity removal while the actual wash duration was kept at 3 hr. The following Table 5 shows a summary of the results.

TABLE-US-00004 TABLE 5 Wash Temp. Sample (° C.) TMB (ppm) PMVE/MA original — 321 PMVE/MA-1.sup.st wash 75 102 PMVE/MA-2.sup.nd wash 75 63 PMVE/MA-1.sup.st wash 100 26 PMVE/MA-2.sup.nd wash 100 4.1
As can be seen from the table, not only the number of wash cycles, but the wash temperature can effect the rate of impurity removal. The actual GC chromatographs for the wash sequence conducted at 75° C. are included in FIG. 5. The chromatographs have been enlarged and the TMB impurity peak identified.

Example 7: The Effect of Impurity Removal Based on Composition of Solvent System

[0049] PMVE/MA material AN024M underwent one wash cycle using various solvent systems. The wash process was conducted at 70° C. for 3 hr with a 4-fold excess of solvent to copolymer based on weight. The following table 6 is a summary of the results.

TABLE-US-00005 TABLE 6 Sample Wash solvent system TMB (ppm) AN024M original — 31 AN024-CH cyclohexane  35* AN024-IC 25% isopropyl acetate/75% cyclohexane 25 AN024-EC 54% ethyl acetate/46% cyclohexane  5 AN024-IPAc Isopropyl acetate 10 AN024-HTB 75% Hexane/15% t-butanol 23 AN024-TB t-butanol 12 *no significant decrease based on original sample. Within the test data error.