A PROCESS FOR PURIFICATION OF POLYETHER BLOCK COPOLYMERS

Abstract

A process for purification of polyether block copolymers comprising polyoxyethylene and polyoxypropylene moieties using sequential multi-column size exclusion chromatography apparatus operated as a counter current moving bed wherein a process cycle comprises the steps of.

Claims

1. A process for purification of polyether block copolymers comprising polyoxyethylene and polyoxypropylene moieties using a sequential multi-column size exclusion chromatography apparatus operated as a counter current moving bed wherein a process cycle comprises (A) providing a feed mixture comprising the block copolymers dissolved in an eluent in a feed vessel, (B) subjecting the feed mixture to a chromatographic separation by introducing the feed mixture into an apparatus comprising a plurality of chromatographic columns sequentially linked together, each column comprising a stationary bed, (C) after separation collecting a first eluent portion enriched in the purified target block copolymer and a second eluent portion depleted of the purified target block copolymer, (D) collecting the purified block copolymer from the first eluent portion, and (E) recovery of the depleted eluent and recycling the depleted eluent from the solvent recovery zone into the process.

2. The process according to claim 1, wherein the counter current moving bed is operated as a simulated or actual moving bed.

3. The process according to claim 1, wherein the eluent is an organic solvent or water or a mixture thereof.

4. The process according to claim 1, wherein the eluent is an organic solvent or a mixture of organic solvents.

5. The process according to claim 1, wherein the eluent is methanol.

6. The process according to claim 1, wherein the stationary bed comprises a size exclusion chromatographic packing material.

7. The process according to claim 1, wherein the stationary bed comprises as a packing material inorganic carbons, zeolites, aluminas, or silica based adsorbents.

8. The process according to claim 1, wherein the stationary bed comprises as a packing material an inorganic adsorbent selected from the group consisting of silica modified with diols.

9. The process according to claim 8, wherein the stationary bed consisting of silica modified with diols is pre-treated with methanol until stable retention times are achieved.

10. The process according to claim 1, wherein the stationary bed comprises as a packing material an inorganic adsorbent which is a silica material with a pore size of 1-100 nm.

11. The process according to claim 10, wherein the stationary bed comprises as a packing material an inorganic adsorbent which is a silica material with a mean particle size distribution of 5-1000 m.

12. The process according to claim 10, wherein the stationary bed comprises as a packing material an inorganic adsorbent which is a silica material with a pore size of 5-20 nm.

13. The process according to claim 1, wherein the stationary bed comprises as a packing material an organic or organic based adsorbent.

14. The process according to claim 1, wherein the stationary bed comprises as a packing material an organic adsorbent selected from the group consisting of a carbohydrate and carbohydrates crosslinked with agarose or acrylamides or cross linked organic polymers.

15. The process according to claim 1, wherein the chromatographic separation is carried out at a pressure in the range of from 0.01 to 15 MPa.

16. The process according to claim 1, wherein the chromatographic separation is carried out at a pressure in the range of from 0.05 to 0.5 MPa.

17. The process according to claim 16, wherein the chromatographic separation is carried out at a pressure in the range of from 0.05 to 0.5 MPa and with a mean particle size of the packing material in the range of from 50 m to 1000 m.

18. The process according to claim 1, wherein the chromatographic separation is carried out at a pressure in the range of from >0.5 MPa to 10 MPa

19. The process according to claim 18, wherein the chromatographic separation is carried out at a pressure in the range of from >0.5 MPa to 10 MPa and with a mean particle size of the packing material in the range of from 5 to 50 m.

20. The process according to claim 1, wherein the chromatographic separation is carried out at 20 to 25 C.

21. The process according to claim 1, wherein the chromatographic separation is carried out at elevated temperatures in the range of from 26 to 65 C.

22. The process according to claim 1, wherein the first eluent portion and the second eluent portion are independently of each other subjected to a concentration step.

23. The process according to claim 22, wherein the concentration step of the first eluent portion enriched in the block copolymer and the second eluent portion depleted of the block copolymer is carried out by evaporation, drying, or distillation.

24. The process according to claim 22, wherein the concentration step of the first eluent portion enriched in the block copolymer and the second eluent portion depleted of the block copolymer is carried out by liquid extraction, membranes, crystallization, adsorption, or other solvent recovery techniques.

25. The process according to claim 1, comprising a first filter step prior to the separation chromatography by passing the feed mixture through a filter bed of silica or aluminas or molecular sieves or activated carbons or polymeric adsorbents or ion exchangers or mixtures of thereof.

26. The process according to claim 1 comprising a second filter step after the separation chromatography by passing the depleted eluent through a filter bed of silica or aluminas or molecular sieves or activated carbons or polymeric adsorbents or ion exchangers or mixtures of thereof, positioned in the eluent recycling zone.

27. The process according to claim 1, comprising the step of subjecting the first eluent portion rich in the target block copolymer to a second simulated moving bed separation process cycle.

28. The process according to claim 1, comprising one or more eluent concentration steps between the first and the second process cycle

29. The process according to claim 1, wherein the polyether block copolymers comprising polyoxyethylene and polyoxypropylene moieties are poloxamer 188 or poloxamer 407.

Description

[0091] FIG. 1 depicts a 6 columns SMB unit with column arrangement nj=[1 2 2 1] over a complete cycle (from 0 to 6 t.sub.s, where t.sub.s is the ports switching time); (a) until the first switch; (b) from the first switch to the second; eluent=desorbent or solvent; extract and raffinate the streams where the more and the less retained key compounds are collected, respectively.

[0092] By defining a section as the part of the SMB unit where the fluid flow rate is approximately constant (limited by inletFeed and Eluentand outletExtract and Raffinatestreams, FIG. 3), by considering Atarget molecule less retained in the SEC column, and, B target molecule more retained in the SEC column, it is possible to find four different sections with different roles:

[0093] Section I: Regeneration of the adsorbent (desorption of B, and A if still present, from the solid);

[0094] Section II: Desorption of A and adsorption of B (so that the extract, rich in B, is not contaminated with A);

[0095] Section III: Adsorption of B and desorption of A (so that the raffinate, rich in A, is not contaminated with B);

[0096] Section IV: Regeneration of the eluent (adsorption of A, and B if still present, from the fluid).

[0097] If one considers that at certain moment in the operation of an SMB unit the positions of the inlet outlet ports are represented by FIG. 1a, after a period of time (switching time, t.sub.s), all the injection and withdrawal points move one column in the direction of the fluid flow reaching FIG. 1b. The same procedure will continue synchronously after each switching time until the initial location of all the streams is reencountered. When this happens, one cycle has been completed.

[0098] FIG. 2 depicts the set-up of a one-step SMB unit for the purification of poloxamer with solvent recovery wherein the purified target product is collected from the raffinate stream.

[0099] Feed poloxamer Stream 1; Feed Vessel 2; Feed to SMB Unit 3; SMB Unit 4; Extract Stream 5; Extract Solvent Recovery 1 6a; Extract Solvent Recovery 2 6b; Waste Stream 7; Raffinate Stream 8; Raffinate Solvent Recovery 1 9a; Raffinate Solvent Recovery 2 9b; Solvent Recovery Stream 9c; Purified Product Stream 10; Solvent Vessel 11; Solvent Stream to Feed Vessel 12a; Solvent Stream to SMB 12b; Solvent Make-up A.

[0100] FIG. 3 depicts two different set-ups of a two-step SMB unit for removing two different types of impurities. FIG. 3 addresses the embodiment where solvent is recovered after each SMB separation step to avoid extra dilution steps in the downstream when 2 or more SMB steps are involved. Alternatively, an intermediate solvent recovery step can be avoided by directly feeding one of the first SMB step (SMB1) outlets (of interest the one with the product) to the second SMB step (SMB2) with partial of even without any solvent recovery in between. In some cases, one of the solvent recovery (extract solvent recovery 1 or 2 and similar for raffinate) can be avoided, in case of easy solvent recovery systems (where just a single solvent recovery step is enough to meet a separation of commercial interest), or the considerably amounts of solvents are kept in either intermediates, waste or product streams.

[0101] FIG. 3A is a unit where in the first step the LMW impurities are removed, followed by removal of the HMW impurities and recovery of the purified target product from the extract.

[0102] Feed poloxamer stream 1; Feed Vessel 2; Feed to SMB Unit 3; SMB 1 Unit 4; Extract 1 Stream 5; Extract 1 Solvent Recovery 1 6a; Extract 1 Solvent Recovery 2 6b; Waste 1 Stream 7; Raffinate 1 Stream 8; Raffinate 1 Solvent Recovery 1 9a; Raffinate 1 Solvent Recovery 2 9b; Solvent Recovery 1 Stream 9c; Solvent Vessel 1 11; Solvent Stream to Feed Vessel 12a; Solvent Stream to SMB 1 12b; Intermediate Vessel 13; SMB 2 Unit 14; Extract 2 Stream 15; Extract 2 Solvent Recovery 1 16a; Extract 2 Solvent Recovery 2 16b; Purified Product Stream 17; Raffinate 2 Stream 18; Raffinate 2 Solvent Recovery 1 19a; Raffinate 2 Solvent Recovery 2 19b; Solvent Recovery 2 Stream 19c; Solvent Vessel 2 20; Solvent Stream to SMB 2 Unit 21; Waste 2 Stream 22; Solvent Make-up 1 A1; Solvent Make-up 2 A2.

[0103] FIG. 3B is a unit where in the first step the HMW impurities are removed followed by removal of the LMW impurities and recovery of the purified target product from the raffinate stream.

[0104] Feed poloxamer stream 1; Feed Vessel 2; Feed to SMB Unit 3; SMB 1 Unit 4; Extract Stream 5; Extract 1 Solvent Recovery 1 6a; Extract 1 Solvent Recovery 2 6b; Waste 1 Stream 22; Raffinate 1 Stream 8; Raffinate 1 Solvent Recovery 1 9a; Raffinate 1 Solvent Recovery 2 9b; Solvent Recovery 1 Stream 9c; Solvent Vessel 1 11; Solvent Stream to Feed Vessel 12a; Solvent Stream to SMB 1 12b; Intermediate Vessel 23; SMB 2 Unit 24; Extract 2 Stream 25; Extract 2 Solvent Recovery 1 26a; Extract 2 Solvent Recovery 2 26b; Waste 2 Stream 27; Raffinate 2 Stream 28; Raffinate 2 Solvent Recovery 1 29a; Raffinate 2 Solvent Recovery 2 29b; Solvent Recovery 2 Stream 29c; Purified Product Stream 30; Solvent Vessel 2 31; Solvent Stream to SMB 2 Unit 32; Solvent Make-up A1; Solvent make-up 2 A3.

[0105] FIG. 4: Feed Chromatogram for example 1 (LMW removal from P188); injection=0.05 ml of 0.5 wt.-% Poloxamer 188 in methanol; Ahigh molecular weight; Btarget molecular weight polymer; and C target low molecular weight impurity

[0106] FIG. 5: Raffinate Chromatogram for example 1 (LMW removal from P188); injection=0.05 ml of 10 times dilution (wt. ratio) of SMB raffinate over complete 8 switches cycle at cyclic steady state; Ahigh molecular weight; Btarget molecular weight polymer; and C target low molecular weight impurity

[0107] FIG. 6: Extract Chromatogram for example 1 (LMW removal from P188); injection=0.5 ml of SMB extract over complete 8 switches cycle, at cyclic steady state; Ahigh molecular weight; Btarget molecular weight polymer; and C target low molecular weight impurity

[0108] FIG. 7: Feed Chromatogram for example 2a (HMW removal from P188); injection=0.05 ml of feed; Ahigh molecular weight; Btarget molecular weight polymer; and C target low molecular weight impurity

[0109] FIG. 8: Raffinate Chromatogram for example 2a (HMW removal from P188); injection=0.05 ml of SMB raffinate over complete 8 switches cycle at cyclic steady state; Ahigh molecular weight; Btarget molecular weight polymer; and C target low molecular weight impurity

[0110] FIG. 9: Extract Chromatogram for example 2a (HMW removal from P188); injection=0.05 ml of SMB extract over complete 8 switches cycle, at cyclic steady state; Ahigh molecular weight; Btarget molecular weight polymer; and C target low molecular weight impurity

[0111] FIG. 10: Feed Chromatogram for example 3 (LMW removal from P407); injection=0.05 ml of feed at 0.5 wt.-% in methanol; Ahigh molecular weight; Btarget molecular weight polymer; and C target low molecular weight impurity

[0112] FIG. 11: Raffinate Chromatogram for example 3 (LMW removal from P407); injection=0.05 ml of SMB raffinate at cyclic steady state diluted 10 times (wt. ratio); Ahigh molecular weight; Btarget molecular weight polymer; and C target low molecular weight impurity.

[0113] FIG. 12: Extract Chromatogram for example 3 (LMW removal from P407); injection=0.05 ml of SMB extract at cyclic steady state diluted 10 times (wt. ratio); Ahigh molecular weight; Btarget molecular weight polymer; and C target low molecular weight impurity

[0114] In FIGS. 4 to 12, the units of the x-axis are minutes and the units of the y-axis are mAu (RI response)

[0115] The invention is further characterized by the following embodiments:

[0116] Embodiment 1 represents a process for purification of polyether block copolymers comprising polyoxyethylene and polyoxypropylene moieties using sequential multi-column size exclusion chromatography apparatus operated as a counter current moving bed wherein a process cycle comprises the steps of (A) providing a feed mixture comprising the block copolymers dissolved in an eluent in a feed vessel, (B) subjecting the feed mixture to a chromatographic separation by introducing the feed mixture into an apparatus comprising a plurality of chromatographic columns sequentially linked together, each column comprising a bed, (C) after separation collecting a first eluent portion enriched in the purified target block copolymer and a second eluent portion depleted of the purified target block copolymer, (D) collecting the purified block copolymer from the first eluent portion, and (E) recovery of the depleted eluent and recycling the depleted eluent from the solvent recovery zone into the process.

[0117] Embodiment 2 represents a process according to Embodiment 1, wherein the counter current moving bed is operated as a simulated or actual moving bed.

[0118] Embodiment 3 represents a process according to Embodiment 1 or 2, wherein the bed is a phase comprising the size exclusion chromatographic packing material.

[0119] Embodiment 4 represents a process according to Embodiments 1 to 3 wherein the eluent is an organic solvent or water or a mixture thereof.

[0120] Embodiments 5 represents a process according to any of Embodiments 1 to 4, wherein the eluent is an organic solvent or a mixture of organic solvents.

[0121] Embodiment 6 represents a process according to any of Embodiments 1 to 5, wherein the eluent is methanol.

[0122] Embodiment 7 represents a process according to any of Embodiments 1 to 6, wherein the bed comprising a size exclusion chromatographic packing material is a stationary bed.

[0123] Embodiment 8 represents a process according to any of Embodiments 1 to 7, wherein the stationary bed comprises as a packing material inorganic carbons, zeolites, aluminas or silica based adsorbents.

[0124] Embodiment 9 represents a process according to any of Embodiments 1 to 8, wherein the stationary bed comprises as an inorganic adsorbent packing material a silica modified with diols.

[0125] Embodiment 10 represents a process according to Embodiments 9, wherein the stationary bed comprises as an inorganic adsorbent packing material a silica modified with 1,2-dihydroxypropane.

[0126] Embodiment 11 represents a process according to any of Embodiments 8 to 10 wherein the stationary bed consisting of silica modified with diols is pre-treated with methanol until stable retention times are achieved.

[0127] Embodiment 12 represents a process according to Embodiments 11, wherein the retention times for a specific peak or the relative retention times do not change during a separation run for 24 hours.

[0128] Embodiment 13 represents a process according to any of Embodiments 1 to 12, wherein the bed is a stationary bed comprising as a packing material a chromatographic adsorbent with a pore size of 1-100 nm.

[0129] Embodiment 14 represents a process according to any of Embodiments 8 to 13, wherein stationary bed comprises as a packing material an inorganic adsorbent which is a silica material with a pore size of 1-100 nm.

[0130] Embodiment 15 represents a process according to any of Embodiments 8 to 13, wherein stationary bed comprises as a packing material an inorganic adsorbent which is a silica material with a mean particle size distribution of 5-1000 m.

[0131] Embodiment 16 represents a process according to any of Embodiments 8 to 15, wherein the stationary bed comprises as a packing material an inorganic adsorbent which is a silica material with a mean particle size of 5-20 m.

[0132] Embodiment 17 represents a process according to any of Embodiments 1 to 7, 15 or 16 wherein the stationary bed comprises as a packing material an organic or organic based adsorbent.

[0133] Embodiment 18 represents a process according to any of Embodiments 1 to 7, wherein stationary bed comprises as a packing material an organic adsorbent selected from the group consisting of carbohydrate, carbohydrates cross-linked with agarose or acrylamides or cross linked organic polymers.

[0134] Embodiment 19 represents a process according to any of Embodiments 1 to 18, wherein the chromatographic separation is carried out at a pressure in the range of from 0.01 to 15 MPa.

[0135] Embodiment 20 represents a process according to any of Embodiments 1 to 15, wherein the chromatographic separation is carried out at a pressure in the range of from 0.05 to 0.5 MPa.

[0136] Embodiment 21 represents a process according to Embodiment 20, wherein the chromatographic separation is carried out at a pressure in the range of from 0.05 to 0.5 MPa and with a mean particle size of the packing material in the range of from 50 m to 1000 m.

[0137] Embodiment 22 represents a process according to any of Embodiments 1 to 19, wherein the chromatographic separation is carried out at a pressure in the range of from >0.5 MPa to 10 MPa

[0138] Embodiment 23 represents a process according to Embodiment 22, wherein the chromatographic separation is carried out at a pressure in the range of from >0.5 MPa to 10 MPa and with a mean particle size of the packing material in the range of from 5 to 50 m.

[0139] Embodiment 24 represents a process according to any of Embodiments 1 to 23, wherein the chromatographic separation is carried out at 20 to 25 C.

[0140] Embodiment 25 represents a process according to any of Embodiments 1 to 20, wherein the chromatographic separation is carried out at elevated temperatures in the range of from 26 to 65 C.

[0141] Embodiment 26 represents a process according to any of Embodiments 1 to 25, wherein the first eluent portion and the second eluent portion are independently of each other subjected to a concentration step.

[0142] Embodiment 27 represents a process according to any of Embodiments 1 to 26, wherein the concentration step of the first eluent portion enriched in the block copolymer and the second eluent portion depleted of the block copolymer is carried out by evaporation, drying or distillation.

[0143] Embodiment 28 represents a process according to any of Embodiments 1 to 27, wherein the concentration step of the first eluent portion enriched in the block copolymer and the second eluent portion depleted of the block copolymer is carried out by liquid extraction, membranes, crystallization, adsorption or other solvent recovery techniques.

[0144] Embodiment 29 represents a process according to any of Embodiments 1 to 28, comprising a first filter step prior to the separation chromatography by passing the feed mixture through a filter bed of silica or aluminas or molecular sieves or activated carbons or polymeric adsorbents or ion exchangers or mixtures of thereof.

[0145] Embodiment 30 represents a process according to any of Embodiments 1 to 29 comprising a second filter step after the separation chromatography by passing the depleted eluent through a filter bed of silica or aluminas or molecular sieves or activated carbons or polymeric adsorbents or ion exchangers or mixtures of thereof, positioned in the eluent recycling zone.

[0146] Embodiment 31 represents a process according to any of Embodiments 1 to 30, comprising the step of subjecting the first eluent portion rich in the target block copolymer to a second simulated moving bed separation process cycle.

[0147] Embodiment 32 represents a process according to any of Embodiments 1 to 31, comprising one or more eluent concentration steps between the first and the second process cycle

[0148] Embodiment 33 represents a process according to any of Embodiments 1 to 32, wherein the polyether block copolymers comprising polyoxyethylene and polyoxypropylene moieties are poloxamer 188 or poloxamer 407.

[0149] Embodiment 34 represents a process according to any of Embodiments 1 to 33, wherein in the feed mixture comprising a solution of the block copolymer in an eluent, and wherein the concentration of the block copolymer preferably lies in the range of from 5 to 50% by weight, more preferably 20 to 40% by weight.

EXAMPLES

[0150] All samples obtained according to any of the following examples were analyzed by HPLC under the following conditions:

[0151] Injection=0.05 ml of a SMB sample at cyclic steady state mobile phase=methanol; flow rate=0.5 ml/min; stationary phase=YMC (JP) Silica Diol 12 nm, 5 m (ID=0.8 cmLc=30.0 cm); detection=RI refractive index; room temperature.

[0152] n.d.: not detected

Example 1SMB Removal of LMW Impurities from Poloxamer 188

[0153] A lab scale SMB unit (Octave 100 from Semba Bio sciences, USA) was assembled with 8 columns packed with YMC (JP) Silica Diol 12 nm, 20 m (ID 2 cmLc 10 cm) and arranged as 2 columns per section (section defined by inlet/outlet nodes: section Ibetween the solvent and extract node; section IIbetween extract and feed nodes; section IIIbetween feed and raffinate nodes; and, section IVbetween raffinate and solvent nodes. HPLC grade methanol (Sigma Aldrich) was used as solvent and runs operated at room temperature (23-25 C.).

[0154] The following operating parameters were set on the SMB and the unit the system operated until cyclic steady state, determined when the overall cycle purity of both extract and raffinate streams do not change over two non-consecutive cycles.

[0155] t.sub.switch=152 sec (port synchronous shift)

[0156] Q.sub.Feed=0.7 ml/min at 25 wt.-% of Poloxamer 188 in methanol (Feed stream)

[0157] Q.sub.Raffinate=4.7 ml/min (Product stream)

[0158] Q.sub.Extract=7.4 ml/min (Waste stream)

[0159] Q.sub.Eluent=10.8 ml/min of pure methanol (Solvent stream)

[0160] The results obtained by GPC HPLC method are described in Table 1, and the Feed, Raffinate (product) and extract (waste) streams chromatograms in FIGS. 4-6.

TABLE-US-00001 TABLE 1 HPLC area percentage purity for Poloxamer 188 after SMB purification step in solvent free basis. A-high molecular weight; B-target molecular weight polymer; and C target low molecular weight impurity. total wt. %* A Purity B Purity C Purity Feed 25.0 0.9% 94.6% 4.5% Extract 0.5 n.d. 76.7% 23.3% Raffinate 3.7 1.1% 98.9% n.d. *Total product/waste weight in methanol

[0161] The data according to Table 1 show that the full extent of the LMW impurities (C) from Poloxamer 188 was removed from the Initial product grade (Feed), resulting in a high purity product (above 98.9% by HPLC area) in the raffinate with near 85% target product recovery.

[0162] As consequence of a high feed concentration, also an high product concentration was obtained (above 3.7 wt.-%).

Example 2SMB Removal of HMW Impurities from Poloxamer 188 (from Raffinate in SMB)

[0163] The same SMB unit with the same columns as mentioned for example 1 was used to test the HMW impurities removal from a raffinate stream with the same quality of the one reported in Example 1 (FIG. 7). The following operating parameters were set on the SMB and the unit the system operated until cyclic steady state, determined when the overall cycle purity of both extract and raffinate streams do not change over two non-consecutive cycles.

[0164] t.sub.switch=130 sec (port synchronous shift)

[0165] Q.sub.Feed=0.7 ml/min (Feed stream, similar to raffinate from example 1)

[0166] Q.sub.Raffinate=5.7 ml/min (Product stream)

[0167] Q.sub.Extract=7.4 ml/min (Waste stream)

[0168] Q.sub.Eluent=9.8 ml/min of pure methanol (Solvent stream)

[0169] Pressure

[0170] The results obtained by GPC HPLC method are described in Table 2, and the Feed, Raffinate (waste) and extract (product) streams chromatograms in FIGS. 7-9.

TABLE-US-00002 TABLE 2 HPLC area percentage purity for purified poloxamer (raffinate from example 1) after SMB purification step in solvent free basis. A-high molecular weight; B-target molecular weight polymer; and C target low molecular weight impurity. total wt. %* A Purity B Purity C Purity Feed 3.3 1.4% 98.6% n.d. Extract 0.2 n.d. 100.0 n.d. Raffinate 0.2 6.2 93.8 n.d. *Total product/waste weight in methanol

[0171] The data according to Table 2 show that the full extent of the HMW impurities was removed from the pre-purified poloxamer 188, resulting on a high purity product (near 100% by HPLC area) in the extract with near 80% target product recovery.

Example 3SMB Removal of LMW Impurities from Poloxamer 407

[0172] The same SMB unit as mentioned for example 1, but now operated only with 6 columns (2 columns per section2:2:2) in open loop SMB mode (no section IV in FIG. 1) was used to remove LMW impurities from Poloxamer 407. The following operating parameters were set on the SMB and the unit the system operated until cyclic steady state, determined when the overall cycle purity of both extract and raffinate streams do not change over two non-consecutive cycles.

[0173] t.sub.switch=150 sec (port synchronous shift)

[0174] Q.sub.Feed=0.7 ml/min (Feed stream, similar to raffinate from example 1)

[0175] Q.sub.Raffinate=8.9 ml/min (Product streamopen loop SMB)

[0176] Q.sub.Extract=8.3 ml/min (Waste stream)

[0177] Q.sub.Eluent=16.5 ml/min of pure methanol (Solvent stream)

[0178] The results obtained by GPC HPLC method are described in Table 3, and the Feed, Raffinate (product) and extract (waste) streams chromatograms in FIGS. 10-12.

TABLE-US-00003 TABLE 3 HPLC area percentage purity for Poloxamer 407 after SMB purification step in solvent free basis. A-high molecular weight; B-target molecular weight polymer; and C target low molecular weight impurity. total wt. %* A Purity B Purity C Purity Feed 25.0 0.7% 78.3% 21.0% Raffinate 1.5 0.9% 98.9% 0.2% Extract 0.5 n.d. 31.2% 68.8% *Total product/waste weight in methanol

[0179] The data according to Table 3 show that the full extent of the LMW impurities was removed from the poloxamer 407, resulting on a high purity product (near 99% by HPLC area) in the extract with near 90% target product recovery.

Example 4

[0180] SMB removal of LMW impurities from Poloxamer 188 (40 wt.-%) in open loop SMB and heated solvent and system

[0181] The same SMB unit as mentioned for example 1, was operated only with 6 columns (2 columns per section2:2:2) in open loop SMB mode (no section IV in FIG. 1), solvent fed at 35 C. and unit operated around 30 C. to decrease overall viscosity and used to remove LMW impurities from Poloxamer 188 on a feed solution of 40 wt.-% in methanol.

[0182] The following operating parameters were set on the SMB and the unit the system operated until cyclic steady state, determined when the overall cycle purity of both extract and raffinate streams do not change over two non-consecutive cycles.

[0183] t.sub.switch=158 sec (port synchronous shift)

[0184] Q.sub.Feed=0.7 ml/min (Feed stream, 40 wt.-% of Poloxamer 188 in methanol)

[0185] Q.sub.Raffinate=8.9 ml/min (Product streamopen loop SMB)

[0186] Q.sub.Extract=7.3 ml/min (Waste stream)

[0187] Q.sub.Eluent=15.5 ml/min of pure methanol at 35 C. (Solvent stream)

TABLE-US-00004 TABLE 4 HPLC area percentage purity for Poloxamer 188 after SMB purification step in solvent free basis. A-high molecular weight; B-target molecular weight polymer; and C target low molecular weight impurity. total wt. %* A Purity B Purity C Purity Feed 40.0 0.9% 94.6% 4.5% Extract 0.9 0.3% 89.8% 9.9% Raffinate 2.5 1.2% 97.9% 0.9% *Total product/waste weight in methanol

[0188] The data according to Table 4 show that the almost the full extent of the LMW impurities was removed from the P188 even from solutions with a feed polymer concentration as high as 40 wt.-%, when the limit of the maximum operational pressure was achieved (1.86 MPa).

[0189] The procedure was characterized by the following performance parameters: Productivity=2.2 kg of treated product per kg of stationary phase per day; [0190] Dilution=130 L of solvent per kg of treated product; [0191] Recovery=70-80%

Example 5SMB Removal of LMW and HMW Impurities from Poloxamer 188 Using Pre-Filters and Solvent Recovery Steps

[0192] a) Pre-Filters

[0193] The following procedure was applied to treat a feed mixture of 25 wt.-% P188 in methanol: Pre-filter 1: +/40 ml bed volume (0.22 m0.015 m packing, LcxID) Cation exchange resin Amberlite FPC 22 Hflow rate about 0.25 ml/min; pre-washed with 10 fold bed volume of distilled water and then 10 bed volumes of methanol;

[0194] Pre filter 2: +/40 ml packed bed (0.22 m0.015 m) of Normal phase silicaGrace DAVISIL LC150A 40-63 m, flow rate about 3 ml/minthis bed is only used to treat about 500-600 ml of Poloxamer solution; pre washing of bed with 10 fold bed volume of methanol.

[0195] b) SMB LMW Cut (25 wt.-% Feed)

[0196] After washing the pre filter beds, the solution to be treated is fed and the 1st bed volume discarded (to avoid dilution of solvent inside bed). The outlet solution is kept at 25 wt % (or same as inlet).

[0197] This treated solution was then fed to the SMB described in example 1 and the following operating parameters were set and the system operated continuously over 48 hours.

[0198] t.sub.switch=152 sec (port synchronous shift)

[0199] Q.sub.Feed=0.7 ml/min at 25 wt.-% of Poloxamer 188 in methanol (Feed stream)

[0200] Q.sub.Raffinate=4.2 ml/min (Product stream)

[0201] Q.sub.Extract=7.3 ml/min (Waste stream)

[0202] Q.sub.Eluent=10.8 ml/min of pure methanol (solvent fed at 35 C.)

[0203] The results obtained by GPC HPLC method are described in Table 5.

TABLE-US-00005 TABLE 5 HPLC area percentage purity for Poloxamer 188 after cation exchange, silica and SMB purification step in solvent free basis. A-high molecular weight; B-target molecular weight polymer; and C target low molecular weight impurity. total wt. %* A Purity B Purity C Purity Feed 25.0 0.9% 94.6% 4.5% Extract 0.5 n.d. 77.9% 22.1% Raffinate 4.0 0.9% 99.1% n.d. *Total product/waste weight in methanol

[0204] The system proved to be stable for the whole 48 hours run. The procedure characterized by following performance parameters: [0205] Productivity=1.3 kg of treated product per kg of stationary phase per day; [0206] Dilution=98 I of solvent per kg of treated product; [0207] Recovery=82.5 wt.-%

[0208] c) Solvent Evaporation or SMB LMW Cut Raffinate

[0209] The solvent from the LMW raffinate cut was evaporated in a rotovapor up to a concentration of dry solid (purified P188) of about 57 wt.-% below a max temperature of 90 C.

[0210] After evaporation the concentrated product was tested using the GPC method described before (HPLC pulse injection) and no difference was detected between the product according to Table 5 and the one obtained after partial solvent evaporation.

[0211] d) Pre Filters

[0212] The solution from step c) was diluted down to a 25 wt.-% mixture and, due to the colour profile, passed through a silica bed as follows.

[0213] Pre filter 2: +/40 ml packed bed (0.22 m0.015 m packing) of Normal phase silicaGrace DAVISIL LC150A 40-63 m, flow rate about 3 ml/minthis bed is only used to treat about 500-600 ml of Poloxamer solution; pre washing of bed with 10 fold bed volume of methanol.

[0214] e) SMB HMW Cut (25 wt.-% Feed)

[0215] The solution collected from step d) was then fed to the SMB described in step b) and the following operating parameters were set and the system operated continuously over 24 hours.

[0216] t.sub.switch=130 sec (port synchronous shift)

[0217] Q.sub.Feed=0.6 ml/min at 25 wt.-% of purified 188 in methanol (residual LMW)

[0218] Q.sub.Raffinate=3.0 ml/min (Product stream)

[0219] Q.sub.Extract=7.4 ml/min (Waste stream)

[0220] Q.sub.Eluent=9.8 ml/min of pure methanol (solvent fed at 35 C.)

[0221] The results obtained by GPC HPLC method are described in Table 6.

TABLE-US-00006 TABLE 6 HPLC area percentage purity for Poloxamer 188 after cation exchange, silica and SMB purification step in solvent free basis. A-high molecular weight; B-target molecular weight polymer; and C target low molecular weight impurity. total wt. %* A Purity B Purity C Purity Feed 25.0 0.9% 99.1% n.d. Extract 2.0 n.d. 100.0% n.d. Raffinate 0.7 7.0% 93.0% n.d. *Total product/waste weight in methanol

[0222] The system proved to be stable for the whole 24 hours run. The procedure was characterized by the following performance parameters: [0223] Productivity=1.3 kg of treated product per kg of stationary phase per day; [0224] Dilution=93 L of solvent per kg of treated product; [0225] Recovery=88.1%

[0226] No salts were detected in the final product.