Styrene-Maleic Anhydride Copolymers for Bioapplications and Their Preparation - DocsLib

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(11) EP 2 502 943 A1

(12) EUROPEAN PATENT APPLICATION

(43) Date of publication: (51) Int Cl.: 26.09.2012 Bulletin 2012/39 C08F 212/08 (2006.01) C08F 222/08 (2006.01) C08F 2/02 (2006.01) (21) Application number: 12173168.1

(22) Date of filing: 30.03.2007

(84) Designated Contracting States: (72) Inventors: AT BE BG CH CY CZ DE DK EE ES FI FR GB GR • Colt, Monica HU IE IS IT LI LT LU LV MC MT NL PL PT RO SE 76300 Rehovot (IL) SI SK TR • Bucevschi, Mircea Dan Designated Extension States: 76300 Rehovot (IL) AL BA HR MK RS (74) Representative: Zeestraten, Albertus W. J. (30) Priority: 30.03.2006 US 787191 P Exter Polak & Charlouis B.V. (EP&C) P.O. Box 3241 (62) Document number(s) of the earlier application(s) in 2280 GE Rijswijk (NL) accordance with Art. 76 EPC: 07759822.5 / 2 007 824 Remarks: This application was filed on 22-06-2012 as a (71) Applicant: Exotech Bio Solutions Ltd. divisional application to the application mentioned 32100 Kiryat Gat (IL) under INID code 62.

(54) Styrene-maleic anhydride copolymers for bioapplications and their preparation

(57) The present invention discloses styrene-maleic maleic anhydride monomers, which makes the copoly- anhydride copolymers preparations using solventless mers particularly suitable for bioapplications. techniques. The solventless method resulted in reduced amounts of residues, such as unreacted styrene and/or EP 2 502 943 A1

Printed by Jouve, 75001 PARIS (FR) 1 EP 2 502 943 A1 2

Description study, and antimicrobial properties of acriflavine bound to SMA. Patel, H. A. et al. Die Angewandte Makromole- Related Applications kulare Chemie 1998, 263, 25-30. Patel, H. A. et al. report similar findings for SMA bound ampicillin. Patel, H. A. et [0001] This application claims the benefit of priority to 5 al. Die Angewandte Makromolekulare Chemie 1999, United States Provisional Patent Application serial 271, 24-27. In both cases, advanced purification of the number 60/787,191, filed March 30, 2006, which is here- SMA copolymer was necessary to make the composition by incorporated by reference in its entirety. suitable for bio-application. [0008] Ottenbrite, R. M. and Spiridon, D. disclose the Field of the Invention 10 use of SMA copolymers as antitumor effectors. Ot- tenbrite, R. M. and Spiridon, D demonstrate the biocom- [0002] The invention relates to, in part, styrene- maleic patibility of the SMA copolymers but only after rigorous anhydride copolymers. It relates to methods of synthe- purification steps. Ottenbrite, R. M. J. Macromol. sizing such polymers using bulk polymerization methods Sci.-Chem. 1985, A22(5-7), 819-832; Spiridon D. Poly- which yield partially hydrolysed polymers in acidic form. 15 mer International, 1997, 43, 175-181. The invention also relates to methods of preparing sty- [0009] US Pat. Nos. 3,980,663 and US Pat. No rene-maleic anhydride copolymers that have a low resid- 4,381,784 disclose using SMA copolymers as water ab- ual content of monomers (styrene and maleic acid) and sorbing materials for hygienic care. US Pat. No. which are suited to bioapplications as solutions, hydro- 3,939,108 and US Pat. No. 6,590,019 disclose SMA co- gels or solids for medical bioengineering, tissue engi- 20 polymers as an adhesive useful for bottle labeling. US neering, pharmaceutical products, hygienic care, cos- Pat. No. 5,080,888 discloses SMA copolymers in cosmetics, biotechnology, food industry, agriculture, absorb- metics. US Pat. No. 4,980,403; US Pat. No. 5,104,957; ent textiles and the like. US Pat. No. 5,480,427; and US Pat. No. 6,127,451 disclose using SMA copolymers as biomaterials. US Pat. Background of the Invention 25 No.4,153,682; US Pat. No. 6,500,447; and US Pat. No. 6,531,160 disclose using SMA copolymers in pharma- [0003] Styrene-maleic anhydride copolymers (SMA ceutical products as drug delivery systems. copolymers) are used in numerous applications but their [0010] A condition for using SMA copolymers in a bio- use in bio-applications is hindered by their lack of purity application is that its chemical purity be as high as pos- and residual hazardous contaminates. 30 sible, while its hazardous contaminant content be as low [0004] The FDA approved SMA copolymers as indirect as possible. Contamination of SMA copolymers has two food additives for use as articles or components of arti- causes derived from the polymerization processes used: cles that contact food items (Code of Federal Regula- 1) non-reacted monomers, and 2) auxiliaries of polym- tions, Sec. 177.1820 "Styrene-maleic anhydride copoly- erization such as: organic solvents, initiators...etc. mers", Title 21, Volume 3 p 304-305, revised as of April 35 [0011] For example, SMA coplymers are prepared 1, 2000). The FDA specified that SMA copolymers have mainly by solvent based methods, but these methods are a minimum average molecular mass of 70,000 and con- also the most contaminating because, besides unreacted tain not more that 15 weight percent maleic anhydride, monomers and initiators, there is residual solvent to re- 0.3 weight percent residual styrene monomer, 0.1 weight move. See US Pat. No. 2,286,062; US Pat. No. percent residual maleic anhydride monomer, 0.00640 2,378,629; US Pat. No. 2,866,775; US Pat. No. weight percent maximum extractible fractions in distillat- 3,157,595; US Pat. No. 3,989,586; 4,105,649; and US ed water at reflux temperature for 1 hr, and 0.02 weight Pat. No. 4,126,549. The additional purification steps re- percent maximum extractible fractions in n-heptane at quired represent an important economical restriction to 73 °F for 2 hr. using SMA copolymers in bio-applications compared to [0005] Sethi, N. et al. demonstrated the biocompatibil- 45 other category of polymers. ity of SMA commercial products, but a multistep, complex [0012] Bulk polymerization is less contaminating than purification procedure was required before utilization. solution polymerization because there are no organic sol- Sethi, N. et al. Contraception 1989, 39, 217-226. The vents. See Voss, A. et al. in US Pat. No. 2,047,398; same conclusion was reported by Lohiya, N. K et al. Lo- Graves, G. D. in US Pat No. 2,205,882 and Lee Y. C. et hiya, N. K. et al. Int. J. Androl. 2000, 23, 36-42. 50 al. in US Pat No. 4,051,311 disclosing maleic anhydride [0006] Wagner J. G. et al in US Pat. No. 2,897,121 and copolymers of styrene, vinyl acetate, and others by bulk Chen, Y. R. et al in Colloids and Surfaces A: Physico- polymerization methods, with and without peroxidic initi- chem. Eng. Aspects, 2004, 242, 17-20 present the utili- ators. The content of maleic anhydride monomers is less zation of SMA copolymers as additives for a pharmaceu- than 55% by weight in the initial mixture of comonomers. tical carrier for oral administration. Although the authors 55 Baer, M. in US Pat. No. 2,971,939 presents the synthesis assert that the polymers can be used for bio-applications, of styrene maleic anhydride copolymers with a content supporting data, such as purity, is not presented. of maleic anhydride less than 12% by weight using bulk [0007] Patel, H. A. et al. disclose the synthesis, release polymerization methods. In these disclosures, a mixture

2 3 EP 2 502 943 A1 4 of styrene and peroxidic initiator is allowed to homopol- number of potential bio-applications. ymerize until a 3-5% conversion. At this point, maleic [0016] Copolymerization yields are highest (approxi- anhydride monomer is added at a constant rate to form mately 95%) when using equimolecular monomer feeds, a maleic anhydride in styrene solution. The SMA copol- and with processes that achieve good mass transfer of ymer is then extracted from the reaction mass with ben- 5 reactants (such as those achieved by polymerization in zene and ultimately separated from the solution by pre- organic solvent media). Processes that don’t use equi- cipitation with methanol. molecular monomer feeds induce a high value of con- [0013] Disadvantages with these bulk polymerization version only for the monomer which is present in the least methods include a) incomplete conversion of monomers amount. Klumperman, B. et al. Polymer 1993, 34, to copolymer due to increasing impedance of diffusion 10 1032-1037; Klumperman, B. Macromolecules, 1994, 27, of the reactants to reaction centers because of increasing 6100-6101; Klumperman, B. et al. Eur. Polym. J. 1994, reaction mass viscosity; b) purification to remove non- 30, 955-960. reacted monomer is difficult and realized by dissolution [0017] The most difficult aspect of purifying SMA co- into specific solvents (such as acetone or benzene), fol- polymers is removal of unreacted styrene because it is lowed by precipitation, extraction with alcohols or water, 15 an organic compound liquid, insoluble in water, but sol- and drying; c) generation of large amounts of reaction uble in organic solvents with high boiling points that make heat risking explosion; d) handling of reaction mass is it difficult to dry, even in high vacuum. Boundy, R. H. difficult; and e) purification solids after precipitation by "Styrene, its polymers, Copolymers and Derivatives," Re- extraction is neither cost effective nor ecologically friend- inhold Publishing Corporation, New York, 1952, pp. ly. 20 860-865. [0014] Cutter, L. A. in US Pat. No. 4,145,375 presents [0018] Unreacted maleic anhydride can be removed a process for copolymerizing styrene and maleic anhy- by simple hydrolysis with water to form maleic acid which dride which involves a sequence of operations in which has a high solubility in water (greater than 4.4 x 10 5 ppm maleic anhydride is first gradually admixed with styrene (wt) at 25°C; Yaws C.L. in "Chemical Properties in a mass stage under polymerizing conditions to rapidly 25 Handbook " McGraw-Hill Companies,lnc. New York, form styrene-maleic anhydride polymer. The styrene- rich 1999), allowing its efficient and economical elimination mixture is then suspended in water and the styrene po- from copolymers. In addition, the rate of hydrolysis of lymerization completed as in a conventional mass/sus- free maleic anhydride is much higher than that of polym- pension polymerization system. The suspension step fur- erized maleic anhydride. Ratzch, M. et al. J. Macromol. ther modifies the polymer by opening the anhydride30 Sci-Chem. 1987, A24, 949-965; Wang, M. et al. J. AppL. group to form free carboxylic acid groups on the polymer Polym. Sci. 2000, 75, 267-274. chain. Following the heating period, the polymerization mixture is cooled; the polymer beads are separated from Summary of the Invention the water by a solid- bowl centrifuge, and dried in a rotary air drier. The polymers resulted have Mw =100,000 -35 [0019] In one aspect, the invention relates to a styrene- 500,000, and the content of residual styrene is between maleic anhydride copolymer having less than 0.050% by 0.02 and 0.1 % by weight. A disadvantage of this process weight unreacted styrene monomer. is that the final product is a blend of polystyrene and SMA [0020] In a further embodiment, the styrene- maleic an- copolymer, the polystyrene being a major contaminant, hydride copolymer has less than 0.090% by weight un- with multiple implications making it unfavorable for bio- 40 reacted maleic anhydride and maleic acid combined. applications. Similar problems exist for front polymeriza- [0021] In a further embodiment, the weight percent of tion which uses excess of styrene. Szalay, J. et al., Mac- styrene monomer to maleic anhydride and maleic acid romol. Rapid Commun. 1999, 20, 315-318. monomer as defined as styrene/(maleic anhydride + [0015] Methods of copolymerization of maleic anhy- maleic acid) is 42:58 - 52:48. dride and other monomers in an aqueous medium have 45 [0022] In a further embodiment, the viscosimetric mo- been disclosed. See Bomer B. et al. in US Pat. No. lecular weight, Mv, of the styrene-maleic anhydride co- 4,737,549; Saraydin D. et al. in J. Appl. Polym. Sci. 2001, polymer is 200,000-2,500,000. 79, 1809-1815; Caycara, T. et al. in J. Polym. Sci. A: [0023] In a further embodiment, the amount of unre- Polym. Chem. 2001, 39, 277-283; Akkas, P. et al. in J. acted styrene in the styrene- maleic anhydride copolymer Appl. Polym. Sci. 2000, 78, 284-289; Sen, M. et al. in 50 is 0.015% to 0.042% by weight. Polymer 1999, 40, 913-917; Sen, M. et al. in Polymer [0024] In a further embodiment, the amount of unre- 1998, 39, 1165-1172; Karadag, E. et al. in J. Appl. Polym. acted maleic anhydride and maleic acid combined in the Sci. 1997, 66, 733-739; Saraydin, D. et al. in Biomaterials styrene-maleic anhydride copolymer is 0.045% to 0.2% 1994, 15, 917-920; and Karadag, E. et al. in Biomaterials by weight. 1996, 17, 6770. However, these methods cannot be used 55 [0025] In another aspect, the present invention relates for copolymerizing styrene due to the differences in sol- to a medicament comprising the styrene-maleic anhy- ubility of the two comonomers. Additionally, the resulting dride copolymers of the present invention. polymer will have few carboxylic groups, limiting the [0026] In another aspect, the present invention relates

3 5 EP 2 502 943 A1 6 to an article of manufacture comprising the styrene- atmospheric pressure and at a temperature between maleic anhydride copolymers of the present invention. 85°C and 115°C for a period of time between 60 and 180 [0027] In a further embodiment, the article of manu- minutes. facture is used in the field of medical bioengineering, tis- [0043] In a further embodiment, the method further sue engineering, pharmaceutical products, body hy-5 comprises the step of allowing the styrene- maleic anhy- giene, cosmetics, biotechnology, food industry, agricul- dride copolymer formed in step c) to cool to a temperature ture, or absorbent textiles. between 55°C and 85°C. [0028] In another aspect, the present invention relates [0044] In a further embodiment, the styrene- maleic an- to a method of preparing a styrene- maleicacid copolymer hydride copolymer formed in step c) is cooled to between comprising: a) melting an amount of maleic anhydride 10 60°C and 80°C. monomer; b) adding an amount of styrene containing dis- [0045] In a further embodiment, the method further solved initiator to the maleic anhydride; and c) stirring comprise hydrolyzing at least a portion of the maleic an- the maleic anhydride, styrene, and initiator mixture for hydride to maleic acid by adding water to the styrene- an effective amount of time to form a styrene- maleic acid maleic anhydride copolymer. copolymer. 15 [0046] In a further embodiment, the amount of water [0029] In a further embodiment, the initiator is a free is between 5 % and 40% by weight of the styrene- maleic radical initiator. anhydride copolymer [0030] In a further embodiment, the initiator is selected [0047] In a further embodiment, the amount of water from the group consisting of diacyl peroxides, dibenzoyl is between 10% and 35% by weight of the styrene- maleic peroxide, di-tertbutyl peroxide, tert-butyl perbenzoate, 20 anhydride copolymer. tert-butyl perethylhexanoate, peresters, tert.-butyl per- [0048] In a further embodiment, the water is added pivalate, aliphatic azo, azoisobutyronitrile, azo-4-cyan- over a period of time between 30 and 180 minutes. opentanoic acid, peroxodisulphuric acid, and hydrogen [0049] In a further embodiment, the water is added peroxide. over a period of time between 60 and 120 minutes. [0031] In a further embodiment, the initiator is diben- 25 [0050] In a further embodiment, after the water is add- zoyl peroxide or azoisobutyronitrile. ed to the copolymer the mixture is mixed for a period of [0032] In a further embodiment, during synthesis the time between 20 and 90 minutes. amount of styrene: maleic anhydride is between 1 : 6 and [0051] In a further embodiment, the mixture is mixed 1 : 14 by weight. for a period of time between 30 and 60 minutes. [0033] In a further embodiment, during synthesis the 30 [0052] In a further embodiment, the method further amount of styrene: maleic anhydride is between 1 : 8 to comprises allowing the copolymer to cool to room tem- 1 : 12 by weight. perature. [0034] In a further embodiment, the amount of initiator [0053] In a further embodiment, the method further is between 0.01% and 0.05% versus the weight of the comprises purifying the copolymer by extracting free reaction mass. 35 maleic acid with water. [0035] In a further embodiment, the amount of initiator [0054] In a further embodiment, the copolymer is is between 0.025% and 0.035% versus the weight of the mixed with a quantity of water about 6 times the weight reaction mass. of the copolymer at a temperature between 5°C and 40°C [0036] In a further embodiment, melting the maleic an- before removing the water. hydride is carried out by heating the maleic anhydride at 40 [0055] In a further embodiment, the copolymer is least to 75°C. mixed with the water at a temperature between 15°C and [0037] In a further embodiment, the styrene is added 35°C. to the maleic anhydride between 55°C and 100°C. [0056] In a further embodiment, the copolymer is [0038] In a further embodiment, the styrene is added mixed with the water for a period of time between 1 and to the maleic anhydride between 65°C and 90°C. 45 6 hours before removing the water. [0039] In a further embodiment, the styrene is added [0057] In a further embodiment, the copolymer is to the maleic anhydride over a period of time between mixed with the water for a period of time between 2 and 10 minutes and 60 minutes. 4 hours before removing the water. [0040] In a further embodiment, the styrene is added [0058] In a further embodiment, the water is removed to the maleic anhydride over a period of time between 50 by filtration under pressure. 20 and 40 minutes. [0059] In a further embodiment, the extraction is re- [0041] In a further embodiment, the mixing of the peated until the content of maleic acid in the supernatant maleic anhydride, styrene, and initiator is carried out at is less than 0.001 % by weight. atmospheric pressure and at a temperature between [0060] In a further embodiment, the method further 60°C and 150°C for a period of time between 45 minutes 55 comprises a drying step wherein the copolymer is dried and 300 minutes. at a temperature between 50°C and 90°C. [0042] In a further embodiment, the mixing of the [0061] In a further embodiment, the copolymer is dried maleic anhydride, styrene, and initiator is carried out at at a temperature between 60°C and 80°C.

4 7 EP 2 502 943 A1 8

[0062] In a further embodiment, the copolymer is dried heating-cooling mantle, thermometer, and dosing funnel under vacuum of 50 mbar or less. for liquids, in which is loaded at ambient temperature a [0063] In a further embodiment, the copolymer is dried predetermined quantity of technical grade maleic anhy- for a period of time between 4 and 10 hours. dride. The maleic anhydride is mixed at temperatures of [0064] In a further embodiment, the copolymer is dried 5 about 75°C for about 30 minutes to yield a transparent for a period of time between 6 and 8 hours. fluid mass of melted maleic anhydride. A persistent semi- opaque melt indicates the presence of maleic acid. Detailed Description of the Invention Transforming maleic acid to maleic anhydride can be achieved by connecting the kneader to a vacuum distil- Definitions 10 lation apparatus and adjusting the pressure to 400 mbar at the above temperature for about 30 minutes. The [0065] The term "bio-applications" as used herein re- maleicanhydride melt at atmospheric pressure is brought fers to all applications for which the most important prop- to a temperature not less than 55°C and not greater than erty is biocompatibility. 100°C. In another embodiment, the temperature is be- [0066] The term "biocompatibility" as used herein re- 15 tween 65°C and 90°C. Technical grade styrene and dis- fers to biochemical characteristics which a material pos- solved initiator are added to the maleic anhydride melt sess that make it acceptable to living organisms (human, over a period of time not less than 10 minutes and not animals and plants), as an integral part of them, without greater than 60 minutes. In another embodiment, period have spontaneous or in time the manifestation of some of time is between 20 and 40 minutes. Mixing is continued repulsive or toxic phenomena under the form of inflam- 20 at atmospheric pressure and a temperature not less than mation, infections and others (Black J., "Biological Per- 60°C and not greater than 150°C for a period of time not formance of Materials: Fundamentals of Biocompatibili- less than 45 minutes and not greater than 300 minutes. ty", 2d ed. M. Dekker, N.Y., 1992). This interpretation is In another embodiment the mixing temperature is main- given both to pure materials (100% purity, other sub- tained between 85°C and 115°C. In another embodi- stances not detected) and those that have a purity less 25 ment, the mixing time is between 60 and 180 minutes. than 100% (because they contain contaminants). [0071] The yellow-brown, viscous and transparent re- [0067] The standards that have guided biocompatibil- action mass is processed to transform unreacted excess ity testing are the 1) Tripartite Guidance; 2) the Interna- maleic anhydride to maleic acid by hydrolysis. The con- tional Organization for Standardization (ISO) 10993 tent of the kneader is cooled to not less than 55°C and standards (which are known as the Biological Evaluation 30 not greater than 85°C by adding deionized water (with a of Medical Devices and remain under development in- conductivity less than 10 PS). In another embodiment, ternationally); and 3) the FDA Blue Book Memoranda. the content of the kneader is cooled to temperatures between 60°C and 80°C. The amount of deionized water Methods of Polymerization added is not less than 5 % and not greater than 40 % by 35 weightversus the reaction mass. In another embodiment, [0068] In one embodiment, the present invention re- the amount of deionized water added is between 10 % lates to a process of obtaining styrene- maleic-anhydride and 35 % by weight during a period of time not less than copolymers using bulk- polymerization methods and free- 30 minutes and not greater than 180 minutes. In another radical initiators, with monomer feeds of styrene (Sty) : embodiment, the deionized water is added between 60 maleic anhydride (MAnh) of 1 : 6, 1 : 14 , 1: 8, or 112 : 40 minutes and 120 minutes. After finishing dosing with the and a quantity of initiator not less than 0.01 % and not deionized water, the reaction mass is mixed for a period more than 0.05% versus the reaction mass. In another of time not less than 20 minutes and not greater than 90 embodiment, the quantity of initiator is not less than 0.025 minutes. In another embodiment, the reaction mass is % and not more than 0.035 %. mixed for a period of time between 30 minutes and 60 [0069] Examples of suitable initiators for initiating po- 45 minutes. Alternatively, the reaction mass is cooled to am- lymerization are the customary agents which form free bient temperatures by circulating through the mantle liq- radicals by thermal decomposition. Non-limiting exam- uid with temperatures of 5-7°C. ples include: diacyl peroxides, such as dibenzoyl perox- [0072] The maleic acid is then extracted from the con- ide, di-tertbutyl peroxide, tert-butyl perbenzoate or tert- tent of the kneader according to the following process. A butyl perethylhexanoate peresters, such as tert-butyl 50 stainless steel mixing vessel equipped with a Nuce filter perpivalate, aliphatic azo compounds, such as azoisobu- and having a useful volume three times larger than that tyronitrile, azo-4-cyanopentanoic acid or other water- sol- of the kneader is used. The mixing vessel is further uble aliphatic azo compounds, salts of peroxodisulphuric equipped with an impellerstirrer with twoblades, a mantle acid or hydrogen peroxide. In one embodiment, the ini- for heating or cooling, a thermometer, a dosing nipple for tiator is dibenzoyl peroxide and azoisobutyronitrile. 55 liquids, an inlet-pipe connection for compressed air, an [0070] Polymeric reactions are carried out in a knead- outlet nipple, and, in the interior, a filter based on two er-extruder connected to a vacuum that includes a trap pierced stainless steel plates with a polyamide cloth (100 for condensed water cooled at temperature of 5-7°C, a micron mesh) between them. The vessel is filled with

5 9 EP 2 502 943 A1 10 deionized water (with a conductivity less than 10 PS) in [0077] The above characteristics were determined by an amount that is approximately six times the volume of the following procedures: the reaction mass at a temperature not less than 5°C and not greater than 40°C. In another embodiment, the tem- a) The amount of residual styrene was measured by perature is between 15°C and 35°C. While stirring the 5 extraction with benzene (spectroscopic grade) of 1 deionized water moderately (stirrer speed = 40-60 rpm) g of polymer for 12 hours by Sohxlet extraction. The the reaction mass is added via the helical conveyer. The benzene extractions were then analyzed by gas coarse, aqueous suspension formed is mixed for not less spectroscopy (Perkin-Elmer equipment). than 1 hour and not greater than 6 hours. In another embodiment, the suspension is mixed between 2 and 410 b) The amount of residual maleic acid was measured hours. The stirring is then stopped and the aqueous by dialysis with distilled water of a 2 g sample of phase is eliminated by filtration under pressure. polymer at 40°C using a Spectr/Por CE dialyze mem- [0073] The process is repeated for as many times as brane in 14 cycles of 24 hours each (500 ml water it takes to obtained a maleic acid content in the super- per cycle), the water was changed after each cycle. natant of less than 0.001% by weight as determined by 15 The accumulated water was analyzed for maleic acid volumetric titration with a solution of NaOH 0.01 N. by HPLC method (WATERS equipment). [0074] The wet solid, substantially free of the maleic acid, and with a humidity content of 70%, is transferred c) Monomeric concentration expressed as Sty : Mal to a circular dryer equipped with a heating and cooling (styrene : maleic comonomer [maleic anhydride + mantle, thermometer, helicoidally stirrer, breaking device 20 maleic acid]) was estimated by conductometric titra- with rotary knife, and is connected to a vacuum distillation tion of a solution prepared by dissolving 0.1 g of dry apparatus comprising a filter with sackcloth, condenser, polymer in a solution of NaOH 0.5 N and HCl 0.5N. and collecting vessel for the condensation water. The granular mass is dried at a temperature of not less than d) Functionality ratio, expressed as MAnh : Mal 50°C and not greater than 90°C. In another embodiment, 25 (maleic anhydride [maleic anhydride + maleic acid]), the drying temperature is between 60°C and 80°C, and [(mol/g) : (mol/g)] , was estimated using FTIR quan- the vacuum is at 50 mbar for a period of time not less titative analysis (SHIMAZU equipment): Maleic An- than 4 hours and not more than 10 hours. In another hydride p.a. (ACROSS) and Maleic Acid p.a. embodiment, the drying period of time is between 6 and (ACROSS) versus the characteristic absorption 8 hours. Lastly, the material is cooled to ambient tem- 30 bands: 1770-1790 cm 1for anhydride and 1700-1720 perature, removed from dryer, and packed in welded pol- cm1for COOH. yethylene bags. [0075] The aqueous solution of maleic acid resulting e) Viscosimetric average molecular weight, M v, was from the extraction is processed by thermal dehydration estimated using the evaluation of intrinsic viscosity 35 to obtain maleic anhydride using one of the proceeding [ηrel] based on relative viscosity [η] of one solution known methods in art and adapted to the present inven- of polymer with concentration c = 0.5 g/100 ml in tion (see for example US Pat.No. 3,993,671 ; US Pat.No. tetrahydrofuran at 25°C , using thecalculus formulae 4,118,403 ; US Pat.No.4,414,898 or US Pat.No. (Raju K.V.S.N.,Yaseen M. J.Appl.Polym.Sci., 45, 4,659,433 ). 677-681, 1992; Chee K. K. J. Appl. Polym. Sci., 34, 40 891-899, 1987 and Spiridon D. et al. Polymer Inter- SMA Copolymers national, 43, 175-181, 1997).

[0076] SMA copolymers prepared in conformity with the methods described above have the following characteristics: 45

1. Sty: Mal = 42:58 - 52:48 weight percent (styrene/ [maleic anhydride + maleic acid]).

2. MAnh / Mal = 0.17 - 0.79. 50

3. Viscosimetric molecular weight (Mv) = 200,000 - 2,500,000.

4. Styrene residual = 0.015 - 0.042 weight percent. 55 [0078] Further examples for realizing the invention are 5. Mal (maleic anhydride + maleic acid) residual = presented below. 0.045 - 0.2 weight percent.

6 11 EP 2 502 943 A1 12

Exemplification obtained as a white powder: 94.598% SMA copolymer; 5.31 % water; 0.029% styrene and 0.063% (maleic an- Example 1 hydride + maleic acid), all as weight percent. The purified SMA copolymer had the following structural characteris- [0079] In a kneader- extruder apparatus (60 liters) con- 5 tics: My = 1,251,000; Sty : Mal = 46 : 54and MAnh : Mal nected to a vacuum that includes: a trap for condensed = 0.49. water cooled at temperatures of 5-7°C, a heating- cooling mantle, thermometer, and dosing funnel for liquids, 25 Example 2 kg of technical grade maleic anhydride was added at am- bienttemperatures. The maleic anhydride was mixedand 10 [0085] Same equipment and procedure as described heated at 75°C for about 30 minutes to obtain a trans- in Example 1 except 3.4 liters of styrene having 6.8 grams parent fluid mass of melted maleic anhydride. Technical of dibenzoyl peroxide dissolved therein was added at grade styrene with 8 g of dissolved dibenzoyl peroxide 80°C. Maximum temperature during the exothermic was added under ambient pressure over 20 minutes phase was 121 °C. The last supernatant from the extrac- bringing the temperature of the mixture to 65°C. After 15 tion had a maleic acid content of 0.00095% by weight adding the styrene, the temperature of the reaction in- and drying was at 80°C for 6 hours. creased rapidly during a period of 15 minute from 78°C [0086] The process yielded 6.28 kg of SMA copolymer to 116°C due to polymerization. When the exothermic as a white powder: 95.267% SMA; 4.63 % water; 0.031 phase of polymerization is completed, mixing continued styrene and 0.072 % (maleic anhydride + maleic acid), at atmospheric pressure at 100°C for another 60 minutes. 20 all as weight percent. The purified SMA copolymer had The reaction mass was a viscous, transparent, yellow the following structural characteristics: M v= 546,000; Sty: brown solution which was cooled to 65°C by adding 8 Ma1 = 48: 52 and MAnh : Mal = 0.68. liters of deionized water (with a conductivity less than 10 PS) while mixing over 60 minutes. After finishing water Example 3 dosing, the reaction mass was mixed for another 45 min- 25 utes at 65°C. Alternatively, the reaction mass can be [0087] Same equipment and procedure as in Example cooled to ambient temperatures by circulating cooled wa- 1 except that 2.5 liters of styrene having 8.5 grams of ter (5-7°C) through the mantle of the kneader. initiator dissolved therein was added over 40 minutes. [0080] The reaction mass is transferred through the Maximum temperature during the exothermic phase was helical conveyer located in the interior central zone of the 30 128°C. Polymerization was complete after 180 minutes apparatus to a stainless steel vessel (Nutsche Filter) con- with a final temperature of 85°C. Hydrolysis utilized 6 taining 160 liters of deionized water at 18°C under mod- liters of water addedover 120minutes andthe extractions erate stirring (stirrer speed adjusted to 40-60 ppm). The were made at 35°C. Nutsche Filter has a useful volume three times larger [0088] The process yielded 4.72 kg of SMA copolymer than that of the kneader. The Nutsche Filter has a mantle 35 as a white powder: 93.08% SMA; 6.82 % water; 0.018% for heating and cooling, a stirrer, a thermometer, a dosing styrene and 0.082% (maleic anhydride + maleic acid), nipple for liquids, an inlet-pipe connection for com- all as weight percent. The purified SMA copolymer had pressed air, an outlet nipple, and, in the interior, a filter the following structural characteristics: Mv = 726,000; media based on two pierced plates of stainless steel with Sty : Mal = 51 : 49 and MAnh : Mal = 0.27. a polyamide cloth between them (100 microns mesh). 40 The coarse aqueous suspension was mixed for 2 hours. Example 4 The aqueous phase was then removed by filtration under pressure. [0089] In the same type of kneader- extruder apparatus [0081] The process was repeated 3 times. The last su- that used in Example 1, 25 kg of technical grade maleic pernatant had a maleic acid concentration of only45 anhydride was loaded at ambient temperatures. The 0.00073 % by weight. maleic anhydride was heated and mixed at 75°C for 30 [0082] The wet solid had a humidity content of 68.3% minutes to yield a fluid transparent mass of melted maleic and was transferred to a circular dryer equipped with a anhydride. 3 liters of technical grade styrene having 9.8 heating and cooling mantle, thermometer, helicoidally grams of dibenzoyl peroxide dissolved thereinwas added stirrer, breaking device with a rotary knife and was con- 50 at atmospheric pressure over a period of 40 minutes. nected to a vacuum. The wet mass was dried at 65°C at After adding the styrene, the temperature of reaction in- 50 mbar for 5 hours. Lastly, the material was cooled to creased rapidly from 83°C to 132°C over 12 minutes. ambient temperature, removed from the dryer, and pack- After the exothermic phase of reaction was completed, aged in welded polyethylene bags. mixing at atmospheric pressure at 115°C continued for [0083] The aqueous solution of maleic acid resulting 55 120 minutes. At this time 9.8 liters of deionized water from the extraction was collected for maleic anhydride (with conductivity less than 10 PS) was added over 120 recovery. minutes cooling the reaction mass to 60°C. The reaction [0084] From this process, 5.17 kg SMA copolymer was mass was mixed at 60°C for 60 minutes at 60°C. Alter-

7 13 EP 2 502 943 A1 14 natively, the reaction mass can be cooled to ambient tem- 4. Styrene-maleic anhydride copolymer of any one of peratures by circulating cooled water (5-7°C) through the claims 1 to 3, wherein the viscosimetric molecular mantle. weight, Mv, of the copolymer is 200,000-2,500,000. [0090] The granular mass from the kneader was transferred through the helical conveyer to a vessel containing 5 5. Article of manufacture comprising the styrene- 160 liters of water at 15°C under moderate stirring. The maleic anhydride copolymer of any of the preceding coarse aqueous suspension was mixed for 4 hours be- claims, the article preferably used in the field of med- fore removing the aqueous phase by filtration under pres- ical bioengineering, tissue engineering, pharmaceu- sure. This process was repeated 3 times. The last su- tical products, body hygiene, cosmetics, biotechnol- pernatant removed had a maleic acid content of 0.00091 10 ogy, food industry, agriculture, or absorbent textiles. % by weight. [0091] The purified wet solid had a humidity content of 6. Method of preparing a styrene-maleic acid copoly- 72.8% and was transferred to a circular dryer connected mer comprising: to a vacuum and dried at 80°C at 50 mbar for 4 hours. Lastly, the material was cooled to ambient temperature, 15 a) melting an amount of maleic anhydride mon- removed from dryer, and packed in welded polyethylene omer; bags. b) adding an amount of styrene containing dis- [0092] The aqueous solutions of maleic acid from the solved initiator to the maleic anhydride; and extractions were collected for maleic anhydride recovery. c) stirring the maleic anhydride, styrene, and in- [0093] The process yielded 6.93 kg of SMA copolymer 20 itiator mixture for an effective amount of time to as a white powder: 92.114% SMA; 7.82% water; 0.021 form a styrene-maleic acid copolymer. % styrene and 0.045% (maleic anhydride + maleic acid), all as weight percents. The purified SMA copolymer had 7. Method of claim 9, wherein the initiator is a free rad- the following structural characteristics: v M= 251,000; ical initiator, preferably selected from the group con- Sty : Ma1 = 42: 58 and MAnh : Mal = 0.17. 25 sisting of diacyl peroxides, dibenzoyl peroxide, di- tertbutyl peroxide, tert-butyl perbenzoate, tert-butyl Example 5 perethylhexanoate, peresters, tert. -butyl perpivalate, aliphatic azo, azoisobutyronitrile, azo-4- cy- [0094] The same type of equipment and procedure as anopentanoic acid, peroxodisulphuric acid, and hy- in Example 4 was used except 2.4 liters of styrene having 30 drogen peroxide, the initiator preferably being diben- 6.8 grams of dibenzoyl peroxide dissolved therein was zoyl peroxide or azoisobutyronitrile, and/or wherein added, the reaction mass was added to 2.1 liters of deion- the amount of initiator is between 0.01% and 0.05%, ized water, and drying was carried out at 80°C for 8 hours. preferably between 0.025% and 0.035% versus the [0095] The process yielded 4.72 kg of SMA copolymer weight of the reaction mass. as a white powder: 96.121% SMA; 3.78% water; 0.041% 35 styrene and 0.058% (maleic anhydride + maleic acid), 8. Method of claim 6 or 7, wherein the amount of sty- all as weight percents. The purified SMA copolymer had rene: maleic anhydride is between 1:6 and 1:14 by the following structural characteristics: Mv = 1,780,000; weight, preferably being between 8 1: to 1:12 by Sty : Mal = 49 : 51 and MAnh : Mal = 0.79. weight. 40 9. Method of any one of claims 6 to 8, wherein melting Claims the maleic anhydride is carried out by heating the maleic anhydride at least 75°C, and/or 1. Styrene-maleic anhydride copolymer having less wherein the styrene is added to the maleic anhydride than 0.050% by weight unreacted styrene monomer, 45 between 55 C and 100°C, preferably between 65 C the amount of unreacted styrene preferably being and 90°C. 0.015% to 0.042% by weight. 10. Method of any one of claims 6 to 9, wherein the sty- 2. Styrene-maleic anhydride copolymer having less rene is added to the maleic anhydride over a period than 0.2%, preferably 0.045% to 0.2% by weight un- 50 of time between 10 minutes and 60 minutes, prefer- reacted maleic anhydride and maleic acid combined. ably between 20 and 40 minutes, and/or wherein the mixing of the maleic anhydride, styrene, 3. Styrene-maleic anhydride copolymer of claim 1 or 2, and initiator is carried out at atmospheric pressure wherein the weight percent of styrene monomer to and at a temperature between 60°C and 150°C for maleic anhydride and maleic acid monomer as de- 55 a period of time between 45 minutes and 300 min- fined as styrene/(maleic anhydride + maleic acid) is utes, and/or 42:58 - 52:48. wherein the mixing of the maleic anhydride, styrene, and initiator is carried out at atmospheric pressure

8 15 EP 2 502 943 A1 16

and at a temperature between 85°C and 115°C for a period of time between 60 and 180 minutes.

11. Method of any one of claims 6 to 10, further comprising the step of allowing the styrene- maleic anhy- 5 dride copolymer formed in step c) to cool to a temperature between 55°C and 85°C, preferably between 60°C and 80°C.

12. Method of any of claims 6 to 11, further comprising 10 hydrolyzing at least a portion of the maleic anhydride to maleic acid by adding water to the styrene-maleic anhydride copolymer.

13. Method of claim 12, wherein the amount of water is 15 between 5 % and 40%, preferably between 10% and 35% by weight of the styrene-maleic anhydride copolymer, and/or wherein the water is added over a period of time between 30 and 180 minutes, preferably between 60 and 120 minutes, and/or 20 wherein after the water is added to the copolymer the mixture is mixed for a period of time between 20 and 90 minutes, preferably between 30 and 60 minutes, and/or wherein the copolymer is further allowed to cool to 25 room temperature.

14. Method of any one of claims 6 to 13, further comprising purifying the copolymer by extracting free maleic acid with water ,the copolymer preferably be- 30 ing mixed with a quantity of water about 6 times the weight of the copolymer at a temperature between 5°C and 40°C preferably between 15°C and 35°C before removing the water, and/or wherein the copolymer is mixed with the water for a 35 period of time between 1 and 6 hours, preferably between 2 and 4 hours before removing the water, and/or wherein the water is removed by filtration under pressure, and/or 40 wherein the extraction is repeated until the content of maleic acid in the supernatant is less than 0.001 % by weight.

15. Method of any one of claims 6 to 14, further com- 45 prising a drying step wherein the copolymer is dried at a temperature between 50°C and 90°C, preferably between 60°C and 80°C, and/or wherein the copolymer is dried under vacuum of 50 mbar or less, and/or wherein the copolymer is dried for a period 50 of time between 4 and 10 hours, preferably between 6 and 8 hours.

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10 EP 2 502 943 A1

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REFERENCES CITED IN THE DESCRIPTION

This list of references cited by the applicant is for the reader’s convenience only. It does not form part of the European patent document. Even though great care has been taken in compiling the references, errors or omissions cannot be excluded and the EPO disclaims all liability in this regard.

Patent documents cited in the description

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