WO2009071999A2 - Preparations of poly(styrene-co-maleic anhydride/acid) - Google Patents

Abstract

The present invention discloses poly(styrene-co-maleic anhydride/acid) and methods for their preparation using solventless techniques. In addition to the absence of potentially toxic solvents, the methods results in reduced amounts of residues, such as unreacted styrene and/or maleic anhydride monomers, which makes the copolymers suitable for bioapplications.

Description

Preparations of Poly(Styrene-co-Maleic Anhydride/Acid)

Related Applications

This application claims the benefit of priority of United States Provisional Patent Application No. 60/974,270 filed on September 21, 2007, and 60/977,846 filed on October 5, 2007, both of which are hereby incorporated by reference in their entirety.

Field of the Invention

The invention relates to, in part, poly(styrene-co-maleic anhydride/acid) copolymers and methods of synthesizing such polymers using bulk polymerization methods which yield partially hydro lyzed polymers in acidic form. The invention also relates to methods of preparing poly(styrene-co-maleic anhydride/acid) copolymers that have a low residual content of monomers (styrene and maleic anhydride and maleic acid) and which are suited to bioapplications as solutions, hydrogels or solids for medical bioengineering, tissue engineering, pharmaceutical products, hygienic care, cosmetics, biotechnology, food industry, agriculture, absorbent textiles and the like.

Background of the Invention

Poly(styrene-co-maleic anhydride) polymers are used in numerous applications but their use in bio-applications is hindered by their lack of purity and residual hazardous contaminates. The FDA approved poly(styrene-co-maleic anhydride) copolymers as indirect food additives for use as articles or components of articles that contact food items (Code of Federal Regulations, Sec. 177.1820 "Styrene-maleic anhydride copolymers", Title 21, Volume 3, p. 304-305, revised as of April 1, 2000). The FDA specified that poly(styrene- co-maleic anhydride) copolymers have a minimum average molecular mass of 70,000 and contain not more that 15 percent maleic anhydride units by weight, 0.3 weight percent residual styrene monomer, 0.1 weight percent residual maleic anhydride monomer, 0.006 weight percent maximum extractible fractions in distillated water at reflux temperature for 1 hr, and 0.02 weight percent maximum extractible fractions in n-heptane at 73 ⁰F for 2 hr.

Sethi, N. et al. demonstrated the biocompatibility of SMA commercial products, but a multistep, complex purification procedure was required before utilization (Sethi, N. et al. Contraception 1989, 39, 217-226). The same conclusion was reported by Lohiya, N. K et al. (Lohiya, N. K. et al. Int. J. Androl. 2000, 23, 36-42).

Wagner J. G. et al. in US Pat. No. 2,897,121 and Chen, Y. R. et al in Colloids and Surfaces A: Physicochem. Eng. Aspects, 2004, 242, 17-20 present the utilization of poly(styrene-co-maleic anhydride) as additives for a pharmaceutical carrier for oral administration. Although the authors assert that the polymers can be used for bio- applications, supporting data, such as purity, is not presented.

Patel, H. A. et al. disclose the synthesis, release study, and antimicrobial properties of acriflavine bound to poly(styrene-co-maleic anhydride) (Patel, H. A. et al. Die Angewandte Makromolekulare Chemie 1998, 263, 25-30). Patel, H. A. et al. report similar findings for poly(styrene-co-maleic anhydride) bound ampicillin (Patel, H. A. et al. Die Angewandte Makromolekulare Chemie 1999, 271, 24-27). In both cases, advanced purification of the poly(styrene-co-maleic anhydride) copolymer was necessary to make the composition suitable for bio-application. Ottenbrite, R. M. and Spiridon, D. disclose the use of poly(styrene-co-maleic anhydride) as antitumor effectors (Ottenbrite, R. M. J. et al. Macromol. Sci.-Che. 1985, 819-832). Spiridon D. also demonstrates the biocompatibility of the poly(styrene-co-maleic anhydride), but only after rigorous purification steps (Spiridon D. Polymer International 1997, 43, 175-181). US Pat. Nos. 3,980,663 and 4,381,784 disclose use of poly(styrene-co-maleic anhydride) as water absorbing materials for hygienic care. US Pat. Nos. 3,939,108 and 6,590,019 disclose poly(styrene-co-maleic anhydride) as an adhesive useful for bottle labeling. US Pat. No. 5,080,888 discloses poly(styrene-co-maleic anhydride) in cosmetics. US Pat. No. 4,980,403; US Pat. No. 5,104,957; US Pat. No. 5,480,427; and US Pat. No. 6,127,451 disclose using poly(styrene-co-maleic anhydride) as biomaterials. US Pat. No. 4,153,682; US Pat. No. 6,500,447; and US Pat. No. 6,531,160 disclose using poly(styrene- co-maleic anhydride) in pharmaceutical products as drug delivery systems.

Poly(styrene-co- maleic anhydride) is used as an efficient, reversible male contraceptive which is injected into the vas deferens (S. K. Guha, et al. Contraception 1997, 56, 245-250, and S. K. Guha et al. Contraception 1998, 58, 165-174). The safety of long- term vas occlusion with poly(styrene-co-maleic anhydride) has also been assessed on accessory reproductive organs in langur monkeys (Manivannan B. et al., Asian J. Androl., 2000, 7, 195-204).

A condition for using poly(styrene-co-maleic anhydride) in a bio-application is that its chemical purity be as high as possible, while its hazardous contaminant content be as low as possible. Contamination of poly(styrene-co-maleic anhydride) has two causes derived from the polymerization processes used: 1) non-reacted monomers, and 2) auxiliaries of polymerization such as: organic solvents, initiators . . . etc.

For example, poly(styrene-co-maleic anhydride) copolymers are prepared mainly by solvent based methods, but these methods are also the most contaminating because, besides unreacted monomers and initiators, there is residual solvent to remove. See US Pat. No. 2,286,062; US Pat. No. 2,378,629; US Pat. No. 2,866,775; US Pat. No. 3,157,595; US Pat. No. 3,989,586; 4,105,649; and US Pat. No. 4,126,549. The additional purification steps required represent an important economic restriction to using poly(styrene-co-maleic anhydride) in bio-applications compared to other categories of polymers. Bulk polymerization does not require organic solvents and therefore does not result in solvent residues, which is the case when using solution polymerization. See Voss, A. et al. in US Pat. No. 2,047,398; Graves, G. D. in US Pat. No. 2,205,882; and Lee Y. C. et al. in US Pat. No. 4,051,311 which disclose maleic anhydride copolymers of styrene, vinyl acetate, and others by bulk polymerization methods, with and without peroxidic initiators. The content of maleic anhydride monomers is less than 55% by weight in the initial mixture of comonomers. In these disclosures, a mixture of styrene and peroxidic initiator is allowed to homopolymerize until a 3-5% conversion. At this point, maleic anhydride monomer is added at a constant rate to form a maleic anhydride in styrene solution. The poly(styrene- co-maleic anhydride) is then extracted from the reaction mass with benzene and ultimately separated from the solution by precipitation with methanol.

Disadvantages with these bulk polymerization methods include a) incomplete conversion of monomers to copolymer due to increasing impedance of diffusion of the reactants to reaction centers because of increasing reaction mass viscosity; b) purification to remove non-reacted monomer is difficult and realized by dissolution into specific solvents (such as acetone or benzene), followed by precipitation, extraction with alcohols or water, and drying; c) generation of large amounts of reaction heat risking explosion; d) handling of reaction mass is difficult; and e) purification solids after precipitation by extraction is neither cost effective nor ecologically friendly.

Baer, M. in US Pat. No. 2,971,939 presents the synthesis of poly(styrene-co-maleic anhydride) with a content of maleic anhydride less than 12% by weight using bulk polymerization methods. Although Baer discloses that the thermal properties of poly(styrene-co-maleic anhydride) are dependent on the method of preparation, and that products with the best thermal properties are made by slow addition of maleic anhydride to excess styrene and then removing excess styrene to recover the poly(styrene-co-maleic anhydride), the material is a random poly(styrene-co-maleic anhydride). If the excess styrene is polymerized rather than removed, the resulting product is reported to be a mixture of poly(styrene-co-maleic anhydride) with homopolystyrene. Polymerization of excess styrene at the termination of the normal polymerization cycle yields the styrene homopolymer because the highly reactive maleic anhydride is consumed by the end of the process. The product is extremely difficult to handle and to cool. The Baer process and other similar methods for copolymerizing styrene and maleic anhydride in nonequimolar composition are bulk or solution processes, which require the handling of highly viscous polymer solutions, with attendant difficulties in heat transfer for the removal of the heat of reaction and in materials handling. Polymerizing styrene and some of its copolymers in aqueous suspension, in large measure circumvents the heat transfer problem, and greatly simplifies materials handling. On the other hand, it is very difficult to polymerize styrene directly with maleic anhydride in aqueous suspension, because of the rapid hydrolysis of maleic anhydride to maleic acid, a strongly ionized acid.

Cutter, L. A. in US Pat. No. 4,145,375 presents a process for copolymerizing styrene and maleic anhydride which involves a sequence of operations in which maleic anhydride is first gradually mixed with styrene in a mass stage under polymerizing conditions to rapidly form poly(styrene-co-maleic anhydride). The styrene-rich mixture is then suspended in water and the styrene polymerization completed as in a conventional mass/suspension polymerization system. The suspension step further modifies the polymer by opening the anhydride group to form free carboxylic acid groups on the polymer chain. Following the heating period, the polymerization mixture is cooled; the polymer beads are separated from the water by a solid-bowl centrifuge, and dried in a rotary air drier. The polymers resulted have molecular weight between 100,000 and 500,000, and the content of residual styrene is between 0.02 and 0.1 % by weight. A disadvantage of this process is that the final product is a blend of polystyrene and poly(styrene-co-maleic anhydride), the polystyrene being a major contaminant, with multiple implications making it unfavorable for bio-applications. Similar problems exist for front polymerization which uses excess of styrene. Szalay, J. et al. Macromol. Rapid Commun. 1999, 20, 315-318. Methods of copolymerization of maleic anhydride and other monomers in an aqueous medium have been disclosed. See Bomer B. et al. in US Pat. No. 4,737,549; Saraydin D. et al. in J. Appl. Polym. Sci. 2001, 79, 1809-1815; Caycara, T. et al. in J. Polym. Sci. A: Polym. Chem. 2001, 39, 277-283; Akkas, P. et al. in J. Appl. Polym. Sci. 2000, 78, 284-289; Sen, M. et al. in Polymer 1999, 40, 913-917; Sen, M. et al. in Polymer 1998, 39, 1165-1172; Karadag, E. et al. in J. Appl. Polym. Sci. 1997, 66, 733-739;

Saraydin, D. et al. Biomaterials 1994, 15, 917-920; and Karadag, E. et al. in Biomaterials 1996, 17, 6770. However, these methods cannot be used for copolymerizing styrene due to the differences in solubility of the two comonomers. Additionally, the resulting polymer will have few carboxylic groups, limiting the number of potential bio-applications. Copolymerization yields are highest (approximately 95%) when using equimolecular monomer feeds, and with processes that achieve good mass transfer of reactants (such as those achieved by polymerization in organic solvent media). Processes that don't use equimolecular monomer feeds induce a high value of conversion only for the monomer which is present in the least amount (Klumperman, B. et al. Polymer, 1993, 34, 1032-1037; Klumperman, B. Macromolecules, 1994, 27, 6100-6101; Klumperman, B. et al. Eur. Polym. J. 1994, 30, 955-960).

The most difficult aspect of purifying poly(styrene-co-maleic anhydride) is removal of unreacted styrene because it is an organic compound liquid, insoluble in water, but soluble in organic solvents with high boiling points that make it difficult to dry, even in high vacuum. Boundy, R. H. "Styrene, its Polymers, Copolymers and Derivatives," Reinhold Publishing Corporation, New York, 1952, pp. 860-865.

Unreacted maleic anhydride can be removed by simple hydrolysis with water to form maleic acid which has a high solubility in water (greater than 4.4 x 10⁵ ppm (wt) at 25 ⁰C; Yaws, Ch. L. in "Chemical Properties Handbook" McGraw-Hill Companies, Inc. New York, 1999), allowing its efficient and economical elimination from copolymers. In addition, the rate of hydrolysis of free maleic anhydride is much higher than that of polymerized maleic anhydride (Ratzch, M. et al. J. Macromol. Sci-Chem. 1987, A24, 949-965; Wang, M. et al. J. Appl. Polym. Sci. 2000, 75, 267-274).

Maleic anhydride is converted into maleic acid when it is hydrolyzed. The two monomers, maleic acid and maleic anhydride are recognized as separate chemical entities and have each been assigned different CAS Registry Numbers by the Chemical Abstract Services (e.g., 108-31-6 for maleic anhydride and 110-16-7 for maleic acid). In addition, the chemical properties of maleic acid and maleic anhydride differ (e.g., the melting point of maleic anhydride is 53 ⁰C while the melting point of maleic acid is 131 ⁰C). Therefore a polymer that incorporates maleic anhydride will behave differently than a polymer that incorporates maleic acid. For instance, poly(styrene-co-maleic anhydride) which incorporates maleic anhydride, differs from poly(styrene-co-maleic anhydride/acid) which includes maleic acid or a mixture of maleic anhydride and maleic acid.

C. Elvira et al. discussed the use poly(styrene-co-maleic anhydride/acid) as the backbone for polymer-drug conjugates used as drug delivery systems (Elvira, C. et al., Molecules, 2005, 10, 114-125). Maeda reported that these poly(styrene-co-maleic anhydride/acid)' s had low molecular weight around 16,000 Daltons (Maeda, H. et al. J. Protein Chem. 1984, 3, 181-193). M. Kovac Filipovic et al. reported the heterogeneous copolymerization of styrene and maleic anhydride in toluene, (Kovac Filipovic, M. et al. Polimeri 1989, 10, 157-159) to form poly(styrene-co-maleic anhydride/acid). It is desired to synthesize poly(styrene-co-maleic anhydride/acid) with a highmolecular weight and purity for bioapplications.

Summary of the Invention

One aspect of the invention relates to poly(styrene-co-maleic anhydride/acid) copolymers. In one embodiment of the invention, the viscometric molecular weight, M_v, of the poly(styrene-co-maleic anhydride/acid) is about 200,000 to about 5,000,000.

In one embodiment of the invention, the viscometric molecular weight, M_v, of the poly(styrene-co-maleic anhydride/acid) is about 500,000 to about 3,000,000.

In one embodiment of the invention, the viscometric molecular weight, M_v, of the poly(styrene-co-maleic anhydride/acid) is about 650,000 to about 3,000,000. In one embodiment of the invention, the viscometric molecular weight, M_v, of the poly(styrene-co-maleic anhydride/acid) is about 500,000 to about 2,500,000.

In one embodiment of the invention, the viscometric molecular weight, M_v, of the poly(styrene-co-maleic anhydride/acid) is about 500,000 to about 1,500,000. In one embodiment of the invention, the viscometric molecular weight, M_v, of the poly(styrene-co-maleic anhydride/acid) is about 750,000 to about 2,000,000.

In one embodiment of the invention, the viscometric molecular weight, M_v, of the poly(styrene-co-maleic anhydride/acid) is about 800,000 to about 1,500,000.

In one embodiment of the invention, the viscometric molecular weight, M_v, of the poly(styrene-co-maleic anhydride/acid) is about 850,000 to about 1,000,000.

In one aspect, the invention relates to a poly(styrene-co-maleic anhydride/acid) having less than 0.050% by weight unreacted styrene monomer.

In another aspect, the invention relates to a s poly(styrene-co-maleic anhydride/acid) having 0.045 to 0.2% by weight unreacted maleic anhydride and maleic acid combined. In a further aspect of the invention, the ratio of styrene monomer to maleic anhydride and maleic acid monomer as defined as styrene/(maleic anhydride + maleic acid) is 42:58 - 52:48.

In a further embodiment, the ratio of styrene to maleic acid in the poly(styrene-co- maleic anhydride/acid) backbone is substantially 1 : 1. In another aspect, the present invention relates to a medicament comprising the poly(styrene-co-maleic anhydride/acid) of the present invention.

In another aspect, the present invention relates to an article of manufacture comprising the poly(styrene-co-maleic anhydride/acid) of the present invention.

In a further embodiment, the article of manufacture is used in the field of medical bioengineering, tissue engineering, pharmaceutical products, body hygiene, cosmetics, biotechnology, food industry, agriculture, or absorbent textiles.

In another aspect, the present invention relates to a synthesis method of preparing a poly(styrene-co-maleic anhydride/acid) without solvents comprising: a) melting an amount of maleic anhydride monomer by heating it to its melting point; b) adding an amount of styrene containing a dissolved initiator to the melted maleic anhydride; and c) stirring the maleic anhydride, styrene, and initiator mixture for an effective amount of time to form a copolymer.

In a further embodiment, the initiator is a free radical initiator.

In a further embodiment, the initiator is selected from the group consisting of diacyl peroxides, dibenzoyl peroxide, di-tertbutyl peroxide, tert-butyl perbenzoate, tert-butyl perethylhexanoate, peresters, tert-butyl perpivalate, aliphatic azo, 2,2'-azoisobutyronitrile, azo-4-cyanopentanoic acid, peroxodisulphuric acid, hydrogen peroxide,

In a further embodiment, the amount of initiator is between 0.025% and 0.035% versus the weight of the reaction mass. In another embodiment of the invention, the maleic anhydride is used as both a reactant and media for the synthesis.

In a further embodiment, during synthesis the amount of styrene :maleic anhydride is between 1 :6 and 1 : 14 by weight.

In a further embodiment, during synthesis the amount of styrene :maleic anhydride is between 1 :8 to 1 : 12 by weight.

In a further embodiment, the amount of initiator is between 0.01% and 0.05% versus the weight of the reaction mass.

In a further embodiment, the amount of initiator is between 0.025% and 0.035% versus the weight of the reaction mass. In a further embodiment, melting the maleic anhydride is carried out by heating the maleic anhydride to or above its melting point.

In a further embodiment, the styrene is added to the maleic anhydride between 55 ⁰C and 100⁰C.

In a further embodiment, the mixing of the maleic anhydride, styrene, and initiator is carried out at atmospheric pressure and at a temperature above the melting point of maleic anhydride.

In a further embodiment, the mixing of the maleic anhydride, styrene, and initiator is carried out at atmospheric pressure and at a temperature between 55 ⁰C and 130 ⁰C In a further embodiment, the method further comprises the step of allowing the poly(styrene-co-maleic anhydride) formed to cool to a temperature between 55 ⁰C and 85

⁰C.

In a further embodiment, the poly(styrene-co-maleic anhydride) formed is cooled to between 60 ⁰C and 80 ⁰C.

In a further embodiment, the method further comprises adding water to the copolymer.

In a further embodiment, the method further comprises hydrolyzing at least a portion of the maleic anhydride to maleic acid by adding water to the poly(styrene-co- maleic anhydride).

In a further embodiment, 10-85% of the maleic anhydride in the copolymer backbone is hydro lyzed through the addition of water.

In a further embodiment, the amount of water is between 5 % and 40% by weight of the poly(styrene-co-maleic anhydride). In a further embodiment, the amount of water is between 10% and 35% by weight of the poly(styrene-co-maleic anhydride).

In a further embodiment, the method further comprises allowing the copolymer to cool to room temperature.

In a further embodiment, the method further comprises purifying the copolymer by extracting free maleic anhydride and acid with water.

In a further embodiment, the copolymer is mixed with a quantity of water about 6 times the weight of the copolymer at a temperature between 5 ⁰C and 40 ⁰C before removing the water.

In a further embodiment, the copolymer is mixed with the water at a temperature between 15 ⁰C and 35 ⁰C.

In a further embodiment, the copolymer is mixed with the water for a period of time sufficient to saturate the water with maleic acid and styrene.

In a further embodiment, the method further comprises purifying the copolymer by extracting free maleic acid with aqueous media. In a further embodiment, the aqueous media is water. In a further embodiment, the water is removed from the copolymer suspension by filtration under pressure.

In a further embodiment, the extraction is repeated until the content of maleic acid in the supernatant is less than 0.001 % by weight. In a further embodiment, the copolymer is maintained in a wet state.

In a further embodiment, the method further comprises a drying step wherein the copolymer is dried at a temperature between 50 ⁰C and 90 ⁰C.

In a further embodiment, the copolymer is dried at a temperature between 60 ⁰C and 80 ⁰C. In a further embodiment, the copolymer is dried under vacuum of 50 mbar or less.

In a further embodiment, the copolymer is dried for a period of time needed to reduce the water in the poly(styrene-co-maleic anhydride/acid) to less than 40% by weight.

In a further embodiment, the copolymer is dried for a period of time between 6 and 8 hours.

Detailed Description of the Invention

Definitions

The term "bio-applications" as used herein refers to all applications for which the most important property is biocompatibility.

The term "biocompatibility" as used herein refers to biochemical characteristics which a material possess that make it acceptable to living organisms (human, animals and plants), as an integral part of them, without have spontaneous or in time the manifestation of some repulsive or toxic phenomena under the form of inflammation, infections and others (Black J., "Biological Performance of Materials: Fundamentals of Biocompatibility", 2d ed. M. Dekker, N. Y., 1992). This interpretation is given both to pure materials (100% purity, other substances not detected) and those that have a purity less than 100% (because they contain contaminants).

The standards that have guided biocompatibility testing are the 1) Tripartite Guidance; 2) the International Organization for Standardization (ISO) 10993 standards (which are known as the Biological Evaluation of Medical Devices and remain under development internationally); and 3) the FDA Blue Book Memoranda. The term "poly(styrene-co-maleic anhydride/acid)" as used herein refers to a copolymer comprising styrene units and maleic anhydride units, wherein at least a portion of the maleic anhydride units are hydro lyzed to the corresponding maleic acid units. The term poly(styrene-co-maleic anhydride/acid), however, is not limited to the manner in which the copolymer is made. For example, the poly(styrene-co-maleic anhydride/acid) can be formed by polymerization of styrene and maleic anhydride to form a poly(styrene- co-maleic anhydride), followed by hydrolysis of at least a portion of the anhydride units to maleic acid units. Poly(styrene-co-maleic anhydride/acid) also may be formed, for example, by polymerization of styrene monomers and a mixture of maleic anhydride and maleic acid monomers. Thus, the term poly(styrene-co-maleic anhydride/acid) refers to the final structure of the copolymer, and not the method by which it was made.

PolvfStyrene-co-Maleic Anhydride/acid) Copolymers

The present invention is directed to a poly(styrene-co-maleic anhydride/acid) copolymer having high purity. In some embodiments, the poly(styrene-co-maleic anhydride/acid) copolymer has about 0.01 to about 0.20 % by weight unreacted styrene monomer. In other embodiments, the copolymer has about 0.015% to about 0.050% by weight of unreacted styrene.

In other embodiments, the poly(styrene-co-maleic anhydride/acid) copolymer has about 0.045 to about 0.2% by weight unreacted maleic anhydride and maleic acid combined. In other embodiments, the copolymer has about 0.05% to about 0.1% unreacted maleic anhydride and maleic acid combined.

The ratio of styrene units and combined maleic acid anhydride units in the copolymer can be expressed as styrene/(maleic anhydride + maleic acid). In some embodiments, the poly(styrene-co-maleic anhydride/acid) copolymer has a ratio of styrene units to combined maleic anhydride and maleic acid units (styrene/(maleic anhydride + maleic acid)), of about 30:70 to about 70:30, 40 to 60 to 60:40, or 45:55 to 55:45. In other embodiments, the styrene/(maleic anhydride + maleic acid) ratio is about 42:58 to about 52:48.

The ratio of maleic anhydride units to the sum of maleic anhydride units and hydrolyzed maleic anhydride units, i.e., maleic acid units, can be expressed as maleic anhydride/(maleic acid + maleic anhydride). In some embodiments, the poly(styrene-co- maleic anhydride/acid) copolymer has a ratio of maleic anhydride/(maleic acid + maleic anhydride) of about 0.2 to about 0.8. In other embodiments, the ratio is about 0.17 to about 0.79.

The poly(styrene-co-maleic anhydride/acid) copolymers of the present invention have a high molecular weight represented as Weight Average Molecular Weight as determined by Gel Permeation Chromatography (GPC, M_w) and / or viscometric average molecular weight (M_v).

The Weight Average Molecular Weight of the copolymers can be determined by a chromatographic method in which polymers are separated based on their size (i.e. their hydrodynamic volume). GPC can be used as a measure of both the size and the polydispersity of the polymers. If standards of a known size are run previously, then a calibration curve can be created to determine the sizes of polymer molecules of interest. Alternatively, techniques such as light scattering and/or viscometry can be used online with GPC to yield absolute molecular weights that do not rely on calibration with standards of known molecular weight. Viscometric molecular weight of the copolymers can be determined, for example, by using the evaluation of intrinsic viscosity [η_rel] based on relative viscosity [η] of one solution of copolymer with concentration c = 0.5 g/100 ml in tetrahydrofuran at 25°C , using the calculus formulae (Raju K.V.S.N.,Yaseen M. J. Appl. Polym. Sci. 1992, 45, 677- 681; Chee K. K. J. Appl. Polym. Sci. 1987, 34, 891-899; and Spiridon D. et al. Polymer International 1997, 43, 175-181) (Eq. 1).

[τ7]= O.77 *io^ *M"^M

(Eq. 1) Note that M_w and M_v are used herein interchangeably.

In some embodiments, the viscometric molecular weight, M_v, of the copolymer is about 200,000 to about 5,000,000, while in other embodiments, M_v is about 500,000 to about 3,000,000, or about 650,000 to about 3,000,000. In other embodiments, M_v is about 500,000 to about 2,500,000, while in other embodiments, M_v is about 500,000 to about 1,500,000. In other embodiments, M_v is about 750,000 to about 2,000,000, or about 800,000 to about 1,500,000, or about 850,000 to about 1,000,000.

The present invention is also directed to an article of manufacture comprising the aforementioned poly(styrene-co-maleic anhydride/acid) copolymer. For example, the article of manufacture may be used in the field of medical bioengineering, medical devices, tissue engineering, pharmaceutical products, body hygiene, cosmetics, biotechnology, food industry, agriculture, or absorbent textiles. In some embodiments, the article of manufacture is a medical device.

In certain embodiments, the poly(styrene-co-maleic anhydride/acid) of the present invention has the following characteristics:

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

2. Maleic anhydride / MaI = 0.17 - 0.79.

3. Viscometric molecular weight (M_v) = 500,000 - 2,500,000.

4. Styrene residual = 0.015 - 0.042 weight percent. 5. MaI (maleic anhydride + maleic acid) residual = 0.045 - 0.2 weight percent.

The above characteristics can be determined, for example, by following procedures: a) The amount of residual styrene was measured by extraction with benzene

(spectroscopic grade) of 1 g of polymer for 12 hours by Soxhlet extraction. The extracted benzene was analyzed by gas spectroscopy (Perkin-Elmer equipment). b) The amount of residual maleic acid was measured by dialysis with distilled water as a 2 g sample of polymer at 40⁰C using a Spectra/Por® CE dialyze membrane (Spectrum Laboratories, CA, USA) in 14 cycles of 24 hours each (500 ml water per cycle), the water was changed after each cycle. The accumulated water was analyzed for maleic acid by HPLC method (WATERS, MA, USA). c) Monomeric concentration expressed as Sty : MaI (styrene : maleic comonomer [maleic anhydride + maleic acid]) was estimated by conductometric titration of a solution prepared by dissolving 0.1 g of dry polymer in a solution of NaOH 0.5 N and HCl 0.5N. d) Functionality ratio, expressed as MAnh : MaI (maleic anhydride [maleic anhydride + maleic acid] ), [(mol/g) : (mol/g)] , was estimated using FTIR quantitative analysis (SHIMAZU equipment): Maleic anhydride p. a. (ACROS Organics, Geel, Belgium) and maleic acid p.a.(ACROS Organics, Geel, Belgium) versus the characteristic absorption bands: 1770-1790 cm¹ for anhydride and 1700-1720 cm¹ for COOH. e) Viscometric average molecular weight, M_v, was estimated using the evaluation of intrinsic viscosity [η_rel] based on relative viscosity [η] of one solution of polymer with concentration c = 0.5 g/100 ml in tetrahydrofuran at 25 ⁰C, using Eq. 1, above.

Methods of Polymerization

The present invention is also directed to methods of making the aforementioned poly(styrene-co-maleic anhydride/acid) copolymers, wherein the method does not use solvents, comprising the steps of:

(a) melting an amount of maleic anhydride monomer;

(b) adding an amount of styrene containing dissolved initiator to the maleic anhydride to form a mixture; and (c) mixing the maleic anhydride, styrene, and initiator mixture for an effective amount of time to form a copolymer.

In some embodiments, the maleic anhydride serves as both as a reaction medium and a reactant. In some embodiments, the solvents that are absent from the method are organic solvents. For example, organic solvents commonly used in polymerization processes include methylene chloride, dichloroethane, ethylacetate, dimethylformamide, dimethylsulfoxide, ether, tetrahydrofuran, benzene, toluene, xylenes, etc. Such organic solvents are not used in the present methods, thereby avoiding contamination of the end product with the residual amounts of solvents, and avoiding the step of removing and disposing of such organic solvents. Examples of suitable initiators for initiating polymerization are the customary agents which form free radicals by thermal decomposition. Non-limiting examples include: diacyl peroxides, such as dibenzoyl peroxide, di-tertbutyl peroxide, tert-butyl perbenzoate or tert-butyl perethylhexanoate peresters, such as tert-butyl perpivalate, aliphatic azo compounds, such as 2,2'-azoisobutyronitrile, azo-4-cyanopentanoic acid or other water- soluble aliphatic azo compounds, salts of peroxodisulphuric acid or hydrogen peroxide. In one embodiment, the initiator is dibenzoyl peroxide or azoisobutyronitrile. In some embodiments, the amount of styrene and the amount of maleic anhydride have a ratio (styrene:maleic anhydride) of between about 1 :6 and about 1 : 14 by weight of the reaction feed. In other embodiments, the ratio is between about 1 :8 to about 1 : 12 by weight.

In some embodiments, the amount of the initiator is between about 0.01% and about 0.05% by weight of the total reaction mixture, i.e., the combined, styrene, maleic anhydride and initiator, while in other embodiments, the initiator is between about 0.025% and about 0.035% of the weight of the reaction mixture.

The maleic anhydride is melted in melting of the maleic anhydride is carried out by heating the maleic anhydride to at least its melting point. In some embodiments, the melting of the maleic anhydride is carried out by heating the maleic anhydride to about 51⁰C to about 56 ⁰C. In other embodiments, the maleic anhydride is heated to a temperature of about 55 ⁰C to about 80 ⁰C, or to about 75 ⁰C. In some embodiments, the styrene is added to the maleic anhydride while maintaining the reaction mixture temperature in a range of about 56 ⁰C and about 100 ⁰C. In certain embodiments, the initiator is a free radical initiator. The initiator has an initiation temperature (e.g., the mixing of the maleic anhydride, styrene, and initiator is carried out at a temperature of at least the initiation temperature of the initiator). In some embodiments, the reaction is carried out at atmospheric pressure.

In certain embodiments, the copolymer formed in step (c) of the aforementioned method consists essentially of poly(styrene-co-maleic anhydride). This poly(styrene-co- maleic anhydride) contains styrene units and all or substantially all maleic anhydride units, and contains zero, or a very small percentage of maleic acid units.

In other embodiments, the copolymer of step (c) is poly(styrene-co-maleic anhydride/acid). In some embodiments, a portion of the maleic anhydride monomer is hydro lyzed to maleic acid prior to forming the copolymer. When the maleic anhydride monomer is hydro lyzed to form a mixture of maleic acid and maleic anhydride, the resulting copolymer formed in step (c) is poly(styrene-co-maleic anhydride/acid).

In some embodiments, the method further comprises adding water to the copolymer formed in step (c). In some embodiments, the water hydro lyzes unreacted maleic anhydride monomers, maleic anhydride units in the copolymer, or both. In some embodiments, the method further comprises hydro lyzing a portion of the maleic anhydride units in the copolymer. In some embodiments, 10-85% of the maleic anhydride units of the copolymer are hydro lyzed by adding water to the copolymer. When the copolymer formed in step (c) is poly(styrene-co-maleic anhydride), the step of hydrolyzing 10 to 85% of the maleic anhydride units provides a poly(styrene-co-maleic anhydride/acid) copolymer having about 10 to 85% maleic acid units.

In some embodiments, the amount of water added is between about 5 % and about 40% by weight of the copolymer, or between about 10% and about 35% by weight of the copolymer. In some embodiments, the aforementioned method further comprises cooling the copolymer to room temperature. For example, the copolymer may be cooled to a temperature in a range of about room temperature to about 65 ⁰C. In some embodiments, the copolymer is cooled to room temperature, e.g. about 18 ⁰C. In some embodiments, the cooling occurs when the water is added to the copolymer. In some embodiments, the method further comprises extracting unreacted maleic anhydride and/or maleic acid from the copolymer with water. For example, the copolymer formed in step (c) is mixed with a quantity of water about 6 times the weight of the copolymer to hydrolyze the unreacted maleic anhydride, and extract maleic acid from the copolymer. The water can be removed from the copolymer by filtration. In some embodiments, the aforementioned extraction step is repeated until the content of maleic acid in the removed water, also called the supernatant, is less than about 0.001 % by weight.

In some embodiments, the extraction is carried out at a temperature of about 5 ⁰C to about 40 ⁰C, or about 15 ⁰C to about 35 ⁰C.

In some embodiments the copolymer is maintained in a wet state. In some embodiments, the methods further comprises drying the copolymer at a temperature between about 50 ⁰C and about 90 ⁰C, or between about 60 ⁰C and about 80 ⁰C. In some embodiments, the copolymer is dried under a vacuum of about 50 mbar or less. In some embodiments, the copolymer is dried until its moisture content is less than about 20%. Thus, the present invention relates in part to a process of obtaining poly(styrene-co- maleic anhydride/acid) using bulk-polymerization methods and free-radical initiators, with monomer feeds of styrene (Sty) : maleic anhydride (MAnh) of 1 :6 to 1 : 14 and a quantity of initiator between 0.01% and 0.05% (w/w) versus the reaction mass.

Polymeric reactions can be carried out, for example, in a kneader-extruder (such as Sigma Mixer by Jaygo, Union, NJ, USA) connected to a vacuum that includes a trap for condensed water cooled at temperature of 5-7°C, a heating-cooling mantle, thermometer, and dosing funnel for liquids, in which is loaded at ambient temperature a predetermined quantity of technical grade maleic anhydride. The maleic anhydride is mixed at temperatures of about 75 ⁰C for about 30 minutes to yield a transparent fluid mass of melted maleic anhydride. A persistent semi-opaque melt indicates the presence of maleic acid. Transforming maleic acid to maleic anhydride can be achieved by connecting the kneader to a vacuum distillation apparatus and adjusting the pressure to 400 mbar at the above temperature for about 30 minutes. The maleic anhydride melts at atmospheric pressure is brought to a temperature not less than 55 ⁰C and not greater than 100 ⁰C. In another embodiment, the temperature is between 65 ⁰C and 90 ⁰C. A separate vessel is charged with technical grade styrene and an initiator is added to the styrene. The resulting solution is added to the melted maleic anhydride. Mixing is continued at atmospheric pressure and a temperature not less than 60 ⁰C and not greater than 150 ⁰C for a period of time not less than 45 minutes and not greater than 300 minutes. In another embodiment the mixing temperature is maintained between 85°C and 115°C. In another embodiment, the mixing time is between 60 and 180 minutes.

The yellow-brown, viscous and transparent reaction mass is processed to transform unreacted excess maleic anhydride to maleic acid by hydrolysis. The content of the kneader is cooled to not less than 55 ⁰C and not greater than 85 ⁰C by adding purified water (with a conductivity less than 10 μS). In another embodiment, the content of the kneader is cooled to temperatures between 60 ⁰C and 80 ⁰C. The amount of purified water added is not less than 5 % and not greater than 40 % by weight versus the reaction mass. After completing the addition of the water, the reaction mass is continued to be mixed. Alternatively, the reaction mass is cooled to ambient temperatures by circulating through the mantle liquid with temperatures of 5-7 ⁰C. The maleic acid is extracted from the reaction mass according to the following process: a stainless steel mixing vessel (Nutsche filter) equipped with an impeller stirrer with two blades, a mantle for heating or cooling, a thermometer, a dosing nipple for liquids, an inlet-pipe connection for compressed air, an outlet nipple, and, in the interior, a filter based on two pierced stainless steel plates with a polyamide cloth (100 micron mesh) between them. The vessel is having a useful volume three times larger than that of the kneader. The vessel is filled with purified water (with a conductivity less than 10 μS) in an amount that is approximately six times the volume of the reaction mass at a temperature not less than 5 ⁰C and not greater than 40 ⁰C. In another embodiment, the temperature is between 15°C and 35 ⁰C. While stirring the purified water at a stirring rate of 40-60 rpm the reaction mass is added via the helical conveyer. The formed aqueous suspension is stirred for not less than 1 hour and not greater than 6 hours. In another embodiment, the suspension is mixed between 2 hours and 4 hours. The stirring is stopped and the aqueous phase is eliminated by filtration under pressure.

The extraction process is repeated for as many times as it takes to obtained a maleic acid content in the supernatant of less than 0.001% by weight as determined by volumetric titration with a solution of NaOH 0.01 N. The wet solid, substantially free of the maleic acid, and with a moisture content of

70%, is transferred to a circular dryer equipped with a heating and cooling mantle, thermometer, helicoidally stirrer, breaking device with rotary knife, and is connected to a vacuum distillation apparatus comprising a filter with sackcloth, condenser, and collecting vessel for the condensation water. The granular mass is dried at a temperature of not less than 50 ⁰C and not greater than 90 ⁰C. In another embodiment, the drying temperature is between 60 ⁰C and 80 ⁰C, and the vacuum is at 50 mbar for a period of time not less than 4 hours and not more than 10 hours. In another embodiment, the drying period of time is between 6 and 8 hours. Lastly, the material is cooled to ambient temperature, removed from dryer, and packed in welded polyethylene bags. The aqueous solution of maleic acid resulting from the extraction is processed by thermal dehydration to obtain maleic anhydride using one of the proceeding known methods in art and adapted to the present invention (see for example US Pat. No. 3,993,671; US Pat. No. 4,118,403; US Pat. No. 4,414,898; and US Pat. No. 4,659,433).

Further examples for realizing the invention are presented below. Examples

The invention now being generally described, it will be more readily understood by reference to the following examples, which are included merely for purposes of illustration of certain aspects and embodiments of the present invention, and are not intended to limit the invention.

Example 1

In a kneader-extruder apparatus (60 liters, Sigma Mixer by Jaygo, Union, NJ, USA) connected to a vacuum that includes: a trap for condensed water cooled at temperatures of 5-7°C, a heating-cooling mantle, thermometer, and dosing funnel for liquids, 25 kg of technical grade maleic anhydride was added at ambient temperatures. The maleic anhydride was mixed and heated at 75 ⁰C for about 30 minutes to obtain a transparent fluid mass of melted maleic anhydride. Technical grade styrene with 8 g of dissolved dibenzoyl peroxide was added under ambient pressure over 20 minutes bringing the temperature of the mixture to 65 ⁰C. After adding the styrene, the temperature of the reaction increased rapidly during a period of 15 minute from 78 ⁰C to 116 ⁰C due to polymerization. When the exothermic phase of polymerization is completed, mixing continued at atmospheric pressure at 100 ⁰C for another 60 minutes. The viscous, transparent, yellow brown reaction mass was cooled to 65 ⁰C by adding 8 liters of purified water (with a conductivity less than 10 μS) while mixing over 60 minutes. After adding the water, the reaction mass was mixed for another 45 minutes at 65 ⁰C. Alternatively, the reaction mass can be cooled to ambient temperatures by circulating cooled water (5-7⁰C) through the mantle of the kneader.

The reaction mass is transferred through the helical conveyer located in the interior central zone of the apparatus to a stainless steel vessel (Nutsche Filter) containing 160 liters of purified water at 18 ⁰C under moderate stirring (stirrer speed 40-60 rpm). The Nutsche Filter has a useful volume three times larger than that of the kneader. The Nutsche Filter has a mantle for heating and cooling, a stirrer, a thermometer, a dosing nipple for liquids, an inlet-pipe connection for compressed air, an outlet nipple, and, in the interior, a filter media based on two pierced plates of stainless steel with a polyamide cloth between them (100 microns mesh). The coarse aqueous suspension was mixed for 2 hours. The aqueous phase was then removed by filtration under pressure.

The process was repeated 3 times. The last supernatant had a maleic acid concentration of only 0.00073 % by weight. The wet solid had a humidity content of 68.3% and was transferred to a circular dryer equipped with a heating and cooling mantle, thermometer, helicoidally stirrer, breaking device with a rotary knife and was connected to a vacuum. The wet mass was dried at 65 ⁰C at 50 mbar for 5 hours. Lastly, the material was cooled to ambient temperature, removed from the dryer, and packaged in welded polyethylene bags.

The aqueous solution of maleic acid resulting from the extraction was collected for maleic anhydride recovery.

From this process, 5.17 kg of poly(styrene-co-maleic anhydride/acid) was obtained as a white powder: 94.598% poly(styrene-co-maleic anhydride/acid); 5.31% water; 0.029% styrene and 0.063% (maleic anhydride + maleic acid), all as weight percent. The purified copolymer had the following structural characteristics: M_v = 1,251,000; Sty : MaI = 46 : 54 and MAnh : MaI = 0.49.

Example 2

Same equipment and procedure as described in Example 1 except 3.4 liters of styrene containing 6.8 grams of dibenzoyl peroxide dissolved therein was added at 80 ⁰C. Maximum temperature during the exothermic phase was 121 ⁰C. The last supernatant from the extraction had a maleic acid content of 0.00095% by weight and drying was at 80 ⁰C for 6 hours.

The process yielded 6.28 kg of poly(styrene-co-maleic anhydride/acid) as a white powder: 95.267% poly(styrene-co-maleic anhydride/acid) copolymer; 4.63 % water; 0.031 styrene and 0.072 % (maleic anhydride + maleic acid), all as weight percent. The purified poly(styrene-co-maleic anhydride/acid) copolymer had the following structural characteristics: M_v = 546,000; Sty: MaI = 48: 52 and MAnh : MaI = 0.68 .

Example 3 Same equipment and procedure as in Example 1 except that 2.5 liters of styrene containing 8.5 grams of initiator dissolved therein was added over 40 minutes. Maximum temperature during the exothermic phase was 128 ⁰C. Polymerization was complete after 180 minutes with a final temperature of 85 ⁰C. Hydrolysis utilized 6 liters of water added over 120 minutes and the extractions were made at 35 ⁰C. The process yielded 4.72 kg of poly(styrene-co-maleic anhydride/acid) as a white powder: 93.08% poly(styrene-co-maleic anhydride/acid) copolymer; 6.82 % water; 0.018% styrene and 0.082% (maleic anhydride + maleic acid), all as weight percent. The purified poly(styrene-co-maleic anhydride/acid) copolymer had the following structural characteristics: M_v = 726,000; Sty : MaI = 51 : 49 and MAnh : MaI = 0.27.

Example 4 In the same type of kneader-extruder apparatus that used in Example 1, 25 kg of technical grade maleic anhydride was loaded at ambient temperatures. The maleic anhydride was heated and mixed at 75 ⁰C for 30 minutes to yield a fluid transparent mass of melted maleic anhydride. 3 liters of technical grade styrene containing 9.8 grams of dibenzoyl peroxide dissolved therein was added at atmospheric pressure over a period of 40 minutes. After adding the styrene, the temperature of reaction increased rapidly from 83 ⁰C to 132 ⁰C over 12 minutes. After the exothermic phase of reaction was completed, mixing at atmospheric pressure at 115 ⁰C continued for 120 minutes. 9.8 liters of purified water (with conductivity less than 10 μS) was added over 120 minutes cooling the reaction mass to 60 ⁰C. The reaction mass was mixed for 60 minutes at 60 ⁰C. Alternatively, the reaction mass may be cooled to ambient temperatures by circulating cooled water (5-7 ⁰C) through the mantle.

The granular mass from the kneader was transferred through the helical conveyer to a vessel containing 160 liters of water at 15 ⁰C under moderate stirring. The coarse aqueous suspension was mixed for 4 hours before removing the aqueous phase by filtration under pressure. This process was repeated 3 times. The last supernatant removed had a maleic acid content of 0.00091% by weight.

The purified wet solid had a moisture content of 72.8% and was transferred to a circular dryer connected to a vacuum and dried at 80⁰C at 50 mbar for 4 hours. Lastly, the material was cooled to ambient temperature, removed from dryer, and packed in welded polyethylene bags.

The aqueous solutions of maleic acid from the extractions were collected for maleic anhydride recovery.

The process yielded 6.93 kg of poly(styrene-co-maleic anhydride/acid) as a white powder: 92.114% poly(styrene-co-maleic anhydride/acid) copolymer; 7.82% water; 0.021% styrene and 0.045% (maleic anhydride + maleic acid), all as weight percents. The purified poly(styrene-co-maleic anhydride/acid) copolymer had the following structural characteristics: M_v= 251,000; Sty : MaI = 42: 58 and MAnh : MaI = 0.17. Example 5

The same type of equipment and procedure as in Example 4 was used except 2.4 liters of styrene containing 6.8 grams of dibenzoyl peroxide dissolved therein was added, the reaction mass was added to 2.1 liters of deionized water, and drying was carried out at 80 ⁰C for 8 hours.

The process yielded 4.72 kg of poly(styrene-co-maleic anhydride/acid) as a white powder: 96.121% poly(styrene-co-maleic anhydride/acid) copolymer; 3.78% water; 0.041% styrene and 0.058% (maleic anhydride + maleic acid), all as weight percents. The purified poly(styrene-co-maleic anhydride/acid) had the following structural characteristics: M_v = 1,780,000; Sty : MaI = 49 : 51 and MAnh : MaI = 0.79.

Incorporation by Reference

All of the U.S. patents and U.S. published patent applications cited herein are hereby incorporated by reference.

Equivalents Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the following claims.

Claims

We claim:

1. A poly(styrene-co-maleic anhydride/acid) copolymer having about 0.01 to about 0.20 % by weight unreacted styrene monomer.

2. A poly(styrene-co-maleic anhydride/acid) copolymer having about 0.045 to about 0.2 % by weight unreacted maleic anhydride and maleic acid combined.

3. The poly(styrene-co-maleic anhydride/acid) copolymer of claim 1 or 2, wherein the ratio of styrene units to combined maleic anhydride and maleic acid units defined as styrene/(maleic anhydride + maleic acid) is about 30:70 to about 70:30.

4. The poly(styrene-co-maleic anhydride/acid) copolymer of claim 3, wherein the ratio of styrene/(maleic anhydride + maleic acid) is about 42:58 to about 52:48.

5. The poly(styrene-co-maleic anhydride/acid) copolymer of any one of claims 1 to 4, wherein the ratio of maleic anhydride/(maleic acid+ maleic anhydride) is about 0.2 to about 0.8.

6. The poly(styrene-co-maleic anhydride/acid) copolymer of any one of claims 1 to 4, wherein the ratio of maleic anhydride/(maleic acid+ maleic anhydride) is about 0.17 to about 0.79.

7. The poly(styrene-co-maleic anhydride/acid) copolymer of any one of claims 1 to 6, wherein the viscometric molecular weight, M_v, of the copolymer is about 200,000 to about 5,000,000.

8. The poly(styrene-co-maleic anhydride/acid) copolymer of any one of claims 1 to 6, wherein the viscometric molecular weight, M_v, of the copolymer is about 500,000 to about 3,000,000.

9. The poly(styrene-co-maleic anhydride/acid) copolymer of any one of claims 1 to 6, wherein the viscometric molecular weight, M_v, of the copolymer is about 650,000 to about 3,000,000.

10. The poly(styrene-co-maleic anhydride/acid) copolymer of any one of claims 1 to 6, wherein the viscometric molecular weight, M_v, of the copolymer is about 500,000 to about 2,500,000.

11. The poly(styrene-co-maleic anhydride/acid) copolymer of any one of claims 1 to 6, wherein the viscometric molecular weight, M_v, of the copolymer is about 500,000 to about 1,500,000.

12. The poly(styrene-co-maleic anhydride/acid) copolymer of any one of claims 1 to 6, wherein the viscometric molecular weight, M_v, of the copolymer is about 750,000 to about 2,000,000.

13. The poly(styrene-co-maleic anhydride/acid) copolymer of any one of claims 1 to 6, wherein the viscometric molecular weight, M_v, of the copolymer is about 800,000 to about 1,500,000.

14. The poly(styrene-co-maleic anhydride/acid) copolymer of any one of claims 1 to 6, wherein the viscometric molecular weight, M_v, of the copolymer is about 850,000 to about 1,000,000.

15. The poly(styrene-co-maleic anhydride/acid) copolymer of any one of claims 1 to 14, wherein the amount of unreacted styrene monomer is about 0.015% to about 0.050 % by weight.

16. An article of manufacture comprising the poly(styrene-co-maleic anhydride/acid) copolymer of any one of claims 1 to 15.

17. The article of manufacture of claim 16, used in the field of medical bioengineering, medical devices, tissue engineering, pharmaceutical products, body hygiene, cosmetics, biotechnology, food industry, agriculture, or absorbent textiles.

18. A method of preparing a poly(styrene-co-maleic anhydride/acid) copolymer without solvents comprising:

(a) melting an amount of maleic anhydride monomer;

(b) adding an amount of styrene containing dissolved initiator to the maleic anhydride to form a mixture; and

(c) mixing the maleic anhydride, styrene, and initiator mixture for an effective amount of time to form a copolymer.

19. The method of claim 18, wherein the solvents that are absent from the method are organic solvents.

20. The method of claim 18 or 19, wherein the initiator is a free radical initiator.

21. The method of claim 20, wherein the initiator is selected from the group consisting of diacyl peroxides, dibenzoyl peroxide, di-tertbutyl peroxide, tert-butyl perbenzoate, tert-butyl perethylhexanoate, peresters, tert.-butyl perpivalate, aliphatic azo, 2,2'- azoisobutyronitrile, azo-4-cyanopentanoic acid, peroxodisulphuric acid, and hydrogen peroxide.

22. The method of claim 21, wherein the initiator is dibenzoyl peroxide or 2,2'- azoisobutyronitrile.

23. The method of any one of claims 18 to 22, wherein the amount of styrene and the amount of maleic anhydride have a ratio (styrene :maleic anhydride) of between about 1 :6 and about 1 : 14 by weight.

24. The method of claim 23, wherein the ratio is between about 1 :8 to about 1 : 12 by weight.

25. The method of any one of claims 18 to 24, wherein the amount of initiator is between about 0.01% and about 0.05% by weight of the reaction mixture.

26. The method of claim 25, wherein the amount of initiator is between about 0.025% and about 0.035% versus the weight of the reaction mixture.

27. The method of any one of claims 18 to 26, wherein the melting of the maleic anhydride is carried out by heating the maleic anhydride to its melting point.

28. The method of any one of claims 18 to 26, wherein the melting of the maleic anhydride is carried out by heating the maleic anhydride to a temperature of about 51 ⁰C to about 56 ⁰C.

29. The method of any one of claims 18 to 24, wherein the styrene is added to the maleic anhydride while maintaining the mixture at a temperature of between about 56 ⁰C and about 100 ⁰C.

30. The method of any one of claims 18 to 29, wherein the mixing of the maleic anhydride, styrene, and initiator is carried out at atmospheric pressure and at a temperature of at least the initiation temperature of the initiator.

31. The method of any one of claims 18 to 30, wherein the maleic anhydride serves as both as a reaction medium and a reactant.

32. The method of any one of claims 18 to 31 , wherein the copolymer of step (c) consists essentially of poly(styrene-co-maleic anhydride).

33. The method of any one of claim 18 to 32, further comprising adding water to the copolymer formed in step (c).

34. The method of any one of claims 18 to 33, further comprising hydrolyzing a portion of the maleic anhydride monomer prior to forming the copolymer.

35. The method of any one of claims 18 to 34, wherein the copolymer formed in step (c) comprises maleic anhydride units, and further comprising hydrolyzing a portion of the maleic anhydride units.

36. The method of claim 35, wherein 10-85% of the maleic anhydride units are hydrolyzed by adding water to the copolymer.

37. The method of claim 35 or 36, wherein the amount of water is between 5% and 40% by weight of the copolymer.

38. The method of claim 37, wherein the amount of water is between 10% and 35% by weight of the copolymer.

39. The method of any one of claims 18 to 38, further comprising cooling the copolymer to room temperature.

40. The method of any one of claims 18 to 39, further comprising extracting unreacted maleic acid from the copolymer with water.

41. The method of claim 40, wherein the copolymer is mixed with a quantity of water about 6 times the weight of the copolymer.

42. The method of claim 40 or 41 , wherein the copolymer is mixed with the water at a temperature between about 5 ⁰C and about 40 ⁰C.

43. The method of claim 42, wherein the copolymer is mixed with the water at a temperature between about 15 ⁰C and about 35 ⁰C.

44. The method of any one of claims 40 to 43, wherein the water is removed from the copolymer by filtration

45. The method of any one of claim 44, wherein the extracting is repeated until the content of maleic acid in the removed water is less than about 0.001% by weight.

46. The method of any one of claims 18 to 45, further comprising maintaining the copolymer in a wet state.

47. The method of any one of claims 18 to 46, further comprising drying the copolymer at a temperature between about 50 ⁰C and about 90 ⁰C.

48. The method of claim 47, wherein the temperature is between about 60 ⁰C and about 80 ⁰C.

49. The method of claim 47 or 48, wherein the copolymer is dried under a vacuum of about 50 mbar or less.

50. The method of any one of claims 47 to 49, wherein the copolymer is dried until its moisture content is under about 20% by weight.