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 ”, 2 d 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 . in one embodiment , the present invention relates to a process of obtaining styrene - maleic - anhydride copolymers using bulk - polymerization methods and free - radical initiators , with monomer feeds of styrene ( sty ): maleic anhydride ( manh ) of 1 : 6 , 1 : 14 , 1 : 8 , or 1 : 12 and a quantity of initiator not less than 0 . 01 % and not more than 0 . 05 % versus the reaction mass . in another embodiment , the quantity of initiator is not less than 0 . 025 % and not more than 0 . 035 %. 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 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 and azoisobutyronitrile . polymeric reactions are carried out in a kneader - extruder 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 ° c . 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 melt at atmospheric pressure is brought to a temperature not less than 55 ° c . and not greater than 100 ° c . in another embodiment , the temperature is between 65 ° c . and 90 ° c . technical grade styrene and dissolved initiator are added to the maleic anhydride melt over a period of time not less than 10 minutes and not greater than 60 minutes . in another embodiment , period of time is between 20 and 40 minutes . mixing is continued at atmospheric pressure and a temperature not less than 60 ° c . and not greater than 150 ° c . 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 ° c . and not greater than 85 ° c . by adding deionized water ( with a conductivity less than 10 μs ). in another embodiment , the content of the kneader is cooled to temperatures between 60 ° c . and 80 ° c . the amount of deionized water added is not less than 5 % and not greater than 40 % by weight versus the reaction mass . in another embodiment , the amount of deionized water added is between 10 % and 35 % by weight during a period of time not less than 30 minutes and not greater than 180 minutes . in another embodiment , the deionized water is added between 60 minutes and 120 minutes . after finishing dosing with the deionized water , the reaction mass is mixed for a period of time not less than 20 minutes and not greater than 90 minutes . in another embodiment , the reaction mass is mixed for a period of time between 30 minutes and 60 minutes . alternatively , the reaction mass is cooled to ambient temperatures by circulating through the mantle liquid with temperatures of 5 - 7 ° c . the maleic acid is then extracted from the content of the kneader according to the following process . a stainless steel mixing vessel equipped with a nuce filter and having a useful volume three times larger than that of the kneader is used . the mixing vessel is further 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 filled with deionized 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 ° c . and not greater than 40 ° c . in another embodiment , the temperature is between 15 ° c . and 35 ° c . while stirring the deionized water moderately ( stirrer speed = 40 - 60 rpm ) the reaction mass is added via the helical conveyer . the coarse , aqueous suspension formed is mixed for not less than 1 hour and not greater than 6 hours . in another embodiment , the suspension is mixed between 2 and 4 hours . the stirring is then stopped and the aqueous phase is eliminated by filtration under pressure . the 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 humidity 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 ° c . and not greater than 90 ° c . in another embodiment , the drying temperature is between 60 ° c . and 80 ° c ., 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 u . s . pat . no . 3 , 993 , 671 ; u . s . pat . no . 4 , 118 , 403 ; u . s . pat . no . 4 , 414 , 898 or u . s . pat . no . 4 , 659 , 433 ). sma copolymers prepared in conformity with the methods described above have the following characteristics : a ) the amount of residual styrene was measured by extraction with benzene ( spectroscopic grade ) of 1 g of polymer for 12 hours by sohxlet extraction . the benzene extractions were then analyzed by gas spectroscopy ( perkin - elmer equipment ). b ) the amount of residual maleic acid was measured by dialysis with distilled water of a 2 g sample of polymer at 40 ° c . using a spectr / por ce dialyze membrane 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 equipment ). c ) monomeric concentration expressed as sty : mal ( 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 : mal ( maleic anhydride [ maleic anhydride + maleic acid ]), [( mol / g ): ( mol / g )], was estimated using ftir quantitative analysis ( shimazu equipment ): maleic anhydride p . a . ( across ) and maleic acid p . a . ( across ) versus the characteristic absorption bands : 1770 - 1790 cm 1 for anhydride and 1700 - 1720 cm 1 for cooh . e ) viscosimetric 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 ° c ., using the calculus formulae ( raju k . v . s . n ., yaseen m . j . appl . polym . sci ., 45 , 677 - 681 , 1992 ; chee k . k . j . appl polym . sci ., 34 , 891 - 899 , 1987 and spiridon d . et al . polymer international , 43 , 175 - 181 , 1997 ). [ η ] = 2 ⁢ ( η rel - ln ⁡ ( η rel ) - 1 ) c ⁢ [ η ] = 0 . 77 ⋆ 10 - 4 ⋆ m v 0 . 725 in a kneader - extruder apparatus ( 60 liters ) 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 ° c . 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 ° c . after adding the styrene , the temperature of the reaction increased rapidly during a period of 15 minute from 78 ° c . to 116 ° c . due to polymerization . when the exothermic phase of polymerization is completed , mixing continued at atmospheric pressure at 100 ° c . for another 60 minutes . the reaction mass was a viscous , transparent , yellow brown solution which was cooled to 65 ° c . by adding 8 liters of deionized water ( with a conductivity less than 10 μs ) while mixing over 60 minutes . after finishing water dosing , the reaction mass was mixed for another 45 minutes at 65 ° c . alternatively , the reaction mass can be cooled to ambient temperatures by circulating cooled water ( 5 - 7 ° c .) 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 deionized water at 18 ° c . under moderate stirring ( stirrer speed adjusted to 40 - 60 ppm ). 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 ° c . 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 sma copolymer was obtained as a white powder : 94 . 598 % sma copolymer ; 5 . 31 % water ; 0 . 029 % styrene and 0 . 063 % ( maleic anhydride + maleic acid ), all as weight percent . the purified sma copolymer had the following structural characteristics : m y = 1 , 251 , 000 ; sty : mal = 46 : 54 same equipment and procedure as described in example 1 except 3 . 4 liters of styrene having 6 . 8 grams of dibenzoyl peroxide dissolved therein was added at 80 ° c . maximum temperature during the exothermic phase was 121 ° c . the last supernatant from the extraction had a maleic acid content of 0 . 00095 % by weight and drying was at 80 ° c . for 6 hours . the process yielded 6 . 28 kg of sma copolymer as a white powder : 95 . 267 % sma ; 4 . 63 % water ; 0 . 031 styrene and 0 . 072 % ( maleic anhydride + maleic acid ), all as weight percent . the purified sma copolymer had the following structural characteristics : m v = 546 , 000 ; sty : mal = 48 : 52 and manh : mal = 0 . 68 . same equipment and procedure as in example 1 except that 2 . 5 liters of styrene having 8 . 5 grams of initiator dissolved therein was added over 40 minutes . maximum temperature during the exothermic phase was 128 ° c . polymerization was complete after 180 minutes with a final temperature of 85 ° c . hydrolysis utilized 6 liters of water added over 120 minutes and the extractions were made at 35 ° c . the process yielded 4 . 72 kg of sma copolymer as a white powder : 93 . 08 % sma ; 6 . 82 % water ; 0 . 018 % styrene and 0 . 082 % ( maleic anhydride + maleic acid ), all as weight percent . the purified sma copolymer had the following structural characteristics : m v = 726 , 000 ; sty : mal = 51 : 49 and manh : mal = 0 . 27 . 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 ° c . for 30 minutes to yield a fluid transparent mass of melted maleic anhydride . 3 liters of technical grade styrene having 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 ° c . to 132 ° c . over 12 minutes . after the exothermic phase of reaction was completed , mixing at atmospheric pressure at 115 ° c . continued for 120 minutes . at this time 9 . 8 liters of deionized water ( with conductivity less than 10 μs ) was added over 120 minutes cooling the reaction mass to 60 ° c . the reaction mass was mixed at 60 ° c . for 60 minutes at 60 ° c . alternatively , the reaction mass can be cooled to ambient temperatures by circulating cooled water ( 5 - 7 ° c .) 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 ° c . 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 humidity content of 72 . 8 % and was transferred to a circular dryer connected to a vacuum and dried at 80 ° c . 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 sma copolymer as a white powder : 92 . 114 % sma ; 7 . 82 % water ; 0 . 021 % styrene and 0 . 045 % ( maleic anhydride + maleic acid ), all as weight percents . the purified sma copolymer had the following structural characteristics : m v = 251 , 000 ; sty : mal = 42 : 58 and manh : mal = 0 . 17 . the same type of equipment and procedure as in example 4 was used except 2 . 4 liters of styrene having 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 ° c . for 8 hours . the process yielded 4 . 72 kg of sma copolymer as a white powder : 96 . 121 % sma ; 3 . 78 % water ; 0 . 041 % styrene and 0 . 058 % ( maleic anhydride + maleic acid ), all as weight percents . the purified sma copolymer had the following structural characteristics : m v = 1 , 780 , 000 ; sty : mal = 49 : 51 and manh : mal = 0 . 79 .
the present invention discloses styrene - maleic anhydride copolymers preparations using solventless techniques . the solventless method resulted in reduced amounts of residues , such as unreacted styrene and / or maleic anhydride monomers , which makes the copolymers particularly suitable for bioapplications .