A Staff=IradustrwCollabosatiue Beport RICHARD L. ICEIVYON
K. H. HASEK, LEE G. DAVY,
AND
T i . J.BROADBOOKS
in collaboration w-ith
Associate Editor
r .
I ennessee Eastman Corporution, Kingsport, Tenrs.
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Oxidized cellulose reruttined
N 1936, in fundamental research studies oi the oxidation of cellulose, W. 0. Kenyon, of the Eastman Kodak Research Laboratories found that a new type of product could be made by the use of nitrogen dioxide as an oxidizing agent (12). This material was soluble in alkali and, in contrast t o the usual friable materials resulting from other methods of oxidation of cellulose, maintained its original form and much of its original tensile strength. It was shown that the product was a coplymer of anhydroglucose and anhydroglucuronic acid; this became polyanhydroglucuronic acid on more extensive oxidation ( I S , 15, 28). '"I
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tt
laboratory curiosity until latc in
1940 when it, was examined a.t Columbia University as a possible
substitute for blood plasma. It' was rejected for this use because of its rapid elimination from the body. However, its solubility at the pH of blood and the observation that it produced no anaphylactic reaction in the body led to its being tested as an absorbable material for implantation in body tissues t o prevent adhesions. Experimental worli by Virginia K. Frants showed Lhat it could be absorbed by thc body in 7 to 20 days without unt,owar.d effects (9). It t,hen was 'examined by T. J. Putnam as
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Janlluy 1949
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I N D U S T R I A L A N D E N G I ~ E E R I N GC H E M I S T R Y
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teated by Parke, Davis & Company and found pbarmacolodoaUy Lording Surgical Gnu= Pad into Oxidizer
an absorbable carrier for thrombin, a natural hemostatic agent, (IO). Putnam wrote C. E.K. Mees, and found highly mc&ul director of d of the Eastman Kodak Company, in Janusry 1943 m& that oxidhed cellulosehe produced commercially. The Eastman Kodak Company asked Parke, Davis & Company to cooperate in developing and marketing oxidized cellulose and the suggestion was accepted. Parke,Davis & Company began PICducing, for experimental purposes, sterile gauae and cotton made of oxidiaed celluloae providd by the Esstman Kodak Company. In the meantime Frank, with Clarke and L a t h (4), reported the discoverg that oxidized cellulase itself posseaaed hemostatic pM@k. By January 1945, clinical tests under the direction of the Committee for Medical Research of the 0 5 of~Scientific Re4and Development, were yielding such satiafactory result@ and the potential importance of thin development in wartime was 80 great that the need for wmmercial scale pioduction was clearly revealed. The Enatman organization decided to manufacture o x i W cellulose as a pharmaceutical raw material, a type of product which it had not made previoualy. The Tennessee Eastman Corporation undertook the designing and building of a plant for ita manufacture. Parke, Davis & Company w e e d to wllsbomte by processing the chemical product for pharmaceutical w.
satisfactory. Usiog information then available and general experience in development work, the following comparison was made: NorCCI. Bolution
NOI Vapor Anticipated sdvant8imp!ioity of o~mplete.y.tem Poesihb 10Emt E.aa of removal olwasow reddue
nimple. oxidation *ppe.r*ttU. Higher conaent.rition of NOI in h o t with c e U u 1 ~
COD-
Antioipated d i s a d v a n t w
B u l b appsrstu. Eigh 1- of nitrogeo oxidea by leak-
Rwovery carts and solvent 1CCI. prmurament diiaooulb Poaaihle oontnmimtion of ~ 4 ~ 0 8 with pomonoua solrent Hazards of hand& CCL. in a ~ h n * Cmrosioo problems offered b ahlofmm the b d d o m of CCI,. DartiCularIy in the PrweIO. of nitrosen diodde
It was concluded that whereas some of the disadvantage8 foreseen in the solvent process were inberent, the dieadvantesas anticipated for the vapor process might be overcome in *thedeBign of equipment. The vapor process was selected. A d l scale continuous procese was attempted and a b doned The oxidation was found to require 14 to 16 hours and a continuous pmoess called'for extremely slow movement of a train of gauze or a very large holdup in bulky equipment. No satisfactory deaign wa8 conceived for the movement of the oxidieed gauze, carrying nitrogen oxidea, from the oxidixer to the TEE PROBLEM TO BE SOLVED washer; capillary action carried water back into the n n d e d oxidked gauze and formed nitric acid which damaged tbe gauze. These decision8 presented the problem of the development, as Sc&@Jp Process. Urgency prevented development of lapidly ea possible, of a plant which wuld supply up to 50,000 through a small pilot plant prior to production. the proceas pounaS per ywa of oxidized dulose, a quantity Bstimated to be d by the light of labonrConsequently, it wa8 neoesasry to p 10%of the coneumption of gauze in *aid packeta by the armed tory experhmta designed to indicate, as nearly'as possible, the fmin 1943d agrSea upon by repre8entativeaof F&tmrm and wndition8 which would he met in a plsnt. Parke, Davis & Company. Itaeemed lilrely that asUipment to pD. d u c e t h a t ~ ~ t o f ~ e d o e l l u l o a e w o u l d b e ~ u a n t l y l a r g e t o It was deoided that in a bath proceas plant the gauze could be treated most effectivelyin multiple-layer pads of large m a . A reveal most of the problem that might be met if production were n d to slawex d e . In dditiw to the specifications normally dram for the manufacture of a ohemid product, pharmaceutioal requirements a l s ~ had to be met. Aspeoial problem waa presented by the fa& that the m a W wan a mlid whiah was net purifiable by diewlation or cytdkation, and had to be capable of being inserted inin W y tiaaue and absorbed into the b l d atresm Without und&rable physiological reaation. Only g e m d requirementa for the quality of the gauze could he drawn up on the basin of knowledge existiog a t that time. One ' 'c certainly required wan alkali solubility. P-
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A tamtatve miuimum requirement of solubility in 1% sodium hydroxide mlution within 1 minute w w adoptad. other w sideratione known to he important w8m low ash wntant and the preservation of tensile ntrangth. These general specifications serrred ea guidea during the early Btagee of pdevelopment while a aat of speciscations w m p r i s k chemical and physicsl teeta waa king w o r M out on the !XI& of biological experiments chdce of Rocw'Yeth& The following s t e p were known to be newmry in the wnvemion of raw muse from stgpdard rob, 88 inches wide, into Bimilar rolls of oxidhed celluloae gauze metiug the speoifioations for the mugical product: oxidation of the d u h e by oxidea of nitrogen; thorough and rapid washing to remove nitrogm oxidea and nitric acid; and drying at ternoenrturcs not above 60° C. Protection from wntarnination wan
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that d & e could be oxidhed to the desired product either With nitrogen dioxide vapor or with a &n tetrachloride solution of nitrogem dioxide. The pmducta from each method had been
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Vol. 41, No. I
I N D U S T R I A L A N D E N G I N E E R I N G CHEMISTRY
I X 7 inch frame was designed for small scale study, to carry such a pad of small area; thus a reasonably true study could be made of the problems of penetration, uniformity, washing, draining, drying, etc., the d t e of which would apply, except for -, to large male operations. Small experiments in 30Ihc. p m u r e bottles had shown that at least part of the reduction prcducta derived from the reaction between cellulase and nitrogen dioxide must be retained in the oxidiaing gas to yield a product meeting specificntiom Another pmhlem important in design consideratiom waa that involving heat tranafer, as it was known that when nitrogen dioxide is brought into contact with d u l a s e it can cause ignition. The solution to the latter problem lay in providing a gns velocity through the gauze d c i e n t to remove the heat of reaction as &hle heat of the gas stream. Both of these problems were solved by controlled recycling of tho oxides (Figurc 1). The wlylhing proceas dm was studied on a 7 X 7 inch scale. Rapid penetration of the wash water was found neccseary If water was brought slowly into contact with the pad it was carried inward by capillary action, causing the formation of a damaging concentration of nitric acid in advance of the flooding by wssh water Thus it was neceeaary to drown the product as rapidly lyl possible. Flooding from beneath the pad gave most e6ective washing as buoyancy caused some separation of the layers. @utinuous wnshing was first considered for acid m o v a l . However, it was found that auch a lqug period of soaking was ueceasary for complete removal of the acid that the volume of water required would be prohibitive. Batch wasbing with prcgmaively i n c d periods of Boaking wlyl adopted. While the hoal wash water contained less than O.ooZ% of nitric acid, it could not be used as the b t wash for the following batch of
gauze; oxidized cellulase is such a strong cation a b r b e r that the trass of imn dissolved in this very dilute solution of nitric acid, on ntsnding in the stainless steel tank betweau batchcs, would deposit an amount of imu on the sucooedingbatch of gauze which would c a w color in exceas of speciEcations. Demhwa!izcd water wlyl available frnm a Permutit system in the Tennessea Eastman plant. Bccaw of wartime shortages g a l v a n i d pipe, approximately 2100 feat in lcngth, was used to conduct the water to thc oxidized d u l c a e plant. After h v e m ing thin line, the water contained about 7 p.p.m. of solids. W h e n this water was w d in washing the o x i d i d cellulase, the solids rctaincd by ion-cxchunge action prcduccd an ash content above 8pcciIication. Tbcrefore, the water wan h t pcrcolatcd thmugh somo oxidiaed cclldase to reduce ita mlids content. The perm lated water was then satisfactory for washing the o x i d i d celluloea prcduct. Rctention of wash watcr by capillary action was minimiaed by draining the pad at an angle of 45' to prnvide tbe minimum volume in which capillary action was e6cctive. Drying studies showed that temperaturea as high as 50' C. could he used without damage of coosaquenea to the product. A f o r d stream of air was necessary to achieve satisfactory drying in the center of the pad within a reasonable time. Because of the increase in watcr content toward the bottom of the pad, a downward stream of air was used for mast e5cient drying. PLANT
APPLICATION
Plant scale units were designed and built for the full stated capacity, applying the principlw and techniques worked out io the laboratory experiments. All equipment which was to contact nitrogen oxides was built of Type 316 staidem steel.
PLANT PROCLSS SLRlfS
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January 1949
INDUSTRIAL AND ENGINEERING CHEMISTRY
Gauze Support Frame. A 300-layer pad 20 feet long of the 3-foot strip of gauze afforded optimum efficiency of operation and a support frame was constructed accordingly. The frame, approximately 20 by 3 feet outside dimensions, was constructed of 2-inch stainless steel angle iron, with faces to the out and up sides and cantilever bracing on the under side and was mounted on small wheels. Pointed vertical pins of 0.125-inch diameter were set a t 1-inch intervals on the upper face of all four sides of the frame. Loading Apparatus. A loading apparatus was designed for placing a continuous strip of gauze, in layers, on the support frame by moving the frame back and forth on a rack, under rollers feeding an endless' strip of gauze. The gauze is drawn from a 36 inch X 4000 yard roll through a tension device and guides into feed rolls which are synchronized with the reciprocation of the frame. From the feed rolls the gauze passes under a slotted shoe which presses it down onto the pins. Frames to brace the pins against deformation by the tendenry of the gauze to shrink during treatment are placed at intervals through the pad. By this means gauze shrinkage is prevented throughout processing. Oxidizer. The oxidizer is a horizontal stainless steel tubular chamber, 40 inches in diameter and slightly longer than the gauze frame; it contains a lengthwise horizontal track which receives the gauze frame. The track is attached to the sides of the chamber and is built to a tolerance which gives a nearly complete seal with the frame to prevent by-passing of the gauze by the nitrogen oxides. Liquid expansion thermometer tubes, connected to temperature recorders, are located above and below the gauze pad at the middle of the chamber. Above the entries from the lower manifold are baffles which prevent spraying of the gauze with nitric acid droplets entering with thc oxides and also prevent channeling of the oxides through the gauze. Four-branch manifolds, 16 feet long, are attached lengthwise to the top and bottom of the oxidizer. An ob!ong door a t the end of the reactor, which admits the gauze frame, is sealed during the reaction by a Roroseal gasket and secured by thrust bolts. A fume removal duct intake is located outside and just below the door, extending across its width. All gases which escape from the door during removal of the gauze frame or during operation are drawn off through this duct. Gas Circulatory System. The circulatory system (Figure 2) comprises the oxidizer, a blower, and a heat exchanger, connected in a circuit by 11-inch diameter pipe; it has valved connections to an evaporator, an air intake, and condenser and vent systems. The lower manifold of the oxidizer receives the fresh nitrogen dioxide a t A from the evaporator. The gas passes up through the gauze pad and out the upper manifold. A variable controlled fraction passes into the condenser system through the valve a t B, while the remainder continues through the blower and is forced through the heat exchanger back to the oxidizer, The condensed, partially reduced oxides collected in the condenser system are admitted in controlled amounts to the evaporator to maintain the desired gas composition in the oxidizer. A stainless steel blower of the desired specifications was not available for immediate installation in the plant so the project staff designed a blower to move 2500 cubic feet per minute of gas against a 14inch head of water; it was built in the Tennessee Eastman Corporation shops and has functioned satisfactorily throughout. The heat exchanger is a shell and tube unit. The tubPs arc! Btted w,ith fins improvised in the Tennessee Eastman shops. The heat transfer medium is water a t controlled temperature. An air intake, which draws filtered air from the room, is connected to the circulatory system through a valve just above the heat exchanger, a t point C. Purging with air is accomplished by closing the valve just above C and the condensing system valves and opening the valve a t D. Air then is pulled through the circulating system by the blon-el and forced out the rtactk.
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Condensing System. The condensing system consists of three multiple-tube condensers connectpd in series. The condensate returns in controlled amount to the top of the evaporator. Condenser 3 is vented to the stack to take off any uncondensed vapors. The condensing system has a liquid holdup capacity i n excess of 250 pounds of nitrogen oxides. Evaporator. The evaporator is a tank, with a capacity of 400 pounds of liquid oxides. A steel jacket surrounding thiq tank is connected to a 50-gallon water reservoir containing both refrigerant and steam coils to give rapid production of either hot or cold water for flexible control of the evaporator temperature. All lines leading to the evaporator are valved and of such volume that condensed, partially reduced oxides may be withheld completely or returned in controlled amounts during the oxidation cycle to give the desired composition of oxides. Gas Vents. Gases are vented through two outlets, a steam jet ejector, and a stack. The steam jet is connected to the circulatory system through a valve between the oxidizer and the blower and is used to evacuate the system immediately aftel completion of the oxidation cycle. The effluent from the ejector. which sometimes has a high content of nitrogen oxides, is passed through a water scrubber to reduce contamination of the atmosphcre. Water from the scrubber is drained to the sewer. Gases from the fume suction duct a t the front'of the oxidizer, from condenser 3, and from the washer are all vented through the stack and into the air above the building. Oxide Feed. Fresh nitrogen dioxide is introduced into the evaporator a t E. The oxide is received in 125-pound steel cylinders, Type 3D-480,approved for the shipment of nitrogen dioxide. These cylinders are closed with a plug which is covered with a gasketed cap. The closure is protected by a high steel collar. The cylinders are cooled for a t least 4 hours in a bath a t 5 C., opened, and fitted with a standpipe with a pressure inlet collar. Three standpipes are connected to a manifold serving the oxide feed line, which provides continuous service. The nitrogen dioxide is forced from the cylindcrs by the pressure of nitrogen from standard nitrogen cylinders. Watep pumped nitrogen, as differentiated from oil-pumped nitrogen (i.e., nitrogen compressed into cylinders by the supplier with an oil-lubricated compressor), is used to ensure against contamination of the nitrogen dioxide cylinders with oil. For the same reason compressed air is not used. The nitrogen pressure is controlled by a reducing valve and its flow is regulated by a manuallyoperated needle valve. The maximum pressure is limited bv a 150 pounds per square inch gage rupture disk. Gauze Washer. The washer is a stainless steel box, 20 feet 3 inches long, 3 feet 6 inches wide, and 3 feet high. An eightbranch manifold for introduction of water enters the bottom : there are flat baffle plates over the entries. The outlet for waste water is connected by a valve to this same manifold. A vent manifold to carry off gases is attached to the top. Gmes are drawn off by a fan with a capacity of 1000 cubic feet per minute and ventpd through the stack. A rack for receiving the frame lies on the floor of thc washer. Along one side are attached stainless steel cables which pass through the top and are activated by a manually-operated winch This device allows flushing of the gauze in a horizontal position and draining a t an angle. The purification system for the wash water includes a percolation tank packed with oxidized cellulose, to demineralize further the ordinary demineralized water. Oxidized cellulose meeting product specifications is used to avoid contamination. One 35pound charge of oxidized cellulose from scraps will demineralize a t least 50,000 gallons of water. A 3000-gallon storage tank is located 16 feet above the floor of the washer. Dryer. The dryer is a stainless steel box of approximately the same dimensions as the washer, with air inlet and outlet manifolds on the top and bottom, respectively. Air is drawn O
. ODerations in
the Oxidation of Cellulose & OXIDATION Surgical gauze, 36 inches wide, is loaded from roll onto support frame (right) in 300-layer pads and moved into horimntal stainless steel tubular oxidizer (left. rear).
4 WASHING Covered table (right) is used to transfer auze between promsing units. In washer Zeft) the frame containing gauze is placed on rack which allows flushing in horizontal position and draining a t an angle. Gauze is weshed m e n or eight times w i t h demineralized water.
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4 DRYING
Air heated to 50' C. is forced through gauze a t rate of 2500 cubic feet per minute in the e&inIw steel drycr (right). When g a m is packaged for sbipmemt in ro or cut into pads to prceawr's specification.
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January 1949
INDUSTRIAL AND ENGINEERING CHEMISTRY
from the filtered air syhem, heated to 50' C. by a steam finned tube heater, and forced through the gauze a t the rate of about 2500 cubic feet per minute by a blower. The effluent air is vented directly to the outdoors. Frame Transfer Table. For transferring the gauze frame between units, a covered table, mounted on rubber-tired wheels, is used. All units which receive the gauze frame are built so that the tracks are a t the same level. Frame tracks were originally angle iron in an upright L position; these formed a trough in which the frame moved. However, rubbing of the frame against the sides of the track dislodged particles of metal which contaminated the product. Angle irons in an inverted V position provided tracks which received the grooved-surface wheels of the frame without allowing sidewise motion or rubbing. The wheels of the frame have bearings and washers of polytetrafluoroethylene to prevent shearing off fragments of metal, The end of the transfer table fits flush against the end of each unit during transfer of the frame. A cable, running over pulleys at either end of the table beneath the frame rack and operated by a winch, is attached to the underside of the frame and used to load or unload it. Building and Ventilation. The entire operation is housed in a brick building constructed so that there are no interior ledges or obscure recesses for the collection of dirt. This allows the interior to be washed down frequently with a hose. The floor is concrete with a dustproof finish. The interior is painted white to promote cleanlinessand make red-brown oxide fumes easily visible. The entire building is pressure ventilated with 25,000 cubic feet per minute of filtered air, effecting a complete change of air 20 times per hour. The vents are located to remove effectively atmospheric contamination from leaks or sampling points. Individual ventilation systems are provided to handle fumes from the door of the oxidizer and from the washer. The combined ventilation systems keep the concentration of poisonous nitrogen oxides a t a minimum and prevent infiltration of dust and other foreign materials. A high-head fan draws air from the filtered-air duct to supply a system having air mask connections located at strategic points. These connections are of the instantaneous action, bayonet plugin type. Standard Acme air masks, with a modified head clamp for quick donning, are used with this system. All-purpose gas masks also are kept available. Safety showers are provided a t suitable points. PROCESS IN ACTION
As the process is now operated, the starting product is surgical gauze in 36-inch wide roll form and the final product is oxidized cellulose gauze in 300-layer pads. Raw gauze from the roll is loaded on the support frame as a pad. The frame is transferred to the oxidizer, which is then closed. Nitrogen dioxide is admitted to the reactor manifold from the evaporator and the circulating fan is started. A temperature of 25 C. is maintained in the circulating gas by the heat exchanger. The percentage of nitric oxide (NO) in the vapor is checked a t intervals of 30 minutes by analysis of samples taken from a valve on the oxidizer. The NO percentage is compared with an NO content US. time curve developed on the basis of previous satisfactory results. The nitric oxide balance is controlled by regulation of the rate of return of condensate to the evaporator and thence to the circulatory system. The desired conditions are maintained for 16 to 18 hours. Variation in the assay of commercial nitrogen dioxide requires some variation in the time required for optimum results. After completion of the oxidation the circulatory system is closed off from the evaporator and condenser systems, the blower is shut down, and the reactor and circulatory system are evacuated by the steam ejector for 30 minutes to about 23 to 25 inches of vacuum. The vacuum system then is disconnected and the reactor system is opened to the
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gas escape vents and blown with filtered air a t atmospheric pressure for 30 minutes. The oxidizer is opened and the gauze support frame is loaded onto the transfer table and carried to the washer. After oxidation a minimum of contact between the cellulose and the oxides in the presence of moisture is desirable to avoid degradation. Before the frame is loaded into the washer, 1-inch square samples are cut from the top and bottom gauze layers and tested for solubility. The test results are used as a guide for the oxidation of the next batch. The condenser lines are drained to the evaporator, the evaporator jacket is cooled to 0-5' C., where it is held while oxygen is blown into the liquid oxides a t a rate to maintain a pressure of 10 pounds per square inch. Oxidation is continued until the green color of the liquid has disappeared, indicating the presence of less than 0.1% NO. After addition of make-up nitrogen dioxide the oxidation system is ready for the next run. Oxides remaining in the oxidizer at the end of the cycle are lost in evacuation and purging, but on t,he present scale, their recovery is not justifiable economically. After the gauze frame has been placed in the washer, water is admitted rapidly, at the rate of approximately 320 gallons per minute, to cover the pad completely. After standing 2 minutes the wash water is drained, the pad is tilted to an angle of 45" and allowed t o stand for 10 minutes. Then it is returned to the horinontal, flushed with water again, allowed to soak 15 minutes and drained as before. This is repeated, usually 7 to 8 times, until the acid content of the wash water has been reduced to 0.002% (calculated as nitric acid); after this the gauze is given a final 1hour soak and allowed to drain 1 hour. The drained pad, on the frame, is removed and three 1-square foot samples are cut from the front, middle, and back of the bottom layer for ash determinations. It then proceeds to the dryer where filtered air is forced through it in a downward direction for about 8 huurs; this reduces the average moisture content to approximately 6%. The produot is sold to pharmaceutical processors in either roll or pad form. For the rolled form, the gauze is drawn directly off the frame on which it was oxidized onto a mechanical roller. Pad sizes vary and are made to order. Rolls are wrapped in glassine paper, then in waterproof paper and placed in fiber drums for shipping. Pads are shipped in wooden boxes lined with waterproof paper, corrugated cardboard, and glassine paper, in that order. Surgical cotton also is treated with oxides of nitrogen in a similar fashion to make an absorbable, hemostatic cotton for surgical use; the cotton is handled in layers sandwiched between layers of gauze.
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PRODUCT SPECIFICATIONS
Specifications for oxidized cellulose as a pharmaceutical raw material were set up in the form of physical and chemical tests. These tests necessarily were based on biological tests, particularly those for physiological reaction and absorbability. A complete set of standards had not been defined previously. The urgency of the problem required that they be developed concurrently with the manufacturing process. It wits decided that the following characteristics were to be covered by specifications: Chemical Properties 1. Solubility in dilute sodium hydroxide solution 2. Solubility in dilute sodium bicarbonate solution 3. Stability in dilute sodium bicarbonate solution 4. Carboxyl content 5 . Nitrogen content 6. Moisture content 7. Ash content Physical Properties 8. Tensile strength 9. Shrinkage 10. Color
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INDUSTRIAL AND ENGINEERING CHEMISTRY
The solubility and stability tests, which were deemed of thc greatest importance, were difficult to standardize because interpretations of the tests were largely dependent on the analyst's judgment. Attempts to apply instrumcntd analysis were unsatisfactory. Agreement on acceptability vas reached only through a meeting of rrpresentativcs of the analytical laboratories of Tennessee Eastman and Parka, Davis nhere ctemonstratdons and interpretations of the tests were studied. The following requirements for the oxidized cellulose were formulated: Sodium Hydroxide Solubility. h 2-gram sample of the product shall be soluble in 100 ml. of 1% aqueous sodium hydroxide solution. The solution resulting from the test may shorn only a few fibcrs and only a slight haze. Sodium Bicarbonate Solubility, -4 sample of the product shall be soluble in an excess of 0.15 144 sodium bicarbonat'e solution within 5 days a t 37" C. The 0.15 M strength was chosen because its pM approximates that of the blood. Extensive biological testing failed to justify this test, and it was disc,arded fin.ally when she carboxyl specification was found to eliminate all material not meeting the bicarbonate solubility requirement. S o d h m Bicarbonate Stability. It i s necessary to neutralize oxidized cellulose in sodium bicarbonate solution before using it as a carrier for thrombin, in order t,o avoid deactivation of the Lhrombin. The neutplized gauze must resist disintegration by the bicarbonate solution long enough t o permit necesmry surgical handling. In the stability test, a sample of oxidized cellulose @;auzeis dipped repeatedly into IT0sodium bicarbonate solution. When the main bulk of sample cannot be picked up with a pair of forceps, disintegration is judged complete. Minimum disintegration time shall be 3 minutes. Content, The well-known method of estimating uronic acids, by measurement of the carbon dioxide evolved during decomposition of the sample in aqueous hydrochloric acid a t elevated temperat,ure (6, Q, I T ) , was applied as an analytical method for carboxyl content. nsatisfactory because it was time-consuniing discarded in favor of the calcium acetate method, which is based on the ion-exchange properties of oxidized cellulose. An extensive discussion of the two methods and their applications has been published ( 7 , I d , 1 4 ) ~ In the procedure finally specified, a sample of oxidized celluloue is allom-ed to stand in excess 8.26 N calcium acetate solution for 30 minutes, and the liberated acetic acid is titrated with standard alkali. The minimum carboxyl content shall be 16%. en ~~n~~~~~ A maximum nitrogen content of O A % is A modified Devarda ( 2 ) procedure is uscd, employing B packed distillation column to avoid carrying over entrained alkali. The ammonia is absorbed in boric acid solution to permit ion with standard acid (8), Content. Although a,n approximate moisture uficiont to allow calculation of carboxyl and nitrogen contents on a dry basis, B more accurate value is necessary for calculating shipping weights. The Karl Fischer method, which was used for some time, was rapid, but the accuracy was not satisfactory. By the method now used, a %gram sample of oxidized cell%u%ose, packed in ar drying tube, is heated to 50." @. by infrared l a m p while a slow strea,m of dry air is drawn through the Lube at a prmsuss below 100 mm. Moisture content is calculated from the l o ~ sin weight. Results from this method, which rcrate a8 those obtained by drying to in itpl ovon at 50 C. over phosphoru.; nt shall plot exceed 1570~ The ~~~o~~~~~ash content, of oxidiEed cellulose shall be 0.L5~o. This value and the method of analysis &reidentical with the United tates Pharmacopoeia specifications r'o (1 ssile strength is specified relative to the original uraoxidized gauze. Proper. sampling and ronditioiiiny ~~~~~~~
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VOl. 41,
NO. 1
procedures for unoxidized arid oxidized gauze are specified, and testing is according to a standard method ( 1 ) . Minimum spccification is 40y0 of the tensile strength of t'he unoxidizcd gauzc. Shrinkage. Shrinkage, measured by thread count of suniples before and after oxidation, is limiled to a maximum of %0?& Color. Visible stains are cut out by the packing inspectors. Over-all color of the oxidized gauze i s measured by- preparing a reflectance curve of a, 70-layer pad of gauze in a Cknerd Eiectrir recording spectrophotorneter according t o directions which accompany the instrument. The curve obtaiiiod must 1101 f ~ l l helox a standard reflectance curve. PROCESS CONTIIOL METHODS-NITROGEN
OXIDES
It was found that succcssful oxidation of cellulose to the dcsirotl product required maintenance of t'he proper balance between nitric oxide and nitr0ge.n dioxide in the oxidizing vapor. 111con. sidering the nitrogen oxides mixture, it is understood that the otc., which material consists of the species YO, NOz, N,Oa, N20a, are present under the conditions specified. The system i s described adequately by specifying the amount of NO, whether frev or combined. The problem was t,o devise a rapid method for de. termining the amount of NO in the nitrogen oxides mixture. A number of methods were tried without satisfaction, The procedure finally adopted was a determination of the boiling point of a sample of the oxides, which is a function of the NO content. By this method the per cent of NO could be dotermined, in a few minutes, with an accuracy of about 1% NO. APPLXCATIONS
The instability of oxidized cellulose to heat and to alkalinnv reagents (8) has barred its application in fields now using such carboxylated materia& as carboxymethylcellulose and alginic acid. It is believed, however, that the charactelistic instability of oxidized cellulose accounts for it5 usefulness in surgery as an absorbable packing, Applications of oxidiaed ccllulose probably will remain in the pharmaceutical field, where it already has taken its place as an important medical specialty, All of the oxidized mllulose marketed ~ t present c is processed by Johnson $: Johnson and sold a5 Herno-Pak, or by Parke, Davis (6 Cnmpany and sold as Oxyeel. LITERATURE CITED
(1) Ani. SOC. Testing Materials, Standards f o r Textile Materials, No. 11, p. 78 (October 1944). (2) Doree, C., "Methods cf Cellulose Chemistry," 2nd ed.? p. 247. London, Chapman and Hall, 1947. (3) Frantz, V. K., Ann. Surg., 118, 116 (1943, (4) Frants, V. K., Clarke, H. T . , and Lattes, R., Ibtd., 120, 181
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(1942) XLChaVsIa
November 23, 1948,
