INJECTABLE SODIUM ACETYLSALICYLATE COMPOSITION AND METHOD BACKGROUND OF THE INVENTION The present invention relates in general to aspirin compositions, and in particular to a new and useful aspirin composition which may be administered to mammals by subdermal injection, a method of making the composition, and a method of using such composition.

Aspirin is the most widely used drug in the world. It has a number of important uses in medicine: It is a valuable analgesic. antipyretic, and heart-attack and stroke-preventive.

Aspirin is also one of the most potent anti--inflammatory agents, and is the drug of choice and mainstay of arthritis therapy. It stimulates the immune system, reduces opportunistic infections and is potentially useful as an adjunct in treating cancer, AIDS, and other immune disorders. It shows promise in treatment of Alzheimer's Disease; it is used in rheumatic fever, gout and cataracts; it provides pain relief from tendinitis, headaches, backaches, muscle strains, and other injuries. It has a specific analgesic effect in migraine headaches, a condition in which acetaminophen and ibuprofen show no activity. No other drug in the history of medicine has exhibited such an array of multifaceted therapeutic properties.

Due to the large doses required when taken orally, aspirin is not widely used as an anti-inflammatory agent, even though it is actually the mainstay and-drug of choice in arthritis -- a disease directly caused by inflammation. Instead, its use in arthritis is limited mostly to alleviating pain, for which low 325-500 mg dosages suffice. To be an effective anti- inflammatory agent, daily aspirin dosages of 5,000+ mg are required. Taken orally, at such levels, large amounts of undissolved aspirin particles adhere to the gastrointestinal mucosa, greatly aggravating topical irritation and side effects.

Narcotics are often used to control arthritis pain. However, narcotics are addictive, depress respiration and can produce other serious adverse reactions as osteoporosis peptic ulcers. conwlsions, hypertension and allergic reactions. Steroids are often used to treat arthritis and control pain.

However, either or both of these may produce such adverse reactions as narcotic addiction, osteoporosis, peptic ulcers, respiration depression, convulsions, hypertension and allergic reactions.

Clearly, the potential advantages of aspirin in an injectable form have great pharmacological potential. For instance, the potency of aspirin injected directly into the spinal column of patients has shown to be 100 to 500 times greater than orally administered aspirin. An injectable form of aspirin thus provides a non-addictive and safe alternative to steroids and narcotics now commonly used to treat arthritic and injured joints. Injectable aspirin could also be used for post-surgery treatments to control pain, fever and inflammation. Aspirin also shows promise in cancer treatments for treating pain, as it has effects comparable to morphine, without the narcotic side effects. Injectable aspirin could also be used in sports medicine and in veterinary applications, i. e. the invention is broadly applicable to mammals.

The FDA imposes stringent requirements of fundamental pharmaceutical purity for compositions acceptable for use in administration by subdermal injection. Accordingly, approval for such an acceptable subdermal injectable aspirin composition can be expected to require a high level of purity and significant stability at ambient temperatures for an extended shelf life.

Among the potentially available soluble compounds of aspirin (i. e., sodium and potassium), the most promising as an injectable salt is sodium acetylsalicylate. It is non-toxic, essentially neutral, readily soluble in water, and is compatible with blood serum.

However, preparation of sodium acetylsalicylate of a purity and stability suitable for injection has not been possible in the past. Sodium acetylsalicylate prepared according to prior art is unstable and deteriorates on storage.

For example, the sodium acetylsalicylate composition described in U. S. Patent 3,985, 792, the disclosure of which in its entirety is incorporated herein by reference, is made by reacting aspirin with sodium bicarbonate in water, cooling the mixture, isolating the crystalline dihydrate from the aqueous solution by addition of an organic polar solvent (generally a lower alkanol), followed by filtering of the crystals, washing with cold isopropanol and subsequently with benzene, drying the crystals and then removing the water of hydration from the di-hydrate to produce anhydrous sodium acetylsalicylate.

Thus, the old art ignored the criticality of the rate of water removal, with no special precaution being instructed or taken in this regard during the dehydration step. The compositions as thus produced, while then thought to have good stability, actually tended to deteriorate via decomposition at a compound rate of about 3.5% per year, or at least about 5-7-% within two years of storage.

Such a decomposition of sodium acetylsalicylate resulto in formation of byproducts such as salicylic acid, sodium salicylate, acetic acid and others. While a limited amount of deterioration may be considered acceptable for orally administered drugs, it is unacceptable for injectable drugs. Injectable drugs are held to higher standards of purity and stability since the danger of toxic reactions and allergic reactions is much greater.

More recently, other pharmaceutical agents have been touted as providing a substitute for the effects of aspirin. However, these newer medications have yet to withstand the test of prolonged treatments, and may not be as safe or effective as now viewed.

It is thus clear that there is a present need for an injectable form of aspirin, which is of sufficient stability to have a suitable shelf life of at least about two years under normal conditions, while retaining a high level of purity, and remaining substantially free of toxic compounds which cause side- effects.

SUMMARY OF THE INVENTION It is, therefore, an object of the present invention to provide an anhydrous sodium acetylsalicylate composition suitable for subcutaneous

injection, having a very high purity and a shelf life of 2-3 years with little or no deterioration.

It is a further object of the invention to provide a method for making the aforesaid anhydrous sodium acetylsalicylate composition.

Accordingly, the invention provides a composition of sodium acetylsalicylate having very high purity and substantial shelf life. It has been discovered that anhydrous sodium acetylsalicylate of such high purity and stability suitable for injection can be formed by a dehydration procedure involving removing water of hydration from the dihydrate form of the sodium acetylsalicylate at a rate which is no less than the rate at which the free water vapor is formed. The free water vapor rate of formation may be monitored by various known means, for instance by using a calibrated gas-flow meter. On a small scale this may be accomplished by weighing a flask containing the sodium acetylsalicylate dihydrate, and then balancing the weight-loss therefrom with the weight gain of a (tared) connected vessel containing a water-absorbing agent such as calcium chloride or sulfuric acid. Conditions for the dehydration process, such as vacuum pump capacity and applied temperature, should then be adjusted so that the rate of removal of water from the dihydrate is at the rate of formation of the water vapor, and of its removal from the atmosphere above the dihydrate salt itself.

The shelf life of such anhydrous sodium acetylsalicylate as thus prepared according to this invention is about 2-3 years, and will continue to exhibit between about 97% and 100% purity after three years storage at room temperature, provided that it is stored under a substantially anhydrous atmosphere. Sodium acetyl salicylate has therapeutic value substantially equivalent to aspirin itself.

One method for preparing anhydrous sodium acetylsalicylate is by using a vacuum dehydration technique. Sodium acetylsalicylate dihydrate in particulate form is placed in a suitable container or vessel connected to a vacuum pump. A strong vacuum pump with a large capacity is then used to evacuate and remove the water of hydration, as water vapor, from the dihydrate form of the sodium acetylsalicylate at no less than the same rate as the rate of formation of the water vapor. A sufficiently large-diameter tube or other conduit is provided between the vessel and the pump to allow a free and unimpeded flow of water vapor to be removed.

The various features of novelty that characterize the invention are pointed out with particularity in the claims annexed to and forming a part of this disclosure. For a better understanding of the invention, its operating advantages and specific objects attained by its uses, reference is made to the accompanying descriptive matter in which preferred embodiments of the invention are illustrated.

BRIEF DESCRIPTION OF THE DRAWINGS FIGURE 1 is a schematic illustration of a device used in certain of the experiments disclosed herein; <BR> <BR> <BR> <BR> <BR> <BR> FIGURE 2 is a kinetic plot for drying the dihydrate at 22° C. ;<BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> FIGURE 3 is a kinetic plot for drying the

dihydrate at 40° C. ;<BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> <BR> FIGURE 4 is a kinetic plot for drying the dihydrate at 56. 5° C.; and FIGURE 5 is a comparative kinetic plot for drying the dihydrate at the above three indicated temperatures.

DESCRIPTION OF THE PREFERRED EMBODIMENTS The injectable aspirin composition of the invention is produced from sodium acetylsalicylate dihydrate by removing the water formed during dehydration thereof at the same rate at which it is formed. The sodium acetylsalicylate dihydrate may be prepared by first reacting aspirin with sodium bicarbonate in water, and then crystallizing the sodium acetylsalicylate in the form of the dihydrate using, for instance, a suitable solvent/non-solvent medium. An improved modification, described hereinbelow, of the procedure described in U. S. Patent 3,985, 792 may be employed for preparation of the dihydrate as the starting material for the present invention.

This step is then followed by dehydration under carefully controlled conditions.

The anhydrous sodium acetylsalicylate obtained by the process of this invention is extremely stable. After being stored three years at room temperature, the injectable composition exhibits virtually no decomposition.

The composition retains a purity level of between about 97% and 100%.

The following examples are provided to illustrate the invention.

Example 1 One hundred grams (lOOg. ) of sodium acetylsalicylate dihydrate, prepared as described herein, and in fine particulate form were placed in a layer of between 3 and 4 cm deep in a shallow dish inside a vacuum desiccator. A suitable dehydrating agent may be employed in a separate or connected vessel downstream of the desiccator. The desiccator is in turn connected to a vacuum pump. The water-collecting dehydrating agent may be either calcium chloride or sulfuric acid, or one of the phosphorus oxides, for instance. A vacuum of 3-15 mm Hg was imposed in the desiccator for about one hour. At this point, the desiccator was opened and the particulate partially dehydrated sodium acetylsalicylate dihydrate platelets contents of the dish were briefly stirred. The vacuum was then reapplied for about another 4-5 hours.

A stable and acceptably substantially pure anhydrous sodium acetylsalicylate, pharmaceutically suitable for injection into a mammal, was obtained.

Example 2 Four hundred grams (400g) of particulate sodium acetylsalicylate dihydrate, prepared as described above and in the form of large crystalline plates was placed on a stainless steel drying pan and dried overnight in a Stokes Vacuum Oven in air at room temperature without heat under a 1.5 mm Hg vacuum. The product was then removed from the oven, stirred and broken apart. It was observed that at this stage there was some caking of the particulate material. Thereafter, the vacuum was reapplied for 3 more hours.

Again, a highly pure particulate dehydrated sodium acetylsalicylate suitable for injection was obtained.

Example 3 Particulate sodium acetylsalicylate dihydrate was prepared as described above and suspended in current of dry air at about 20°C. The air temperature was gradually raised to 45°C over one hour, and then raised again to 65°C during one additional hour. Anhydrous sodium acetylsalicylate having a purity and stability suitable for injection was obtained.

Examples 1-3 above illustrate different methods for obtainina suitably pure and stable- anhydrous sodium acetylsalicylate. In each case, the technique employed is to remove the water vapor expelled from the dihydrate at a rate such as to be no less than the rate of its formation from the water of hydration. A further important factor in dehydrating the sodium acetylsalicylate dihydrate is ensuring that the particulated surface of the sodium acetylsalicylate dihydrate is constantly exposed to a (relatively) dry atmosphere wherefrom the water vapor is evacuated. One way in which this is accomplished is to use thin layers of the particulate sodium acetylsalicylate dihydrate. Alternatively, the product may be stirred, either intermittently or continuously by any suitable mechanical device.

If the dehydration is run under vacuum, the diameter of the tubing leading from the drying vessel to the vacuum source can be critical, and should be of sufficient dimension so as to permit unimpeded rapid removal of the water vapor containing atmosphere above the particulate material. For instance, if either the tubing by which the water vapor is removed from the system is of insufficient diameter, or if the vacuum-pump used for the removal does not have sufficient capacity or is inefficient, the resulting anhydrous sodium acetylsalicylate may in fact be unstable and may decompose too rapidly to be useful. On the other hand, if the vacuum is sufficiently high and the pump capacity is sufficiently large, but a tubing of, for example, only 3-5 mm in diameter is used, the product may be unstable because the removal/flow of water vapor is impeded. However, in such instance, use of a tubing, or in general an evacuation conduit, having a diameter of at least 10 mm or greater produces a stable product suitable for injection, due to the unimpeded removal or flow of the water vapor.

When the condition is met that the water of hydration is removed at the same rate as the rate of water vapor formation, the resulting product is stable, and pure anhydrous sodium acetylsalicylate suitable for use as injectable aspirin is obtained.

Stated another way, the technique of this invention is believed to achieve the dehydration under conditions such that the partial water vapor pressure in the atmosphere above the sodium acetylsalicylate dihydrate is maintained at minimum levels throughout the process.

While I do not wish to be bound by any specific theory, I believe that this procedure substantially prevents re-hydration of the anhydrous sodium acetylsalicylate crystals and that the latter then form a stable anhydrous crystal lattice structure.

It is particularly valuable in the process of this invention that the crystal lattice structure for both the sodium acetylsalicylate dihydrate and for the anhydrous sodium acetylsalicylate should be in the form of platelets rather than in a needle form. On occasion in the process of forming the sodium acetylsalicylate dihydrate, it may tend to have a portion, or even all, of its crystal structure in the form of needles. Much preferred is the practice of the process whereby the crystal structure is substantially entirely composed of crystals in a platelet form.

Other techniques for the preparation of the anhydrous sodium acetylsalicylate may also employed. For instance, various inert, that is inactive, gases may be employed such as nitrogen or argon, in place of air. A batch or continuously operated fluidized bed technique may be employed wherein the bed is formed from the particulate sodium acetylsalicylate dihydrate itself. In such a case, the apparatus desirably includes equipment to permit collection of fines developed during the fluidization and for the removal and recovery of the anhydrous sodium acetylsalicylate. Alternatively, a constant stirring may be employed using a micro-perforated elastomeric support for the particulate aspirin for passage therethrough of air, or any inert dry gas, optionally also utilizing a continuous belt system. Such various forms of apparatus may of course also be used in sequential combination, in any desired order.

Additionally, an azeotropic distillation technique may be employed for the removal of the water of hydration in a suitable, preferably non-polar, azeotrope-forming organic liquid. The azeotropic boiling point may be lowered somewhat by use of a somewhat reduced pressure, desirably with reflux to accelerate the process while maintaining a lower temperature.

This can be useful where azeotrope-forming non-polar or weakly polar solvents are employed to avoid decomposition of the starting material while also achieving removal of the water of hydration.

The product obtained is thereafter stored in moisture proof air tight containers under an atmosphere of less than 50% relative humidity. The product is not hygroscopic under these conditions. The table following is illustrative of the stability of the material obtained by the various techniques as described above.

Example 4 SODIUM ASPIRIN PREPARATION The following procedure was used to produce 0.55-mole laboratory batches of sodium acetylsalicylate: Reagents: Aspirin 100 gm Sodium bicarbonate 50 gm Toluene 8 ml Water 45 ml Isopropanol 1 liter 1. Aspirin, sodium bicarbonate, toluene, and water are initially mixed in a 400 ml beaker.

2. The beaker was set in a water bath at 40°-45° C. and the mixture was stirred until the effervescence ceased (approximately 60 minutes). The foam was controlled by adding small portions (in addition to the 8 ml) of toluene as needed.

3. Isopropanol (300 ml) was added, the mixture stirred and filtered from unreacted sodium bicarbonate, (the filter was not washed).

The solution was then cooled to 5-6°C and seeded with platelet crystals of sodium acetylsalicylate dihydrate (for seed preparation, see below). Isopropanol (525 ml, T=5-6°C) was added. The mixture was then stirred in a water-bath (ice+water) for 2 hours during which crystallization of sodium aspirin dihydrate took place. It was then kept in refrigerator overnight. The product obtained was in the form of platelet crystals.

4. The mixture was stirred, filtered and washed with isopropanol (150 ml, T=5-6°C) and benzene (100 ml) and dried at room temperature or under a lamp in a large shallow dish. During drying, the mixture was frequently stirred and lumps were broken up with a spatula (such lumps may become very hard unless continuously broken).

Weight = about 55 gm, nearly 50 % of theory.

5. The dried product was placed in vacuum desiccator under vacuum using calcium chloride as desiccant in a separate chamber from the sodium acetylsalicylate dihydrate product.

The following day, the product was stirred and placed under vacuum again for another 24 hours. These operations were all conducted in an air atmosphere of at most about 40% or less relative humidity. The resulting anhydrous product in the form of platelet crystals was then placed in airtight bottles.

PREPARATION OF SEED CRYSTALS 6. Sodium acetylsalicylate (5 gm) from an earlier run, and 1.5 ml of water were stirred with a glass rod in a wide test-tube for several minutes, forming a fluid mixture. Isopropanol (5 ml) was added and stirred in a warm water-bath until almost all dissolved. It was then cooled in ice-water, stirred and rubbed until crystallization was induced. The crystallized material was kept in an ice-bath with occasional stirring until used above (#3). The dihydrate platelet seed crystals should be freshly made and kept in a refrigerator or freezer until used. On long standing, however, they will hydrolyze.

For the initial runs, when seed crystals are not available, they are prepared by placing a small portion of the solution (#3, above) in a test tube, and scratching the walls with a glass rod in an ice-water bath to induce initial crystallization, followed by allowing the mixture to further crystallize over a 2-3 hour period with occasional stirring.

Example 5.

The following procedure was used to produce 8.9 mole laboratory batches: Reagents: Aspirin 1, 600 gm Sodium bicarbonate 800 gm Toluene 120 ml Water 720 ml Isopropanol 16 liters Benzene 300 ml 1. The aspirin and sodium bicarbonate were mixed in a 5-liter beaker, and 120 ml of toluene was added with stirring, followed by 720 ml of water.

2. The beaker was set in a water-bath at 40°C. 2°C. and mechanical stirring was begun and continued until effervescence ceased (approximately 75minutes).

Note: During the reaction, the mixture became a syrupy fluid with a slight pink hue. Some sodium bicarbonate remained unreacted.

3. Isopropanol (4,800 ml) was added to the beaker and stirred.

The suspension was then filtered through a Watman #2 paper using suction to remove the unreacted sodium bicarbonate, and the filtrate divided into two equal portions.

4. Each portion was placed in a 12-liter round-bottom flask placed in an ice-salt bath and equipped with a paddle-stirrer, addition funnel, and thermometer.

5. The solutions were stirred for a half-hour or until the temperature reached 2-5° C. Crystallization was induced by seeding with sodium acetylsalicylate dihydrate platelets.

Note: Immediate crystallization does not usually occur, and the solution should be stirred until crystals form. The preparation of sodium acetylsalicylate dihydrate platelet crystal seeds is described elsewhere herein.

6. Approximately 15 minutes after crystallization had developed, 5-6 liters of isopropanol were added dropwise to each flask over a period of 3 hours with constant stirring.

7. The crystal content of both flasks was suction-filtered each through the same Biichner funnel using Watman #2 filter paper, then washed with approximately 300 ml of benzene.

8. The two lots of crystals were combined, then subdivided into 4 stainless-steel drying pans, and were dried overnight in a Stokes vacuum-oven without heat at 1.5 mm vacuum.

9. The product was removed from the oven, stirred, any caking was broken apart, and then replaced under vacuum for an additional 3 hours.

10. The now dry dehydrated platelet crystals were removed from the oven and passed through a #20 screen, placed in bottles containing silica-gel drying bags, and sealed with plastic tape.

Wide-mouth amber bottles complete with plastic-coated cardboard liners were used for packaging the anhydrous sodium acetylsalicylate. The bottles were flushed with dry air and allowed to equilibrate overnight in the low-humidity room.

Steps #9 and #10 were conducted in a low-humidity environment with relative humidity at 15%.

Results: Theory 1,782 grams Actual Yield 1,344 grams NOTES: a. The method of preparation described herein is based along the general lines of US Patent No. 3,985, 782. However, this method has been further improved to make the product more suitable for the present injection-grade preparation. b. For successful preparation, it is important to avoid formation of the needle-like crystal form of sodium acetylsalicylate. When a

concentrated aqueous solution of sodium acetylsalicylate is treated with such solvents as isopropanol, while taking no special precautions, the tendency is to get the needle-like form preferentially. This form is inferior in many respects to the plate form: The needle form is difficult to manage, stir, filter, wash and dry. Also, the yield is considerably lower than with plates. Needle form crystals may also present difficulties in filling vials for injection.

Formation of the needle-form is prevented by a strict control of conditions: proportion of reactants, amounts of water and isopropanol, temperature, speed of stirring, and employment of sufficient amounts of carefully prepared crystalline seeds of the platelet form. c. Conditions for preparing a stable product were discovered on observing that controlling the rate of removal of water of hydration from sodium acetylsalicylate di-hydrate is critical ; the water of hydration must be removed from the system at no less than the same rate as it is formed. This is achieved bv use of good vacuum and use of large-diameter tubing or conduits. The dehydration may also be accomplished very efficiently by use of a fluidized-bed. d. As to storage of anhydrous sodium acetylsalicylate. the product was kept in moisture-proof airtight glass containers. This product is not hygroscopic at RH<50% and was therefore packed at this condition. e. Regarding stability and decomposition, the following table indicates stability of the product prepared under diverse conditions: The column % Free Salicylate shows the quantity of non-aspirin salicylate content in various prepared lots. Thus, after a year's storage at room temperature stability was, on the average, very high with purity of about 99%. Accelerated aging tests (30 days at 50° C.) showed similar stability (see following table, Lots A, B, C, D). f. As to dehydration, the water-content may be determined by Karl Fisher or IR-assay, and was found to be about 0. 1% (see following table.) g. Ambient temperatures were used in Examples unless otherwise indicated. h. As to drying agents, CaS04, P205, MgS04, and molecular sieves may all be suitably employed for removing water of hydration inasmuch as the dihydrate starting material quite easily loses its water of hydration. Even so, the most effective and industrially practical method may be the fluidized bed, or other suitable, at least semi-continuous, method. i. Regarding Example 2, as the product is dehydrated, it tends to cake. Here again, the use of a fluidized-bed technique can prevent this. With other methods, caking is prevented during dehydration by various stirring methods. For instance, one method described is the use of a rotating flask under vacuum.

Owing to the constant movement of particles, caking can be avoided.

ANALYTICAL PROCEDURES FOR ANHYDROUS SODIUM ASPIRIN The procedure described here is manual. Most stability assays can be practiced with an automated form of this procedure. All solutions are kept ice-cold.

1. REAGENTS (a). Buffer - mix equal volumes of 2-propanol and a pH 2.2 HCl/KCI solution- The latter latter prepared prepared dissolving dissolving 72 gm KCI in distilled water, and adding 39 ml or 0.2 molar HCI ; the mixture is diluted to 1 liter.

(b). Ferric nitrate - five grams of ferric nitrate and 2.5 ml of concentrated nitric acid are dissolved in water and diluted to 500 ml.

2. PREPARATION OF STANDARD Approximately 40 mg of accurately weighed sodium salicylate is dissolved in the buffer solution and diluted to 25.0 ml with the buffer.

3. ASSAY Described here for initial assays. Stability samples may require different dilutions.

Accurately weigh approximately 60 mg of sample into a 10 ml volumetric flask. Dissolve and dilute the sample to mark with cold buffer solution. Keep the solution in ice. In a spectrophotometer curette, mix 4.0 ml of the sample solution and 2.0 ml of the cold ferric nitrate solution. Read the absorbences of these solutions at 520 mt using a mixture of 4.0 ml of buffer and 2.0 ml of ferric nitrate solution as a blank.

Aunk Conc. std. * x x 100 = % salicylate as sodium salicylate tlstd W t. unk *Concentration of standard in 10 ml of final dilution.

ANALYSIS FOR SALICYLATE CONTENT 1. REAGENTS a) Ferric Solution: Fe Alum (1 g) in 200 ml water containing 1 ml of conc. HCl b) Standard Salicylic Solution: 1 gm in 1 1. water (0. 1 wt.

2. COLOR COMPARISON TEST-TUBES (Nessler) length: 154 mm; ED ; 19 MM; od: 22 mm 3. PROCEDURE: (a). dissolve 50 mg of compound in 20 ml of water, place into first Nessler tube; add 4 drops of glacial acetic acid, followed by 8 drops of ferric solution (b). place 20 ml of water in the second Nessler tube, add 4 drops of glacial acetic acid, add 8 drops of ferric solution; then, with shaking, add dropwise the 0. 1 % salicylic solution until the color matches that of the solutions in the first Nessler tube (viewing through the width, not the depth, of the Nessler, and against a white background.) Each drop of 0. 1% salicylic solution corresponds to 0.05 mg of salicylic acid.

The concentration or the solution being tested should be adjusted so that not more than 6-7 drops of salicylic solution is required; otherwise the color is too deep for comparison.

4. NOTE: This test requires less than 5 minutes to perform. Since aspirin salts hydrolyze in water, the test should be completed as fast as possible.

ANHYDROUS SODIUM ASPIRIN (Physical Properties) a) Appearance: Free-flowing white granular powder ; monoclinic plates. b) Identity: Melting/Decomposition point: 210°-213 C.

(literature: 217. 5° C.) c) Purity (as measured): 97-103% (by aspirin content) d) Water Content: Maximum: 0. 1% as determined by Karl Fisher or IR assay. e) Solubility: Extremely soluble in water, and as follows, Methanol: 3.50% w/v Ethanol: 0.30% w/v Isopropanol: 0.05% w/v f) Free Salicylate: Less than 1% salicylate. g) Mol. Wt. = 202

Sodium = 12. 8 wt. % h) Hygroscopic at RH>50% Stability data are indicated in the following table.

Table I STABILITY OF ANHYDROUS SODIUM ACETYLSALICYLATE Lot No. Time Wt. % Free- Dehydration Conditions Salicylate A30 days @50° 0. 7 RV: 3 hrs, vac desiccator 14 months @ RT 0.8 (4 days, sulfuric acid) B 30 days @ 50° 1. 0 RV: 3 hrs. C 30 days @ 50° 1. 2 Vacuum desiccator 14 months @ RT 0.6 (5 days, CaCl2) D 30 days @ 50° 0. 8 Vacuum desiccator 14 months @ RT 0.9 (12 days,, CaCl2) E 13 months @ RT 1.2 Vacuum desiccator (17 hrs. CaC12) then RV F 13 months @ RT 0.8 Vacuum desiccator (21 days, CaCl2) G 13 months @ RT 1.2 FB Lot No. Time Wt. % Free- Dehydration Conditions Salicylate (45'@55° ; 35' @ 65°) H 12 months @ RT 0.8 FB (1 hr @ 45° ; 2 hrs @ 85°) I 12 months @ RT 1.5 FB (5 hrs @ 55°) 9 months @ RT 1.0 FB J (1 hr @ 20° C. 1hr ²@ 45°C. 1 hr @ 6° C.) NOTES :"RT"= Room Temperature "RV"= Rotating flask, vacuum, water-bath 20°-50°-85° "FB"= Fluid-bed The initial free-salicylate in all runs is <0.05%.

Further Examples of improved preparations are described hereinafter.

Example 6 A mixture of aspirin (25.0 g, 0.139 mol) and sodium bicarbonate (12.5 g, 0.147 mol) and toluene (2.0 ml) was placed in a 250 ml ehrlenmeyer flask and water (12. 2 ml) was added. The reaction mixture was stirred magnetically in a water bath at 40-45°C. Effervescence and frothing were observed. Additional portions of toluene (3 ml) were added to reduce the frothing. After 45 minutes the effervescence and frothing ceased, and isopropanol (75 ml) was added portionwise. The reaction mixture was filtered, and the clear filtrate was cooled in an ice bath and treated with an additional portion of isopropanol (130 ml). The clear solution was scratched with a stirring rod to induce crystallization and placed in the refrigerator overnight. The resultant crystalline product was filtered and washed with <BR> <BR> <BR> <BR> isopropanol (37 ml) and dried at room temperature. A total of 8.73 g (26. 4% yield) of dihydrate product was obtained; mp: softens at 143°C., resolidified at 165°C. and melts with decomposition at 238°C.

A portion of this product (5.50 g) was recrystallized by dissolving in water (2.0 ml) and warming in a water bath at 45°C to give a clear solution. Isopropanol (7 ml) was added and the clear solution was cooled in an ice bath for 30 minutes. During this time there was a crystallization of dihydrate in the form of beautiful white platelets which were filtered and dried at room temperature. A total of 2.54 g of product was obtained; mp: begins to soften at 74°C, completely softens at 90°C, and melts with decomposition at 237°C. Anal: H2O content (14.51%) [Karl Fischer Analysis].

The dihydrate sodium acetylsalicylate product from this preparation was subsequently subjected to kinetic studies using various drying conditions to form the desired anhydrous sodium acetyl salicylate, as described hereinafter.

Example 7 Sodium acetylsalicylate dihydrate was placed in a tared vial and introduced into an abderholden drying chamber which was charged with dry calcium chloride. This

device is illustrated in FIGURE 1. The abderholden was connected to a vacuum pump at a reduced pressure of 45 mm. At various times the vial containing the sodium acetylsalicylate dihydrate was weighed and the loss of weight (equivalents of water) was plotted versus time (minutes). For sodium acetylsalicylate dihydrate the theoretical number of equivalents of water is 2.00. The following tables summarize the drying curves for each temperature studied.

As generally shown in Figure 1, the abderholden device 10 has a flask 12 for a distillable fluid in communication with an outer chamber 14 through the connecting tube 16. Outer chamber 14 has a generally concentrically mounted inner chamber 18 for containing the sample 20 to be treated and isolated from any communication with outer chamber 14. Outer chamber 14 is in turn fitted with a reflux condensor 22 for return of the condensed refluxing liquid in flask 12. The inner chamber 18 is fitted with a second flask 24 for containing, in this instance, a drying agent. Flask 24 is further provided with means permitting a connection to a vacuum pump (not shown) via line 26 fitted with a stopcock 28 or other valve device.

Connections between flask 12, outer chamber 14, condensing column 22. and inner chamber 18 with flask 24 are conveniently provided with respectively ground glass joints 30. By placing a liquid of suitable boiling point in flask 12 the sample (here, sodium acetyl salicylate dihydrate) placed in inner chamber 18, which is isolated from outer chamber 14 (as by a ring seal at 32), can be maintained at a suitable predetermined temperature via the function of the condensor 22. The drying agent in flask 24 is selected so as to effectivelv absorb the water of hydration as it is removed from the initial dihydrate starting material by the applied heat at the temperature of the refluxing medium and under the imposed vacuum.

Table II Drying at 22. 0°C Sodium acetylsalicylate dihydrate (485.3 mg, 2.037 mmol) Amount of HoO removed from dihydrate Time (min) Samplewt(mg)(mg) Mmols Equivalents 0 485.3 0.0 0.000 0.000 20 478.8 6.5 0.361 0.177 40 477.0 8.3 0.461 0.226 60 475.6 9.7 0.539 0.265 80 474.5 10.8 0.600 0. 295 145 471.2 14.1 0.783 0.384 1300 419.4 65.9 3.660 1.800 4140 410.3 75.0 4.167 2.045 FIGURE 2 is a plot of the resulting drying process, illustrating the asymptotic curve as the procedure forms the anhydrous sodium acetyl salicylate of this invention.

Table m Drying at 40. 0°C Sodium acetylsalicylate dihydrate (477.5 mg, 2.003 mmol) Amount of H90 removed from dihydrate Time (min) Sample wt (mg) (mg) mmols Equivalents 0 477.5 0.0 0.000 0.000 30 472.1 5.4 0.300 0.150 135 454.0 23.5 1.306 0.652 275 443.2 34.3 1.906 0.952 1445 412.0 65.5 3.638 1.816 1535 412.1 65.4 3.633 1.814 FIGURE 3 is a plot similar to Figure 2 of the resulting drying curve, again showing the asymptotic shape.

Table IV Drying at 56. 5°C Sodium acetylsalicylate dihydrate (527.8. mg, 2.215 mmol) Amount of HO removed from dihvdrate Time (min) Sample wt (mg) (mg) mmols Equivalents 0 527.8 0.0 0.000 0.000 40 471.8 56.0 3.111 1.404 65 466.6 61.2 3.400 1.534 90 463.1 64.7 3.594 1.622 115 461.8 66.0 3.667 1.655 175 458.6 69.2 3.844 1.736 235

458.6 69.2 3.844 1.736 295 458.6 69.2 3.844 1.736 FIGURE 4 is a plot, similar to that of Figures 2 and 3, again showing the asymptotic shape of the drying curve.

FIGURE 5 is a comparative plot of the curves of Figures 2,3 and 4 and illustrates that the process of this invention and the rate of conversion of the sodium acetylsalicylate dihydrate to the anhydrous form is dependent on temperature (as noted above, for this series of plots, the same reduced pressure of 45 mm Hg was employed). At 22° C., conversion to the anhydrous form proceeded to 50% completion in about 10 hours. At 40° C., conversion to the anhydrous form proceeded to 50% completion in about 4 hours. At 56. 5° C., the highest temperature used in this study, 50% conversion of the dihydrate to the anhydrous form proceeded in less than 40 minutes.

The dihydrate samples used in the drying experiments at 40° and 56. 5° C. (tables III and IV) show a less than theoretical ultimate removal of water of hydration probably due to the fact that prior to use in the above experiments they were stored overnight in a desiccator in a refrigerator over calcium chloride and had therefore undergone some initial loss of water of hydration. The validity of the experiment is unaffected by this circumstance.

There was no indication of any decomposition of sodium acetylsalicylate dihydrate at the temperatures studied over the course of these kinetic studies. However, it is generally advised that drying should not be carried out at temperatures that are much greater than about 60°C since sodium acetylsalicylate dihydrate begins to soften and may decompose at higher temperatures (see, mp information below).

As obtained by the above procedure, after drying, the anhydrous sodium acetylsalicylate was recovered as white platelets; mp: begins to soften at 107°C, completely softens at 121°C, and begins to decompose at 174°C and completely decomposes at 205°C. Anal: H2O content (0.85%) [Karl Fischer Analysis].

The Karl Fischer analysis is very useful for measuring the course of the conversion of the dihydrate to the anhydrous form of sodium acetylsalicylate. For example, a sample of partially dehydrated sodium acetylsalicylate dihydrate (taken at the 1300 minute point during the course of <BR> <BR> drying a sample at 22. 0°C (see, Table I, as expected, had a water content of<BR> <BR> 6. 11% by the Karl Fisher analysis).

It can also be concluded that azeotropic removal of the water from sodium acetylsalicylate dihydrate is possible. However, in practice, especially on large scale, the boiling point of such azeotropic mixtures could lead to decomposition of the product unless carried out under a reduced pressure. Drying at no more than about 60°C. (i. e. at about 56° C. which is the bp of refluxing acetone as used in the abderholden device referred to above) is the preferred method for conversion to the anhydrous form since the process proceeds rapidly (complete within 2 hours). Of course, larger scale drying processes may require periodic mixing or rotation of sample and may require longer times and/or lower temperatures.

The foregoing Examples demonstrate that drying to a constant weight is a sufficient measurement of the complete conversion to anhydrous sodium acetylsalicylate.

Thus, this invention provides a novel advantageous process for the dehydration of sodium acetylsalicylate dihydrate to produce a novel anhydrous sodium acetylsalicylate composition which is particularly distinguished by the dominant presence of a platelet crystal morphology and by a high purity which is retained with an extended shelf life of at least 2-3 years. This product is of sufficient purity and stability to permit its use for subdermal injection into mammals for therapeutic purposes. The dehydration process is especially characterized by the rapid removal of the water vapor from the system as it is formed so as to prevent re-hydration of the sodium acetylsalicylate and the ultimate deterioration of its desired characteristics.

Such process is to be conducted at temperatures insufficiently high to induce decomposition of the fundamental sodium acetylsalicylate molecular structure so that high purity is achieved. Various specific techniques to accomplish this goal are described in the foregoing description which are in accord with the application of the principles of the invention. For instance, in place of isopropanol there may be used other C3 to C4 alcohols in the precipitation and crystallization of the dihydrate, as is also indicated in the process of the above- mentioned U. S. 3,985, 792. It will therefore be understood that the invention may be embodied otherwise without departing from such principles, and is therefore limited only by the spirit and scope of the following claims.

WHAT IS CLAIMED IS: 1. A therapeutic sodium acetylsalicylate composition having a long shelf life and pharmaceutical-acceptability suitable for mammalian subcutaneous injection, comprising the essentially completely anhydrous form of sodium acetylsalicylate, formed by removing the water of hydration from the sodium acetylsalicylate dihydrate, at a rate which corresponds to the rate of formation of water vapor from the water of hydration, and obtained in the form of monoclinic platelets.

2. The composition of claim 1 wherein the product is composed of essentially completely anhydrous sodium acetylsalicylate having a melting point of about 210° - 213° C.

3. A composition according to claim 2, wherein the anhydrous sodium acetylsalicylate is sufficiently stable so that it has a purity of at least about 97% to 100% after storage at room- temperature under an air atmosphere of no more than about 50% relative humidity for at least three years.

4. A therapeutic acetylsalicylate composition composed of essentially completely anhydrous sodium acetyl salicylate in the form of white monoclinic platelets and having a melting point of about 210° - 213° C., and an H20 content of less than about 1 wt. %, and a free salicylate content of less than 1 wt. %.

5. A composition according to claim 4, wherein the anhydrous sodium acetylsalicylate is sufficiently stable so that it has a purity of at least about 97% to 100% after storage at

room- temperature under an air atmosphere of no more than about 50% relative humidity for at least three years.

6. A method of preparing a therapeutic composition of acetyl salicylate having a long shelf life and pharmaceutical-acceptability for mammalian subcutaneous injection, the method comprising: providing an initial amount of solid particulate sodium acetylsalicylate dihydrate at least substantially in the form of platelet crystals; and removing the water of hydration from the said acetylsalicylate dihydrate at a rate that is not less than the rate of water vapor formation from the dihydrate to a level of a residual amount of water of hydration of less than about 2 wt. %, to produce thereby anhydrous sodium acetylsalicylate in the form of white monoclinic platelet crystals and having a melting temperature of about 210° - 213° C.

7. A method according to claim 6, wherein removing the water of hydration further comprises placing the said acetylsalicylate dihydrate under a vacuum.

8. A method according to claim 6, wherein the vacuum is between about 1 mm Hg and 50 mm Hg.

9. A method according to claim 6, wherein the water of hydration is removed using a vacuum oven.

10. A method according to claim 6, wherein removing the water of hydration further comprises exposing the solid sodium acetylsalicylate dihydrate crystals to a current of dry inactive gas for a required period of time sufficient to effect substantially complete removal of the water of hydration of the dihydrate.

11. A method according to claim 6, wherein removing the water of hydration further comprises placing the solid sodium acetylsalicylate dihydrate crystals in a current of a substantially dry inactive gas at a temperature of from about 50°C., to a temperature of about 60° C.

12. A method according to claim 6, wherein removing the water of hydration further comprises agitating or stirring the solid sodium acetylsalicylate dihydrate crystals to prevent caking thereof.

13. An improved method for the production of sodium acetylsalicylate dihydrate crystals which comprises first forming an aqueous suspension of acetylsalicylic acid and treating the same with sodium bicarbonate, thereafter inducing precipitation of sodium acetylsalicylate dihydrate by the addition of a C3 to C4 alcohol to the resulting aqueous solution with cooling the same, inducing the formation of crystals by seeding with pre-formed monoclinic platelet crystals of sodium acetylsalicylate dihydrate, and allowing further crystallization of sodium acetylsalicylate dihydrate to take place whereby a product is formed consisting essentially of sodium acetylsalicylate dihydrate in the form of monoclinic platelet crystals.

14. The method of claim 13 wherein said alcohol is isopropanol.

15. A therapeutic acetylsalicylate composition having a long shelf life and pharmaceutically acceptably suitable for mammalian subcutaneous injection, comprising the essentially completely anhydrous form of sodium acetylsalicylate formed by removing the water of hydration from the sodium acetylsalicylate dihydrate at a rate which corresponds to the rate of formation of water vapor from the water of hydration and obtained in the form of monoclinic platelets having a melting/decomposition temperature of about 210°-213°C.

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Jernihkan Air dengan Ampas Tahu

Setelah penelitian selama 3 tahun, akhirnya mahasiswa Fakultas Teknik Kimia berhasil membuktikan cara lain untuk menjernihkan air, yaitu dengan menggunakan membran dari ampas tahu. Membran ampas tahu ini memanfaatkan bakteri celulose. Cara dasar pembuatan membran tahu sama dengan cara pembuatan nata de coco yang banyak diproduksi sebagai bahan makanan.

Proses pembuatan membran berawal dari penelitian tentang limbah atau ampas tahu yang disebut w-tahu.Menurut pemilik ide awal ini, Ery Susiany R. MT, dosen Teknik Kimia Unika WM, "Selama ini banyak ampas tahu dari pabrik-pabrik pembuatan tahu yang

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dibiarkan, untuk itu kami mencoba untuk memanfaatkannya." Hasil penelitian awal menyatakan bahwa ampas tahu dapat diolah menjadi nata, sama seperti nata de coco yang banyak dikenal. Menurut Wenny Irawaty MT, rekan Ery sesama dosen UK WM, "Pada dasarnya ampas tahu memiliki sifat asam jadi sangat memungkinkan untuk diubah menjadi nata."

Cara pengolahan cukup mudah, dengan menambahkan tetes tebu sebagai sumber karbon, ampas tahu diberi bakteri Acetobacter xylinum. Setelah melalui masa fermentasi  selama tujuh hari, sudah bisa didapat hasil berupa nata. Untuk mendapatkan membran yang dapat menahan kandungan garam dalam air payau, nata dari ampas tahu diolah kembali dengan memberi bahan kimia denagn cara merendam dalam suhu tertentu. Sedangkan untuk mendapat lapisan yang tipis dan rata, membran yang terbentuk ditekan dengan menggunakan pemanas.  Membran dari ampas tahu ini bisa menahan hingga 98 persen kandungan garam dalam air payau. Hal ini dipastikan setelah uji coba dengan air payau sintetik. Hasil dari uji coba  dapat diartikan bahwa air hasil penyaringan telah layak digunakan sesuai standart kesehatan. Saat ini pengembangan dari penemuan masih terus dilakukan guna meningkatkan kekuatan fisik dan daya hisap membran.

Jika dibandingkan dengan membran yang terbuat dari bahan lain, membran dari ampas tahu inmemiliki kelebihan biaya pembuatan yang lebih murah karena bahan kimia hanya sebagai pembantu bukan sebagai bahan baku. Selain itu, membran ini sangat ramah lingkungan karena dapat terurai langsung di alam setelah tidak digunakan.

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MATERIAL SAFETY DATA SHEET FOR ISOPROPYL ALCOHOL  

I. CHEMICAL PRODUCT IDENTIFICATION  Product Name: ISOPROPANOL ANHYDROUS, USPChemical Name: Isopropyl AlcoholChemical Family: AlcoholsFormula: (CH3)2 CHOHSynonym: ISOPROPANOL, ANHYDROUS, USP, ISOPROPANOL, ANHYDROUS SEMI CONDUCTOR GRADE, dimethyl carbinol, 2-PropanolEMERGENCY TELEPHONE NUMBER: For all transportation accidents, call CHEMTREC at 800-424-9300Effective Date: 1/1/2004 

II. COMPOSITION INFORMATION Component CAS# Amount

lsopropanol 67-63-0 <100%

 III. HAZARDS IDENTIFICATION

  3.1 EMERGENCY OVERVIEW Appearance: Transparent colorless Physical State: Liquid Odor: Slight ethanol/acetone-like Hazards of product: WARNING! FLAMMABLE. CAUSES EYE IRRITATION.

MAY CAUSE DIZZINESS AND DROWSINESS.

 3.2 POTENTIAL HEALTH EFFECTS Effects of Single Acute Overexposure Inhalation: High concentrations of vapor may cause central nervous system depression, with weakness, drowsiness, and loss of consciousness. Vapor causes irritation of the respiratory tract, with coughing and chest discomfort. Eye Contact: Causes irritation, experienced as stinging and discomfort or pain. Corneal injury may occur.Skin Contact: May cause minor irritation with itching and possible slight local redness. Prolonged or repeated contact may cause defatting and drying of the skin. Skin Absorption: Exposure to small quantities is not expected to cause adverse health effects. Widespread or prolonged exposure may result in the absorption of harmful amounts of material, particularly in infants, leading to signs and symptoms as described for swallowing.

Swallowing: Slightly toxic. May cause dizziness, faintness, drowsiness, decreased awareness and

responsiveness, lack of coordination, abdominal discomfort, nausea, vomiting and diarrhea.

 

Chronic, Prolonged or Repeated OverexposureEffects of Repeated Overexposure: Prolonged or repeated skin exposure may cause defatting

of the skin.

Other Effects of Overexposure: None currently known.

Medical Conditions Aggravated by Exposure: Skin contact may aggravate an existing

dermatitis. 

IV. FIRST AID PROCEDURES  4.1 INHALATION: Remove to fresh air. Give artificial respiration if not breathing. If breathing

is difficult, oxygen may be given by qualified personnel. Obtain medical attention. 4.2 EYE CONTACT: Immediately flush eyes with water and continue washing for several

minutes. Remove contact lenses, if worn. Obtain medical attention 4.3 SKIN CONTACT: Remove contaminated clothing. Wash skin with soap and water. If

irritation persists or if contact has been prolonged, obtain medical attention. 4.4 SWALLOWING: If patient is fully conscious, give two glasses of water. Induce vomiting.

This should be done only by medical or experienced first-aid personnel. Obtain medical attention. 4.5 NOTES TO PHYSICIAN: There is no specific antidote. Treatment of overexposure

should be directed at the control of symptoms and the clinical condition of the patient. 

V. FIRE FIGHTING MEASURES  5.1 FLAMMABLE PROPERTIES

Flash Point - Closed Cup: Tag Closed Cup ASTM D 56 12 0C 53 0F

Flash Point - Open Cup: Tag Open Cup ASTMD 1310 170C 63 0F

Autoignition Temperature: Not currently available.

Flammable Limits In Air:Lower 2.0 %(V)Upper 12.7 %(V) 200 0F

5.2 EXTINGUISHING MEDIA: Extinguish fires with water spray or apply alcohol-type or all-purpose-type foam by manufacturers recommended techniques for large fires. Use carbon dioxide or dry chemical media for small fires.

 

5.3 EXTINGUISHING MEDIA TO AVOID: No information currently available. 5.4 SPECIAL FIRE FIGHTING PROCEDURES: Use water spray to cool fire-

exposed containers and structures. Use water spray to disperse vapors; reignition is possible. 5.5 SPECIAL PROTECTIVE EQUIPMENT FOR FIREFIGHTERS: Use self- contained breathing apparatus and protective clothing. 5.6 UNUSUAL FIRE AND EXPLOSION HAZARDS: Vapors form from this

product and may travel or be moved by air currents and ignited by pilot lights, other flames, smoking, sparks, heaters, electrical equipment, static discharges or other ignition sources at locations distant from product handling point. Vapors from this material may settle in low or confined areas or travel a long distance to an ignition source and flash back explosively. Static ignition hazard can result from handling and use. Electrically bond and ground all containers, personnel and equipment before transfer or use of material. Use proper bonding and grounding during product transfer as described in National Fire Protection Association Document NFPA 77.

 This material may produce a floating fire hazard.Flame may be invisible. Approach fire with caution. 5.7 HAZARDOUS COMBUSTION PRODUCTS: Burning can produce the following products: Carbon monoxide and/or carbon dioxide. Carbon monoxide is highly toxic if inhaled; carbon dioxide in sufficient concentrations can act as an asphyxiant 

VI. ACCIDENTAL RELEASE MEASURES  Steps to be taken if Material is Released or Spilled: Extinguish and do not turn on any ignition source until the area is determined to be free from fire or explosion hazard. Small spills can be flushed with large amounts of water-~ larger spills should be collected for disposal. Personal Precautions: Avoid contact with eyes. Wear suitable protective equipment. 

 VII. HANDLING AND STORAGE

 General Handling: Keep away from heat, sparks and flame. Avoid contact with eyes. Keep container closed. Use with adequate ventilation. Vapor forms from this product and may travel or be moved by air currents and ignited by pilot lights, other flames, smoking, sparks, heaters, electrical equipment, static discharges or other ignition sources at locations distant from product handling point and may flash back explosively.Wash thoroughly after handling. FOR INDUSTRY USE ONLY. Ventilation: General (mechanical) room ventilation is expected to be satisfactory where this product is stored and handled in closed equipment. Special, local ventilation is needed at points where vapors can be expected to escape to the workplace air. Other Precautions: Vapor may settle in low or confined areas, or travel a long distance to an ignition source and flash back explosively.STORAGE: Store in grounded fireproof cabinets. 

VIII. EXPOSURE CONTROLS AND PERSONAL PROTECTION  8.1 EXPOSURE LIMITS Component Exposure Limits Skin Form Isopropanol 400 ppm W/A8 ACGIH 983 mg/m3 TWA8 ACGIH 1230 mg/m3 STEL ACGIH 500 ppm STELACGIH 400 ppm TWA8 OSHA 980 mg/m3 TWA8 OSHAIsopropanol 1225 mg/m3 STEL OSHA-Vacated 500 ppm STEL OSHA-Vacated In the Exposure Limits Chart above, if there is no specific qualifier (L e., Aerosol) listed in the Form Column for a particular limit~, the listed limit includes all airborne forms of the substance that can be inhaled. A “Yes” in the Skin Column indicates a potential significant contribution to overall exposure by the skin route, including mucous membranes and the eyes, either by contact with vapors or by direct skin contact with the substance. A “Blank” in the Skin Column indicates that exposure by the skin route is not a potential significant contributor to overall exposure.  8.2 PERSONAL PROTECTION Respiratory Protection: Use self-contained breathing apparatus in high vapor concentrations. Ventilation: General (mechanical) room ventilation is expected to be satisfactory where this product is stored and handled in closed equipment. Special, local ventilation is needed at points where vapors can be expected to escape to the workplace air. Eye Protection: Monogoggles. Protective Gloves: Plastic, Rubber Other Protective Equipment: Eye Bath, Safety Shower 8.3 ENGINEERING CONTROLS PROCESS HAZARD: Sudden release of hot organic chemical vapors or mists from process equipment operating at elevated temperature and pressure, or sudden ingress of air into hot equipment under a vacuum, may result in ignitions without the presence of obvious ignition sources. Published “autoignition” or “ignition” temperature values cannot be treated as safe operating temperatures in chemical processes without analysis of the actual process conditions. Any use of this product in elevated-temperature processes should be thoroughly evaluated to establish and maintain safe operating conditions.   

IX. PHYSICAL AND CHEMICAL PROPERTIES  Physical State: LiquidAppearance: Transparent colorlesspH: Not currently available.Solubility in Water (by weight): 20 0C 100 %Odor: Slight ethanol/acetone-likeFlash Point - Closed Cup: Tag Closed Cup ASTM D 56 120C 530FFlash Point - Open Cup: Tag Open Cup ASTMD 1310 17 0C 63 0FPercent Volatiles: 100 Wt%Molecular Weight: 60.10 g/molLiquid Density: 20 0C 6.5475 g/cm3Boiling Point (760 mmHg): 82.3 0C 180.1 0FFreezing Point: -89 0C -127 0FSpecific Gravity (H2O = 1): 0.787 20 0C /20 0CVapor Pressure at 200C: 4.4 kPa 33 mmHgVapor Density (air = 1): 2.1Evaporation Rate (Butyl Acetate = 1): 2.9Melting Point: Not applicable. 

X. STABILITY AND REACTIVITY  10.1 STABILITY/INSTABILITY: Stable Incompatible Materials: Strong oxidizing agents. Halogens. Strong inorganic acids. Aldehydes. Halogen compounds. 10.2 HAZARDOUS POLYMERIZATION: Will not occur. 10.3 INHIBITORS/STABILIZERS: Not applicable.  

XI. TOXICOLOGICAL INFORMATION  ACUTE TOXICITY Peroral: Rat LD5O 6.48 (4.80 - 8.76) mI/kg Major Signs: unsteady gait, prostration, and heavy breathingGross Pathology: lungs and abdominal viscera discolored Percutaneous: Rabbit LD5O 24 hr occluded 8.0 (4.9 - 13.1) mI/kg Gross Pathology: lungs, liver, stomach discolored Inhalation: static generation of vapor Exposure Time 2 h RabbitRoom temperature

Mortality:4/6Major Signs: lacrimation, loss of coordination, prostrationGross Pathology: lungs discolored Inhalation: dynamic generation of vapor Exposure Time 4 h 12000 ppm RabbitMortality: 0/12Major Signs: prostrationGross Pathology: lungs, kidneys and liver discolored Inhalation: dynamic generation of vapor Exposure Time 8 h 12000 ppm RabbitMortality: 8/12Major Signs: prostrationGross Pathology: lungs, kidneys and liver discolored Inhalation: dynamic generation of vapor Exposure Time 8 h 8000 ppm RabbitMortality: 0/12Major Signs: prostrationGross Pathology: lungs, kidneys and liver discolored Inhalation: static generation of vapor Exposure Time 4 h RabbitRoom temperatureMortality: 6/6Major Signs: lacrimation, loss of coordination, prostrationGross Pathology: lungs discolored Inhalation: static generation of vapor Exposure Time I h RabbitRoom temperatureMortality: 0/6Major Signs: lacrimation, loss of coordination, prostrationGross Pathology: lungs discolored IRRITATION Skin: Rabbit 24 hr uncovered no irritationEye: Rabbit 0.02 ml moderate corneal injury SIGNIFICANT DATA WITH POSSIBLE RELEVANCE TO HUMANS The following is a summary of TSCA Section 4 Test Rule results: Large doses (>800 mg/kg/day) of lsopropanol given orally to pregnant rats during the critical period of gestation produced slight decreases in fetal weight. These doses also caused evidence of toxicity in the mothers. Oral doses as high as 480 mg/kg/day caused evidence of toxicity in pregnant rabbits but did not produce evidence of embryo or fetal toxicity. lsopropanol did not produce an increased incidence of malformations (teratogenicity) in either species. An indication of reduced mating performance in 2nd generation male rats was noted at oral doses of 1000 mg/kg/day in a two-generation reproductive study. Increased neonatal mortality was also seen at doses of 500 mg/kg/day and greater in this study. No evidence of neurotoxic effects was observed in studies specifically designed to assess neurobehavioral functions in neonatal rats after oral dosing of mothers during gestation and lactation. In an acute vapor inhalation study, high concentrations of lsopropanol

(1500 ppm and greater) caused a spectrum of transient effects indicative of narcosis. In repeated inhalation exposure studies, high vapor concentrations (5000 ppm) produced an increase in motor activity in rats first noted after 4 weeks of exposure. The effect was reversible completely resolving within 14 days after 13 weeks of exposure. No evidence of damage to nerve tissue was seen in this study. Lifetime exposure of laboratory animals to high concentrations of lsopropanol vapor (greater than 1500 ppm) exacerbated chronic progressive nephropathy commonly seen in aged animals. The relevance of this finding to human health hazard evaluation is unknown. No evidence suggestive of carcinogenic activity was noted in chronic vapor inhalation studies with lsopropanol in rats and mice. 

XII. ECOLOGICAL INFORMATION  12.1 ENVIRONMENTAL FATE 

BOD (% Oxygen consumption)Day 5 Day 10 Day 15 Day 2O Day 3O

28% 77% 78% 12.2 ECOTOXICITY Toxicity to Microorganisms: Bacterial/NA lC5O 5000 mg/IToxicity to Aquatic Invertebrates: Daphnia LC5O 48 h 7550 mg/IToxicity to Fish: Fathead Minnow LC5O 96 h 8300 mg/I  12.3 FURTHER INFORMATION THOD (measured) 2.30 mg/mgTHOD (calculated) 2.40 mg/mgOctanoli/Water Partition Coefficient - Measured: 0.14 

XIII. DISPOSAL CONSIDERATIONS  13.1 WASTE DISPOSAL METHOD: Incinerate in a furnace where permitted under Federal, State, and local regulations. Dispose in accordance with all applicable Federal, State, and local environmental regulations. Empty containers should be recycled or disposed of through an approved waste management facility.  13.2 DISPOSAL CONSIDERATIONS: At very low concentrations in water, this product is

biodegradable in a biological wastewater treatment plant. 

XIV. TRANSPORT INFORMATION  14.1 U.S. D.O.T. NON-BULKProper Shipping Name: ISOPROPANOLID Number: UN1219Hazard Class : 3

Packing Group: PG II BULKProper Shipping Name: ISOPROPANOLID Number: UN1219Hazard Class : 3Packing Group: PG Il This information is not intended to convey all specific regulatory or operational requirements/information relating to this product. Additional transportation system information can be obtained through an authorized sales or customer service representative. It is the responsibility of the transporting organization to follow all applicable laws, regulations and rules relating to the transportation of the material

 XV. REGULATORY INFORMATION

 15.1 FEDERAL/NATIONAL COMPREHENSIVE ENVIRONMENTAL RESPONSE. COMPENSATION. AND LIABILITY ACT OF 1980 SECTION 103 (CERCLA) The following components of this product are specifically listed as hazardous substances in 40 CFR 302.4 (unlisted hazardous substances are not identified) and are present at levels which could require reporting: None. SUPERFUND AMENDMENTS AND REAUTHORIZATION ACT OF 1986 (SARA) TITLE Ill SECTIONS 302 AND 304 The following components of this product are listed as extremely hazardous substances in 40 CFR Part 355 and are present at levels which could require reporting and emergency planning: None. SUPERFUND AMENDMENTS AND REAUTHORIZATION ACT OF 1986 (SARA) TITLE Ill SECTION 313 The following components of this product are listed as toxic chemicals in 40 CFR 372.65 and are present at levels which could require reporting and customer notification under Section 313 and 40 CFR Part 372: This product does not contain toxic chemicals at levels that require reporting under the statute.    SUPERFUND AMENDMENTS AND REAUTHORIZATION ACT OF 1986 (SARA) TITLE Ill SECTIONS 311 AND 312Delayed Hazard: YesFire Hazard: YesImmediate Health Hazard: YesReactive Hazard: NoSudden Release of Pressure Hazard: No TOXIC SUBSTANCES CONTROL ACT (TSCA) All components of this product are on the TSCA Inventory or are exempt from TSCA Inventory

requirements. EUROPEAN INVENTORY OF EXISTING COMMERCIAL CHEMICAL SUBSTANCES (EINECS)The component of this product is on the EINECS inventory.

 CEPA - DOMESTIC SUBSTANCES LIST (DSL)The component of this product is on the DSL.

 15.2 STATE/LOCAL 

PENNSYLVANIA (WORKER AND COMMUNITY RIGHT-TO-KNOW ACT) 

This product is subject to the Worker and Community Right-to-Know Act. The following components of this product are at levels that could require identification in the MSDS: 

Component CAS# Amount lsopropanol 67-63-0 <=100.0000% 

MASSACHUSETTS (HAZARDOUS SUBSTANCES DISCLOSURE BY EMPLOYERS) 

The following components of this product appear on the Massachusetts Substance List and are present at levels that could require identification in the MSDS:

Component CAS# Amountlsopropanol 67-63-0 <=100.0000%

 CALIFORNIA PROPOSITION 65 (SAFE DRINKING WATER AND TOXIC ENFORCEMENT ACT OF 1986)

 

This product contains no listed substances known to the State of California to cause cancer, birth defects

or other reproductive harm, at levels that would require a warning under the statute. CALIFORNIA SCAQMD RULE 443.1 (SOUTH COAST AIR QUALITY MANAGEMENT DISTRICT RULE 443.1 LABELING OF MATERIALS CONTAINING ORGANIC SOLVENTS)

 VOC: 785 g/l Vapor pressure 33 mmHg @ 200 C This section provides selected regulatory in formation on this product including its components. This is not intended to include all regulations. It is the responsibility of the user to know and comply with all applicable rules, regulations and laws relating to the product being used.  

XVI. OTHER INFORMATION  16.1 AVAILABLE LITERATURE AND BROCHURES: ADDITIONAL INFORMATION: There may be additional product safety information on this product, which may be obtained by calling your Injectorall Electronics Corporation Sales or Customer Service Contact. 16.2 SPECIFIC HAZARD RATING SYSTEM HMIS ratings for this product are: H-2 F-3 S-0 NFPA ratings for this product are: H-2 F-3 S-0

 These ratings are part of specific hazard communications program(s) and should be disregarded where individuals are not trained in the use of these hazard-rating systems. You should be familiar with the hazard communication applicable to your workplace. 16.3 RECOMMENDED USES AND RESTRICTIONS: FOR INDUSTRY USE

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