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WO2000002565A1 - Composition d'acetylsalicylate de sodium injectable et procede afferent - Google Patents

Composition d'acetylsalicylate de sodium injectable et procede afferent Download PDF

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Publication number
WO2000002565A1
WO2000002565A1 PCT/US1999/015434 US9915434W WO0002565A1 WO 2000002565 A1 WO2000002565 A1 WO 2000002565A1 US 9915434 W US9915434 W US 9915434W WO 0002565 A1 WO0002565 A1 WO 0002565A1
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WIPO (PCT)
Prior art keywords
dihydrate
water
sodium acetylsalicylate
acetylsalicylate
hydration
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Ceased
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PCT/US1999/015434
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English (en)
Inventor
Alexander Galat
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Individual
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Individual
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Application filed by Individual filed Critical Individual
Priority to EP99932352A priority Critical patent/EP1094819A1/fr
Priority to KR1020017000384A priority patent/KR20010079522A/ko
Priority to AU48677/99A priority patent/AU4867799A/en
Priority to CA002336789A priority patent/CA2336789A1/fr
Priority to HU0103287A priority patent/HUP0103287A2/hu
Priority to IL14080699A priority patent/IL140806A0/xx
Publication of WO2000002565A1 publication Critical patent/WO2000002565A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/017—Esters of hydroxy compounds having the esterified hydroxy group bound to a carbon atom of a six-membered aromatic ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/02—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen
    • C07C69/12—Acetic acid esters
    • C07C69/14—Acetic acid esters of monohydroxylic compounds
    • C07C69/145—Acetic acid esters of monohydroxylic compounds of unsaturated alcohols
    • C07C69/157—Acetic acid esters of monohydroxylic compounds of unsaturated alcohols containing six-membered aromatic rings

Definitions

  • 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 therap ⁇ 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 lbuprofen show no activity No other drug in the history of medicine has exhibited such an array of multifaceted therapeutic properties
  • Narcotics are often used to control arthritis pain.
  • narcotics are addictive, depress respiration and can produce other serious adverse reactions as osteoporosis peptic ulcers, convulsions, 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.
  • the potential advantages of aspirin in an injectable form have great pharmacological potential.
  • 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 sodium acetylsalicylate composition described in U.S. Patent 3,985,792 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.
  • an organic polar solvent generally a lower alkanol
  • 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.
  • 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.
  • 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.
  • 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.
  • FIGURE 1 is a schematic illustration of a device used in certain of the experiments disclosed herein;
  • FIGURE 2 is a kinetic plot for drying the dihydrate at 22° C
  • FIGURE 3 is a kinetic plot for drying the dihydrate at 40° C
  • FIGURE 4 is a kinetic plot for drying the dihydrate at 56.5° C.
  • FIGURE 5 is a comparative kinetic plot for drying the dihydrate at the above three indicated temperatures.
  • 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.
  • One hundred grams (lOOg.) of sodium acetylsalicylate dihydrate, prepared as described herein, and in fine paniculate 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 paniculate partially dehydrated sodium acetylsalicylate dihydrate platelets contents of the dish were briefly stirred. The vacuum was then reapplied for about another 4-5 hours.
  • Paniculate 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 obtaining suitably pure and stable anhydrous sodium acetylsalicylate.
  • 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 paniculate sodium acetylsalicylate dihydrate.
  • the product may be stirred, either intermittently or continuously by any suitable mechanical device.
  • 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 paniculate 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.
  • the product may be unstable because the removal/flow of water vapor is impeded.
  • 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.
  • 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.
  • 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.
  • 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.
  • anhydrous sodium acetylsalicylate may also be employed.
  • 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.
  • 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.
  • 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.
  • 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.
  • the beaker was set in a water bath at 40°-45° C. and the mixture was stirred until the effervescence ceased
  • the foam was controlled by adding small portions (in addition to the 8 ml) of toluene as needed.
  • Weight about 55 gm, nearly 50 % of theory.
  • 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.
  • seed crystals 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.
  • 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.
  • Steps #9 and #10 were conducted m a low-humidity environment with relative humidity at 15%.
  • 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.
  • 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).
  • the water-content may be determined by Karl Fisher or ER-assay, and was found to be about 0.1% (see following table.)
  • drying agents CaSO 4 , P 2 O 5 , MgSO 4 , 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.
  • Example 2 As the product is dehydrated, it tends to cake.
  • a fluidized-bed technique can prevent this.
  • 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.
  • HCl/KCl solution " The latter is prepared by dissolving 3.72 gm KC1 in distilled water, and adding 39 ml or 0.2 molar HC1; the mixture is diluted to 1 liter.
  • Stability samples may require different dilutions.
  • Each drop of 0.1% salicylic solution corresponds to 0.05 mg of salicylic acid.
  • Solubility Extremely soluble in water, and as follows,
  • the initial free-salicylate in all runs is ⁇ 0.05%.
  • 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 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.
  • 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.
  • the vial containing the sodium acetylsalicylate dihydrate was weighed and the loss of weight (equivalents of water) was plotted versus time (minutes).
  • the theoretical number of equivalents of water is 2.00.
  • the following tables summarize the drying curves for each temperature studied.
  • 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.
  • the sample here, sodium acetyl salicylate dihydrate
  • the drying agent in flask 24 is selected so as to effectively 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.
  • 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 is a plot of the resulting drying process, illustrating the asymptotic curve as the procedure forms the anhydrous sodium acetyl salicylate of this invention.
  • FIGURE 3 is a plot similar to Figure 2 of the resulting drying curve, again showing the asymptotic shape.
  • 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 Karl Fischer analysis is very useful for measuring the course of the conversion of the dihydrate to the anhydrous form of sodium acetylsalicylate.
  • a sample of partially dehydrated sodium acetylsalicylate dihydrate taken at the 1300 minute point during the course of drying a sample at 22.0°C (see, Table H), as expected, had a water content of 6.11 % by the Karl Fisher analysis).
  • 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.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne une composition injectable d'acétylsalicylate de sodium présentant une très grande pureté, qui est extrêmement stable et est acceptable d'un point de vue pharmaceutique pour être utilisée comme médicament injectable de façon sous-cutanée. L'acétylsalicylate de sodium anhydre est formé par élimination de vapeur d'eau de la forme dihydrate de l'acétylsalicylate de sodium à la même vitesse que celle à laquelle elle se forme. La durée de conservation d'un tel acétylsalicylate de sodium est d'au moins environ 2-3 ans, le produit présentant entre 97 % et 100 % de pureté après 3 ans à température ambiante. L'invention concerne également un procédé de fabrication de la composition d'aspirine injectable d'acétylsalicylate de sodium anhydre.
PCT/US1999/015434 1998-07-09 1999-07-09 Composition d'acetylsalicylate de sodium injectable et procede afferent Ceased WO2000002565A1 (fr)

Priority Applications (6)

Application Number Priority Date Filing Date Title
EP99932352A EP1094819A1 (fr) 1998-07-09 1999-07-09 Composition d'acetylsalicylate de sodium injectable et procede afferent
KR1020017000384A KR20010079522A (ko) 1998-07-09 1999-07-09 주사용 소디움 아세틸살리실레이트 조성물 및 그 제조방법
AU48677/99A AU4867799A (en) 1998-07-09 1999-07-09 Injectable sodium acetylsalicylate composition and method
CA002336789A CA2336789A1 (fr) 1998-07-09 1999-07-09 Composition d'acetylsalicylate de sodium injectable et procede afferent
HU0103287A HUP0103287A2 (hu) 1998-07-09 1999-07-09 Injekciózható nátrium-acetilszalicilát-készítmény és eljárás előállítására
IL14080699A IL140806A0 (en) 1998-07-09 1999-07-09 Injectable sodium acetylsalicylate composition and method

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US11293998A 1998-07-09 1998-07-09
US09/112,939 1998-07-09

Publications (1)

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WO2000002565A1 true WO2000002565A1 (fr) 2000-01-20

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PCT/US1999/015434 Ceased WO2000002565A1 (fr) 1998-07-09 1999-07-09 Composition d'acetylsalicylate de sodium injectable et procede afferent

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EP (1) EP1094819A1 (fr)
KR (1) KR20010079522A (fr)
AR (1) AR019764A1 (fr)
AU (1) AU4867799A (fr)
CA (1) CA2336789A1 (fr)
HU (1) HUP0103287A2 (fr)
IL (1) IL140806A0 (fr)
TR (1) TR200100024T2 (fr)
WO (1) WO2000002565A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001003774A3 (fr) * 1999-07-07 2002-03-21 Zoltan Dardai Composition pharmaceutique de traitement de la calcification
WO2018222583A1 (fr) * 2017-05-30 2018-12-06 Rho Pharmaceuticals, Llc Dépôt en flacon d'acide o-acétylsalicylique (aspirine) stable, stérile et cristallin
US11793748B1 (en) 2019-04-05 2023-10-24 Good Health, Llc Pharmaceutical compositions of aspirin for parenteral administration

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1097025A (en) * 1965-02-23 1967-12-29 Miles Lab Acetylsalicylate salts and processes for the preparation thereof
US3985792A (en) * 1971-12-23 1976-10-12 Alexander Galat Stable sodium acetylsalicylate and method for its manufacture
US4117603A (en) * 1976-12-28 1978-10-03 Smith Walton J High vacuum freeze-drying
WO1987005010A1 (fr) * 1986-02-20 1987-08-27 Pharmacontrol Corp. Production d'acetylsalicylate de sodium cristallin stable

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1097025A (en) * 1965-02-23 1967-12-29 Miles Lab Acetylsalicylate salts and processes for the preparation thereof
US3985792A (en) * 1971-12-23 1976-10-12 Alexander Galat Stable sodium acetylsalicylate and method for its manufacture
US4117603A (en) * 1976-12-28 1978-10-03 Smith Walton J High vacuum freeze-drying
WO1987005010A1 (fr) * 1986-02-20 1987-08-27 Pharmacontrol Corp. Production d'acetylsalicylate de sodium cristallin stable

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001003774A3 (fr) * 1999-07-07 2002-03-21 Zoltan Dardai Composition pharmaceutique de traitement de la calcification
WO2018222583A1 (fr) * 2017-05-30 2018-12-06 Rho Pharmaceuticals, Llc Dépôt en flacon d'acide o-acétylsalicylique (aspirine) stable, stérile et cristallin
US10959955B1 (en) 2017-05-30 2021-03-30 Rhoshan Pharmaceuticals, Inc. In-vial deposition of a stable, sterile and crystalline o-acetyl salicylic acid (aspirin)
US11096949B2 (en) 2017-05-30 2021-08-24 Rhoshan Pharmaceuticals, Inc. In-vial deposition of a stable, sterile and crystalline O-acetyl salicylic acid
US11911400B1 (en) 2017-05-30 2024-02-27 Rhoshan Pharmaceuticals, Inc. In-vial deposition of a stable, sterile and crystalline O-acetyl salicylic acid (aspirin)
US12048708B2 (en) 2017-05-30 2024-07-30 Rhoshan Pharmaceuticals, Inc. In-vial deposition of a stable, sterile and crystalline o-acetyl salicylic acid (aspirin)
US11793748B1 (en) 2019-04-05 2023-10-24 Good Health, Llc Pharmaceutical compositions of aspirin for parenteral administration

Also Published As

Publication number Publication date
AR019764A1 (es) 2002-03-13
HUP0103287A2 (hu) 2001-12-28
AU4867799A (en) 2000-02-01
KR20010079522A (ko) 2001-08-22
IL140806A0 (en) 2002-02-10
TR200100024T2 (tr) 2001-06-21
EP1094819A1 (fr) 2001-05-02
CA2336789A1 (fr) 2000-01-20

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