EP0297107A1 - Production of stable crystalline sodium acetylsalicylate - Google Patents
Production of stable crystalline sodium acetylsalicylateInfo
- Publication number
- EP0297107A1 EP0297107A1 EP87901924A EP87901924A EP0297107A1 EP 0297107 A1 EP0297107 A1 EP 0297107A1 EP 87901924 A EP87901924 A EP 87901924A EP 87901924 A EP87901924 A EP 87901924A EP 0297107 A1 EP0297107 A1 EP 0297107A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- aspirin
- sodium
- crystals
- usp
- solution
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/28—Preparation of carboxylic acid esters by modifying the hydroxylic moiety of the ester, such modification not being an introduction of an ester group
Definitions
- the present invention relates to a process for preparing sodium aspirin in a form that is free-flowing and stable at ambient temperature for extended periods of time. More particularly, the invention relates to the preparation
- an analgesic, anti-arthritic, anti-inflammatory, and anti-pyretic composition containing dry crystalline sodium aspirin which can be formulated into convenient dosage forms.
- aspirin is the drug of choice for the treatment of arthritis and common aches and pains.
- aspirin the chemical name of which is acetylsalicylic acid
- gastric mucosal irritation gastric distress and intolerance, which are due to the acidic nature of aspirin and to its poor water solubility.
- aspirin tablets disintegrate, often leaving insoluble particles which can lodge in and irritate the gastric mucosa. Because of the irritation caused by such conventional aspirin, many individuals taking aspirin suffer gastric distress.
- Acetaminophen (as present in Tylenol, Datril, etc.) is sometimes taken instead of aspirin to avoid gastric distress, but is ineffective in reducing inflammation.
- Arthritis patients who suffer from inflammation but cannot tolerate aspirin must thus turn to other, more potent drugs which are generally less pharmacologically established.
- Bufferin, Excedrin and Anacin are available today. These compositions neutralize some gastric acid but do not eliminate the basic problem— insoluble aspirin particles which cause gastric mucosal irritation.
- Aspirin can be formulated into enteric coated tablets, but such formulations merely shift the locus of irritation to the duodenal mucosa and other regions of the gastrointestinal tract, where the tablets disintegrate. Moreover, the enteric coating delays the desired effect of the aspirin's activity, and there is always the risk of premature release of the aspirin in the stomach resulting from perforations in the enteric coating. More effective are compositions similiar to Alka- Seltzer, which produce a soluble form of aspirin upon contact with water that is readily assimilated by the body and which therefore does not cause localized irritation. But the way such compositions accomplish this objective is not very efficient.
- the sodium salt of aspirin formed when Alka-Seltzer dissolves in water would be useful in and of itself as an analgesic if such aspirin could be isolated free of excess bicarbonate and formulated into a convenient dosage form, e.g., tablets, but severe problems of stability make the attainment of both of these objectives difficult.
- the preparation of sodium aspirin in aqueous solution is relatively easy, but removal of the water to yield sodium aspirin in solid form is difficult. This is because the acetate group of sodium aspirin tends to hydrolyze to produce undesirable quantities of sodium salicylate and other non-aspirin species during the dehydration step.
- Sodium aspirin can be prepared by a variety of methods, e.g., reacting aspirin with sodium carbonate in the presence of small amounts of organic solvents such as methyl and ethyl formate, methyl and ethyl acetate, and the like.
- the sodium aspirin prepared by this method fuses after prolonged storage due to the formation of acetic and salicyclic acids and their salts.
- Sodium aspirin can also be prepared by reacting aspirin with sodium bicarbonate in aqueous solution.
- distillation or crystallization must be used " to recover the sodium aspirin product. Distillation has several obvious disadvantages, the most apparent being the energy costs, failure to remove impurities and the tendency of the sodium aspirin to undergo hydrolysis during the distillation, which results in low yields of an impure product having poor stability.
- Granular, plate-like, free-flowing crystals of sodium aspirin have been produced by Galat (U.S. Patent 3,985,792) in a process involving precipitation of the compound from aqueous solution and removal of the water of hydration.
- the present invention overcomes the aforementioned difficulties in a process involving the preparation of a solution of sodium aspirin by reacting USP aspirin with USP sodium bicarbonate in water, preferably distilled or deionized water, containing an aliphatic alcohol having 3 to 5 carbon atoms in the molecule.
- Sodium aspirin in the form of plate-like crystals of dihydrate is recovered by crystallization from solution at a reduced temperature while intermittently adding plate-like seed crystals recovered from a previous batch or prepared specifically for the purpose of facilitating the crystallization of the dihydrate.
- the crystallizaion is complete, the cystals are separated from the mother liquor and are dried under careful conditions in a fluidized bed granular dryer.
- Fig. 1 is a schematic view of the type of apparatus used for the preparation sodium aspirin.
- Fig. 2 is a schematic view of a type of commercially available fluid bed dryer for drying the sodium aspirin dihydrate to form a stable, anhydrous sodium aspirin.
- the first step in the process of the present invention is the preparation of sodium aspirin as the dihydrate.
- a quantity of USP grade aspirin powder preferably having a particle size of about 400 to 500 microns (35 to 40 mesh) is reacted with a 5 to 15% 0 stoichiometric excess, preferably a 7 to 14% excess, of sodium bicarbonate in the presence of a quantity of water equal to about 0.4 to 0.45 liter per kilogram of aspirin.
- This water contains from about 15 to 20 volume percent, preferably about 17 to 20 volume percent, of an alcohol 5 having 3 to 5 carbon atoms, preferably isopropyl alcohol.
- the reaction can also be carried out directly in a crystallizer of the type shown in Fig. 1.
- the crystallizer 10 is equipped with an anchor or paddle-type agitator 11 driven by a variable-speed motor (not shown) atop drive 5 shaft 12. Any baffling 13 should be such that the baffles do not contact the liquid at this point to prevent splashing of the liquid onto the walls of the crystallizer which would otherwise result in the formation of undesirable acicular or needle-like (non-hydrated) crystals.
- the solution is 0 stirred slowly and the crystallizer is cooled to approximately 6 * C by means of cooling jacket 14. The temperature is monitored through thermocouple well 15.
- the crystals are separated from the mother liquor, preferably in a basket centrifuge.
- the crystals are washed with a solution of 5 volume percent of distilled or deionized water in isopropyl alcohol.
- the crystals of sodium aspirin dihydrate recovered from the centrifuge are transferred to a fluidized bed dryer of 1100-liter bowl size 20 modified for incremental addition of the crystals as shown in Fig. 2.
- the crystals are fed to the dryer 20 equipped with bowl 24 through funnel 21 at a rate of about 400 to 500 kg, preferably 450-475 kg, over a period of approximately one-half hour.
- Air at a rate sufficient to fluidize the bed of crystals in dryer 20, is passed through the dryer beginning at inlet 22 at an inlet temperature as low as possible to maintain an air temperature at the exit 23 such that the relative humidity at the outlet is below 60% so as to avoid hydrolysis. This depends on the relative humidity of the outside air, but normally requires an initial temperature of about 35*C.
- the temperature of the inlet air is increased to 60 # C and the temperature of the outlet air approaches 60*C.
- the drying is continued until the product exhibits a water content of less than 0.3% by weight as can be determined by means known to those skilled in the art.
- the invention is illustrated in the following nonli iting examples.
- Example I This example illustrates a typical method of preparing the seed crystals that are to be used for addition to the crystallizer.
- a quantity (5 grams) of USP sodium aspirin (anhydrous) is dissolved in a mixture of 2.5 grams of water and 7.5 grams of isopropyl alcohol and the solution is stored in a refrigerator at a temperature of about 4 ⁇ C until several crystals are formed.
- the well-formed, plate like, needle-free crystals can then be used to seed a laboratory- scale glassware batch to make a sufficient quantity for production scale runs.
- Example II A quantity of sodium aspirin dihydrate is prepared by reacting 841 kg of USP grade aspirin having a particle size of 420 microns (40 mesh) with 420 kg of USP grade sodium bicarbonate in the presence of 377 liters of water containing 65 liters of isopropyl alcohol. When the reaction is complete, a quantity (1400 liters) of isopropyl alcohol is added to the reaction mixture and stirring was continued for several minutes. The mixture is then filtered and the filtrate is introduced into a crystallizer of the type shown in Fig. 1.
- the crystallizer 10 is equipped with an agitator blade 11 driven by a variable-speed motor (not shown) .
- the crystallizer is equipped with a jacket 14 for cooling the liquid to facilitate crystallization.
- a baffle 13 is positioned at the side of the crystallizer.
- the crystallizer is equipped with a thermocouple in a well 15 to record the temperature as crystallization progresses. After the solution was added to the crystallizer, the agitator blade is rotated at approximately 15 rpm to assure that no splashing of the liquid onto the walls occurs.
- a cooling medium at approximately -20*C is fed to the jacket of the crystallizer and the solution is cooled to 6'C.
- the slurry is centrifuged in a basket-type centrifuge to separate the crystals from the supernatent liquor.
- the crystals are washed in the centrifuge with 50-liter quantities of a mixture of isopropyl alcohol containing approximately 5 percent by volume distilled water.
- Example III This example illustrates a typical drying operation.
- the drying is carried out in a commercially available Glatt WDG-UD 300 dryer with a 1100-liter bowl capacity.
- the dryer was modified in the manner shown in Fig. 2.
- the dryer 20 is equipped with a funnel element 21 so that the material can be continuously sucked into the drying chamber.
- the product bowl 24 is inserted into the chamber and the material from the centrifuge is fed into the dryer.
- a total 465 kg of wet cake was fed to the dryer over a period of approximately one-half hour.
- the material was fed through the feed funnel with the fan open and the flap set so that the material can be sucked into the chamber and fluidized.
- the dryer is operated in this manner because, in addition to 15.1 percent water of hydration contained within the molecule, the crystal is wet with approximately 5 to 6 percent of isopropyl alcohol and 0.5 percent water. Adding the crystals over a period of one-half hour avoids the possibility of the concentration of isopropyl alcohol in dryer reaching explosive limits.
- the temperature of the air entering the dryer is maintained as indicated hereinabove to prevent hydrolysis of the product.
- the temperature of the inlet air is increased to 60*C.
- samples of the material are taken for determination of the water content.
- the dryer is operated at a temperature of 60*C until it was found that the material taken from the bowl has a water content of 0.3 percent or less. The dryer was then shut down and the product recovered.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Procédé de préparation d'acétylsalicylate de sodium (aspirine de sodium) sous la forme de cristaux en plaquettes, consistant à préparer une solution d'aspirine de sodium, à transférer la solution dans un cristalliseur, à agiter la solution tout en refroidissant le cristalliseur, à ajouter par intermittence des cristaux de précipitation pendant l'étape de cristallisation, à séparer les cristaux de la liqueur mère et à sécher le produit obtenu dans un sécheur à lit fluidisé.Process for the preparation of sodium acetylsalicylate (sodium aspirin) in the form of platelet crystals, consisting in preparing a solution of sodium aspirin, transferring the solution to a crystallizer, stirring the solution while cooling the crystallizer, intermittently adding precipitation crystals during the crystallization step, separating the crystals from the mother liquor and drying the product obtained in a fluid bed dryer.
Description
Claims
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US83014186A | 1986-02-20 | 1986-02-20 | |
US830141 | 1986-02-20 |
Publications (2)
Publication Number | Publication Date |
---|---|
EP0297107A1 true EP0297107A1 (en) | 1989-01-04 |
EP0297107A4 EP0297107A4 (en) | 1989-06-14 |
Family
ID=25256395
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP19870901924 Withdrawn EP0297107A4 (en) | 1986-02-20 | 1987-02-20 | Production of stable crystalline sodium acetylsalicylate. |
Country Status (7)
Country | Link |
---|---|
EP (1) | EP0297107A4 (en) |
CN (1) | CN1020895C (en) |
AU (1) | AU7122187A (en) |
CA (1) | CA1293738C (en) |
HU (1) | HU198440B (en) |
WO (1) | WO1987005010A1 (en) |
ZA (1) | ZA871148B (en) |
Families Citing this family (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU4867799A (en) * | 1998-07-09 | 2000-02-01 | Alexander Galat | Injectable sodium acetylsalicylate composition and method |
WO2013049294A1 (en) * | 2011-09-29 | 2013-04-04 | Alere San Diego, Inc. | 2-hydroxyhippuric acid analogs, and methods for their synthesis and use |
CN102911076B (en) * | 2012-11-07 | 2015-09-02 | 河北冀衡(集团)药业有限公司 | Treatment unit after acetparaminosalol phenol treating and treatment process thereof |
CN106674036B (en) * | 2016-12-22 | 2018-08-14 | 河南中医学院 | The method that non-organic solvent method synthesizes di-lysine-aspirin |
US11793748B1 (en) | 2019-04-05 | 2023-10-24 | Good Health, Llc | Pharmaceutical compositions of aspirin for parenteral administration |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3985792A (en) * | 1971-12-23 | 1976-10-12 | Alexander Galat | Stable sodium acetylsalicylate and method for its manufacture |
-
1986
- 1986-04-24 CN CN86102837A patent/CN1020895C/en not_active Expired - Fee Related
-
1987
- 1987-02-16 CA CA000529849A patent/CA1293738C/en not_active Expired - Lifetime
- 1987-02-17 ZA ZA871148A patent/ZA871148B/en unknown
- 1987-02-20 HU HU871540A patent/HU198440B/en not_active IP Right Cessation
- 1987-02-20 AU AU71221/87A patent/AU7122187A/en not_active Abandoned
- 1987-02-20 WO PCT/US1987/000376 patent/WO1987005010A1/en not_active Application Discontinuation
- 1987-02-20 EP EP19870901924 patent/EP0297107A4/en not_active Withdrawn
Non-Patent Citations (2)
Title |
---|
No relevant documents have been disclosed. * |
See also references of WO8705010A1 * |
Also Published As
Publication number | Publication date |
---|---|
CA1293738C (en) | 1991-12-31 |
ZA871148B (en) | 1987-10-28 |
EP0297107A4 (en) | 1989-06-14 |
CN86102837A (en) | 1987-09-02 |
AU7122187A (en) | 1987-09-09 |
WO1987005010A1 (en) | 1987-08-27 |
HU198440B (en) | 1989-10-30 |
CN1020895C (en) | 1993-05-26 |
HUT46883A (en) | 1988-12-28 |
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Legal Events
Date | Code | Title | Description |
---|---|---|---|
PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
|
17P | Request for examination filed |
Effective date: 19880818 |
|
AK | Designated contracting states |
Kind code of ref document: A1 Designated state(s): AT BE CH DE FR GB IT LI LU NL SE |
|
A4 | Supplementary search report drawn up and despatched |
Effective date: 19890614 |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: THE APPLICATION HAS BEEN WITHDRAWN |
|
18W | Application withdrawn |
Withdrawal date: 19900215 |
|
R18W | Application withdrawn (corrected) |
Effective date: 19900215 |
|
RIN1 | Information on inventor provided before grant (corrected) |
Inventor name: DUCATMAN, FRED, P. |