Acetyl salicylic acid, preparation

The existence of two polymorphs was reported for a NO-releasing derivative of acetyl-salicylic acid [28]. Selection crystallization of one form or the other was achieved from a number of solvent systems (14 solvents and 3 preparative methods), but several systems were identified that yielded mixtures of the two forms. The single-crystal structure of Form I was reported, but the habit of the Form II crystals precluded their characterization. The transition point of the two forms was calculated from intrinsic dissolution data to be higher than the melting points of both polymorphs and thus the two forms bear a monotropic relationship. 

The second method is when TLC is used to compare an unknown substance with the pure substance. For example, an aspirin sample prepared in the laboratory could be compared with a pure sample of aspirin. Three spots are made on the baseline of the TLC plate one of the laboratory-prepared aspirin, a second of a sample of pure acetyl salicylic acid, and a third of a sample of both the laboratory and the pure samples (a co-spot). Once the plate has been developed, analysis is carried out by comparison. If the co-spot shows only one spot, it can be concluded that the laboratory-synthesised sample is exactly the same compound as the pure substance. 

Dosages and routes of administration Codeine is used orally in single doses of 30 to 60 mg up to a total dose of 240 mg per day for pain relief. Codeine is used in the form of different salts such as hydrochloride, phosphate and sulfate. To increase the duration of action, slow-release preparations have been developed. Codeine is often combined with other analgesics e.g. acetyl salicylic acid or paracetamol. For cough inhibition lower doses are sufficient. 

Fig. 25 Differences observed in the deformation of substances during tableting. Potassium chloride at low (A) and high com-pressional forces (B), pellets prepared by spherical agglomeration in a tablet surface (C) and in the inner part of a broken tablet (D), surface of an acetyl salicylic acid (ASA) tablet containing 10% sodium carbox5methyl starch (E) and the same surface after moistening with a finger (F). (From Ref...

Aspirin (acetyl salicylic acid) is a well-known analgesic. Processes for preparing aspirin are described in U.S. 3,235,583, U.S. 3,373,187 (both to Norwich Pharmacal), and U.S. 2,890,240 (to Monsanto). Estimate the cost of production by each route. 

Landin M, Perez-Marcos B, Casalderrey M, et al. Chemical stability of acetyl salicylic acid in tablets prepared with different commercial brands of dicalcium phosphate dihydrate. Int J Pharm 1994 107 247-249. 

Acetic anhydride is often used to prepare acetate esters from alcohols and AT-substituted acetamides from amines. For example, aspirin (acetyl-salicylic acid) is prepared commercially by the acetylation of o-hydroxy-benzoic acid (salicylic acid) with acetic anhydride. Acetaminophen, a drug used in over-the-counter analgesics such as Tylenol, is prepared by reaction of p-hydroxyaniline with acetic anhydride. Note that the more nucleophilic -NH2 group reacts, rather than the less nucleophilic -OH group. 

Caffeine is often present in pharmaceutical preparations in combination with other drugs, such as acetyl salicylic acid, phenacetin,antipyrin, etc. Because classical analytical techniques (e.g. spectrophotometric and colourimetric methods) can be quite time consuming and leave much to be desired in accuracy and precision, gas chromatography has been quite extensively applied for the analysis of such multicomponent preparations. 

It may be prepared by the esterification of acetyl salicylic acid and paracetamol with the elimination of a mole of water. 

In the search for less irritating, but still effective, derivatives of salicylic acid, chemists at the Bayer division of I. G. Farben in Germany prepared acetyl-salicylic acid in 1883 and gave it the name aspirin, a word derived from the German spirsaure (salicylic acid), with the initial a for the acetyl group ... 

In the preparation of many pharmaceuticals we know that some components in the formulation are not compatible. For instance, if we mix acetyl salicylic acid with sodium bicarbonate in solution, there is an immediate reaction and a vigorous release of carbon dioxide. Nevertheless, it might be of interest to freeze-dry them together in order to have instant sparkling aspirin, but this is not possible and the only way around this is to compact the products together in the dry state. The resulting tablet is not very stable and it takes a relatively long time to get back into solution. 

CONVERSION OF ACID ANHYDRIDES INTO ESTERS Acetic anhydride is often used to prepare acetate esters from alcohols. For example, aspirin (acetyl-salicylic acid) is prepared commercially by the acetylation of o-hydroxy-benzoic acid (salicylic acid) with acetic anhydride. 

It should be emphasised that salicylic acid can be readily acetylated by Method 1, and that the above preparation of acetylsalicyclic acid is given solely as an illustration of Method 2. To employ Method 1, add 10 g. of salicylic acid to 20 ml. of a mixture of equal volumes of acetic anhydride and acetic acid, and boil gently under reflux for 30 minutes. Then pour into about 200 ml. of cold water in order to precipitate the acetylsalicylic acid (11 g.) and finally recrystallise as above. Method 2, however, gives the purer product. 

The best known aryl ester is O-acetylsalicylic acid, better known as aspirin. It is prepared by acetylation of the phenolic hydroxyl group of salicylic acid ... 

Essentially, all methods of synthesis are variations of the reaction of acetylchloride, acetic anhydride or ketene11 with salicylic acid using a variety of catalysts such as pyridine12 or sulfuric acid13 and reaction conditions (c.f. 14). The preparation of aspirin labeled with a i4c iaj-,eie(j acetyl group has also been reported.15 Efforts to improve the commercial processes continue to the present day. 

Salicylic acid is manufactured on a large scale. In the dye industry it serves for the production of valuable azo-dyes which exhibit great fastness. To some extent these dyes are applied to mordanted fibres. In addition, the acid and its derivatives are widely used in pharmacy. Being a phenolcarboxylic acid it has a powerful disinfecting action (preservative). It has further proved itself an important antirheumatic and an analgetic. The derivative in which the phenolic hydroxyl group is acetylated (aspirin) has become especially popular. The first medicament of the series was the phenyl ester of salicylic acid, salol, which is produced as a by-product in the technical process. The preparation of salicylaldehyde has been described above (p. 235). 

Lautermann prepared it synthetically from phenol in 1860. Acetylsalicylic acid was first prepared in 1853 by Gerhardt but remained obscure until Hoffmann discovered its pharmacologic activities in 1899. It was first used in medicine by Dreser, who named it aspirin by taking the a from acetyl and adding it to spirin, the old name for salicylic acid. 

Various processes involve acetic acid or hydrocarbons as solvents for either acetylation or washing. Normal operation involves the recovery or recycle of acetic acid, any solvent, and the mother liquor. Other methods of preparing aspirin, which are not of commercial significance, involve acetyl chloride and salicylic acid, salicylic acid and acetic anhydride with sulfuric acid as the catalyst, reaction of salicylic acid and ketene, and the reaction of sodium salicylate with acetyl chloride or acetic anhydride. 

A number of 5//-l,4-benzodioxepin-ones and -diones have been prepared (72HC(26)319, p. 339). The reaction of the sodium salt of salicylic acid with 2-chloroethanol gave (269) (75BSF(2)277) and treatment of the methyl ester of 2-acetyl-6-chloro-3,5-dimethoxyphenoxyacetic acid with 3M hydrochloric acid gave (270). The dione (271) was prepared by heating 2-carboxy-5,6-dimethoxyphenoxyacetic acid in acetic anhydride and (272) was prepared from chloroacetylsalicylic acid. 

A number of 2,3-fused chromones have been prepared from ethyl chloroformate and acetylsalicylic acid, a source of the mixed anhydride of formic and salicylic acids, and piperidinocycloalkenes (69JCS(C)935). A plausible mechanism is outlined in Scheme 165. It has not proved possible to isolate the chromanone (460) but the formation of 3-acetyl-2-methylchromone from 2-pyrrolidinopropene lends support to the intermediacy of the chromanone. The migration of the acyl group from oxygen to carbon is supported by the synthesis of 3-benzoyl-2-methylchromone rather than 3-acetylflavone from benzoylsalicylic acid and the pyrrolidinopropene. 

Preparations from plant materials containing salicylate have been used to treat pain and fever (Stone, 1763) from ancient times into the nineteenth century, when synthetic salicylic acid was synthesized in Germany and used for the same purposes. Acetyl salicylate, aspirin, synthesized as a prodrug for salicylate, was introduced by Bayer in 1899 (Dreser, 1899) and is still widely used to treat pain, fever, and inflammation. In low doses aspirin is also used by many to reduce the incidence of heart attacks by an antithrombotic effect (Antiplatelet Trialists Collaboration, 1994). Eventually, other drugs with therapeutic effects similar to those of aspirin were introduced, including indomethacin, ibuprofen, and naproxen. These... 

Salix alba, S.viminalis) contain salicylic acid derivatives in their bark. Preparations of willow bark were used from antiquity in the 19th century, salicylic acid was isolated as the active principle of this folk remedy. This simple acid still enjoys use as an external agent (keratolytic action) but is no longer taken orally for the treatment of pain, fever, and inflammatory reactions. Acetylation of salicylic acid (introduced around 1900) to yield acetylsali-cylic acid (ASA, Aspirin ) improved oral tolerability. 

The isolation of strychnine (1), morphine (2), atropine (3), colchicine (4), and quinine (5) in the early 1800s from the commonly used plants and their use for the treatment of certain ailments might constitute the early idea of pure compounds as drugs. E. Merck isolated and commercialized morphine (2) as the first pure natural product for the treatment of pain (1-3). Preparations of the Willow tree have been used as a painkiller for a long period in traditional medicine. Isolation of salicylic acid (6) as the active component followed by acetylation produced the semisynthetic product called Aspirin (7) that was commercialized by Bayer in 1899 for the treatment of arthritis and pain (4). 

A) Acetylsalicylic Add (Aspirin). Salicylic acid and its derivatives were among the first synthetic organic compounds to be used for therapeutic purposes. The sodium salt of salicylic acid, the methyl and phenyl esters, and the acetyl derivative of salicylic acid are extensively used to diminish pain (as analgesics) and to reduce the temperature of the body (as antipyretics). The most widely used is the acetyl derivative which is sold under the name aspirin. Salicylic acid is prepared industrially by the carbonation of sodium phenoxide, at 180-200° at atmospheric pressure or 120-130° at a pressure of a few atmospheres. 

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