CA2413901C - An acid washed adsorbent carbon used in a method for the purification of acetaminophen - Google Patents

Abstract

An acid washed adsorbent carbon which has been contacted with an aqueous solution of a reducing sulfite is provided which may be used in a method for purifying a crude N-acetyl-para-aminophenol (APAP) containing color bodies or their precursors, the method comprising: a) forming a hot aqueous solution of the crude APAP; and b) subsequently contacting the hot solution with an acid washed adsorbent carbon, e.g., an activated carbon, which acid washed carbon, prior to such contact, has been pretreated by contacting it with an aqueous solution of a reducing sulfite.

Description

PURIFTCATION OF ACETAMINOPHEN
This is a divisional application of Canadian Patent Application Serial No. 2,053,604, filed on October 17, 1991 (the parent application).
BACKGROUND OF THE INVENTTON
Field of the Invention This invention relates to an improved method for the purification of N-acetyl-para-aminophenol (APAP), also known as acetaminophen. APAP is a well-known over-the-counter analgesic and anti-pyretic agent.
The subject matter of this divisional application is an acid washed adsorbent carbon which has been contacted with an aqueous solution of a reducing su_Lfite. This product is used in the method for the purification of APAP
disclosed herein, and claimed in the parent application. It should be understood that the expression "the invention's and the like as used herein encompasses the subject matter of both the parent and this divisional application.

Oescri.ption of Related Art The following prior art references are disclosed in acc-s~rdance with t:ne terms of 37 CFR 1.56, 1.97 and 1.98.
U.S. patent No. 3,042,719, is cued July 3, 7.962 to Hahn et al., discloses the purification of crude discolored APAP by acidifying zin aqueous solution of the APAP with a mineral acid, filtering the solution while hot, and cooling the filtrate while adding an alkaline reducing sulfite, e.g., sodium hydrosulfite (sodium dithionite). A
"decolorizing°' carbon may be added to the hot solution.
U.S. Pate°;~t No. 3,113,150, issued December 3, 1963 to Young, teaches the preparation of "pure" APAP by adding-acetic anhydxide to a mixture of p--aminophenol and water, cooling the reaction mixture to precipitate the APAP, filtering to remove excess acetic acid, neutralizing the wet APAP with ammonium hydroxide, and agitating the resulting solution with carbon black.
U.S. Patent No. 3,748,358, issued July 24, 1973 to Baran, discloses the purification of APAP by treating it la 1 i:n aqueous solution with carbon which has been 2 preliminarily treated with an acidic solution.

3 U.S. Patent No. 3,781,354, issued December 25, 4 1973 to Kosak, teaches the purification of APAP by treating it in hot aqueous solution with ferric chloride and 6 adsorbing the colored by-product on activated carbon.
7 U.S. Patent No. 4,524,217, issued June 18, 1985 8 to Davenport et al., teaches an integrated process for the 9 production of APAP comprising acetylating phenol by a Friedel-Crafts reaction, or subjecting phenyl acetate to a 11 Fries rearrangement to produce 4-hydroxyacetophenone 12 (4-HAP), reacting the 4-HAP with hydroxylamine. or a.
13 hydroxylamine salt to form 4-HAP oxime, and subjecting the 14 latter oxime to a Beckmann rearrangement to farm APAP.
Additional Background Information 16 In the manufacture of APAP by any of the known 17 methods, it has been found that there is a tendency for 18 color bodies and color body precursors to form which cause 19 the crude product to have or to develop subsequently an undesirably colared appearance. Because of this, various 21 methods haire been developed for the purification of APAP, 22 which remove color bodies in addition to other impurities, 23 such that the purified product has a substantially pure 24 White appearance. These methods often include the addition to a hot aqueous solution of APAP containing color bodies 26 of an adsorbent carbon, which is a well-known decolorizing 1 agent. Some of these methods are described in the 2 disclosures of several of the previously cited references.
3 ~/ It has been found that a disadvantage of 4 decolorizing APAP by contacting a hot aqueous solution of the crude APAP with an adsorbent carbon is that certain 6 impurities appear for the first time or increase as a 7 result of such treatment, which impurities were not present 8 previously, i.e., in the crude APAP before purification.
9 In view of the fact that the main use for APAP is as a pharmaceutical, the presence of these impurities must be 11 kept to a very low practical maximum, either by preventing 12 their formation, or removing the bulk of them subsequent to 13 the carbon treatment.

In accordance with this invention, a crude ARAP
16 containing undesirable color bodies or their precursors is 17 subjected to a purification treatment comprising the steps 18 of forming a hot aqueous solution of the crude APAP, and 19 subsequently contacting said hot solution with an acid washed-adsorbent carbon which, prior to said contact, has 21 been pretreated with an aqueous solution of a reducing 22 sulfite. It has been found that the treatment of the acid 23 washed carbon with the aqueous reducing sulfite solution 24 substantially reduces the formation of certain impurities which are observed to form during the treatment of the hot 26 APAP solution with carbon which has not been treated with the aqueous reducing sulfite solution. The impurities formed during the treatment of APAP with carbon which has not been sulfite treated are different from other impurities present in the crude APAP before carbon treatment, which other impurities do not increase as a result of the carbon treatment, as indicated by liquid chromatographic analysis.
According to one aspect of this divisional application, there is provided an acid washed adsorbent carbon which has been contacted with an aqueous solution of a reducing sulfite.
DESCRIPTIVN OF PREFERRED EMBODIMENTS
The aqueous solution of APAP containing color bodies which is subjected to carbon treatment will in most cases contain at least about 4 wt.~ of APAP and the.
solution will be at least hot enough to dissolve the APAP
substantially completely, e.g., at least about 7o°C and up to the boiling point of the solution. The method of the invention is useful in the preparation of a relatively pure decolorized APAP regardless of the manufacturing process used to produce the APAP, since such method accomplishes the reduction of impurities, formed during treatment of the APAP with acid washed carbon which has not been pretreated with reducing sulfite, no matter which manufacturing process is used. Thus, the APAP may be produced, for example, by the process illustrated in the examples of previously cited U.S. Patent No. 4,524,21 as summed up in the foregoing description of the disclosure of that patent, ~r by the previously developed process ~of acetylating N-?098 1 para-aminophenol with acetic anhydride, as described, for 2 example, in previously cited U.S. Patent No. 3,113,150.
3 The acid washed adsorbent carbon of this 4 invention defines an art-recognized group of materials and is a cammodity of commerce. Such a carbon has a relatively 6 large surface area available .for the adsorption of 7 impurities and is preferably one of the class of materials 8 known as activated carbon or activated charcoal. The 9 feature of the carbon being '°acid washed" is well-known in the art and may be accomplished as described, for example, 11 in previously cited U.S. Patent No. 3,748,858.
12 The reducing sulfite used to pretreat the acid 13 washed carbon may be any water soluble reducing sulfite 14 such as alkali metal, and ammonium reducing sulfites, e.g., sodium, potassium, and ammonium dithionites, 16 metabisulfites, sulfites, and bisulfites. Preferably the 17 sulfite reducing agent is a dithionite, and most preferably 18 sodium dithionite. In pretreating the acid washed carbon 19 with reducing sulfite, the carbon is shaken With a sufficient quantity of an aqueous solution of the sulfite 21 containing-, for example, about 0.1 to 5 wt.% of the 22 sulfite, to completely wet the carbon. The carbon may then 23 be allowed to stand in such wetted condition, e.g., 24 submerged in the solution, for a period of at least 1/2 hour, preferably at least 1 hour. In some cases, it may be 26 desirable to allow the wetted carbon to stand for at least 27 24 hours or longer.

1 After pretreatment with a reducing sulfite, the 2 carbon is contacted with the hot aqueous APAP solution.
3 The amount of carbon used is not critical but is generally 4 such that the weight ratio of APAP to carbon (APAP:carbon) is at least about 2:1 and may be as high as about 200:1.

6 The APAP solution is then agitated with the pretreated 7 carbon, preferably under reflux, for a period of at least 8 about 1 min. 1'he solution is then filtered to rem~ve the 9 carbon and cooled to crystallize out the APAP. In some cases, it may be advantageous to conduct an initial 11 crystallization of the APAP from hot aqueous solution 12 without any carbon treatment, followed by a second.

13 crystallization from a hot aqueous solution which has been 14 subjected to a carbon treatment using a reducing sulfite pretreated acid washed carbon in accordance with this 16 invention. It may also be advantageous fox the purpose of 17 reducing the impurities to the lowest feasible level, to 18 dissolve some reducing sulfite, e.g., from about .05 to 19 about .5 wt.%, (based on the total "solution mixture including the reducing sulfite) in the hot aqueous APAP

21 solution which is subjected to carbon treatment. The 22 latter reducing sulfite may be the same or different from 23 the reducing sulfite used to pretreat the carbon, and is 24 preferably sodium dithionite.

It is critical to this invention that the hot 25 aqueous solution of the colored APAP be initially prepared 27 and that the hot solutian is then contacted with the 1 pretreated acid washed carbon, rather than combining the 2 -APAP water and carbon at room temperature, and heating the 3 entire composition to dissolve the APAP. In the latter 4 procedure, the impurities which the inventive method is intended to minimize, are not formed during treatment With 6 carbon which was not given a reducing sulfite pretreatment.
? While it is not desired to be limited by any theory of the 8 invention, it may be postulated that the impurities which 9 are formed during treatment with carbon which has not been given a sulfite pretreatment are oxidation products of the 11 reaction between the APAP and the oxygen trapped in the 12 pores of the carbon, which reaction can occur at the 13 temperature of the hot solution. On the other hand, if the 14 crude APAP, water and carbon are combined at room temperature and the composition is heated to dissolve the 16 APAP, th~ carbon probably becomes deaerated during heating 17 before the temperature is high enough for the oxidation 18 reaction to occur. Despite this, it is much easier and more 19 convenient in commercial operation to prepare tyre hot solution of crude APAP before the carbon treatment, with a 21 concomitant formation of additional impurities which is 22 minimized by the method of this invention as described.
23 The inventive method is designed to prevent or 24 minimize the formation of primarily two impurities which form during conventional treatment of a hot solution of 26 crude APAP with adsorbent carbon, which may be designated 27 as impurity Y (unknown 18) and impurity Z (unknown 23).

1 These impurities were not analyzed because of the extreme 2 difficulty of extracting them from the carbon treated APAP
3 and purifying them so as to have sufficient quantities of 4 pure samples for detailed analysis. However, their S presence and amaunts in the carbon treated APAP are readily 6 determined by conventional high performance liquid 7 chromatography (HPLC) techniques, as more fully described 8 hereinafter, and such amounts are believed to be 9 undesirable in APAP used as a drug.
l0 The invention is further illustrated by the 11 following examples.
12 Comparative Examples A and B
13 These examples illustrate the separate effects of 14 an air sparge, and treatment with an acid washed adsorbent 15 carbon Which has not been pretreated with a reducing 16 sulfite, on a hot aqueous solution of APAP.
17 A previously purified, pharmaceutical grade APAP
18 sample was subjected to analysis by high performance liquid 19 chromatography (HPLC), using a microbore reverse phase mode 20 of separation and ultraviolet (UV) detection. The 21 instrument-utilized was a Hewlett-Packard LC equipped with 22 a variable volume injection system and autosampler, the 23 detector was a Hewlett-Packard filter photometric detector 24 with wavelength set at 254 nm (filter no. 3), the column 25 was a 10 cm x 2.1 mm id Hewlett-Packard Hypersil ODS 5 26 micron column, the injection volume was 2 microliters, the 27 eluents utilized at a flow rate of 0.2 mL/min. were 1 methanol (A) and 0.5% acetic acid in water (B) which were 2 HPLC grade and filtered through a 0.22 micron Teflon 3 membrane before use. Linear gradient elution was used and 4 the composition of the eluents utilized was 5 vol.% A and 95 vol.% B at up to 33 min. analysis time, 51 vol.% A and 6 49 vol.% 8 at 33'to 35 min., 90 val.% A and 10 vol.% B at 7 35 to 42 min, and 5 vol.% A and 95 vol.% B at 42 to 44 min.

8 The total analysis time was 44 min., including 9 equilibration time, and the analysis was carried out at ambient temperature. The sample was prepared for analysis 11 by dissolving 0.15 g in neat methanol and adding sufficient 12 water to obtain a 5 wt.% solution of the sample in a 5/95 13 methanol/water solvent.

14 Using the foregoing apparatus and procedure, the sample was found to contain 23 ppm of impurity Y, which I6 yielded a peak at 17.50 min. analysis (retention) time, 17 after the peak for chlorinated APAP at 16.00 min. and 18 before the peak for 4-hydroxyacetophenone at 17.77 min., 19 and 19 ppm of impurity Z, which yielded a peak at 19.28 min., after the peak at 22.50 min. for 21 4-hydroxyaeetophenone oxime.

22 In comparative Example A a 500 mL round bottom 23 flask was charged with 50 g of the foregoing purified APAP

24 and 375 mL of water. The contents were refluxed and air was sparged through the solution for 30 min. after which 26 the solution was crash crystallized in an ice bath, 27 filtered, washed with 50 mL of water and dried in a vacuum 1 oven. Using the foregoing HPLC procedure the sample Was 2 found to contain 26 ppm of impurity Y and 28 ppm of 3 impurity Z.
4 In Comparative Example B, the APAP feed was the product of Comparative Example A and the procedure of 6 Comparative Example A was followed except that no air 7 sparge was used. Instead, the contents of the flask were 8 heated until the solids dissolved, 5 g of "ADP" carbon, an 9 acid washed activated carbon manufactured by Calgon Corp., were added for a weight ratio of APAP/C of 10/1, and the 11 solution was refluxed under an air atmosphere far 1 h, hot 12 filtered through a celite pad to remove the carbon, and.
13 crystallized, filtered, washed and dried as described in 14 Comparative Example A. The sample was then subjected to an HPLC analysis as previously described and found to contain 16 88 ppm of impurity Y and 203 ppm of impurity Z.
17 The results of Comparative Examples A and B
18 indicate that an ordinary air sparge of an aqueous APAP
19 solution does not cause the fonaation of impurities Y and Z in appreciable amounts, but that a treatment of the hot 21 aqueous APAP solution with acid washed adsorbent carbon 22 which has not been pretreated with a reducing sulfite does 23' cause the formation of substantial amounts of these 24 impurities.
Comparative Examples C and D illustrate the 26 effect on the levels of impurities Y and ~Z of treating a 27 hat aqueous solution of crude APAP with an acid washed 1 adsorbent carbon which has not been pretreated with a 2 'reducing sulfite, at widely different APAP/C weight ratios, 3 and Example 1 illustrates the effect of treating the same 4 solution with an acid washed adsorbent carbon which was treated with reducing sulfite.
6 Comparative Example C
7 A 250 mL round bottom flask was charged with 100 8 mL of water, and 10 g of crude APAP, prepared in accordance 9 with the disclosure of U.S.. :Patent No. 2,524,217 as described previously, and subjected to an initial 11 crystallization without any carbon treatment. Such crude 12 APAP contained 434 ppm of impurity Y and 19 ppm of impurity 13 Z as determined by HPLC analysis. The contents were heated 14 until the solids dissolved and 1 g of ADP carbon which had not been treated with a reducing sulfite, was added (weight I6 ratio of APAP/C=10/1). Thereafter, the contents of the 17 flask were refluxed under an air atmosphere, hot filtered 18 through a celite pad to remove the carbon, crash 19 crystallized in an ice bath, filtered, and the solids washed with 25 mL of water and dried in a vacuum oven. The 21 sample! was found by HPLC analysis to contain 538 ppm of 22 impurity Y and 739 ppm of impurity Z.

23 Comparative 1~' ample D

24 The procedure of Comparative Example C Was followed except that 5 g of ADP carbon were used, for a 26 APAP/C ratio of 2/1. HPLC analysis .of the product 1 indicated the presence of 466 ppm of impurity Y arid 632 ppm 2 of impurity Z.
r 3 Example 1 4 The procedure of Comparative Example C was followed except that the 1 g of ADP carbon prior to use was 6 pretreated by slurrying it with 25 mL of water containing 7 0.1 g of sodium dithionite and the slurry allowed to stand 8 for 24 h. The APAP was found by HPLC analysis to contain 9 165 ppm of impurity Y and 17 ppm of impurity Z.
The results of Comparative Examples C and D
11 indicate that treatment of a hot aqueous solution of APAP
12 with acid washed adsorbent carbon at widely varying APAP/C
13 ratios of 10/1 and 2/1 caused substantial increases of 14 impurities Y and Z in the APAP. However, comparison of the results of Comparative Example C and Example 1 indicates 16 that a pretreatment of the carbon with a reducing sulfite 17 causes a substantial reduction in the content of these 18 impurities.
19 Comparative Examgles ~ and F and Examples 2 and 3 These examples illustrate the effect of 21 pretreating an acid washed adsorbent carbon with a .reducing 22 sulfite in minimizing the level of impurity Y in APAP, when 23 the hot aqueous APAP solution being treated contains 24 reducing sulfite dissolved therein.
The feed for these examples was a crude APAP
26 prepared in accordance with the disclosure of U.S. Patent 27 No. 2,524,217, containing 24 ppm of impurity Y and 1 previously subjected to a crystallization from a hot 2 aqueous solution without carbon. In each example, a 1 3 liter round bottom flask was charged with 50 g of crude 4 APAP, 0.2 g of sodium dithionite and 375 mL of water, the contents heated to dissolve the APAP, and 1 g of ADF~ carbon 6 added to the flask. The carbon was either untreated 7 (Comparative Examples E and F) or pretreated with a sodium 8 dithionite solution as described in Example 1 (Examples 2 9 and 3). The solution was then either refluxed for 1 h l0 under of nitrogen atmosphere (Comparative Example E and 11 Example 2) or refluxed while air was bubbled through it for 12 1 h (Comparative Example F and Example 3). The contents of.
13 the flask were then hot filtered through a celite pad to 14 remove the carbon and crash crystallized in an ~.ce bath either under nitrogen (Comparative Example E and Example 2) 16 or in air (Comparative Example F and Example 3). The 17 solids in all the examples were then filtered, washed with 18 50 mL of ice water, and dried in a vacuum oven.
19 The conditions of these examples including whether the carbon was pretreated (C Pretr.), and the 21 effect on the Level of impurity Y (Imp. Y) determined by 22 IiPLC analysis, are shown in the table.
23 a~, ble 24 Example Run N4, AirE~ar~ _-C Pretr. Imp. Y, ppm E 2 No No 29 26 2 3 No Yes . 23 27 F 1 Yes No 30 28 3 4 Yes Yes 23 1 The results of these examples indicate that even 2 when a reducing sulfite is dissolved in the hat aqueous 3 APAP solution, and whether or not an air sparge is used, 4 the use of an acid washed adsorbent carbon which has not been pretreated with a reducing sulfite causes a rise in 6 the level of impurit~~ Y in the APAP while the same carbon 7 which has been pretreated with reducing sulfite, does not 8 cause such a rise.
r

Claims (6)

CLAIMS:

1. An acid washed adsorbent carbon which has been contacted with an aqueous solution of a reducing sulfite.

2. The contacted acid washed adsorbent carbon of claim 1, wherein said carbon is an activated carbon.

3. The contacted acid washed adsorbent carbon of claim 1 or 2, wherein said reducing sulfite is sodium dithionite.

4. The contacted acid washed adsorbent carbon of any one of claims 1 to 3, wherein said contact is carried out for at least 1/2 hour.

5. The contacted acid washed adsorbent carbon of any one of claims 1 to 3, wherein said contact is carried out for at least 1 hour.

6. The contacted acid washed adsorbent carbon of any one of claims 1 to 5, wherein said solution contains from about 0.1 to 5 wt.% of said reducing sulfite.