Process for the purification of 5-aminosalicylic acid

Abstract

The subject of the present invention is a method for the purification of 5-ASA, which makes it possible to obtain a product with a low content of impurities and with improved yields.

Description

[Technical field]

[0001] The subject of the present invention is a process for the purification of 5-ASA, which makes it possible to obtain a product with a low content of impurities and with improved yields. [Background technology]

[0002] 5-Aminosalicylic acid, also known by its acronym 5-ASA, or by the name mesalamine or mesalazine, is manufactured in large quantities for use as an anti-inflammatory agent for the gastrointestinal tract.

[0003] Various methods have been proposed for the preparation of 5-ASA, the most frequently used of which are based on salicylic acid nitration and subsequent reduction of the nitro group to an amino group, or on the reaction of salicylic acid with aromatic diazonium salts, which are obtained by nitrosation of the corresponding aromatic amines with sodium nitrite to give the diazo derivatives that must then be reduced to obtain 5-ASA (Scheme 1).

[0004] [ka]

[0005] A synthetic alternative to these methods consists of the conversion of 3-nitrobenzoic acid to 5-ASA via reduction to the corresponding hydroxylamine and its Bamberger rearrangement.

[0006] It is also possible to follow a more rarely mentioned procedure for the synthesis of 5-ASA, which involves the Kolbe carboxylation of p-aminophenol using the Marasse method (Scheme 2).

[0007] [ka]

[0008] This synthetic route has the undoubted advantage of carrying out the synthesis of mesalazine in a single synthetic step with high atom efficiency, even though it involves the use of a reactor for carrying out solid-phase reactions under high pressure and high temperature conditions. Moreover, this method does not use nitrosating agents such as sodium nitrite, which entails the risk of the formation of nitrosamines. Nitrosamines are known to be highly genotoxic substances, and health agencies have set very low limits that must be met by pharmaceuticals. Considering these advantages, the production of 5-ASA based on p-aminophenol carboxylation plays a key role for the production of this drug of paramount utility.

[0009] Despite achieving virtually complete conversion in the carboxylation reaction, several undesirable impurities are also formed in this process. Among these, 3-carboxy-5-ASA of formula 1 was identified.

[0010] [ka]

[0011] It is stipulated that the presence of this dicarboxylation product in 5-ASA must not exceed 0.05% by weight, a limit not dictated by any specific toxicological reasons but by the need to maintain a very high purity profile for 5-ASA.

[0012] However, this upper limit of 0.05% cannot be met without an effective purification process, since even under the best identified conditions, the presence of 3-carboxy-5-ASA at the end of the carboxylation reaction is always higher than 0.10 wt % and this impurity tends to co-precipitate with 5-ASA during its crystallization.

[0013] To date, the purification method employed to remove this dicarboxylated impurity involves isolating 5-ASA directly from the terminally carboxylated mixture using water as the solvent (Scheme 3). In the presence of high concentrations of potassium ions, 5-ASA precipitates from water in the form of its potassium salt, with the potassium salt of 3-carboxy-5-ASA being found primarily in the aqueous phase.

[0014] [ka]

[0015] Although this procedure makes it possible to achieve the desired purification of 5-ASA, it suffers from a poor recovery yield, since about 15% of the 5-ASA remains in solution and is not recovered. Summary of the Invention [Problem to be solved by the invention]

[0016] Therefore, an improved process for the production of 5-ASA that achieves improved purification yields while retaining the characteristic advantages of the Kolbe carboxylation-based procedure, which is atom-efficient and without the risk of nitrosamine formation, remains highly desirable. [Means for solving the problem]

[0017] definition Unless otherwise defined, all technical terms, designations and other scientific terms used herein are intended to have the meaning commonly understood by those skilled in the art to which this disclosure belongs. In some cases, for clarity and / or ease of reference, terms having a commonly understood meaning are defined herein, and therefore the inclusion of such definitions in this disclosure should not be interpreted as representing a substantial difference from the meaning generally understood in the art.

[0018] The terms "approximately" and "about" as used herein refer to the range of experimental error inherent in performing experimental measurements.

[0019] The terms "comprising," "having," "including," and "containing" are intended to be open-ended terms (i.e., meaning "including, but not limited to") and should also be considered as support for the terms "consist essentially of," "consisting essentially of," "consist of," or "consisting of."

[0020] The term "consist essentially of, consisting essentially of" is intended as a semi-closed term, meaning that no other components that affect the novel characteristics of the invention are included (thus, optional excipients may be included).

[0021] "Consist of" is intended as a closed term.

[0022] The present invention relates to a process for the purification of 5-ASA.

[0023] The solubility of 5-ASA is strongly pH dependent due to the presence of ionizable functional groups in its structure.

[0024] 5-ASA exhibits good solubility in water at a pH below 2 due to the presence of a primary amino group.

[0025] On the other hand, deprotonation of the carboxy group favors the solubility of 5-ASA at pH higher than 6.

[0026] In the region close to the isoelectric pH, the value reported in the literature corresponds to 3.7, but the solubility of 5-ASA in water is minimal.

[0027] The precipitation method commonly used at the end of the synthesis for 5-ASA isolation involves dissolution in an acidic environment and subsequent precipitation by addition of base (CN Patent No. 111548283 and Journal of Crystal Growth 181 (1997) 403-409). On the other hand, the effect of different operating conditions for precipitation when this is done by addition of acid starting from an aqueous solution of 5-ASA with a pH of 6 or higher is not known.

[0028] The inventors have surprisingly found that it is possible to obtain a better purification of 5-ASA by precipitating it via acid addition starting from the same aqueous solution having a pH between 6 and 9. With the precipitation method according to the invention, a better purification is achieved than that resulting from the commonly employed precipitation process, which consists in precipitating 5-ASA from an aqueous solution of 5-ASA at acidic pH by adding a base.

[0029] This is an unexpected and surprising result because, regardless of the addition method used, the final mixture reaches the same pH range, close to the isoelectric pH of the product. Therefore, the relative solubilities of 5-ASA and the impurities originating from the carboxylation reaction, primarily 3-carboxy-5-ASA, should be the same, and therefore the same purification effect would also be expected.

[0030] For the purposes of the present invention, different 5-ASA precipitation methods were independently tested using as starting material the solid mixture obtained at the end of the Kolbe-Schmitt carboxylation reaction, using the Malassez variant with p-aminophenol being the main component in the final carboxylation mixture being potassium carbonate. 5-ASA (measured as the non-chlorinated species) is present at a percent content of about 20%, while p-aminophenol, the starting material for the synthesis, is present in the mixture at less than 0.1%. The remainder is represented by inorganic salts, mainly potassium carbonate.

[0031] This composition clearly confirms the high degree of conversion achievable thanks to the carboxylation conditions used.

[0032] 3-Carboxy-5-ASA is a species resulting from double carboxylation of p-aminophenol and is present at levels of 0.10% to 0.15% based on 5-ASA, thus exceeding the 0.05% tolerance limit set for this impurity. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0033] The subject of the present invention is therefore i) preparing an aqueous solution or suspension of 5-ASA, optionally adding at least another solvent; ii) adding a base until a pH of 6 to 9 is reached; iii) adding an acid to the solution resulting from step ii) until a pH of 3.2 to 5.2, preferably 4.3 to 4.6, is reached, resulting in precipitation of 5-ASA; iv) isolating the precipitated 5-ASA obtained from step iii); The present invention is represented by a process for the purification of 5-ASA, comprising:

[0034] Another solvent that can be optionally added to the initial aqueous solution is a polar solvent, preferably C 1 ~C 4 It is selected from alcohol (methanol, ethanol or isopropanol), acetone, dimethylformamide and tetrahydrofuran, or mixtures thereof.

[0035] Once dissolution of 5-ASA (step i) is achieved, a base (step ii) is added, preferably selected from those used in industrial practice. These include sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, ammonia. More preferably, it is sodium hydroxide in an aqueous solution.

[0036] The process is monitored by a pH meter and the addition of base must be stopped when dissolution is complete. The pH of the solution will be between pH=6 and pH=9.

[0037] In this step, the temperature should preferably be between 50°C and 80°C, more preferably between 60°C and 75°C.

[0038] An acid reagent is added to this solution for precipitation of 5-ASA (step iii).

[0039] For the purposes of the present invention, acids are used that are selected from those used in industrial practice, including hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, preferably hydrochloric acid in aqueous solution.

[0040] The precipitation of 5-ASA should be monitored by a pH meter and the addition of acid should be stopped when the pH of the mixture is between pH=3.2 and pH=5.2, preferably when the pH is between pH=4.3 and pH=4.6.

[0041] In this step, the temperature should preferably be between 50°C and 80°C, more preferably between 60°C and 75°C.

[0042] The precipitated product is separated from the liquid phase (step iv), preferably by a suitable filtration system or by centrifugation.

[0043] After drying, 5-ASA is obtained in good yield with a residual percent content of 3-carboxy-5-ASA impurity of less than 0.05% by weight, typically less than 0.04% by weight.

[0044] Preferably, the product is characterized as having a nitrosamine content of less than 1 ng / g.

[0045] In a preferred embodiment of the present invention, 5-ASA is obtained from the carboxylation reaction of p-aminophenol with potassium carbonate in the presence of carbon dioxide according to Scheme 2.

[0046] [ka]

[0047] In a preferred embodiment, once dissolution of the 5-ASA is achieved (step i), an acidic reagent is added (step a) until a pH of 0.5-1.5, preferably about 1, is reached. In this step, the temperature should preferably be between 25°C and 70°C, more preferably between 35°C and 50°C.

[0048] During the acid addition, abundant evolution of carbon dioxide is observed and should be appropriately slowed to avoid problems arising from excessively fast gas evolution. In this step, acid addition is continued until the product precipitates and then completely redissolves.

[0049] For the purposes of the present invention, acids are used that are selected from those used in industrial practice. Of these, hydrochloric acid, sulfuric acid, phosphoric acid and acetic acid are preferred. Preference is given to hydrochloric acid in the form of an aqueous solution.

[0050] Optionally, at the end of redissolution, the acid solution may be treated with decolorizing charcoal to improve the color level.

[0051] A basic reagent for precipitation of 5-ASA is then added to the solution (step b).

[0052] For the purposes of the present invention, bases are used that are selected from those used in industrial practice. Of these, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate and ammonia are preferred. More preferred is sodium hydroxide in the form of an aqueous solution.

[0053] The precipitation of 5-ASA should be monitored by a pH meter and the addition of base to acid should be stopped when the pH of the mixture is between pH=3.0 and pH=4.0, preferably between 3.5-3.7, and more preferably when a pH of about 3.5 is reached.

[0054] In this step, the temperature should preferably be between 50°C and 80°C, more preferably between 60°C and 75°C.

[0055] Optionally, the precipitated product is separated from the liquid phase (step c), preferably by a suitable filtration system or by centrifugation. The solid is optionally dried.

[0056] Optionally, an aqueous solution or suspension of 5-ASA precipitated from step c) is prepared, optionally with the addition of at least one further solvent, before carrying out step ii).

[0057] Alternatively, product isolation (step c) is not performed after the base precipitation step (step b) and the addition of the basic reagent is continued until redissolution of the 5-ASA (step ii).

[0058] Also in this alternative embodiment, the procedure is monitored by a pH meter and the addition of base should be stopped when dissolution is complete and the pH of the solution is between pH=6 and pH=9.

[0059] Also in this embodiment, an acid reagent is then added to the solution to precipitate 5-ASA until a pH between pH=3.2 and pH=5.2 is reached, preferably when the pH is between pH=4.3 and pH=4.6 (step iii).

[0060] This preferred embodiment demonstrates the versatility of the invention, which allows to obtain good purification levels through precipitation of the product without intermediate isolation, even from environments with high ionic strength due to the presence of potassium carbonate salt used in the carboxylation reaction.

[0061] For comparative purposes, a similar series of operations was carried out as in the present invention, without carrying out the precipitation with an acidic reagent, but replacing it with a second precipitation using a basic reagent and adjusting the final pH to a range between pH=4.3 and pH=4.6.

[0062] The following table provides data for the various preparations described in the examples.

[0063] [Table 1]

[0064] Table 1 clearly shows the high efficiency of the purification carried out by precipitation with acid, as described in Examples 3 and 6 according to the invention. The amount of 5-ASA remaining in the precipitation mother liquor is low, therefore a further advantage of this method is the achievement of good isolated yields, typically approaching 96%, therefore much higher than the 85% obtained from the purification procedure based on the isolation of 5-ASA as the potassium salt.

[0065] Surprisingly, the purification effect found by applying the procedure subject of the invention is not due solely to the choice of pH at which the isolation of 5-ASA is carried out.

[0066] A comparison of the results of Example 6 and Comparative Example 1 reveals the following.

[0067] Example 6 illustrates the purification carried out according to the invention, by precipitation of the product by addition of acid to a basic solution, obtaining a final 3-carboxy-5-ASA impurity value equal to 0.04%.

[0068] Comparative Example 1 is performed starting with the same 5-ASA preparation, but continuing the precipitation until the same pH level is obtained by adding base to the acid solution (and not vice versa). The final level of 3-carboxy-5-ASA impurity is 0.10%, exceeding the 0.05 wt% limit.

[0069] Another advantage that comes from the achievement of the present invention is the absence of nitrosamines in the obtained 5-ASA.As is known, nitrosamines are highly genotoxic impurities, and regulatory agencies such as EMA and FDA have set very strict limits on this class of compounds, specifying that their presence requires risk analysis to be carried out on the entire class of nitrosamines.Therefore, it is particularly useful to have a method that allows the level of nitrosamino group (-NNO) to be measured independently of the specific molecule to which it is attached.The luminescence-based method described as an example in a paper by Beretta et al. (Journal of Pharmaceutical and Biomedical Analysis 49 (2009) 1179-1184, incorporated herein by reference) seems to perfectly meet this requirement.

[0070] This analytical method was used to measure the amount of nitrosamino groups in samples of 5-ASA (pharmaceutical tablets for human use marketed in the United States) and 5-ASA obtained in Example 6 according to the present invention. The results are shown in Table 2.

[0071] [Table 2]

[0072] These data confirm the absence of nitrosamines in the products obtained according to the process of the present invention.

[0073] Instead, the presence of nitrosamino groups was confirmed in 5-ASA tablets from the US market, and it is possible to assess how the levels found compare with recently introduced regulations for this subject.

[0074] The tablet weighs 1.44 g and has a 5-ASA content of 1.2 g.

[0075] Therefore, calculating the ratio of NNO groups to the total amount of active ingredient, the result is that every gram of 5-ASA contains 2.4 ng of -NNO groups.

[0076] It is possible to assess the risk associated with the presence of compounds that contain a nitrosamino group but whose structure has not been defined by equating their toxicity to that of the nitrosamines for which the highest levels of genotoxicity have been found, an approach that can be adopted to best protect patients.

[0077] N,N-diethyl-nitrosamine (NDEA) has a molecular weight of 102 daltons and is the species with the highest level of genotoxicity measured.

[0078] Comparing the amount of -NNO groups (molecular weight 44 daltons) with that of NDEA, its amount in the 5-ASA contained in the analyzed tablets corresponds to 5.57 ng / g of NDEA.

[0079] The maximum daily intake limit for NDEA established in the guidelines is 26.5 ng, and considering a dose of 5-ASA that gives a maximum daily intake of 4.8 g of 5ASA, the maximum limit for NDEA in 5-ASA is calculated to be equal to 5.52 ng / g.

[0080] Thus, the data in Table 2 show that there are commercially available end products based on 5-ASA in which species containing nitrosamino groups were detected in amounts very close to the established limits for the most genotoxic substances in the category. The presence of nitrosamines in 5-ASA therefore represents a real problem that the practice of the present invention allows for an unexpected solution. EXAMPLES

[0081] The following examples are intended only as specific embodiments of the present invention and should not be construed as limiting its interpretation and field of application.

[0082] Example 1 Carboxylation of p-aminophenol for the preparation of 5-ASA 1025 kg of potassium carbonate and 225 kg of p-aminophenol are charged into a special reactor dedicated to solid-phase reactions, equipped with a mechanical stirrer and built to withstand high pressure and high temperature operating conditions. The system is pressurized with carbon dioxide up to 30 bar, the temperature is brought to 180°C and the mixture is maintained under stirring for 4 hours. The solid mixture is cooled, the reactor is depressurized and the resulting solid is discharged and analyzed by HPLC. The titer of 5-ASA in this solid is found to be 20.1% and the content of 3-carboxy-5-ASA impurity in this preparation is found to be 0.10% by weight relative to 5-ASA.

[0083] For HPLC analysis, a Restek Pinnacle II C8 150x4.6mm 5μm column is used. For preparation of the mobile phase, 1.39g of KH 2 PO 4 and 2.24 g of sodium octanesulfonate are dissolved in 1000 mL of water. Then, a mixture of this solution with methanol and acetonitrile is prepared in the ratio of 1000:90:35 (by volume), respectively. The analysis is carried out in isocratic mode at 1 mL / min using a UV detector at 220 nm for detection.

[0084] Example 2. Precipitation with base according to the prior art Add 180 mL of water to 120 g of the solid mixture obtained by the carboxylation reaction of Example 1 and dissolve completely by adding about 3.5 M hydrochloric acid to the suspension until a pH of 1 is reached. This addition should be done in small portions to limit the formation of a lot of foam. During the addition, the temperature is gradually increased until it reaches about 45°C. The solution is treated with decolorizing charcoal at 80°C. A large amount of precipitate is obtained by bringing the solution to 65-70°C and adding a 30% aqueous solution of sodium hydroxide until a pH of 3.5 is reached.

[0085] The mixture is gradually cooled to 25° C. and the suspension is then maintained under stirring for 15 minutes.

[0086] After filtering on a Buchner and drying under vacuum at about 50° C., 25.3 g of 5-ASA is obtained.

[0087] HPLC analysis indicates a potency of 92.8% for this product with a 3-carboxy-5-ASA impurity content of 0.09%.

[0088] The precipitation mother liquor is also analyzed by HPLC and finds a concentration of 5-ASA equal to 2.4 g / L.

[0089] Example 3. Precipitation with Acid According to the Invention 24 g of the product obtained in Example 2 are added to 120 mL of water.

[0090] Then, 0.7 M sodium hydroxide solution is added until the pH reaches about 7.4. Heat to 70 °C and add 5 M hydrochloric acid to the solution. By maintaining the temperature and stirring, the addition of acid is continued until the pH of the mixture reaches a value of pH = 4.5. In this step, precipitation is observed. The addition of acid is stopped and, while maintaining stirring, the temperature is brought to 20-25 °C.

[0091] After filtering on a Buchner and drying under vacuum at about 50° C., 22.3 g of 5-ASA is obtained.

[0092] HPLC analysis indicates a potency of 97.8% for this product with a 3-carboxy-5-ASA impurity content of 0.02%.

[0093] The precipitation mother liquor is also analyzed by HPLC and a concentration of 5-ASA equal to 2.5 g / L is found.

[0094] Example 4 Carboxylation of p-aminophenol for the preparation of 5-ASA The carboxylation reaction of p-aminophenol was carried out under the same conditions as reported in Example 1. The 5-ASA assay in the obtained product was 23.1%, while the content of 3-carboxy-5-ASA impurity in this preparation was found to be 0.12% by weight relative to 5-ASA.

[0095] Example 5. Precipitation with base according to the prior art In this example, the carboxylation mixture obtained from Example 4 was used to carry out the precipitation of 5-ASA under the same conditions reported in Example 2.

[0096] HPLC analysis indicates a potency of 97.2% for this product with a 3-carboxy-5-ASA impurity content of 0.12%.

[0097] The precipitation mother liquor is also analyzed by HPLC and a concentration of 5-ASA equal to 1.5 g / L is found.

[0098] Example 6. Acid Precipitation According to the Invention In this example, the product obtained from Example 5 was used to carry out the precipitation of 5-ASA under the same conditions as reported in Example 3.

[0099] HPLC analysis shows that the product contains 0.04% of 3-carboxy-5-ASA impurity.

[0100] The precipitation mother liquor is also analyzed by HPLC and finds a concentration of 5-ASA equal to 2.1 g / L.

[0101] Comparative Example 1: Precipitation with base according to the prior art In this example, for comparative purposes, the same product used in the precipitation described in Example 5 was reprecipitated according to a procedure that does not incorporate the teachings of the present invention but nonetheless results in the isolation of 5-ASA in the same pH range.

[0102] 200 mL of water is added to 20 g of 5-ASA from Example 5, the suspension is heated to 60° C., and about 10 M hydrochloric acid is added to completely dissolve. The solution is treated with decolorizing charcoal at 80° C. The solution is brought to about 65° C. and 5 M sodium hydroxide is added until a pH=4.4 is reached, resulting in a large amount of precipitate.

[0103] The temperature and stirring were maintained for 1 hour.

[0104] The mixture is gradually cooled to 25° C. and the suspension is then maintained under stirring for 15 minutes.

[0105] After filtering on a Buchner and drying under vacuum at about 50° C., 18.9 g of 5-ASA is obtained.

[0106] HPLC analysis shows that the product contains 0.10% of 3-carboxy-5-ASA impurity.

[0107] The precipitation mother liquor is also analyzed by HPLC and finds a concentration of 5-ASA equal to 1.8 g / L.

Claims

1. 1. A process for purifying 5-aminosalicylic acid (5-ASA), comprising: i) preparing an aqueous solution or suspension of 5-ASA, optionally with the addition of at least another solvent; ii) adding a base until a pH of 6 to 9 is reached; iii) adding an acid to the solution resulting from step ii) until a pH of 3.2 to 5.2, preferably 4.3 to 4.6, is reached, causing precipitation of 5-ASA; iv) separating the precipitated 5-ASA obtained from step iii); The process includes:

2. The at least another solvent is a polar solvent, preferably C 1 ~C 4 2. The process according to claim 1, characterized in that the solvent is an alcohol, acetone, dimethylformamide, tetrahydrofuran or a mixture thereof.

3. Said C 1 ~C 4 3. The process of claim 2, wherein the alcohol is methanol, ethanol, or isopropanol.

4. 2. The process according to claim 1, characterized in that 5-ASA is obtained by carboxylation of p-aminophenol with potassium carbonate in the presence of carbon dioxide.

5. 2. The process according to claim 1, characterized in that steps ii) and iii) are carried out at a temperature of from 50°C to 80°C, preferably from 60°C to 75°C.

6. 2. The process according to claim 1, characterized in that the 5-ASA obtained from step iv) has a content of 3-carboxy-5-ASA of less than or equal to 0.05% by weight, preferably less than or equal to 0.04% by weight.

7. 2. The process of claim 1, wherein the nitrosamine content in the 5-ASA obtained from step iv) is less than 1 ng / g.

8. a) adding an acid to the solution or suspension obtained in step i) until a pH of 0.5 to 1.5, preferably about 1, is reached; b) adding a base to the solution resulting from step a) until a pH of 3.0 to 4.0, preferably 3.5 to 3.7, more preferably about 3.5, is reached, causing precipitation of 5-ASA; c) optionally separating the precipitated 5-ASA obtained from step b) and preparing an aqueous solution or suspension of precipitated 5-ASA, optionally adding at least another solvent; 2. The process according to claim 1, wherein step ii) is carried out upstream of step ii).

9. 9. The process according to claim 8, characterized in that step a) is carried out at a temperature between 25°C and 70°C, preferably between 35°C and 50°C.

10. 9. The process according to claim 8, characterized in that step b) is carried out at a temperature of from 50°C to 80°C, preferably from 60°C to 75°C.

11. 2. The process of claim 1, wherein the acid is selected from hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, or mixtures thereof.

12. 2. The process of claim 1, wherein the base is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, ammonia, or mixtures thereof.