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FIELD OF THE INVENTION

The present invention relates to a process for the production of high-density mesalamine.

The present invention originates in the field of industrial processes for the production of active ingredients.

Specifically, the present invention relates to a process for the production of a crystalline form of mesalamine with a high bulk density, pharmaceutical compositions containing same and uses in the therapeutic field of the of form of high-density mesalamine obtained.

BACKGROUND ART

5-Aminosalicylic acid or mesalamine (5-amino-2-hydroxybenzoic acid) is a molecule belonging to the class of salicylates, drugs provided with anti- inflammatory activity (NSAIDs).

Mesalamine may mainly be applied in the treatment of inflammatory bowel diseases (IBD), such as Crohn's Disease and ulcerative colitis.

This latter is an inflammatory disease of the mucous membrane of the rectum and/or colon, localised in particular in the descending part. Ulcerative colitis is a disease whose etiology still remains unknown and which shows with ulcerations of the intestinal mucous membrane and hyperaemia. Crohn's disease, also known as regional enteritis, is also an inflammatory disease, but unlike ulcerative colitis, it is more widespread, being capable of affecting any part of the gastrointestinal tract, although it is mainly localised at the level of the ileum, the end part of the small intestine and the large intestine.

Crohn's disease is believed to be a condition with an autoimmune origin or with a main component of the autoimmune type, wherein the immune system attaches the mucous membrane of the gastrointestinal tract causing a chronic state of inflammation.

Currently there is no definitive pharmacological therapy yet and the treatment options are limited to controlling the symptoms, maintaining remission and preventing relapses. The acute treatment of the disease is based on the use of antibiotic and antiinflammatory drugs, also corticosteroids. The prolonged use of corticosteroids, however, implies significant side effects, therefore, the administration of aminosalicylates, typically mesalamine, is preferred.

Mesalamine is administered in several pharmaceutical forms, mainly tablets coated with gastro-resistant films, delayed-delivery capsules, suppositories, microenemas, foams and rectal suspensions.

Generally, the mesalamine dosage required for treating IBD is high and may range from 400 to 1200 mg of active ingredient/day.

Consequently, currently there is a need for providing high-density 5-aminosalicylic acid which allows formulating high-dosage pharmaceutical preparations with formulation volumes lower than those currently commercially available.

The Patent Application US 2013/0225539A1 describes a process for the production of mesalamine having a bulk density from 300 g/l to 700 g/l, grain size distribution of X(10)= 1-30 pm; X(50)= 15-60 pm; X(90)= 35-220 pm and a tapped density from 510 to 900 g/l. This process comprises pouring a strongly basic alkaline solution in a 5-ASA solution having acidic pH with the formation of a bulk with large 5-ASA crystals in suspension which is wet ground in a homomixer, until reaching the desired particle size.

This process, however, has the drawback of providing a wet grinding step with homomixers of the Supraton or Ytron type, whose use takes place with high consumption of electric energy and management costs which make this technology not economically convenient.

Furthermore, this process requires a thorough monitoring of the crystallisation conditions both because heat develops in the area in which the strongly basic solution contacts the strongly acid solution of mesalamine and because the crystals that form in this exothermic reaction have large sizes.

These drawbacks make this process little attractive and competitive, therefore currently there is a need to provide a more economical and feasible technology to produce mesalamine with a high bulk density.

One of the objects of the present invention therefore consists in providing a process for the production of high-density 5-aminosalicylic acid to prepare pharmaceutical formulations with a high dosage of active ingredient and improved patient compliance.

Another object of the present invention consists in providing a process for the production of high-density mesalamine in a highly pure form, substantially solvent- free.

SUMMARY OF THE INVENTION

The Applicant has found that by adopting specific reaction conditions it is possible to obtain mesalamine with very high apparent density, greater than that of mesalamine obtained with conventional precipitation techniques, in particular with values lower than 0.25 g/ml.

In accordance with a first aspect, the invention relates to a process for the production of mesalamine with a high bulk density in a highly pure form, achieving a progressive crystallisation at controlled pH.

In accordance with a first aspect therefore there is provided a process for the production of mesalamine with a bulk density greater than or equal to 0.30 g/ml, substantially solvent-free, wherein the crystallisation is obtained by slowly pouring optionally in two or more portions, an acid solution of mesalamine hydrochloride in an aqueous solution buffered with a buffer system based on acetic acid or sodium acetate, so as to gradually increase the strongly acidic pH of the solution of mesalamine hydrochloride and promote the crystallisation of mesalamine with a high bulk density.

In particular, in accordance with some embodiments, the process of the invention comprises the steps of

a) Dissolving mesalamine in a solution of HCI obtaining mesalamine hydrochloride,

b) Adding the acid solution containing mesalamine HCI in an aqueous solution buffered with a buffer system based on acetic acid and sodium acetate to increase the pH value of the solution and promote the crystallisation of mesalamine with a high bulk density,

c) Heating the melamine-based mass to make it reflux and maintaining it, typically in these conditions, until complete crystallisation,

d) Cooling and separating the high-density mesalamine obtained. Some embodiments of the process of the invention are provided in the appended dependent claims 2-12.

Typically, the mesalamine with a high bulk density obtained with the process of the invention is in a very pure crystalline form.

The mesalamine obtained in accordance with this first aspect of the invention is in a highly pure form, substantially free of organic solvents, having a bulk density greater than or equal to 0.30 g/ml and suitable for being conveniently granulated. In accordance with certain embodiments the mesalamine of the invention has a bulk density of from 0.30 g/ml to 0.80 g/ml.

In accordance with some embodiments, the process for the production of mesalamine with a high bulk density of the invention may provide also the use of an organic solvent miscible with water.

The Applicant has in fact observed that by using an aprotic organic solvent mesalamine with a bulk density equal to or greater than 0.40 g/ml, conveniently between 0.40 and 0.80 g/ml, is obtained.

Mesalamine with a high bulk density, obtained in accordance with these embodiments, contains amounts in traces of organic solvent.

In accordance with a further aspect, the present invention provides mesalamine substantially totally free of organic solvents having a bulk density greater than or equal to 0.30 g/m and pharmaceutical compositions containing the same.

In accordance with another aspect, the present invention provides mesalamine containing trace amounts of organic solvent having a bulk density greater than or equal to 0.40 g/ml and pharmaceutical compositions containing the same.

In accordance with another aspect of the invention there is provided mesalamine with a bulk density greater than or equal to 0.30 g/ml obtained with the process of the invention for use in medicine.

DETAILED DESCRIPTION OF THE INVENTION

The Applicant has found a process for the production of mesalamine (5- aminosalicylic acid) having a high density (bulk density) wherein the crystallisation is obtained by slowly pouring, optionally in two or more portions, an acid solution of mesalamine hydrochloride in an aqueous solution buffered with a buffer system based on acetic acid or sodium acetate. In accordance with a first aspect, the invention provides a process for the production of mesalamine with a bulk density greater than or equal to 0.30 g/ml, substantially solvent-free, comprising slowly adding an acid solution of mesalamine hydrochloride to an aqueous solution buffered with a buffer system based on acetic acid and sodium acetate so as to gradually increase the pH value of the acid solution and promote crystallisation of mesalamine with a bulk density greater than or equal to 0.30 g/ml.

Therefore, in accordance with certain embodiments, the object of the invention is a process comprising the steps of

a) Dissolving mesalamine in a non-salified form in an aqueous solution of HCI obtaining mesalamine hydrochloride,

b) Adding the acid solution containing mesalamine HCI in an aqueous solution buffered with a buffer system based on acetic acid and sodium acetate to increase the pH value of the solution and promote the crystallisation of mesalamine with a high bulk density,

c) Heating the melamine-based bulk to make it reflux, typically maintaining these conditions until crystallisation is complete,

d) Cooling and separating the high-density mesalamine obtained.

In accordance with certain embodiments the process for the production of mesalamine having a bulk density greater than or equal to 0.30 g/ml comprises the following steps:

i) adding mesalamine, hydrochloric acid and water to a reactor and heating to a temperature conveniently in the range between 30 and 90 °C in order to obtain a solution of mesalamine in the form of hydrochloride, conveniently with pH below 2.0, optionally adding bleaching coal to the solution and filtering to separate the solution, ii) adding water, a weak acid, conveniently acetic acid, and sodium acetate to a second reactor, heating to complete solution and then bringing the temperature of the solution typically to 85-100 °C,

iii) pouring the acid solution of mesalamine in the solution of the second reactor keeping the temperature at 85-100 °C,

iv) cooling the resulting bulk and optionally spinning, rinsing with water and drying the resulting mesalamine.

Typically, the mesalamine obtained in accordance with certain embodiments of the invention is totally free of organic solvents and has a bulk density equal to or greater than 0.3 g/ml.

In some embodiments the mesalamine obtained has a bulk density of from 0.3 g/ml to 0.4 g/ml.

The process according to the invention has high production yields, typically greater than 90% and in some embodiments varying from 93 to 94%.

In step i) of the process of the invention mesalamine is dissolved in an aqueous solution of hydrochloric acid to provide a solution with a pH below 2.0. Typically distilled water, free of impurities which may interact with mesalamine and cause a staining of the solution, is used as a solvent.

In accordance with some embodiments in step i) an anti-oxidant substance is added, such as for example sodium metabisulfite to prevent mesalamine from oxidising.

In some embodiments the acid solution of mesalamine of step i) is supplemented with bleaching coal to adsorb any impurities still present and prevent the solution from staining.

The bleaching coal added to the acid solution of mesalamine is left in suspension and, after reacting, is separated, for example by filtration.

In some embodiments the hydrochloric acid added in step i) inside the first reactor is an aqueous solution with a concentration that may range from 30 to 40%.

Conveniently, the components present in the first reactor are subjected to mixing by heating at a temperature comprised between 40 and 60°C until solution.

According to some embodiments, the acetic acid used in step ii) of the process is provided as an aqueous solution with a concentration comprised between 70 and 90% by weight, typically equal to about 80% by weight. According to some embodiments, the solution of step ii) has an acidic pH, typically comprised between 4 and 5.5.

In accordance with some embodiments step ii) of the process comprises heating the mixture present in the second reactor at a temperature comprised between 40 and 60°C until complete solution. Later the temperature of the solution ii) is further heated, conveniently at a temperature of 85-100°C.

In accordance with certain embodiments in the second reactor there is also added an anti-oxidant agent, typically sodium metabisulfite.

In accordance with some embodiments in step ii) of the process in the second reactor there is added a chelating agent, EDTA in particular in the form of sodium salt, in order to prevent the mesalamine from oxidising or the formation of complexes with any ions present in the solution.

In step iii) of the process of the invention the acid solution of mesalamine prepared in step i) is poured in the solution of step ii), heated at temperatures close to reflux, typically in the range of 85-100°C.

Typically the addition of the acid solution containing mesalamine in the solution obtained in step ii) is carried out slowly; in certain embodiments the acid solution of mesalamine in poured in no less than one hour.

In some embodiments at the end of the pouring operations of the acid solution of mesalamine the temperature is kept at 85-100°C for a period of time of at least 10 minutes.

In the subsequent step iv) of the process the bulk obtained is conveniently cooled at a temperature of from 25 to 40°C and optionally centrifuged performing a rinse with water.

The bulk obtained in the previously described process is based on mesalamine with a high density, typically equal to or greater than 0.30 g/ml, conveniently totally free of organic solvents.

In certain embodiments the mesalamine bulk obtained is dried out for example by processing at a temperature comprised between 60 and 70°C.

In a second aspect, the invention relates to a variation of the process previously described, wherein a water-soluble aprotic organic solvent is added which is suitable for further increasing the bulk density of the mesalamine obtained.

In accordance with some embodiments therefore there is provided the addition, inside the second reactor, of a water-soluble aprotic organic solvent in step ii), in particular in a step following the formation of the solution.

A suitable aprotic organic solvent is a water-soluble ketone wherein the alkyl radicals comprise 1 to 6 carbons. Particularly suitable water-soluble ketones comprise acetone, 2-butanone, 2-pentanone, 3-pentanone, with acetone being the preferred ketone.

The mesalamine obtained using the aprotic organic solvent in the process of the invention has a purity of the pharmaceutical grade and contains only trace amounts of the organic solvent.

In particular, the mesalamine obtained using a water-soluble aprotic organic solvent has a bulk density greater than or equal to 0.4 g/ml and in some embodiments has an amount of aprotic organic solvent lower than 1000 ppm. In some embodiments the mesalamine obtained using the water-soluble aprotic organic solvent, in particular acetone is comprised from 0.4 to 0.6 g/ml and preferably from 0.45 to 0.55 g/ml.

Within the scope of the invention, the bulk density is measured using methods known to those skilled in the art for example such as those described in the United States Pharmacopeia (USP) for example USP 27, Vol.1 pages 226-227 1 May 2009-30 April 2010, Bulk density 616, Method 1.

One of the advantages of the process of the invention consists in obtaining mesalamine with a bulk density greater than or equal to 0.30 g/ml with high production yields, typically greater than 92%.

Another advantage consists in the possibility of obtaining 5-aminosalicylic acid with a bulk density greater than or equal to 0.30 g/ml in a crystalline form essentially free of impurities and solvents.

Another advantage consists in the possibility of modulating and increasing the degree of density of active ingredient by adding in the production step a water- soluble aprotic organic solvent, typically acetone, and obtaining a highly pure product wherein the solvent is present in trace amounts, for example in an amount of less than 1000 ppm.

Within the scope of the present invention, the term reactor is to be intended in a broad sense as a suitable environment wherein the two solutions to be mixed are prepared to obtain mesalamine in the pure form.

Within the scope of the present invention, the terms mesalamine, mesalazine and 5-ASA indicate the same substance and are to be considered as equivalent to each other. Typically the mesalamine obtained by means of the process of the invention has a purity of the pharmaceutical grade and finds application in the production of medicaments.

In accordance with a further aspect, the present invention provides mesalamine having a bulk density greater than or equal to 0.30 g/ml, conveniently comprised between 0.30 and 0.40 g/ml obtained with the process of the invention.

In accordance with another aspect, the present invention provides mesalamine with a content of an aprotic organic solvent, in particular acetone lower than 1000 ppm and having a bulk density greater than or equal to 0.40 g/ml, conveniently comprised between 0.40 and 0.60 g/ml obtained with the process of the invention. In accordance with another aspect the present invention relates to a pharmaceutical composition comprising a pharmaceutically active amount of highly pure mesalamine obtained with a process according to any of the embodiments previously described, and a pharmaceutically acceptable carrier and/or excipient.

Pharmaceutically acceptable carriers and excipients comprise the substances generally used in the production techniques of the pharmaceutical and medical device industry.

The present invention claims priority over the Italian patent application MI2013A001497 of 10 September 2013, the contents of which are incorporated herein by reference.

The present invention shall now be described with reference to the following examples which are provided for illustration purposes and shall not be intended as limiting of the scope of the present invention.

EXAMPLES

EXAMPLE 1

In a first reactor, there are loaded:

300 kg mesalamine

or alternatively

300 kg crude mesalamine (use the amount equivalent of wet product)

2000 kg deionised water 4,5 kg sodium metabisulfite

254 kg 37% hydrochloric acid

Heat the bulk at 40-60°C until complete solution

Add

5.5 kg bleaching coal

Filter the suspension and put aside

In another reactor, there are loaded:

1650 kg deionised water

2.25 kg disodium EDTA

225 kg sodium acetate

9,0 kg sodium metabisulfite

45 kg 80% acetic acid

Heat at 40-60°C until complete solution

Take the temperature of the solution to 85-100°C then slowly pour (pour the first quarter of the solution in about 30', wait for precipitation, then pour the remaining solution in further about 30') all the acid solution containing the product

Then keep at 85-100°C for at least 10'

Cool the bulk at 25-40°C then centrifuge washing with

3000 kg deionised water

Dry at 60-70°C

About 280 kg solvent-free heavy mesalamine is obtained (bulk density greater than or equal to 0.30 g/ml - free of organic solvents)

Yield: 93.3% EXAMPLE 2

In a first reactor, there are loaded:

15.0 kg mesalamine

or alternatively

300 kg crude mesalamine (use the amount equivalent of wet product)

100 kg deionised water

12.7 kg 37% hydrochloric acid

Heat the bulk at 40-60°C until complete solution Add

0.275 kg bleaching coal

Filter the suspension and put aside

In a second reactor, there are loaded:

82.5 kg deionised water

0,11 kg disodium EDTA

1 ,25 kg sodium acetate

0.45 kg sodium metabisulfite

2.25 kg 80% acetic acid

Heat at 40-60°C until complete solution, then add

8.3 kg acetone

Take the temperature of the solution to 75-85°C then slowly pour (pour the first quarter of the solution in about 30', wait for precipitation, then pour the remaining solution in further about 30') all the acid solution containing the product

Then keep at 75-85°C for at least 10'

Cool the bulk at 25-40°C then centrifuge washing with

150 kg deionised water

Dry at 60-70°C

About 14.0 kg heavy mesalamine is obtained (bulk density greater than or equal to 0.40 g/ml - residual acetone lower than 1000 ppm)

Yield: 93.3%