Process for preparing salcaprozate sodium in crystalline form i

Abstract

Process for preparing salcaprozate sodium of Formula I in the Crystalline Form I, said process comprising : a ) preparing a salcaprozate sodium solution; b ) subjecting the salcaprozate sodium solution to spray-drying in order to obtain particles of salcaprozate sodium in the crystalline Form I. Advantageously, the solution can be prepared using salcaprozate sodium of Formula I in any crystalline or amorphous form. The particles thus obtained have a substantially spherical shape, which improves the flowability of the product, with obvious advantages during subsequent handling and processing.

Description

[0001] PROCESS FOR PREPARING SALCAPROZATE SODIUM IN CRYSTALLINE FORM I .

[0002] Field of the invention .

[0003] The present invention relates to a process for the preparation of salcaprozate sodium of Formula I : Formula I in crystalline Form I .

[0004] Prior art .

[0005] Salcaprozate sodium ( SNAC ) is used as an excipient in the formulation of drugs with the function of enhancing chemical permeation and thus promoting the oral absorption of macromolecules , peptides and proteins such as insulin ( diabetes ) , heparin (heart attacks and angina ) and cyanocobalamin (vitamin B12 deficiency and anaemia ) that would otherwise have poor bioavailability . SNAC is considered safe for human consumption by the Food and Drug Administration ( FDA) .

[0006] Patent application WO 96 / 30036 relates to pharmaceutical compositions useful in the administration of active agents , such as biologically or chemically active peptides , for example calcitonin and insulin; polysaccharides or mucopolysaccharides , for example heparin; antibiotics or other organic substances . These active agents , i f not properly delivered, are rapidly deactivated or destroyed in the gastrointestinal tract by acid or enzymatic hydrolysis . To avoid such drawbacks , at least one organic acid ( or its salt ) having in its chemical structure an aromatic amide with a hydroxyl group in the ortho position of the aromatic ring and a lipophilic chain with a number of carbon atoms comprised between 4 and 20 is added to pharmaceutical compositions . Among organic acids with the above chemical structure , salcaprozate sodium of Formula I has shown particular ef fectiveness as a delivery carrier for active agents in selected biological systems .

[0007] The procedure reported in WO 96 / 30036 requires the use o f an aqueous solution of a metal hydroxide , speci fically sodium hydroxide , as the solvent of the condensation step between 8- aminooctanoic acid of Formula IV and 2-acetoxybenzoic acid chloride of Formula I I I to prepare the intermediate of Formula V :

[0008] Formula III Formula IV Formula V

[0009] However, the water present in the reaction medium causes partial hydrolysis of the compound of Formula I I I , resulting in a low reaction yield and the formation of 2-acetoxybenzoic acid, which remains as an impurity in the compound of Formula V, which must then be puri fied, further reducing the overall yield of the process .

[0010] Patent application WO 2001 / 070219 describes another synthetic route for the preparation of salcaprozate sodium, which includes an alkylation step of a protected / activated salicylamide by reaction with a dicarboxylate as an alkylating agent . This synthesis process involves a step that i s conducted at a temperature of 140 ° - 150 ° C, with evident energy expenditure and thus increased production costs . In addition, high quantities of organic solvents are required and reaction times are long . Finally, the solid intermediates of this process are poorly crystalline and di f ficult to filter, which makes it di f ficult to remove impurities from the finished product .

[0011] Patent application WO 2005 / 107462 describes the crystalline Form I of salcaprozate sodium of Formula I as an anhydrous polymorph that is stable at room temperature and does not change crystalline form when subjected to grinding or compression. Form I analysed by differential scanning calorimetry (DSC) shows a melting point with an onset temperature of about 198 °C and an XRPD dif f ractogram with characteristic peaks (expressed in degrees 20 ± O.2°0) at 2.98°, 14.53°, 15.72°, 26.36°. Form I is prepared by heating Forms III, V, VI, or mixtures thereof, to a temperature comprised between 50° and 110°C, or by heating the amorphous form to a temperature comprised between 30° and 90°C. Another method of preparing Form I by freeze-drying Forms II-VI and the amorphous form is also described.

[0012] The Applicant found that the process of preparing Form I by drying involves keeping the product in the dryer at a high temperature, above 80°C, for a long time, over 65 hours, with limited process efficiency and considerable energy expenditure. On the other hand, the freeze-drying as a method of preparation of Form I suggested by WO 2005 / 107462 is a process of deep vacuum drying of a frozen product (at very low temperatures, between -20° and -50°C) by means of sublimation, i.e. the direct transition from the solid to the vapour state. However, freeze-drying is particularly expensive due to the amount of energy required and the time needed to complete the process, which can be up to 4 days.

[0013] Therefore, there is the need for an improved process for the preparation of salcaprozate sodium in crystalline Form I, which is easy to implement on an industrial scale.

[0014] The Applicant has found that it is possible to obtain salcaprozate sodium in crystalline Form I via a spray-drying step of a salcaprozate sodium solution, which results in substantially spherical product particles, with numerous advantages that will be discussed in more detail below. Summary of the invention. The present invention thus relates to a process for preparing salcaprozate sodium of Formula I Formula I, in the crystalline Form I, said process comprising: a) preparing a solution of salcaprozate sodium; b) subjecting the solution of salcaprozate sodium to spraydrying so as to obtain particles of salcaprozate sodium in the crystalline Form I.

[0015] Advantageously, the solution referred to in step a) can be prepared using salcaprozate sodium of Formula I in any crystalline or amorphous form.

[0016] Furthermore, the solution mentioned in step a) can be prepared by avoiding the isolation step of salcaprozate sodium at the end of the synthesis process. As a result, the process is advantageously simplified with significantly reduced process times.

[0017] Advantageously, the salcaprozate solution can be prepared using water as a solvent, thus making the process environmentally compatible as it uses a reduced amount of organic solvents per kilogram of salcaprozate sodium produced. It can therefore be classified as a "green process".

[0018] Further aspects, features and advantages of the invention will become more apparent from the following detailed description .

[0019] Brief description of the figures.

[0020] Figure 1: XRPD dif fractogram of salcaprozate sodium of Form I obtained by spray-drying (bars indicate the position of typical Form I peaks) .

[0021] Figure 2: Electron microscope (SEM) analysis of salcaprozate sodium of Form I obtained by spray-drying. Figure 3: Electron microscopic (SEM) analysis of salcaprozate sodium of Form I obtained by crystallisation as reported in Example 1 of WO 2005 / 107462.

[0022] Figure 4: DSC analysis of salcaprozate sodium of Form I obtained by spray-drying.

[0023] Figure 5: TGA analysis of salcaprozate sodium of Form I obtained by spray-drying.

[0024] Figure 6: DVS analysis of salcaprozate sodium of Form I obtained by spray-drying (vapour adsorption and desorption isotherms and kinetic adsorption / desorption graph are shown) .

[0025] Figure 7: FT-IR spectrum of salcaprozate sodium of Form I obtained by spray-drying. List of abbreviations.

[0026] DMF: dimethyl formamide

[0027] NaOH: sodium hydroxide (or soda ash)

[0028] HC1 : hydrochloric acid

[0029] EDTA: ethylenediaminetetraacetic acid

[0030] SOC12: thionyl chloride

[0031] PCI3: phosphorus trichloride

[0032] PCI5: phosphorus pentachloride

[0033] DIPEA: N-ethyl-diisopropylamine

[0034] HMDA: hexamethylenediamine

[0035] NaHSCh: sodium hydrogen sulphite

[0036] XRPD: X-ray diffraction analysis

[0037] DSC: differential scanning calorimetry

[0038] TGA: thermogravimetric analysis

[0039] DVS: Dynamic Vapor Sorption

[0040] FT-IR: Fourier transform infrared spectroscopy.

[0041] Further aspects, features and advantages of the invention will become more apparent from the following detailed description . Detailed description of the invention. For the purposes of the present invention, in the following description and claims the definitions of numerical ranges comprise the individual values within the range itsel f and the corresponding extremes , unless speci fied otherwise . For the purposes of the present invention, in the following description and claims the term "comprising" also includes the terms "consisting of" or "essentially consisting of" .

[0042] The following is a synthesis scheme ( Scheme 1 ) of salcaprozate sodium according to a particular embodiment of the process according to the invention :

[0043] Scheme 1 According to a preferred aspect, in step a) the solution of salcaprozate sodium is prepared using salcaprozate sodium of Formula I in crystalline form, amorphous form, or combinations thereof.

[0044] According to a further preferred aspect, in step a) the solution of salcaprozate sodium is prepared using the compound of Formula V and at least one inorganic base containing Na+ . More specifically, the solution of salcaprozate sodium can be prepared using salcaprozic acid (compound of Formula V)

[0045] Formula V brought into contact with an inorganic base containing Na+ . This avoids the step of isolating salcaprozate sodium. Preferably, the inorganic base containing Na+ is selected from: sodium hydroxide, sodium carbonate, sodium bicarbonate, more preferably it is sodium hydroxide. Preferably, the inorganic base containing Na+ and the compound of formula V are in a molar ratio comprised between 0.95 and 1.10.

[0046] According to a further preferred aspect, in step a) the solvent is selected from: water; R-OH alcohols, where R is a straight or branched, preferably straight, Ci-Cg alkyl group, more preferably the alcohol is ethanol; ketones of general formula R1-CO-R2, wherein R1 and R2 groups, equal to or different from each other, are straight or branched Ci-Cg alkyl groups, preferably R1 is equal to R2, more preferably the ketone is acetone; or mixtures thereof.

[0047] Preferably, when in step a) the solution of salcaprozate sodium is prepared using the compound of Formula V and at least one inorganic base containing Na+, the solvent is water.

[0048] Preferably, when in step a) the solution of salcaprozate sodium is prepared using salcaprozate sodium of Formula I in crystalline form, amorphous form or combinations thereof, the solvent is a mixture of water / ethanol or water / acetone .

[0049] With reference to step a) , the ratio of the quantity of solvent to salcaprozate sodium of Formula I, calculated as weight / weight, is preferably comprised between 1.5 and 18.0, more preferably between 2.0 and 12.0, even more preferably between 2.5 and 10.0.

[0050] Preferably, in step a) the temperature is comprised between 15°C and 45°C, preferably between 20°C and 40°C.

[0051] According to a preferred aspect, in step a) the solution of salcaprozate sodium is stirred for a time comprised between 15 minutes and 1 hour.

[0052] With reference to step b) , the solution obtained in step a) is spray-dried by feeding it to a spray-dryer, selected from those known in the art.

[0053] Preferably, the temperature at the inlet of the spraydryer is comprised between 160°C and 240°C, preferably between 180 °C and 230 °C.

[0054] Preferably, the temperature at the outlet of the spraydryer is comprised between 80°C and 200°C, preferably between 100°C and 120°C.

[0055] According to a preferred aspect, the feeding rate of the solution to the spray-dryer is comprised between 5% and 50%, preferably between 5% and 15%.

[0056] Preferably, the spray-drying step is carried out under an inert atmosphere, in particular a nitrogen atmosphere. Preferably, the nitrogen pressure in the spray-dryer is comprised between 2.5 bar and 6.5 bar, more preferably between 3.5 bar and 5.5 bar.

[0057] According to a preferred aspect, the salcaprozate sodium particles in crystalline Form I obtained from step b) have a specific physical form. Preferably, such particles have a substantially spherical shape. The shape of the particles affects several bulk properties: fluidity, processability, delivery efficiency, handling, packaging. Advantageously, the substantially spherical particles obtained by the process of the invention (see Figure 2) exhibit better flow properties than more irregular particles, such as the needle-like particles obtained by the process described in WO 2005 / 107462 (see Figure 3) . In fact, irregularly needle-shaped particles are more cohesive and have a greater tendency to form aggregates than particles with a smooth surface, causing clogging problems during processing. Particle shape can also affect the viscosity of the final formulation of the active ingredient .

[0058] The following examples are provided for illustrative purposes only, so these examples are not intended to limit the scope of the invention.

[0059] Example 1. Preparation of a toluene solution of 2- acetoxybenzoyl chloride of Formula III.

[0060] A reactor was equipped with coolant and a drip funnel and kept in an inert atmosphere by means of nitrogen flow. The reactor was connected to a trap containing soda ash to neutralise the acid vapours. 90.9 g of 2-acetoxybenzoic acid of Formula II, 3.8 g of dimethylformamide (DMF) and 632 g of toluene were loaded into the reactor and the temperature was increased to 45±5°C. Over a period of approximately 60 minutes, while maintaining a temperature of 45±5°C, 78.2 g of thionyl chloride was dripped and then the reaction was stirred for 1.5 hours at a temperature of 45±5°C. After stirring, the end-of- reaction check was performed (residual acetylsalicylic acid less than 5%) . A total of 553 ml of toluene was then distilled under vacuum, keeping the temperature below 60 °C. In the reactor, 159 g of toluene was loaded and 184 ml of toluene was distilled under vacuum, keeping the temperature below 60°C. In the reactor, 159 g of toluene was loaded again and 184 ml toluene was distilled under vacuum, keeping the temperature below 60°C. After distillation, the reactor was brought back to atmospheric pressure and 236 g of toluene was loaded. The toluene solution obtained containing 100.0 g of 2- acetoxybenzoyl chloride of Formula III was used as such in the next step.

[0061] Example 2. Preparation of 8- ( 2-hydroxybenzamide ) octanoic acid, compound of Formula V.

[0062] (2a) Preparation of an aqueous solution of the compound of Formula IV-A.

[0063] A reactor was equipped with coolant and a drip funnel and kept in an inert atmosphere by means of nitrogen flow. 100.0 g of 8-aminoctanoic acid of Formula IV was loaded into the reactor. A solution was prepared with 111.0 g of soda ash in beads (NaOH) and 927.5 g of water by cooling to keep the temperature below 40°C. The soda solution was transferred to the reactor containing 8-aminoctanoic acid, keeping the temperature below 25°C. Stirring continued for 20 minutes, after which the solution of the compound of Formula IV-A was cooled to 0°-5°C.

[0064] (2b) Preparation of an aqueous solution of the compound of Formula V-A.

[0065] Over a period of about 3 hours, while maintaining a temperature of 0-5°C, the toluene solution of 2-acetoxybenzoyl chloride of Formula III prepared in Example 1 was added to the reactor containing the aqueous solution of the compound of Formula IV-A. After addition, the reaction was stirred for 1 hour at a temperature of 0°-5°C, the temperature was then increased to 20-25°C and stirring continued for a further 8 hours. An end-of-reaction check was carried out (2- acetoxybenzoyl chloride residue <1.0%) . Stirring was stopped and the two phases were separated. The overlying toluene phase was sent for disposal. The underlying aqueous phase containing the product (aqueous solution of the compound of Formula V-A) was reloaded into the reactor.

[0066] (2c) Preparation of the compound of Formula V.

[0067] A 6% (w / w) dilute solution of hydrochloric acid was prepared by diluting 167.1 g of 37% (w / w) HC1 in 862.0 g of water. Keeping the temperature T<25°C, the dilute hydrochloric acid solution thus prepared was slowly dripped into the reactor containing the aqueous solution of the compound of Formula V- A until a pH of 6.010.2 was reached. During addition, precipitation of the product (compound of Formula V) was observed. When the pH was stable at 6.010.2, stirring continued for about 1 hour. The pH was checked again and, if necessary, it was brought back within the range of 6.010.2. The suspended solid was filtered and the panel was washed twice with 200.0 g of water. The solid was not dried, but left moist. Based on weight loss, 100.0 g of compound of Formula V was obtained (72% molar yield, informative value) .

[0068] (2d) Purification of the compound of Formula V.

[0069] In cases where the compound of Formula V obtained from the previous step had a purity of less than 98%, at least one of the following purifications was performed.

[0070] Purification 1.

[0071] Maintaining the temperature T<40°C, a 2 M solution of soda ash (NaOH 2M) was prepared by dissolving 32.0 g of soda ash beads in 385.0 g of water. A suitable reactor was equipped with coolant and a drip funnel and kept in an inert atmosphere by means of nitrogen flow. The wet compound of Formula V obtained from the previous step and the previously prepared 2 M solution of soda ash were loaded into the reactor and stirred for about 20 minutes at a temperature of 20°-25°C. During this time the solid melts. To the solution containing the compound of Formula V and soda ash, 1.0 g EDTA (1% w / w) was added and stirred for 20 minutes. The solution was then filtered onto cellulose and the panel was washed with 20.0 g of water. The solution of the compound of Formula V and filtered soda ash was reloaded into the reactor. A 1.2 M solution of HC1 was prepared by diluting 65.3 g of HC1 37% (w / w) with 665.0 g of water. The 1.2 M solution of HC1 was slowly dripped into the reactor containing the solution of the compound of Formula V and soda ash until a pH of 6.010.2 was reached. During addition, precipitation of the product (compound of Formula V) was observed. When the pH was stable at 6.010.2, stirring continued for about 1 hour. The pH was checked again and, if necessary, it was brought back within the range of 6.010.2. The suspended solid was filtered and the panel was washed three times with 100.0 g of water. The solid was not dried, but left wet by water. Based on weight loss, 90.0 g of the compound of Formula V was obtained (purification yield 90% molar, informative value) . The weight loss (corresponding to the wetting water) had to be comprised between 20% and 30%.

[0072] Purification 2.

[0073] A reactor was equipped with coolant and a drip funnel and kept in an inert atmosphere by means of nitrogen flow. The wet compound of Formula V obtained from the previous step was loaded into the reactor; if the weight loss was less than 20%, water was loaded into the reactor until the amount of water present was between 20% and 30%. A total of 355.5 g of methanol was loaded into the reactor and the mass was heated to a temperature of 50°C13°C, resulting in a complete solution. Stirring was continued for 20 minutes. Maintaining a temperature of 50°C±3°C, over a period of approximately 2 hours, 450.0 g of water was dripped into the reactor; product precipitation was observed during addition. After addition, the suspension was stirred at 50°C±3°C for at least 30 minutes, then cooled to 20°-25°C and kept stirring for 2 hours. The product was filtered and the panel was washed twice with 180.0 g water. The wet solid was dried in an oven at 50°C under vacuum for 16 hours, yielding 81.0 g of the compound of Formula V.

[0074] Example 3. Preparation of salcaprozate sodium of Formula I.

[0075] A reactor was equipped with coolant and a drip funnel and kept in an inert atmosphere by means of nitrogen flow. 81.0 g of compound of Formula V and 243 ml of absolute ethanol were loaded into the reactor. The reaction mixture was heated to a temperature of 35°C. A soda ash solution was prepared by dissolving 11.6 g of soda ash beads in 40 ml of water. The soda solution thus prepared was dripped into the reactor containing the compound of Formula V and ethanol. Stirring continued for 1 hour resulting in a solution of salcaprozate sodium of Formula I. The solution of salcaprozate sodium of Formula I was microfiltered. Maintaining a temperature of 30°- 35°C, 243 ml ethanol and then 296 ml heptane were added to the filtered solution. During this addition, the product precipitated. The suspension was cooled to a temperature of 10°C and stirred for 3 hours. The suspended solid was filtered and the panel was washed with 160 ml of heptane. 83.0 g of salcaprozate sodium were obtained. Example 4. Preparation of salcaprozate sodium of Formula I.

[0076] In a reactor, 81 g of the compound of Formula V was suspended in 162 g of water, the temperature was stabilised at 20°-25°C, stirring was initiated and maintained for half an hour. Keeping the temperature T<30°C, over a period of about 1 hour, 152 ml of NaOH 2M were dripped until a pH=8.610.1 was obtained. The suspended product dissolved slowly. After the addition, the temperature was raised to 33°±3°C and stirring continued for 30-45 minutes. The resulting solution was sent to the spray-dryer and sprayed with an inlet temperature of 220°C and an outlet temperature of 112°C. The sprayed product was recovered from the spray-dryer collection vessel, yielding 73 g of salcaprozate sodium in the crystalline Form I (see Figure 1 ) .

[0077] Example 5. Preparation of salcaprozate sodium of Formula I.

[0078] In a reactor, 83 g salcaprozate sodium was dissolved with a previously prepared mixture of 373 g water and 373 g ethanol. The resulting solution was sent to the spray-dryer and sprayed with an inlet temperature of 220°C and an outlet temperature of 112 °C. The sprayed product was recovered from the spraydryer collection vessel, yielding 73 g of salcaprozate sodium in the crystalline Form I (see Figure 1) .

[0079] Example 6. Preparation of salcaprozate sodium of Formula I.

[0080] In a reactor, 83 g salcaprozate sodium was dissolved with a previously prepared mixture of 373 g water and 373 g acetone. The resulting solution was sent to the spray-dryer and sprayed with an inlet temperature of 220°C and an outlet temperature of 112 °C. The sprayed product was recovered from the spraydryer collection vessel, yielding 73 g of salcaprozate sodium in the crystalline Form I (see Figure 1) .

[0081] Example 7. Characterisation of salcaprozate sodium in crystalline Form I obtained by spray-drying.

[0082] X-ray diffraction analysis (XPRD) .

[0083] The salcaprozate sodium of Form I obtained from the above examples was characterised by XPRD. The XRPD dif f ractogram is shown in Figure 1. Table 1 below shows the positions of the peaks (2Theta) and their relative intensities. Characteristic peaks are indicated by (U) : Table 1

[0084] Differential scanning calorimetry (DSC) .

[0085] The DSC plot obtained is shown in Figure 4 and shows the behaviour of a product sample subj ected to heat treatment with a constant temperature variation : an endothermic onset event 198 . 28 ° C was recorded .

[0086] Thermogravimetric analysis (TGA) .

[0087] The TGA plot obtained is shown in Figure 5 and shows the change in mass undergone by the sample as a function of a constant temperature change ( constant heating rate ) : an overall mass change of 75 . 17 % was recorded .

[0088] Dynamic Vapour Sorption (DVS) .

[0089] Figure 6 shows the vapour adsorption and desorption isotherms and the kinetic adsorption / desorption graph . The relative changes in sample mass at each relative humidity level are shown in Table 2 : Table 2

[0090] Caption Table 2: RH = Relative Humidity; Mass; Mass change;

[0091] Relative mass change; First Read; After purge.

[0092] Prior to DVS analysis, 120 mg of the test powder was dried under vacuum at 50°C for 48 hours. After at least 2 hours of temperature balancing at 25°C (balance head temperature set at 30°C) , the instrument balances were calibrated using a reference material provided by the instrument manufacturer and then calibrated before adding the sample. A quantity of approximately 20 mg of dried sample powder was placed in the calibrated cup in the sample chamber. After sealing the chamber, the sample was left to balance at approximately 0% relative humidity for at least 500 minutes. The initial mass of the sample was recorded after balance was reached (> 500 min) . The relative humidity of the nitrogen atmosphere was then sequentially increased to levels of approximately 5, 10, 20, 30, 40, 50, 60, 70, 80, 90 and 95% relative humidity, then reduced to approximately 0% relative humidity with decrements of 10% . The system was left to balance for at least 40 minutes and a maximum of 180 minutes for each relative humidity level . The temperature was set to 25 ° C .

[0093] FT-IR: Fourier transform infrared spectroscopy .

[0094] Figure 7 shows the spectrum obtained by FT- IR spectroscopy of the salcaprozate sodium of Form I obtained by spraying in the spray-dryer . Table 3 below shows the allocation o f characteristic peaks :

[0095] Table 3

[0096] Electron microscope analysis (SEM) .

[0097] Analyses using an electron microscope ( SEM) showed particles with an essentially spherical shape , where the particle surfaces are essentially smooth ( see Figure 2 ) . In addition, the presence of irregularly shaped particles due to break-ups caused by collisions between particles was observed, whereas no presence of agglomerates was observed . Comparison with respect to electron microscope analysis ( SEM) of salcaprozate sodium particles in Form I obtained according to WO 2005 / 107462 .

[0098] Electron microscopic analysis ( SEM) of salcaprozate sodium in Form I obtained by means of the crystallisation reported in Example 1 of WO 2005 / 107462 ( see Figure 3 ) shows rather irregular solid particles with a mostly needle-like ( stick-like ) structure . The surfaces appear to be quite smooth . The presence of finer particles resulting from the breaking up of larger particles can also be observed, as well as the presence of agglomerates of various si zes . The tendency to form aggregate structures, typical of needle or stick shapes, makes subsequent processing more difficult.

Claims

CLAIMS1. Process for preparing salcaprozate sodium of Formula IFormula I, in the crystalline Form I, said process comprising: a) preparing a solution of salcaprozate sodium; b) subjecting the solution of salcaprozate sodium to spraydrying so as to obtain particles of salcaprozate sodium in the crystalline Form I.

2. Process according to claim 1, wherein in step a) the solution of salcaprozate sodium is prepared using salcaprozate sodium of Formula I in crystalline form, amorphous form, or combinations thereof.

3. Process according to claim 1, wherein in step a) the solution of salcaprozate sodium is prepared using the compound of Formula VFormula V and at least one inorganic base containing Na+ .

4. Process according to claim 3, wherein the inorganic base containing Na+ is selected from: sodium hydroxide, sodium carbonate, sodium bicarbonate, more preferably it is sodium hydroxide .

5. Process according to claim 3 or 4, wherein the inorganic base containing Na+ and the compound of formula V are in a molar ratio comprised between 0.95 and 1.10.

6. Process according to any one of the preceding claims, wherein in step a) the solvent is selected from: water; R-OH alcohols, where R is a straight or branched, preferablystraight, Ci-Cg alkyl group, more preferably the alcohol is ethanol; ketones of general formula R1-CO-R2, wherein R1 and R2 groups, equal to or different from each other, are straight or branched Ci-Cg alkyl groups, preferably R1 is equal to R2 , more preferably the ketone is acetone; or mixtures thereof.

7. Process according to any one of the preceding claims, wherein in step a) the ratio of the solvent to salcaprozate sodium of Formula I, calculated as weight / weight, is comprised between 1.5 and 18.0, preferably between 2.0 and 12.0, more preferably between 2.5 and 10.0.

8. Process according to any one of the preceding claims, wherein in step a) the temperature is comprised between 15°C and 45°C, preferably between 20°C and 40°C.

9. Process according to any one of the preceding claims, wherein in step b) the solution obtained in step a) is subjected to spray-drying by feeding to a spray-dryer, with a spray-dryer inlet temperature comprised between 160°C and 240°C, preferably between 180°C and 230°C.

10. Process according to any one of the preceding claims, wherein in step b) the solution obtained in step a) is subjected to spray-drying by feeding to a spray-dryer, with a spray-dryer outlet temperature comprised between 80°C and 200°C, preferably between 100°C and 120°C.

11. Process according to any one of the preceding claims, wherein in step b) the solution obtained in step a) is subjected to spray-drying by feeding to a spray-dryer, with a feeding rate comprised between 5% and 50%, preferably between 5% and 15%.

12. Process according to any one of the preceding claims, wherein in step b) the solution obtained in step a) is subjected to spray-drying by feeding to a spray-dryer under nitrogen atmosphere, with a nitrogen pressure comprisedbetween 2.5 bar and 6.5 bar, preferably between 3.5 and 5.5 bar .

13. Process according to any one of the preceding claims, wherein in step b) the salcaprozate sodium particles obtained by spray-drying have a substantially spherical shape.

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