ACID ADDITION SALTS OF BENZIMIDAZOLE DERIVATIVE

Abstract

The present invention relates to a pidolate salt and malate salt of a compound represented by a formula 1 with an excellent liquid-phase stability, solid-phase stability, water solubility, precipitation stability and hygroscopicity all together as a compound for preventing and treating diseases mediated by an acid pump antagonistic activity, as well as a method for preparing the same.

Claims

1-14. (canceled)

15. A pidolate salt of a compound represented by Formula 1, prepared by a process comprising: a) dissolving a compound represented by Formula 1 and pyroglutamic acid in an organic solvent, thereby creating a solution; b) concentrating the solution under decompression to precipitate a solid, then adding a co-solvent and stirring; and c) filtering out and drying the precipitated solid: ##STR00009## .

16. The method of 15, wherein the organic solvent is added in a volume 5 to 20 times (volume/weight) compared to the amount of compound represented by Formula 1.

17. The method of claim 15, wherein the organic solvent is methanol.

18. The method of claim 16, wherein the methanol is added in a volume 5 to 20 times (volume/weight) compared to the amount of compound represented by Formula 1.

19. The method of claim 18, wherein the methanol is added in a volume 10 times (volume/weight) compared to the amount of compound represented by Formula 1.

20. The method of claim 15, wherein the co-solvent is a mixed solution of acetone and ethyl acetate.

21. The method of claim 20, wherein the ratio of acetone to ethyl acetate is 1:4 (v/v).

22. The method of claim 20, wherein the mixed solution of acetone and ethyl acetate is added in a volume 5 to 20 times (volume/weight) compared to the amount of compound represented by Formula 1.

23. The method of claim 22, wherein the mixed solution of acetone and ethyl acetate is added in a 5 times (volume/weight) compared to the amount of compound represented by Formula 1.

24. The method of claim 15, wherein the pyroglutamic acid is L-pyroglutamic acid.

25. A malate salt of a compound represented by Formula 1, prepared by a process comprising: a) dissolving a compound represented by Formula 1 and malic acid in an organic solvent, thereby creating a solution; b) concentrating the solution under decompression to precipitate a solid, then adding a co-solvent and stirring; and c) filtering out and drying the precipitated solid: ##STR00010## .

26. The method of 25, wherein the organic solvent is added in a volume 5 to 20 times (volume/weight) compared to the amount of compound represented by Formula 1.

27. The method of claim 25, wherein the organic solvent is methanol.

28. The method of claim 27, wherein the methanol is added in a volume 5 to 20 times (volume/weight) compared to the amount of compound represented by Formula 1.

29. The method of claim 28, wherein the methanol is added in a volume 10 times (volume/weight) compared to the amount of compound represented by Formula 1.

30. The method of claim 25, wherein the co-solvent is a mixed solution of acetone and ethyl acetate.

31. The method of claim 30, wherein the ratio of acetone to ethyl acetate is 1:4 (v/v).

32. The method of claim 30, wherein the mixed solution of acetone and ethyl acetate is added in a volume 5 to 20 times (volume/weight) compared to the amount of compound represented by Formula 1.

33. The method of claim 32, wherein the mixed solution of acetone and ethyl acetate is added in a 5 times (volume/weight) compared to the amount of compound represented by Formula 1.

34. The method of claim 25, wherein the malic acid is L-malic acid.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0055] FIG. 1 shows a .sup.1H-NMR results of a pidolate salt of an amorphous compound of a formula 1, prepared according to an embodiment of the present invention.

[0056] FIG. 2 shows a .sup.1H-NMR results of a malate salt of an amorphous compound of the formula 1, prepared according to an embodiment of the present invention.

[0057] FIG. 3 shows a PXRD results of a pidolate salt of an amorphous compound of the formula 1, prepared according to an embodiment of the present invention.

[0058] FIG. 4 shows a PXRD results of a malate salt of an amorphous compound of the formula 1, prepared according to an embodiment of the present invention.

[0059] FIG. 5 shows a PXRD results of a fumaric acid salt of an amorphous compound of the formula 1, prepared according to an embodiment of the present invention.

[0060] FIG. 6 shows a PXRD results of an oxalic acid salt of an amorphous compound of the formula 1, prepared according to an embodiment of the present invention.

[0061] FIG. 7 shows a PXRD results of a citric acid salt of an amorphous compound of the formula 1, prepared according to an embodiment of the present invention.

[0062] FIG. 8 shows a PXRD results of a tartaric acid salt of an amorphous compound of the formula 1, prepared according to an embodiment of the present invention.

[0063] FIG. 9 shows a DSC results of a free base of a crystalline compound of the formula 1.

[0064] FIG. 10 shows a DSC results of a pidolate salt of an amorphous compound of the formula 1, prepared according to an embodiment of the present invention.

[0065] FIG. 11 shows a DSC results of a malate salt of an amorphous compound of the formula 1, prepared according to an embodiment of the present invention.

MODE FOR INVENTION

[0066] Hereinafter, configuration and effects of the present invention will be described in more detail in light of the following Examples which are set forth to illustrate, but are not to be construed to limit the present invention.

Example 1: Preparing of a Pidolate Salt of a Compound of a Formula 1

[0067] A 100 g of a crystalline compound of a formula 1 and 34.98 g of L-pyroglutamic acid (1.05eq.) were completely dissolved in 1000 ml of methanol at 25° C., and then a resulting solution was concentrated at 50° C. while being stirred under decompression until a solid was precipitated. A co-solvent of acetone and ethyl acetate was added to a concentrate at 25° C. at a ratio of acetone:ethyl acetate = 1:4 (500 ml), and a resulting solution was stirred agitatedly for 30 minutes. The solid was filtered out under decompression, washed with 100 ml of ethyl acetate, and vacuum-dried at 40° C. for 16 hours, such that a pidolate salt of an amorphous compound of the formula 1 was obtained by 113.8 g (yield 85.4%) in a form of white powder (FIG. 1).

Example 2: Preparing of a Malate Salt of a Compound of a Formula 1

[0068] A 100 g of a crystalline compound of a formula 1 and 36.33 g of L-malic acid (1.05eq.) were completely dissolved in 1000 ml of methanol at 25° C., and then a resulting solution was concentrated at 50° C. while being stirred under decompression until a solid was precipitated. A co-solvent of acetone and ethyl acetate was added to a concentrate at 25° C. at a ratio of acetone:ethyl acetate = 1:4 (500 ml), and a resulting solution was stirred agitatedly for 30 minutes. The solid was filtered out under decompression, washed with 100 ml of ethyl acetate, and vacuum-dried at 40° C. for 16 hours, such that a malate salt of an amorphous compound of the formula 1 was obtained by 120.4 g (yield 89.4%) in a form of white powder (FIG. 2).

Comparative Example 1: Preparing of an Amorphous Free Base of a Compound of a Formula 1

[0069] A 100 g of a compound of a formula 1 was completely dissolved in 1000 ml of methanol at 25° C., and then a resulting solution was concentrated at 50° C. while being stirred under decompression until a solid was precipitated. A co-solvent of acetone and ethyl acetate was added to a concentrate at 25° C. at a ratio of acetone:ethyl acetate = 1:4 (500 ml), and a resulting solution was stirred agitatedly for 30 minutes. The solid was filtered out under decompression, washed with 100 ml of ethyl acetate, and vacuum-dried at 40° C. for 16 hours, such that a free base of an amorphous compound of the formula 1 was obtained by 94.7 g (yield 94.7%) in a form of white powder.

Experimental Example 1: Comparative Test on Solubility

[0070] Amorphous acid addition salts were prepared after 12 acids were selected as shown in a table 3 so that an anion could not act as a nucleophile after the compound was protonated/acidificated by means of acid addition salts, while enhancing a solubility of a compound of the formula 1.

TABLE-US-00003 No. Types of acid for preparing acid addition salts 1 Succinic acid 2 Fumaric acid 3 Oxalic acid 4 Citric acid 5 L-pyroglutamic acid 6 1.5-naphinalene disulfonic acid 7 p-toluenesulfonic acid 8 Benzene sulfonic acid 9 L-malic acid 10 Nicotinic acid 11 2.5-dihydroxybenzoic acid 12 L-tartaric acid

[0071] Specifically, in case of 11 acids excluding 1.5-naphthalene disulfonic acid, acid addition salts were prepared in such a way that an equivalent weight thereof was at a molar ratio of 1:1 between each of the acids and a compound of the formula 1. In case of 1.5-naphthalene disulfonic acid, a hemi-salt was prepared in such a way that an equivalent weight thereof was at a molar ratio of 0.5:1 between this acid and a compound of the formula 1. The above-mentioned preparing method was the same as in Examples 1 and 2.

[0072] A following table 4 indicates a water solubility of the 12 amorphous acid addition salts at a room temperature. Each of water solubility was measured by means of a supersaturation method. Each solubility was not converted based on a free base of the formula 1, but a solubility of acid addition salts per se was measured, wherein results thereof were indicated in a following table 4. Also, a solubility of an amorphous free base of the compound of the formula 1 in the comparative example 1 was measured, wherein results thereof were indicated in a following table 4.

TABLE-US-00004 No. Types of acid used in preparing of acid addition salts of the compound of the formula 1 Water solubility (mg/ml) 1 Succinic acid 15 2 Fumaric add 52 3 Oxalic acid > 100 4 Citric acid 55 5 L-pyroglutamic acid > 100 6 1.5-naphinalenedisulfonic acid 25 7 p-toluenesulfonic acid 27 8 Benzene sulfonic acid 22 9 L-malic acid > 100 10 Nicotinic acid 5 11 2.5-dihydroxybenzoic acid 20 12 L-tartaric acid 58 13 Amorphous free base of the compound of the formula 1 3

[0073] As seen in the table 4, it was identified that out of 12 acid addition salts, six types of salt indicated a water solubility of 50 mg/ml or more. Specifically, fumaric, oxalic, citric, L-pyroglutamic, L-malic and L-tartaric acid salts exhibited an effect on improving solubility. In particular, it was also identified that oxalic, L-pyroglutamic and L-malic acid salts exhibited a remarkably excellent solubility of 100 mg/ml or more.

[0074] Based on the above-mentioned results, it could be seen that amorphous acid addition salts of the compound of the formula 1 had solubility greatly increased compared to an amorphous free base, in particular showing a different effect on improving solubility depending on salt types.

Experimental Example 2: X-ray Powder Diffraction (PXRD) Analysis

[0075] A PXRD analysis was performed to analyze crystalline changes of the compound of the formula 1 present in a salt of the compound of the formula 1.

[0076] Specifically, six types of amorphous acid-addition salt (L-pyroglutamic, fumaric, oxalic, citric, L-malic and L-tartaric acid salts) of a compound of the formula 1, having a water solubility of 50 mg/ml or more, as identified in the above-mentioned experimental example 1, were respectively inserted into each PE-bag and then the resulting bags were stored inside a stable chamber with the condition of 40° C. and 75% RH for one month. After then, a Cu-Kα line was used on an X-ray powder diffractometer (D8 Advance) to perform a PXRD analysis of the salts. The diffractometer was equipped with penetration and a current capacity was set to 45 kV and 40 mA. A divergence and scattering slit was set to 1° and a receiving slit was set to 0.2 mm. A θ-2θ continuous scan of 3°/minute (0.4 second/0.02° interval) was used from 5 to 35° 2θ.

[0077] As a result of checking PXRD in one month after storage, it was identified that all types of salt maintained to be amorphous, thereby having no crystal transition observed (FIGS. 3 to 8).

Experimental Example 3: Comparative Test on Liquid-phase Stability

[0078] Six types of amorphous acid addition salt (L-pyroglutamic, fumaric, oxalic, citric, L-malic and L-tartaric acid salts) of the compound of the formula 1, having a water solubility of 50 mg/ml or more, as identified in the experimental example 1, were respectively dissolved in purified water to be prepared at a concentration of 20 mg/ml, and then a resulting solution was stirred at 40° C., such that the solution was analyzed with an HPLC in an initial stage and on a first day. Accordingly, a generation amount of degradation products (a compound of a formula 4) was converted into a percentage (%) compared to an area under the curve (AUC) of the compound of the formula 1 in a diluent state without a polymorphism, wherein results thereof were indicated in a following table 5.

TABLE-US-00005 Acid addition salts Concentration (%) of degradation product (compound of the formula 4) Initial 1 day (24 hours) elapsed Fumaric acid - 0.20 Oxalic acid 0.10 0.57 Citric acid - 0.27 L-pyroglutamic acid 0.02 0.05 L-malic acid 0.03 0.07 L-tartaric acid 0.06 0.21

[0079] In result, it was identified that L-pyroglutamic and L-malic acid salts of the compound of the formula 1 had liquid-phase stability at least three times more excellent than other salts and a degradation product represented by the formula 4 compound was generated most in an oxalic acid salt of the compound of the formula 1. Therefore, in view of ICH guidelines on active pharmaceutical ingredients (API) of an injection formulation, in which degradation products must be managed to be 0.1% or less, it was identified that salts of L-pyroglutamic and L-malic acid salts only were pharmaceutically available and stable acid addition salts.

[0080] Meanwhile, in terms of physical properties, it was identified that citric and fumaric acid salts formed a sticky gel not to maintain a homogenous liquid-phase state, while the rest of four salts maintained a homogenous liquid-phase state.

Experimental Example 4: Comparative Test on Solid-phase Stability

[0081] Six types of amorphous acid-addition salt (L-pyroglutamic, fumaric, oxalic, citric, L-malic and L-tartaric acid salts) of a compound of the formula 1, having a water solubility of 50 mg/ml or more, as identified in the above-mentioned experiment 1, were respectively inserted into each PE-bag and then the resulting bags were stored inside a stable chamber with the condition of 40° C. and 75% RH for one month. Then, the generation amounts of water checked through Karl Fischer analysis, of impurity checked through HPLC analysis, and of degradation product (a compound of Formula 4) measured under the conditions identical to the experimental example 3, were respectively converted into an area percentage, wherein results thereof were indicated in a following table 6.

TABLE-US-00006 Acid addition salts Moisture (%) Concentration of degradation products (%) Total impurities (%) Initial 1 month elapsed Initial 1 month elapsed Initial 1 month elapsed Fumaric acid 0.1 0.3 0.09 0.12 0.14 0.43 Oxalic acid 0.4 0.4 0.11 0.19 0.16 0.30 Citric acid 0.2 0.2 0.09 0.17 0.12 0.27 L-pyroglutamic acid 0.1 0.1 0.02 0.02 0.07 0.07 L-malic acid 0.1 0.1 0.04 0.04 0.06 0.06 L-tartaric acid 0.6 0.7 0.10 0.18 0.15 0.25

[0082] In result, similarly to results of liquid-phase stability, a solid-phase accelerated stability was most excellent in L-pyroglutamic and L-malic acid salts of the compound of the formula 1, and a total amount of impurities was most in the fumaric acid salt. Therefore, in view of ICH guidelines on active pharmaceutical ingredients (API) of an injection formulation, in which impurities must be managed to be 0.1% or less, it was identified that L-pyroglutamic and L-malic acid salts only were pharmaceutically available and stable acid addition salts.

[0083] Meanwhile, in terms of physical properties, hygroscopicity was not observed in all types of salt and it was identified with naked eyes that a white powder type was maintained therein.

Experimental Example 5: Comparative Test on Precipitation Stability

[0084] Six types of amorphous acid-addition salt (L-pyroglutamic, fumaric, oxalic, citric, L-malic and L-tartaric acid salts) of a compound of the formula 1, having a water solubility of 50 mg/ml or more, as identified in the experimental example 1, were completely dissolved in a buffer solution of pH 6.8 at a concentration of 10 mg/ml respectively and stored at 37° C. for 24 hours. After that, states of such solutions were observed, wherein results thereof were indicated in a following table 7.

TABLE-US-00007 Acid addition salts Soil precipitation or not Fumaric acid Precipitated Oxalic acid Precipitated Citric acid Precipitated L-pyroglutamic acid Homogenous solution maintained L-malic acid Homogenous solution maintained L-tartaric acid Homogenous solution maintained

[0085] In result, it was identified that a solid was precipitated in fumaric, oxalic and citric acid salts, while a homogenous solution was maintained in L-pyroglutamic, L-malic and L-tartaric acid salts. Accordingly, it was identified that L-pyroglutamic, L-malic and L-tartaric acid salts have excellent precipitation stability.

Experimental Example 6: Temperature Differential Scanning Calorimetry (DSC) Analysis

[0086] DSC Q20, available from TA Company, was used to carry out a DSC measurement in an enclosed fan at a scanning speed of 10° C./min from 20 to 300° C. under nitrogen purification. Specifically, a DSC measurement was performed on a crystalline compound of the formula 1, which is a reactant of the examples 1 and 2, as well as an amorphous pidolate salt and malate salt, which are products.

[0087] In result, it was identified that amorphous acid addition salts (pidolate and malate salts) were synthesized from a free base of a crystalline compound of the formula 1 (FIGS. 9 to 11).

[0088] According to the above-mentioned results, it was identified that the pidolate of the compound of the formula 1 represented by the formula 2 as well as the malate salt of the compound of the formula 1 represented by the formula 3 were pharmaceutical ingredients for injection preparation, which are optimized for a benzimidazole derivative of the formula 1.

[0089] While specific parts of the present invention have been described in detail above, it is apparent to those skilled in the art that such detailed description are just exemplary embodiments, but are not to be construed to limit a scope of the present invention.

[0090] Accordingly, the substantial scope of the present invention will be defined based on accompanying claims and equivalents thereof.

[0091] The detailed descriptions about the contents that can be readily understood and inferred by those skilled in the art were omitted herein. In addition to detailed examples described in the present specification, various modifications are possible without departing from the technical idea or essential features of the present invention. Therefore, the present invention can be implemented in other ways than concretely described and illustrated in the present specification, and this is readily understood by those skilled in the art.