WO2007120924A1

WO2007120924A1 - Preparation of tegaserod maleate free of iodide

Info

Publication number: WO2007120924A1
Application number: PCT/US2007/009559
Authority: WO
Inventors: Gustavo Frenkel
Original assignee: Teva Pharmaceutical Industries Ltd.; Teva Pharmaceuticals Usa, Inc.
Priority date: 2006-04-17
Filing date: 2007-04-17
Publication date: 2007-10-25

Abstract

Provided are processes for the preparation of tegaserod maleate free of iodide.

Description

PREPARATION OFTEGASERODMALEATE FREE OFIODIDE

CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 60/792,816, filed April 17, 2006. The contents of which are incorporated herein by reference.

FIELD OF THE INVENTION

The present invention provides processes for the preparation of tegaserod maleate free of iodide.

BACKGROUND OF THE INVENTION

Tegaserod maleate is an aminoguanidine indole 5HT4 agonist for the treatment of irritable bowel syndrome (IBS). Tegaserod maleate has the following structure:

It is reportedly a white to off-white crystalline powder and is slightly soluble in ethanol and very slightly soluble in water. Physician 's Desk Reference, 57^th ed., page 2339.

The purity of the API produced in the manufacturing process is an important consideration in determining commercial feasibility. Impurities introduced during commercial manufacturing processes must be limited to very small amounts, and are preferably substantially_^ absent. For example, the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use ("ICH") Q7A guidance (dated November 10, 2000) for API manufacturers requires that process impurities be maintained below set limits by specifying the quality of raw materials, controlling process parameters, such as temperature, pressure, time, and stoichiometric ratios, and including purification steps, such as crystallization, distillation, and liquid-liquid extraction, in the manufacturing process.

The product of a chemical reaction is rarely a single compound with sufficient purity to comply with pharmaceutical standards. Side products and by-products of the reaction and adjunct reagents used in the reaction will, in most cases, also be present in the product. At certain stages during processing of an API, such as tegaserod maleate, the API must be analyzed for purity, typically, by HPLC or TLC analysis, to determine if it is suitable for continued processing and, ultimately, for use in a pharmaceutical product. The API need not be absolutely pure, as absolute purity is a theoretical ideal that is typically unattainable. Rather, purity standards are set with the intention of ensuring that an API is as free of impurities as possible, and, thus, is as safe as possible for clinical use. In the United States, the Food and Drug Administration guidelines recommend that the amounts of some impurities be limited to less than 0.1 percent.

A common scheme in the art for preparation of tegaserod is reaction of an indole-3-carbaldehyde with an aminoguanidine. (See e.g. US Patent No. 5,510,353, US Publication No. 20060106086). In this scheme, the aminoguanidine is in the form of an hydroiodide salt. It has not been appreciated in the art that this scheme results in a particular impurity that contaminates the final product.

SUMMARY OF THE INVENTION

In one embodiment the present invention provides a process for preparing tegaserod maleate comprising (a) providing a solution of tegaserod or a salt thereof having an iodide content of at least about 0.1% area by HPLC in a polar organic solvent selected from the group consisting of: C₁ -₈ alcohols, C₂-8 aUcyl esters, C_2-8 ethers, C_5-8 aromatic hydrocarbons, C_3-S ketones, acetonitrile and mixtures thereof and, (b) combining maleic acid with the solution at a temperature of about 20⁰C to about reflux to obtaip te.gaserod maleate containing less than about 0.1% area by HPLC iodides.

In one embodiment the present invention provides a process for preparing tegaserod maleate comprising (a) providing a solution of tegaserod hemi-maleate hemihydrate having an iodide content of at least about 0.1% area by HPLC in a polar organic solvent selected from the group consisting of: Ci_-8 alcohols, C₂-S alkyl esters, C2-8 ethers, C5.8 aromatic hydrocarbons, C3-8 ketones, acetonitrile and mixtures thereof; and (b) combining maleic acid with the solution at a temperature of about 20⁰C to about reflux to obtain tegaserod maleate containing less than about 0.1% area by HPLC iodides.

In one embodiment the present invention provides a process for preparing tegaserod maleate containing less than about 0.1% area by HPLC iodides comprising:

(a) reacting N-amino-N'-pentylguanidine hydroiodide ("AGP-HI") and 5- Methoxy-lH-indole-3-carbaldehyde ("MICHO") in an aqueous reaction mixture to obtain tegaserod base;

(b) extracting the tegaserod base with a water immiscible organic solvent to obtain a mixture;

(c) combining the mixture with n-propanol to obtain a solution;

(d) combining maleic acid with the solution at a temperature of about 20⁰C to about reflux, and

(e) recovering the tegaserod maleate containing less than about 0.1% area by HPLC iodides.

DETAILED DESCRIPTION QF THE INVENTION

As used herein, unless otherwise defined, the term "room temperature" refers to a temperature between about 15°C and about 30⁰C.

As used herein, unless otherwise defined, the term "vacuum" refers to a pressure below about 100 mm Hg₅ preferably below about 30 mm Hg.

As used herein, unless otherwise defined, the term "slurry" refers to a hetrogeneous mixture where complete dissolution does not occur.

As used herein, the term "polar solvent" refers to a solvent having a Polarity Index (PI) of about 2.0 or higher. We have now discovered that tegaserod, including its salts such as the maleate, obtained from processes that use a hydroiodide salt of gunaidine are contaminated with iodide impurites. The iodide impurity is not appreciated in the art and is not reported in the literature.

We have discovered that the iodide impurity can be eliminated during a process which converts tegaserod to tegaserod maleate. This process can also be caried out by starting with a salt of tegaserod, such as a maleate or acetate. Accordingly, the present invention provides a process for preparing tegaserod maleate free of iodides. As used herein, unless otherwise defined, the term "free", in reference to the iodide level of tegaserod maleate or tegaserod base, relates to an iodide level of less than about 0.1 % area by HPLC.

The process of the invention comprises: (a) providing a solution of tegaserod or a salt thereof having an iodide content of at least about 0.1% area by HPLC in a polar organic solvent selected from the group consisting of: C_1-8 alcohols, Czs alkyl esters, C₂-₈ ethers, Cs-g aromatic hydrocarbons, C₃..₈ ketones, acetonitrile and mixtures thereof, (b) combining maleic acid with the solution at a temperature of about 20⁰C to about reflux to obtain tegaserod maleate containing less than about 0.1% area by HPLC iodides, and (c) recovering the tegaserod maleate containing less than about 0.1% area by HPLC iodides.

When starting from the TGS-Ma salt, a neutralization is not necessary. Slurrying the TGS-Ma in a polar organic solvent selected from the group consisting of: Ci-8 alcohols, C_2-8 alkyl esters, C_2-8 ethers, Cs-g aromatic hydrocarbons, C₃-8 ketones, acetonitrile and mixtures thereof in a temperature of about 50⁰C to about 70⁰C, would suffice.

An example of a C_2-8 alkyl ester is ethyl acetate.

Examples of C2-8 ethers include methyl-t-butyl ether and diethyl ether.

An example of a Cs_-8 aromatic hydrocarbon is toluene.

Examples of C3-s ketones include acetone and MIBK. .

An example of a C₁-_S alcohol is n-propanol. Preferably n-propanol is used, preferably in the ratio of about 1 : 10 to about 1:35 weight/volume Preferably, the.tegaserod or a salt thereof in the polar organic solvent is maintained at a temperature of of about 20⁰C to about relux until complete dissolution of the tegaserod or a salt thereof. As exemplified, a mixture of the tegaserod hemi- maleate hemi-hydrate in n-propanol is heated to obtain a solution.

Preferably, the solution of tegaserod or a salt thereof is combined with maleic acid at a temperature of about 60⁰C to about 70⁰C, more preferably, at a temperature of about 65°C.

Preferably, after addition of the maleic acid, the reaction mixture is maintained for at least about 1 hour, more preferably for about 4 hours. Preferably, the reaction mixture is maintained while stirring.

The reaction mixture is preferably cooled to room temperature. More preferably, the reaction mixture is cooled to room temperature to about 10⁰C, preferably about 25°C.

In one embodiment, the solvent is n-propanol, the TGS-Ma: n-propanol ratio is about 1 :10-l :35 weight/volume and the slurry is heated to about 65°C. Also, the slurry is preferably maintained, while stirring for about 1-12 hours and further cooled to a temperature of about room temperature to about 1O⁰C.

Tegaserod maleate containing less than about 0.1% area by HPLC iodides may be recovered from the reaction mixture by any method known in the art, such as filtration. The recovered salt can be washed, particularly with a polar organic solvent. It can also be dried. Drying can be accelerated by heating and/or reduced pressure. Preferably drying is carried out at a temperature of about 25°C to 45°C about, and a pressure of less than one atmosphere, more preferably less than about 200mmHg.

The iodide level of the obtained tegaserod maleate may be even further reduced by trituration (syn. slurry) with a polar organic solvent. Preferably the solvent is a Ci- g alcohols, particularly n-propanol. In this embodiment, tegaserod maleate is suspended in the solvent to obtain a heterogenous mixture. The mixture is then maintained to reduce amount of iodide impurites. The mixture may be stirred. The amount of time for which the mixture is maintained is preferably of about 1 to about 24 hours. The concentration of the mixture is is preferably of about 1:10 to about 1 :35 TGS-Ma: n-propanol weight/volume. The tegaserod maleate may be recovered by conventional techniques such as filtraton. When starting jrorn thye hemimaleate hemihydrate, tegaserod maleate containing less than about 0.1% can be obtained without recovery.

The tegaserod maleate obtained by the process of the present invention contains less than about 0.005% area by HPLC iodides.

The tegaserod base having iodide content can be synthesized accroding to the method in US Publication 20060106086 by reacting N-amino-N'-pentylguanidine hydroiodide ("AGP-HI") and S-Methoxy-lH-indole-S-carbaldehyde ("MICHO") in an aqueous reaction mixture. The process disclosed in US Publication 20060106086 is incorporated here by reference. The reaction of AGP-HI with MICHO can be carried out under acidic or basic conditions. For basic conditions, the pH during the reaction is from above 7 to about 14, more preferably about 9 to about 14, and for acidic conditions the pH is about 3 to about 7, more preferably about 3 to about 4.

In one an aqueous solution of AGP-HI is combined with a mixture of MICHO and a solid base. The base can be an alkali or alkaline earth metal base such as K₂CO₃, Na₂CO₃, NaHCO₃, NaOH or KOH. The base can be an organic base such as a C3 to C8 alkyl amine or pyridine, more preferably triethylamine. The organic base can be used as a neat reagent. If an acid is used, the acid can be an organic or inorganic acid. An organic acid such as p-toluensulfonic acid, pyridinium p- toluenesulfonic acid, methanesulfonic acid, acetic acid, maleic acid or mixtures thereof can be used. An inorganic acid such as HCl, HBr, H₃PO₄, H₂SO₄ and mixtures thereof can also be used.

The reaction mixture can be heated to accelerate the reaction. Preferably the temperature range during the reaction is about 50⁰C to about reflux temperature, more preferably of about 35°C to about 45°C. The reaction can be maintained for about 30 minutes to about 24 hours, such as for about 2 hours to about 4 hours.

The resulting tegaserod base can be extracted with a water immiscible organic solvent to obtain a mixture; combined with n-propanol to obtain a solution; the solution combined with maleic acid at a temperature of about 20⁰C to about reflux followed by recovery of the tegaserod maleate containing less than about 0.1% area by HPLC iodides. The tegaserod can be maintained at a temperature of of about 20⁰C to about relux temperature to obtain complete dissolution of the tegaserod. If the starting material is a salt (such as tegaserod acetate, sesquimaleate or maleate), it can be provided in crystalline form. Preferably, the tegaserod starting material is tegaserod hemi-maleate hemi-hydrate. The tegaserod hemi-maleate hemi- hydrate may be prepared by the methods described in PCT publication No. WO 2005/058819.

The amount of iodide impurities can be determined by chromatography. Generally, side products, by-products, and adjunct reagents (collectively "impurities") are identified spectroscopically and/or with another physical method, and then associated with a peak position, such as that in a chromatogram or a spot on a TLC plate. See, e.g., Strobel, H.A.; Heineman, W.R., Chemical Instrumentation: A Systematic Approach, 3rd ed., p.953 (Wiley & Sons: New York 1989). Thereafter, the impurity can be identified, e.g., by its relative position in the chromatogram, where the position in a chromatogram is conventionally measured in minutes between injection of the sample on the column and elution of the particular component through the detector. The relative position in the chromatogram is known as the "retention time."

The retention time can vary around a mean value based upon the condition of the instrumentation, as well as many other factors. To mitigate the effects such variations have upon accurate identification of an impurity, practitioners use the "relative retention time" ("RRT") to identify impurities. See id. at p. 922. The RRT of an impurity is its retention time divided by the retention time of a reference marker. It may be advantageous to select a compound other than the API that is added to, or present in, the mixture in an amount sufficiently large to be detectable and sufficiently low as not to saturate the column, and to use that compound as the reference marker for determination of the RRT.

Pharmaceutical compositions can be prepared by combining the tegaserod maleate of the present invention with at least one pharmaceutically acceptable excipient. The iodide content of the batches can be measured before hand and suitable batches can be selected.

. Having thus described the invention with reference to particular preferred embodiments and illustrative examples, those in the art may appreciate modifications to the invention as described and illustrated that do not depart from the spirit and scope of the invention as disclosed in the specification. The following examples are set forth to aid in understanding the invention but are not intended to, and should not be construed to limit its scope in any way. The examples do not include detailed descriptions of conventional methods. Such methods are well known to those of ordinary skill in the art and are described in numerous publications.

EXAMPLES HPLC method for measuring the iodide level of tegaserod maleate

Column stationary phase dimensions: YMC Basic 100*3 mm, 3μ

Mobile phase: Eluent "A": 20 niM Tetrabutylammonium Hydroxide, pH 7.0 by H₃PO₄;

Eluent "B": Methanol;

Gradient elution: (initial, 7% "B") - (8 min, 7% "B") - (20 min, 80% "B") Detection: UV 225 nm

Flow: 0.6 mL/min

Run time: 20 min

Sample preparation: 5 mg/mL in Methanol

System suitability: 5 mg/mL of TGS std. spiked with 100 ppm of I-. RT of Iodide is 7.8 min. Signal to noise ratio of not less than 10 achieved.

Results: content of iodide calculated versus standard 0.05%.

Argentometric titration for measuring the iodide level of tegaserod maleate

Weigh accurately about 100 mg of tegaserod sample. Add about 25 mL of ethanol and about 0.5 mL of 10% w/w nitric acid and dissolve. If necessary add dropwise 10% nitric acid until complete dissolution. Add about 50 mL purified water. Titrate potentiometrically with 0.002N silver nitrate.

Calculation o_/w |- - ^Vtitra innt (mL) * 0 -002 * Factor x 127 _? ^ _QQ weight sample (mg)

(127 is the molecular weight of Iodine). Example I: Preparation, of Jegaserod maleate free of iodides

A mixture of tegaserod hemi-maleate hemi-hydrate (20 g on dry basis, 0.20% iodides) in 700 mL of n-propanol, was heated to 65°C and stirred for 30 minutes until dissolution was obtained. Maleic acid (4.4 g) was then added and the mixture was stirred at 65°C. After 4 hours, the mixture was cooled to 25 ⁰C and then filtered under vacuum. The wet product was washed twice with 20 ml of n-propanol and dried in a vacuum oven at 40 ⁰C for 12 hours to give 98% of tegaserod maleate containing less than 50 ppm iodides by titration.

Example 2: Preparation of Tegaserod maleate free of iodides

A mixture of tegaserod maleate (Ig on dry basis) in 10 mL of n-propanol, is heated to 65°C and stirred for 1 hour, the mixture is cooled to 25 ⁰C and then filtered under vacuum. The wet product is washed twice with 20 ml of n-propanol and dried in a vacuum oven at 40 ⁰C for 12 hours.

Example 3: -Preparation of Tegaserod maleate free of iodides

Several batches of tegaserod base are made as follows: To a mixture of N- amino-N'-pentylguanidine hydroiodide (AGP.HI) (10.88 g, 0.04 mol) in 100 mL water is added 5-Methoxy-lH-indole-3-carbaldehyde (5-MICHO) (3.50 g, 0.02 mol) followed by NaHCO₃ (6.72 g, 0.08 mol) and heated to reflux for 1 hour. After cooling, 50 mL of EtOAc is added, and the organic phase washed with water.

The organic phase is then added to n-propanol as described in Example 1

Claims

WHAT IS CLAIMED, IS:

1. A process for preparing tegaserod maleate comprising (a) providing a solution of tegaserod or a salt thereof having an iodide content of at least about 0.1% area by HPLC in a polar organic solvent selected from the group consisting of: Ci-s alcohols, C₂-₈ alkyl esters, C_2-8 ethers, C₅-₈ aromatic hydrocarbons, C_3-8 ketones, acetonitrile and mixtures thereof and , (b) combining maleic acid with the solution at a temperature of about 2O⁰C to about reflux to obtain tegaserod maleate containing less than about 0.1% area by HPLC iodides.

2. The process of claim 1, wherein the C₂-₈ alkyl ester is ethyl acetate.

3. The process of claim 1 , wherein the C₂-₈ ether is methyl-t-butyl ether or diethyl ether.

4. The process of claim 1, wherein the C₅.₈ aromatic hydrocarbon is toluene.

5. The process of claim 1, wherein the C₃_₈ ketones is acetone or MIBK.

6. The process of claim 1, wherein Ci-s alcohol is n-propanol.

7. The process of any one of claims 1-6, wherein the tegaserod or a salt thereof is maintained at a temperature of of about 20⁰C to about relux temperature to obtain complete dissolution of the tegaserod or a salt thereof.

8. The process of any one of claims 1-7, wherein the solution of tegaserod or a salt thereof is combined with maleic acid at a temperature of about 6O⁰C to about 70⁰C,

9. The process of claim 8, wherein the temperature is about 65°C.

10. The process of any one of claims 1-9, wherein after addition of the maleic acid, the reaction mixture is maintained for at least about 1 hour.

11. The process of any one of claims 1-10, wherein after addition of maleic acid a mixture is obtained which is cooled to about room temperature to about 10⁰C.

12. The process of any one of claims 1-11, wherein the tegaserod maleate is further recovered.

13. The process of claim 12, wherein the recovered tegaserod maleate is washed with a polar organic solvent.

14. The process of any one of claims 12-13, further comprising drying the recovered tegaserod maleate.

15. The process of claim 14, wherein drying is carried out at a temperature of about 25°C to about 45⁰C, and a pressure of less than one atmosphere.

16. The process of any .qnepf claims 1-15, further comprising slurrying the obtained tegaserod maleate in a polar organic solvent.

17. The process of claim 16, wherein the solvent is a Ci-s alcohol.

18. The process of claim 16, wherein the solvent is n-propanol.

19. The process of any one of claims 16-18, wherein the slurry is maintained for about 1 to about 24 hours.

20. The process of any one of claims 18-19, wherein concentration of the slurry is preferably of about 1:10 to about 1:35 TGS-Ma: n-propanol weight/volume.

21. The process of any one of claims 18-20, wherein the obtained tegaserod maleate contains less than about 0.005% area by HPLC iodides.

22. A method for preparing a pharmaceutical composition comprising combining the tegaserod maleate obtained by the process of any one of claims 1-21 with at least one pharmaceutically acceptable excipient.

23. A process for preparing tegaserod maleate comprising (a) providing a solution of tegaserod hemi-maleate hemihydrate having an iodide content of at least about 0.1% area by HPLC in a polar organic solvent selected from the group consisting of: Ci-8 alcohols, C₂-8 alkyl esters, C₂-S ethers, C5-8 aromatic hydrocarbons, C3-s ketones, acetonitrile and mixtures thereof; and (b) combining maleic acid with the solution at a temperature of about 2O⁰C to about reflux to obtain tegaserod maleate containing less than about 0.1% area by HPLC iodides.

24. The process of claim 23, wherein the C₂-₈ alkyl ester is ethyl acetate.

25. The process of claim 23, wherein the C2-8 ether is methyl-t-butyl ether or diethyl ether.

26. The process of claim 23 wherein the Cs-S aromatic hydrocarbon is toluene.

27. The process of claim 23, wherein the C₃-₈ ketones is acetone or MIBK.

28. The process of claim 23, wherein C_1-8 alcohol is n-propanol.

29. The process of any one of claims 23-28, wherein the tegaserod hemi-maleate hemihydrate is maintained at a temperature of about 20⁰C to about reflux temperature to obtain complete dissolution.

30. The process of any one of claims 28-29, wherein the mixture of the tegaserod hemi-maleate hemi-hydrate in n-propanol is heated to obtain a solution.

31. The process of any βne pf claims 23-30, wherein the solution of tegaserod hemi- maleate hemihydrate is combined with maleic acid at a temperature of about 60⁰C to about 70⁰C,

32. The process of claim 31, wherein the temperature is about 65°C.

33. The process of any one of claims 23-32, wherein after addition of maleic acid a mixture is obtained which is maintained for at least about 1 hour.

34. The process of any one of claims 23-32, wherein after addition of maleic acid a mixture is obtained which is cooled to about room temperature to about 10⁰C.

35. The process of any one of claims 23-34, the reaction mixture is maintained while stirring for about 1-12 hours and further cooled to a temperature of about room temperature to about 10⁰C.

36. The process of any one of claims 23-35, further comprising recovering the tegaserod maleate containing less than about 0.1 % area by HPLC iodides.

37. The process of claim 36, wherein the recovered tegaserod maleate is washed with a polar organic solvent.

38. The process of claim 36, further comprising drying the recovered tegaserod maleate.

39. The process of claim 38, wherein drying is carried out at a temperature of about 25°C to about 45°C, and a pressure of less than one atmosphere.

40. A process for preparing tegaserod maleate containing less than about 0.1% area by HPLC iodides comprising slurrying tegaserod maleate at a temperature of about 50⁰C to about 70⁰C in a polar organic solvent selected from the group consisting of: d-β alcohols, C_2-S alkyl esters, C2-8 ethers, Cs-g aromatic hydrocarbons, C3-8 ketones, acetonitrile and mixtures thereof

41. The process of claim 40, wherein the solvent is a Ci-s alcohol.

42. The process of claim 40, wherein the solvent is n-propanol.

43. The process of claim 40, wherein the amount of time for which the mixture is maintained is of about 1 to about 24 hours.

44. The process of claim 42, wherein concentration of the mixture is preferably of about 1 :10 to about 1:35 TGS-Ma: n-propanol weight/volume.

45. The process of any one of claims 32-40, wherein the obtained tegaserod maleate contains less than about 0.005% area by HPLC iodides.

46. A process for

maleate containing less than about 0.1% area by HPLC iodides comprising:

(c) combining the mixture with n-propanol to obtain a solution;

(d) combining maleic acid with the solution at a temperature of about 2O⁰C to about reflux, and

47. The process of claim 46, wherein the reaction of AGP-HI with MICHO is carried out under acidic or basic conditions.

48. The process of claim 47, wherein pH during the reaction is from above 7 to about 14.

49. The process of claim 47, wherein pH during the reaction is about 9 to about 14.

50. The process of claim 47, wherein an aqueous solution of AGP-HI is combined with a mixture of MICHO and a solid base.

51. The process of claim 50, wherein an alkali or alkaline earth metal base is used.

52. The process of claim 51, wherein the base is selected from the group consisting OfK₂CO₃, Na₂CO₃, NaHCO₃, NaOH and KOH₇

53. The process of claim 47, wherein an organic base is used.

54 The process of claim 53, wherein the organic base is a C₃ to C₈ alkyl amine or pyridine.

55. The process of claim 53, wherein the base is triethylamine

56. The process of claim 53, wherein the organic base acts as a neat reagent.

57. The process of claim 47, wherein the pH is about 3 to about 7.

58. The process of claim 57, wherein the pH is about 3 to about 4.

59. The process of claim 47, wherein an organic acid is used during the reaction.

60. The process of claim 59, wherein the organic acid is selected from the group consisting of p-toluensulfonic acid, pyridinium p-toluenesulfonic acid, methanesulfonic acid, acetic acid, maleic acid and mixtures thereof.

61. The process of claim 47, wherein an inorganic acid is used during the reaction.

62. The process of claim 61, wherein the inorganic acid is selected from the group consisting of HCl, HBr, H₃PO₄, H₂SO₄ and mixtures thereof.

63. The process of any one of claims 46-62, wherein the reaction mixture is heated to accelerate the reaction.

64. The process of claim 63, wherein the temperature range during the reaction is about 5⁰C to reflux temperature.

65. The process of claim 64, wherein heating is carried out to a temperature of about 35⁰C to about 45⁰C.

66. The process of any one of claims 46-65 , wherein the reaction between AGP- HI and MICHO is maintained for about 30 minutes to about 24 hours.

67. The process of claim 66, wherein the reaction between AGP-HI and MICHO is maintained for about 2 hours to about 4 hours.

68. The process of any one of claims 46-67, wherein in step c) the tegaserod is maintained at a temperature of about 20⁰C to about reflux temperature to obtain complete dissolution of the tegaserod.

69. The process of any one of claims 46-68, wherein the mixture of the tegaserod in n- propanol is heated to obtain a solution.

70. The process of any one of claims 46-69, wherein the solution of tegaserod is combined with maleic acid at a temperature of about 6O⁰C to about 70⁰C.

71. The process of claim 70, wherein the temperature is about 65°C.

72. The process of any one of claims 46-71, wherein after addition of the maleic acid, the reaction mixture is maintained for at least about 1 hour.

73. The process of any one of claims 46-72, wherein the reaction mixture is cooled to about room temperature to about 10⁰C.