WO2007119109A2 - Processes for preparing tegaserod maleate and pharmaceutical compositions containing it - Google Patents

Abstract

The invention relates to a new process for the production of tegaserod maleate that includes the isolation of tegaserod hydroiodide as an intermediate. In particular, the invention provides an improved process for preparing 3-(5-methoxy-lH-indol-3- ylmethylene)-N-pentylcarbazimidamide hydrogen maleate (i.e., tegaserod maleate). This process includes reacting 5-methoxyindole-3-carbaldehyde with N-pentyl-N'- aminoguanidine hydroiodide and isolating solid 3-(5-methoxy-lH-indol-3-ylmethylene)-N- pentylcarbazimidamide hydroiodide (i.e., tegaserod hydroiodide).

Description

COMPOSITIONS AND PROCESSES USEFUL FOR PREPARING TEGASEROD MALEATE

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority to United States Provisional Application Nos. 60/723,962 (filed October 6, 2005), 60/725,282 (filed October 12, 2005) and 60/808,960 (filed May 3θ/ 2006), which applications are expressly incorporated herein by reference in their entirety.

BACKGROUND OF THE INVENTION

Field of the Invention

The invention relates to a new process for the production of tegaserod maleate that includes the isolation of tegaserod hydroiodide as an intermediate. In particular, the invention provides an improved process for preparing 3-(5-methoxy-lH-indol-3- ylmethylene)-N-pentylcarbazimidamide hydrogen maleate (i.e., tegaserod maleate). This process includes reacting 5-methoxyindole-3-carbaldehyde withN-pentyl-N'- aminoguanidine hydroiodide and isolating solid 3-(5-methoxy-lH-indol-3-ylmethylene)-N- pentylcarbazimidamide hydroiodide (i.e., tegaserod hydroiodide).

Discussion of the Related Art

Tegaserod maleate ("tegaserod") is the common name for 3-(5-methoxy-lH-indol-

3-ylmethylene)-N-pentylcarbazimidamide hydrogen maleate (Formula I, below).

Tegaserod is alternatively referred to herein as (2_JE)-2-[(5-methoxy-liir-indol-3- yl)methylene]-N-pentylhydrazinecarboximidamide. Tegaserod and related compounds are serotonin 5HT₄ receptor partial agonists and are useful in the treatment of irritable bowel syndrome. According to WO 2005/058819 A2 (discussed below), tegaserod base exhibits polymorphism.

All of the process described in the literature for the preparation of tegaserod involve the reaction of 5-methoxyindole-3-carbaldehyde or S-methoxy-lH-indole-S-carbaldehyde (Compound II) with N-pentyl-N'-aminoguanidine or N-pentylhydrazinecarboximidamide (Compound III) as illustrated in Scheme 1, below.

Scheme 1

U.S. Patent No. 5,510,353 describes a process for obtaining tegaserod that can be prepared according to the process described in Example 2a for 5-benzyloxy-indole-3- carboxaldehyde amino(N-methyl-N-heptylamino) methylene hydrazone. Although there is not provided any specific example for tegaserod base or its maleate salt, Example 13 of Table I describes a melting point of 124° C for the base and 190° C for the hydrogen maleate salt.

The J Med. Chem 1995, 38, 2331-2338 discloses a general method for condensing aminoguanidines with indole-3-carbaldehydes in methanol in the presence of concentrated HCl (pH~3-4) to prepare, among other things, tegaserod base. Tegaserod base prepared according to this method is characterized only by a melting point of 155° C (See Table 3, Compound 5b).

Chinese Patent No. CN 1425651 also describes (Reference 1) a method for the preparation, of tegaserod maleate. In each of the foregoing processes, the aminoguanidine moiety is used as its hydroiodide salt.

Zhongguo Yaowu Huaxue Zazhi 2003, 13(1), 40-41 discloses the production of tegaserod base (Example 1.3) involving the condensation of 5 -methoxyindole-3- carbaldehyde (Compound II) with N-pentyl-N' -aminoguanidine hydrobromide (Compound IHb) in methanol and in the presence of concentrated HCl (pH 3-4).

WO 2005/014544 Al discloses a process (Example 1) for producing tegaserod involving preparing N-pentyl-N' -aminoguanidine (Compound III) by reacting s-odecylisothio semi carbazide hydrobromide with 1-pentylamine. Without isolating the N-pentyl-N' -amino guanidine, ethanol, hydrogen chloride and 5-methoxyindol-3-carbaldehyde (Compound II) are added.

According to the literature, the synthetic manufacture of tegaserod is not generally satisfactory for industrial implementation for a number of reasons, including the need to use non-industrial solvents (e.g., diethyl ether), the need to evaporate solvents to dryness, the use of large amounts of solvents for carrying out the reaction and the neutralization and the need to perform purification by column chromatography.

Thus, several advantages of the invention include high yields in the steps of the process, high purity of the intermediates, the ability to easily scale up the process and high purity of the final product.

According to WO 2005/105740 A2, tegaserod base in solid state shows a purity of at least about 99% as area percentage HPLC, and having about 0.2% as area percentage

HPLC of an impurity characterized by an HPLC RRT of about 1.06 and a molecular weight of 403. No structural formula for this impurity is disclosed in WO 2005/10574 A2. The presence of such impurities in tegaserod maleate may pose a problem for formulation because impurities often affect the safety and shelf life of a formulation.

IPCOM000021161D characterizes the marketed polymorphic form of tegaserod maleate (Zelnorm®) and designates the crystalline form of Zelnorm® as tegaserod maleate Form A, which is characterized by a specific X-ray diffraction pattern. Tegaserod maleate is poorly soluble in water, which necessitates special formulation procedures for achieving a desired pharmacokinetic profile. Low solubility compounds can be problematic in the pharmaceutical arts from a formulations perspective.

Additionally, particle size can affect the solubility properties of a compound, like tegaserod maleate. Particle size reduction may be tried in order to increase a compound's solubility. Particle size reduction increases the surface area of the solid phase that is in contact with the liquid medium.

Increases in specific surface area of low aqueous solubility materials may improve therapeutic activity. For example, the surface area of a solid material provides information about the void spaces on the surfaces of individual particles or aggregates of particles.

Additionally, factors such as chemical activity, adsorption, dissolution, and bioavailabilty of the drug may depend on the surface of the solid.

WO 2005/058819 A2 discloses seven forms of tegaserod maleate characterized by X- ray diffraction patterns that are designated as Form B, Form Bl, Form B2, Form B3, Form C, Form D and Form E. These polymorphic forms have a maximum particle size of less than about 250 μm, more preferably less than about 200 μm, most preferably less than about 100 μm.

There are known instances where the rate of dissolution of a poorly soluble drug is the rate limiting factor in its rate of absorption by the body (i.e., its bioavailability). It is recognized, therefore, that such drugs may be more readily bioavailable if administered in a finely divided state. Particle size can also affect how freely crystals or a powdered form of a drug will "flow" past each other which has consequences in the production process of pharmaceutical products containing the drug.

In view of the foregoing, there is a need in the medical arts for tegaserod maleate with a small particle size and improved bioavailability.

SUMMARY OF THE INVENTION

The invention relates to a new process for the production of tegaserod maleate that includes the isolation of tegaserod hydroiodide as an intermediate. In particular, the invention provides an improved process for preparing 3-(5-methoxy-lH-indol-3- ylmethylene)-N-pentylcarbazimidamide hydrogen maleate (i.e., tegaserod maleate). This process includes reacting 5-methoxyindole-3-carbaldehyde withN-pentyl-N'- aminoguanidine hydroiodide (i.e., N-pentyUiydrazinecarboximidamide hydroiodide) and isolating solid 3-(5-methoxy-lH-indol-3-ylmethylene)-N-pentylcarbazimidamide hydroiodide (i.e., tegaserod hydroiodide).

The invention further includes the preparation of tegaserod maleate without requiring complicated separation procedures and a process for producing tegaserod maleate of high quality and purity (e.g., 99.7% or higher by HPLC).

The invention further includes the crystalline compound 3-(5-methoxy-lH-indol-3- ylmethylene)-N-pentylcarbazimidamide hydroiodide (i.e., tegaserod hydroiodide), designated as tegaserod hydroiodide Form A.

The invention further includes the use of the crystalline compound 3-(5-methoxy- lH-indol-3-ylmethylene)-N-pentylcarbazimidamide hydroiodide (i.e., tegaserod hydroiodide) for the preparation of 3-(5-methoxy-lH-indol-3-ylmethylene)-N-pentyl carbazimidamide (i.e., tegaserod base).

The invention further includes the crystalline compound 3-(5-methoxy-lH-indol-3~yl methylene)-N-pentylcarbazimidamide (i.e., tegaserod base), designated as tegaserod base Form B.

The invention further includes the use of crystalline compound 3-(5-methoxy-lH- indol-3-ylmethylene)-N-pentylcarbazimidamide (i. e. , tegaserod base) for the production of pharmaceutically acceptable salts of 3-(5-methoxy-lH-indol-3-ylmethylene)-N-pentyl carbazimidamide (i.e., tegaserod salts).

The invention further includes tegaserod hydroiodide having less than approximately 0.1% as area percentage HPLC of impurity A.

The invention further includes tegaserod hydroiodide having less than approximately 0.1% as area percentage HPLC of impurity B. The invention further includes tegaserod base having less than approximately 0.1% as area percentage HPLC of impurity A.

The invention further includes tegaserod base having less than approximately 0.1% as area percentage HPLC of impurity B.

The invention further includes tegaserod maleate having less than approximately

0.1% as area percentage HPLC of impurity A.

The invention further includes tegaserod maleate having less than approximately 0.1% as area percentage HPLC of impurity B.

The invention further includes a powder composition of tegaserod maleate having a particle size distribution wherein approximately 10% of the total volume is made of particles having a diameter less than approximately 3 μm, approximately 50% of the total volume is made of particles having a diameter less than approximately 10 μm and approximately 90% of the total volume is made of particles having a diameter less than approximately 20 μm.

The invention further includes tegaserod maleate particles having a surface area of approximately 5 to approximately 20 m²/g. More preferably, the tegaserod maleate particles having a surface area of approximately 8 to approximately 13 m Ig.

BRIEF DESCRIPTION OF THE DRAWINGS

The accompanying drawings, which are included to provide a further understanding of the invention and are incorporated in and constitute a part of this specification, illustrate embodiments of the invention and together with the description serve to explain the principles of the invention. In the drawings:

FIG. 1 illustrates the X-ray powder diffractogram of tegaserod hydroiodide Form A obtained according to one aspect of the invention;

FIG. 2 illustrates the IR spectrum of tegaserod hydroiodide Form A obtained according to another aspect of the invention; FIG. 3 illustrates the x-ray diffractogram pattern of tegaserod base Form B obtained according to a further aspect of the invention;

FIG. 4 illustrates the IR spectrum of tegaserod base Form B obtained according to another aspect of the invention; and

FIG. 5 illustrates the x-ray diffractogram pattern of 5-methoxyindole-3- carbaldehyde Form III.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

Reference will now be made in detail to the preferred embodiments of the invention. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein, hi addition and as will be appreciated by one of skill in the art, the invention may be embodied as a method, system or process.

Processes according to the invention include the reaction of 5-methoxyindole-3- carbaldehyde withN-pentyl-N'-aminoguanidine hydroiodide (i.e., N-pentylhydrazine carboximidarnide hydroiodide) in a solvent system, which includes at least one polar solvent. Preferred polar solvents include ethyl acetate, acetonitrile or water.

The process of the invention can optionally include performing the reaction in the presence of an organic acid, including, more preferably, glacial or aqueous acetic acid.

In a further embodiment of the invention, the quantity of the acid is the amount necessary to achieve a reaction mixture pH in the range of approximately 2 to approximately 4, and preferably in the range of approximately 2.5 to approximately 3.5. The presence of the organic acid reduces reaction time and increases yield of the reaction.¹

In a further embodiment of the invention, the reaction can be conducted at a temperature in the range of approximately 0° C to reflux temperature, and for a time of approximately 10 minutes to approximately 48 hours. Preferably, the reaction is conducted at reflux temperature for at least approximately 20 minutes, and more preferably the reaction is conducted at reflux temperature for approximately 1 hour. When the reaction is complete, the reaction mixture is cooled to room temperature and the precipitate is removed by filtration. Tegaserod hydroiodide produced by this process can be used without further purification to obtain tegaserod base, or alternatively can be purified by traditional purification techniques.

A preferred purification of tegaserod hydroiodide includes contacting tegaserod hydroioide with a solvent system, optionally treating the obtained solution with a decolorizing agent (e.g., activated charcoal, silica gel, ambosol and mixtures thereof) or a reducing agent (e.g., sodium metabisulfite, sodium hydrosulfite and sodium thiosulfate (pentahydrate) and mixtures thereof), and finally contacting the solution with water to precipitate tegaserod hydroiodide. A preferred solvent system includes a mixture of an alcoholic solvent (e.g., methanol, ethanol, isopropanol n-butanol and mixtures thereof) and acetonitrile. A preferred alcoholic solvent is methanol. A preferred decolorizing agent is activated charcoal. A preferred reducing agent is sodium metabisulfite.

The obtained crystalline tegaserod hydroiodide has a powder X-ray diffraction pattern as illustrated in Figure 1 and an infrared spectrum as illustrated in Figure 2.

Tegaserod hydroiodide can be converted to tegaserod base by contacting tegaserod hydroiodide with an inert solvent and a base. The preferred inert solvent is deionized water.

The quantity of the base is an amount necessary to obtain a reaction pH value of approximately 9 to approximately 13. An organic or inorganic base can be used. Preferred organic bases include alkyl amines (e.g., diethylamine or triethylamine), or aryl amines. Preferred inorganic bases include metal alkaline or earth metals (e.g. , KOH or NaOH). Optionally, the reaction media can be seeded with the desired polymorphic form of tegaserod base.

The reaction can be conducted at temperatures in the range of approximately 0° C to 60° C, and for a time of approximately 10 minutes to approximately 6 hours. Preferably, the reaction is conducted at approximately 20-25° C for at least approximately 1 hour, and more preferably the reaction is conducted at approximately 20-25° C for approximately 2 hours.

When the reaction has been carried out, the precipitate is filtered off. The obtained crystalline tegaserod base has a powder X-ray diffraction pattern as illustrated in Figure 3 and an infrared spectrum as illustrated in Figure 4.

The obtained tegaserod base can be used without further purification to prepare tegaserod maleate, or alternatively can be purified by traditional purification techniques. Preferred purification techniques include treatment with a reducing agent, preferably sodium metabisulfite. A preferred additional purification includes treatment with a decolorizing agent. Another preferred further purification includes treatment with acetonitrile, a ketone solvent, an alcoholic solvent or mixtures thereof, preferably methyl isobutyl ketone (MIBK), acetonitrile or methanol.

Another aspect of the invention includes the identification of several by-products arising during the synthesis of tegaserod maleate. One such by-product, referred to herein as impurity A, is characterized by an HPLC RRT (relative retention time) of approximately 0.58 using HPLC Method 1 described below.

Impurity A is very difficult to remove when detected in the final product, tegaserod maleate. Thus, another aspect of the invention includes preparation of crystalline tegaserod hydroioide and tegaserod base having less than approximately 0.1 % as area percentage HPLC of impurity A as characterized by an HPLC RRT of approximately 0.58, using HPLC Method 1 described below and the use of the same to prepare tegaserod maleate.

Impurity A is characterized by an HPLC RRT of approximately 0.93 using HPLC method 2 described below.

Another by-product identified during the synthesis of tegaserod maleate, referred to herein as impurity B, has the following structure:

403

Impurity B is characterized as having an HPLC RRT of approximately 1.10 and a molecular weight of 403, using the HPLC method 2 described below. Another aspect of the invention includes preparation of tegaserod hydroiodide and tegaserod base having less than 0.1% as area percentage HPLC of impurity B₅ as characterized by an HPLC RRT of approximately 1.10 and a molecular weight of 403 using HPLC method 2 described below, and the use of the same to prepare tegaserod maleate.

Another aspect of the invention includes a process for preparing tegaserod maleate by contacting tegaserod base with an inert solvent (e.g., isopropanol, acetone, n-butanol, MDC (methylisobutylketone), iso-butanol, isopropyl acetate, isobutyl acetate, mixtures of isopropyl acetate and isopropanol, mixtures of MIK and methanol, mixtures of isopropanol and water, mixtures of methanol and water and mixtures thereof) and maleic acid. A preferred inert solvent is isopropanol. Optionally, before the addition of the maleic acid, the solution of tegaserod base and the organic solvent can be purified and filtered off, and/or the solution of tegaserod base in the organic solvent can be seeded with the desired polymorphic form of tegaserod maleate.

A preferred procedure for purifying tegaserod maleate includes treating tegaserod maleate with a decolorizing agent, preferably activated charcoal, or a reducing agent, preferably sodium metabisulfite.

The molar quantity of maleic acid used ranges between approximately 0.9 to approximately 1.5 moles per mole of tegaserod base. Preferably the molar quantity of maleic acid is between approximately 1.0 and approximately 1.2 moles per mole of tegaserod base.

The addition of maleic acid can be conducted at temperatures in the range of approximately 0° C to approximately 85° C, and for a time of approximately 10 minutes to approximately 3 hours. Preferably, the addition of maleic acid is conducted at approximately 70° C to approximately 80° C for approximately 1 hour.

Precipitation of tegaserod maleate can be conducted using a range of temperatures of approximately 0° C to approximately 80° C and for a time of approximately 15 minutes to approximately 24 hours. Preferably, the precipitation is conducted at approximately 20° C to approximately 25° C for approximately 1 hour and at approximately 0° C to approximately 10° C for approximately 1 hour and 30 minutes. When the reaction is complete, the precipitate is filtered off or isolated from the solution by methods well known to those skilled in the art.

The crystalline tegaserod maleate obtained by the above-described processes has less than approximately 0.1% as area percentage HPLC of impurity A as characterized by an HPLC RRT (relative retention time) of approximately 0.58, using HPLC Method 1 described below.

The crystalline tegaserod maleate obtained by the above-described processes has less than 0.1% as area percentage HPLC of impurity B characterized by an HPLC RRT of approximately 1.10 and a molecular weight of 403, using the HPLC method 2 described below.

Another aspect of the invention includes a powder composition of tegaserod maleate having a defined particle size distribution. Thus, the invention further includes crystalline tegaserod maleate obtained by the above-described processes having a particle size distribution wherein approximately 10% of the total volume (D₁₀) is made of particles having a diameter less than approximately 3 μm, approximately 50% of the total volume (D₅₀) is made of particles having a diameter less than approximately 10 μm, and approximately 90% of the total volume (Dg₀) is made of particles having a diameter less than approximately 20 μm, and the use of tegaserod maleate having this particle size distribution in powdered compositions and various dosage units (e.g., pill, capsule and tablet formulations).

The crystalline tegaserod maleate obtained by the above-described processes has a surface area of approximately 5 to approximately 20 m²/g. More preferably, the tegaserod maleate has a surface area of approximately 8 to approximately 13 m²/g. The invention further includes formulations containing crystalline tegaserod maleate having these sizes.

The invention further includes a process for preparing a 3-(5-methoxy~lH-indol-3- ylmethylene)-N-pentylcarbazimidamide hydroiodide salt.

Another aspect of the invention includes a process for preparing 3-(5-methoxy-lH- indol-3-ylmethylene)-N-pentylcarbazimidamide hydroiodide salt, which optionally includes using an organic acid to adjust the pH of the reaction mixture. Another aspect of the invention includes a process for preparing tegaserod free base from tegaserod hydroiodide.

Another aspect of the invention includes a process for preparing tegaserod maleate, which includes isolating tegaserod hydroiodide, neutralizing tegaserod hydroiodide to yield tegaserod free base and converting the tegaserod free base to its maleate salt.

Another aspect of the invention includes a process for preparing tegaserod maleate, which includes isolating tegaserod hydroiodide, neutralizing tegaserod hydroiodide to yield tegaserod free base and converting the tegaserod free base to its maleate salt in isopropanol.

Another aspect of the invention includes the crystalline product tegaserod hydroiodide.

Another aspect of the invention includes the crystalline product tegaserod hydroiodide of high purity.

Another aspect of the invention includes the crystalline product tegaserod hydroiodide having a purity higher than 98% when analyzed by reverse phase high performance liquid chromatography (HPLC).

Another aspect of the invention includes the crystalline product tegaserod hydroiodide having a purity higher than 99% when analyzed by reverse phase HPLC.

Another aspect of the invention includes the crystalline product tegaserod hydroiodide having a purity higher than 99.5% when analyzed by reverse phase HPLC.

Another aspect of the invention includes the crystalline tegaserod hydroiodide having an X-ray diffraction pattern substantially similar to that of Figure 1.

Another aspect of the invention includes the solid form of tegaserod hydroiodide having an X-ray diffraction pattern showing characteristics peaks at 5.10, 5.24, 13.96, 18.21, 18.54, 20.90, 21.68, 22.98, 24.40, 26.12, 28.68 and 32.23 degrees two theta.

Another aspect of the invention includes the solid form of tegaserod hydroiodide having an infrared spectrum substantially similar to that of Figure 2. Another aspect of the invention includes purifying isolated tegaserod hydroiodide by using organic solvents.

Another aspect of the invention includes using the crystalline form of tegaserod hydroiodide for the manufacture of tegaserod maleate.

Another aspect of the invention includes using tegaserod hydroiodide of high purity for the manufacture of tegaserod maleate.

Another aspect of the invention includes a process for neutralizing tegaserod hydroiodide to tegaserod base, which includes treating tegaserod hydroiodide with an organic or inorganic base and filtering the resulting solid.

Another aspect of the invention includes a process for neutralizing tegaserod hydroiodide to tegaserod base, which includes treating a suspension of tegaserod hydroiodide in a mixture of water and organic solvent with an organic or inorganic base and filtering the resulting solid.

Another aspect of the invention includes the solid form of tegaserod base that has an X-ray diffraction pattern substantially similar to that of Figure 3.

Another aspect of the invention includes the solid form of tegaserod base having an

X-ray diffraction pattern showing characteristics peaks at 7.66, 9.00, 15.34, 17.38, 18.05, 19.25, 20.90, 21.96, 22.27, 22.48, 23.98, 28.43, 30.34, 30.98 degrees two theta.

Another aspect of the invention includes the solid form of tegaserod base that has an infrared spectrum substantially similar to that of Figure 4.

Another aspect of the invention includes purifying tegaserod free base by decolorizing a dissolution of tegaserod free base in an organic solvent.

Another aspect of the invention includes purifying tegaserod free base by treating tegaserod free base with sodium metabisulfite.

Another aspect of the invention includes tegaserod base of high purity. Another aspect of the invention includes tegaserod base having a purity higher than 98% when analyzed by reverse phase HPLC.

Another aspect of the invention includes tegaserod base having a purity higher than 99% when analyzed by reverse phase HPLC.

Another aspect of the invention includes tegaserod base having a purity higher than

99.5% when analyzed by reverse phase HPLC.

Another aspect of the invention includes using tegaserod base for manufacturing tegaserod maleate.

Another aspect of the invention includes using tegaserod base of high purity for manufacturing tegaserod maleate.

Another aspect of the invention includes using N-pentyl-N'-aminoguanidine hydroiodide having a purity of higher than 95% when analyzed by reverse phase high performance liquid chromatography for manufacturing tegaserod base.

Another aspect of the invention includes using N-pentyl-N'-aminoguanidine hydroiodide having a purity of higher than 95% when analyzed by reverse phase high performance liquid chromatography for manufacturing tegaserod maleate.

It will be apparent to those skilled in the art that various modifications and variations can be made in the present invention and specific examples provided herein without departing from the spirit or scope of the invention. Thus, it is intended that the present invention covers the modifications and variations of this invention that come within the scope of any claims and their equivalents.

Specific Examples

The following examples are for illustrative purposes only and are not intended, nor should they be interpreted to, limit the scope of the invention. General Experimental Conditions:

Starting materials are commercially available or can be obtained according processes described in the literature. 5-methoxyindole-3-carbaldehyde can be additionally treated with an organic solvent (e.g., acetonitrile) or ketone solvents (e.g., MEK, MIBK or acetone).

Undesired impurities in N-pentyl-N'-aminoguanidine hydroiodide can be removed by treatment with ethyl acetate. The filtrate obtained can be used for the reaction. Solids were dried at 40° C under vacuum.

i. TLC Conditions:

The stationary phase was silica gel 60 F₂₅₄. The eluant was AcOEt (16) / Toluene (4) / MeOH (5) / H₂O (2) / HCOOH 85% (1) (v:v). Run to length / total length: 8 cm / 10 cm. Development / Detection: UV₂₅₄ and ninhydrin. Sample Preparation and Application: Samples 1% (5 μL).

ii. HPLC Method 1

Chromatographic separation was carried out using a Symmetry C8, 5 μm, 4.6 x 250 mm LD. column at room temperature (~ 20-25° C).

The mobile phase A was prepared by mixing 30 mL of acetonitrile with 70 mL of buffer (pH=2.5) buffer prepared from 0.88 g of ammonium formate dissolved in 700 mL of water. The pH was adjusted to 2.5 with formic acid. The mobile phase was mixed and filtered through a 0.22 μm nylon filter under vacuum.

The chromatograph was equipped with a 238 nm detector, and the flow rate was 1.0 mL per minute. Test samples (20 μl) were prepared by dissolving the appropriate amount of sample in order to obtain 1 mg per mL of a mixture of mobile phase.

iii. HPLC Method 2

Chromatographic separation was carried out using a Atlantis dC18, 5 μm, 4.6 x 150 mm LD column at 25° C. The mobile phase A was prepared by mixing 200 niL of acetonitrile with 800 mL of 0.02 M OfKH₂PO₄ buffer prepared from 2.18 g OfKH₂PO₄ dissolved in 800 mL of water. The pH was adjusted to 5.0 with orthophosphoric acid. The mobile phase was mixed and filtered through 0.22 μm nylon filter under vacuum.

The mobile phase B was acetonitrile.

The chromatograph was programmed as follows: Initial: 100% mobile phase A; 0- 25 minutes: linear gradient to 50% mobile phase A; 25-30 minutes: isocratic 50% mobile phase A; 30-40 minutes: linear gradient to 100% mobile phase A; and 40-45 minutes: equilibration with 100% mobile phase A.

The chromatograph was equipped with a 238 nm detector, and the flow rate was 1.0 mL per minute. Test samples (20 μl) were prepared by dissolving the appropriate amount of sample in order to obtain 1 mg per mL in a mixture of acetonitrile and water (6:4).

iv. HPLC-MS Method 1

The chromatographic separation was carried out in a Symmetry C8, 5 μm, 4.6 x 150 mm LD column at 25° C.

The mobile phase A was 0.02 M ammonium formate buffer. The pH was adjusted to 2.5 with formic acid. The mobile phase was mixed and filtered through 0.22 μm nylon filter under vacuum.

The mobile phase B was acetonitrile.

The chromatograph was programmed in isocratic mode with 30% mobile phase B and 70% mobile phase A.

The chromatograph was equipped with a triple quadrupole mass spectrophotometer detector with a ionization source at atmospheric pressure (API) with electrospray interface. The flow rate was 1.0 mL per minute. Test samples (10 μl) were prepared by dissolving the appropriate amount of sample in order to obtain 10 mg per mL of a mixture of acetonitrile and mobile phase A (3:7). v. Particle Size Method 1

The particle size for tegaserod maleate was measured using a Malvern Mastersizer S particle size analyzer with an MSl Small Volume Recirculating unit attached. A 300RF mm lens and a beam length of 2.4 mm were used. Samples for analysis were prepared by dispersing a weighed amount of tegaserod maleate (approximately 0.4 g) in 20 mL of paraffin oil/n-butylacetate (50:50). The suspension was sonicated for 2 minutes and delivered drop- wise to a background corrected measuring cell previously filled with paraffin oil/n-butyl acetate (50:50) until the obscuration reached the desired level. Volume distributions were obtained for three times. After completing the measurements, the sample cell was emptied and cleaned, refilled with suspending medium, and the sampling procedure repeated again. For characterization, the values of D₁₀, D₅o and Dg₀ were specifically listed, each one being the mean of the six values available for each characterization parameter.

vi. Specific Surface Area Method 1

The BET (Brunauer, Emmett and Teller) specific surface area for tegaserod maleate was measured using a Micromeritics ASAP2010 equipment. Samples for analysis were degassed at 150° C under vacuum for an hour. The determination of the adsorption of N₂ at 77° K was measured for relative pressures in the range of 0.06-0.2 for a weighed amount of tegaserod maleate (i.e., approximately 0.3 g).

Example 1 : Preparation of "(2jE)-2-[(5-methoxy-llT-mdol-3-yl)methylene]-N- pentylhydrazinecarboximidamide hydroiodide" (tegaserod hydroiodide)

To a 500 mL flask were charged 15.01 g of 5-methoxy-lH-indole-3-carbaldehyde (0.0857 moles, 1.0 molar equivalent) and 100 mL of ethyl acetate. The suspension was stirred at 20-25° C. To the suspension was added 24.46 g of N-pentylhydrazinecarboximidamide hydroiodide (0.0899 moles, 1.050 molar equivalents, Quality 1) dissolved in 50 mL of ethyl acetate over 5 to 10 minutes to yield an orange suspension having a pH of 8.42.

The pH of the resulting suspension was adjusted to 2.5 - 3.5 (actual value 2.95) with glacial acetic acid (7 mL, 1.43 molar equivalents of acid) added at 20-25° C. The suspension was then heated to reflux and maintained at this temperature for 24 minutes. The resulting yellow suspension was then cooled. The reaction mixture was monitored by TLC analysis and stirred for an additional 30 minutes at 20-25° C. The solution was then filtered to yield 29.03 g of wet tegaserod hydroiodide (28.16 g of dry product; Yield: 76.62 %).

Analytical data: HPLC Method 1 (area %): 98.58%; XRD (2Θ): Substantially identical to Figure 1; IR: Substantially identical to Figure 2.

Example 2: Preparation of "(2£)-2-[(5-methoxy-l_JH^r-indol-3-yl)methylene]-iV- pentylhydrazinecarboximidamide hydroiodide" (tegaserod hydroiodide)

To a 500 mL flask were charged 15 g of S-methoxy-lH-indole-S-carbaldehyde (0.0856 moles, 1.0 molar equivalent) and 100 mL of ethyl acetate. The suspension is stirred at 20-25° C. To the solution is added 24.47 g of N-pentylhydrazinecarboximidamide hydroiodide (0.0899 moles, 1.050 molar equivalents, quality 1) dissolved in 50 mL of ethyl acetate over 5 to 10 minutes to yield an orange suspension having a pH of 8.42.

The resulting suspension was heated to reflux and maintained at this temperature for 40 minutes. The reaction mixture was monitored by TLC. The resulting yellow suspension was cooled, stirred for 1 hour at 20-25° C and filtered to yield 18.46 g of wet tegaserod hydroiodide (18.45 g of dry product; Yield: 50.19 %).

Analytical data: HPLC Method 1 (area %): 99.53%; XRD (2Θ): Substantially identical to Figure 1 ; IR: Substantially identical to Figure 2.

Example 3: Preparation of "(2£)-2-[(5-methoxy-lH-indol-3-yl)methylene]-N- pentylhydrazinecarboximidamide hydroiodide" (tegaserod hydroiodide)

To a 250 mL flask were charged 10.00 g of 5-methoxy-lH-indole-3-carbaldehyde (0.0571 moles, 1.0 molar equivalent) and 70 mL of ethyl acetate. The suspension was stirred at 20-25° C. To the solution was added 18.64 g of N-pentylhydrazinecarboximidamide hydroiodide (0.0685 moles, 1.200 molar equivalents, quality 1) dissolved in 30 mL of ethyl acetate added over 5 to 10 minutes to yield an orange suspension having a pH of 8.40.

The pH of the resulting suspension was adjusted to 2.5 - 3.5 (actual value 2.98) with glacial acetic acid (13.6 mL, 4.16 molar equivalents of acid) at 20-25° C. The suspension was heated to reflux and maintained at this temperature for 1 hour. The resulting thick yellow suspension obtained was cooled. The reaction mixture was monitored by TLC, stirred for approximately 1 hour at 20-25° C and filtered to yield 21.35 g of wet tegaserod hydroiodide (20.43 g of dry product; Yield: 83.40 %).

Analytical data: HPLC Method 1 (area %): 98.70%; XRD (2θ)(wet): Substantially identical to Figure 1 ; XRD (2θ)(dry): Substantially identical to Figure 1 ; IR: Substantially identical to Figure 2.

Example 4: Preparation of "(2i^-2-[(5-methoxy-l#-indol-3-yl)methylene]-iV- pentylhydrazinecarboximidamide hydroiodide" (tegaserod hydroiodide)

To a 250 niL flask were charged 10.00 g of S-methoxy-lif-indole-S-carbaldehyde (0.0571 moles, 1.0 molar equivalent) and 70 niL of acetonitrile. The suspension was stirred at 20-25° C. To the suspension was added 18.64 g of N-pentylhydrazinecarboximidamide hydroiodide (0.0685 moles, 1.200 molar equivalents of quality 1) dissolved in 30 mL of acetonitrile and added over 5 to 10 minutes to yield an orange suspension having a pH of 8.70.

The pH of the resulting suspension was adjusted to 2.5 - 3.5 (actual value 3.10) with glacial acetic acid (14 mL, 4.28 molar equivalents of acid) at 20-25° C. The suspension was heated to reflux and maintained at this temperature for 1 hour to yield a solution. The solution was cooled to 20-25° C and a precipitation begins at approximately 61° C. The reaction mixture was monitored by TLC. After stirring for approximately 1 hour at 20-25° C, the solid was filtered to yield 20.05 g of wet tegaserod hydroiodide (17.46 g of dry product; Yield: 71.25 %).

Analytical data: HPLC Method 1 (area %): 99.39%; XRD (2θ)(wet): Substantially identical to Figure 1; XRD (2θ)(dry): Substantially identical to Figure 1; IR: Substantially identical to Figure 2.

Example 5: Preparation of "(21^-2- [(5-methoxy-l//-indol-3-yl)methylene] -iV- pentylhydrazinecarboximidamide hydroiodide" (tegaserod hydroiodide) To a 250 mL flask were charged 10.00 g of 5-methoxy-lH^"-indole-3-carbaldehyde

(0.0571 moles, 1.0 molar equivalent) and 70 mL OfH₂O. The suspension was stirred at 20-25° C. To the suspension was added 18.64 g of N-pentylhydrazinecarboximidamide hydroiodide (0.0685 moles, 1.200 molar equivalents of quality 1) dissolved in 30 niL OfH₂O and added over 5 to 10 minutes to yield an orange suspension having a pH of 9.91.

The pH of the resulting suspension was adjusted to 2.5 — 3.5 (actual value 3.04) with glacial acetic acid (6.4 mL, 1.96 molar equivalents of acid) at 20-25° C. The suspension was heated to reflux and maintained at this temperature for 1 hour to yield an orange suspension with foam. The orange suspension obtained was cooled. The reaction mixture was monitored by TLC, stirred for approximately 1 hour at 20-25° C and filtered to yield 28.55 g of wet tegaserod hydroiodide.

To the same flask of the above step were charged the wet solid and 82.24 mL of ethyl acetate. The suspension was stirred at reflux temperature for 10 minutes and cooled at 20-25° C. The suspension was stirred for 2 hours at this temperature, filtered and the resulting solid was washed twice with ethyl acetate. The wet solid was dried at 40° C under vacuum to yield 17.55 g of dry product (Yield: 71.66 %).

Analytical data: HPLC Method 1 (area %): 99.70%; IR: Substantially identical to Figure 2.

Example 6: Preparation of "(2£)-2-[(5-methoxy-lJ3-indol-3-yl)methylene]-iV- pentylhydrazinecarboximidamide hydroiodide" (tegaserod hydroiodide)

To a 250 mL flask were charged 10.00 g of S-methoxy-lH-indole-S-carbaldehyde (0.0571 moles, 1.0 molar equivalent) and 50 mL of toluene. The suspension was stirred at 20- 25° C. To the suspension was added 18.64 g of N-pentylhydrazinecarboximidamide hydroiodide (0.0685 moles, 1.200 molar equivalents of quality 1) over 5 to 10 minutes dragging it with 50 mL of toluene to yield an orange suspension having a pH of 6.5-7.

The pH of the resulting suspension was adjusted to 2.5 — 3.5 with glacial acetic acid (12 mL, 3.67 molar equivalents of acid) at 20-25° C. The resulting thick suspension was heated to reflux and maintained at this temperature for 1 hour. The orange suspension obtained was cooled. The reaction mixture is monitored by TLC, stirred for approximately 1 hour at 20-25° C and filtered to yield 23.50 g of wet tegaserod hydroiodide (23.10 g of dry product; Yield: 94.29%).

Analytical data: HPLC Method 1 (area %): 82.90%; XRD (2θ)(wet): Substantially identical to Figure 1; XRD (2θ)(dry): Substantially identical to Figure 1; IR: Substantially identical to Figure 2. Example 7: Preparation of "(2JE)-2-[(5-methoxy-lJ3-mdol-3-yl)methyIene]-iV- pentylhydrazinecarboximidamide hydroiodide" (tegaserod hydroiodide)

To a 1 L flask were charged 40.00 g of S-methoxy-lH-indole-S-carbaldehyde (0.2283 moles, 1.0 molar equivalent) and 300 mL of ethyl acetate. The suspension was stirred at 20- 25⁰C. To the suspension was added 77.67 g of N-pentylhydrazinecarboximidamide hydroiodide (0.2854 moles, 1.250 molar equivalents of quality 1) dissolved in 100 mL of ethyl acetate and added over 5 to 10 minutes to yield an orange suspension having a pH of 8.48.

The pH of the resulting suspension was adjusted to 3.0-3.5 (actual value 3.38) with glacial acetic acid (50 mL, 3.83 molar equivalents of acid) at 20-25° C. The suspension was heated to reflux and maintained at this temperature for 1 hour. The orange suspension obtained was cooled, stirred for approximately 1 hour at 20-25° C and filtered to yield 118.63 g of wet tegaserod hydroiodide (93.36 g of dry product, according to loss on drying data; Yield: 95.25%).

Analytical data: HPLC Method 1 (area %): 98.54%; IR: Substantially identical to Figure 2.

Example 8: Preparation of "(2£)-2-[(5-methoxy-l#-indol-3-yI)methylene]-iV- pentylhydrazinecarboximidamide hydroiodide" (tegaserod hydroiodide)

To a 500 mL flask were charged 30.00 g of 5-methoxy-lH-indole-3-carbaldehyde (0.1712 moles, 1.0 molar equivalent) and 226 mL OfH₂O. The suspension was stirred at 20-25° C. To the suspension was added 58.25 g of N-pentylhydrazinecarboximidamide hydroiodide (0.2141 moles, 1.250 molar equivalents of quality 1) dissolved in 75 mL OfH₂O added over five to ten minutes to yield an orange suspension having a pH of ^'9, 77.

The pH of the resulting suspension was adjusted to 3.0-3.5 (actual value 3.45) with 80% aqueous acetic acid (15 mL, 1.22 molar equivalents of acid) at 20-25° C. The suspension was heated to reflux and maintained at this temperature for 1 hour. The orange suspension obtained was cooled, stirred for approximately 1 hour at 20-25° C and filtered to yield 94.01 g of wet tegaserod hydroiodide (70.57 g of dry product, according to loss on drying data; Yield: 96.01%).

Analytical data: HPLC Method 1 (area %): 98.54%; IR: Substantially identical to Figure 2. Example 9: Preparation of 'X2£)-2-[(5-methoxy-liy-indol-3-yl)methylene]-iV- pentylhydrazinecarboximidamide" (tegaserod base)

To a 100 mL flask were charged 5.1O g of wet tegaserod hydroiodide (5.00 g of dry product, 0.0116 moles) and 50 mL of deionized water to yield a thick, yellow suspension having a pH of approximately 2.35. ^•

The pH of the resulting suspension was adjusted to 9-10 (actual value 9.54) with potassium hydroxide (KOH) (0.882 g, 1.35 molar equivalents). The suspension was stirred at 20-25° C for 30 minutes. The resulting solid was filtered and washed twice with 5 mL of water to yield 9.8 g of wet solid.

To the same flask of the above step were charged the wet solid and 50 mL of water.

The suspension was stirred at 20-25° C for a minimum of 30 minutes. The resulting solid was filtered and washed twice with 5 mL of water to yield 7.08 g of wet solid (2.26 g of dry product, according to loss on drying data; Yield: 64.32%).

Analytical data: HPLC Method 1 (area %): 97.30%.

Example 10: Preparation of "(2£)-2-[(5-methoxy-l_JH^r-indol-3-yl)methylene]-iV- pentylhydrazinecarboximidamide" (tegaserod base)

To a 100 mL flask were charged 5.1O g of wet tegaserod hydroiodide (5.00 g of dry product, 0.0116 moles) and 50 mL of deionized water to yield a thick, yellow suspension having a pH of approximately 3.

The pH of the resulting suspension was adjusted to approximately 9 (actual value

8.10) with triethylamine (3.77 mL, 2.33 molar equivalents). After stirring for 30 minutes, a complete solution was observed, and 10 minutes later a precipitate was formed. The suspension was stirred at 20-25° C for 30 additional minutes. The solution was then filtered, and the obtained solid was washed twice with 5 mL of water. The wet solid was dried at 40° C under vacuum until constant weight to yield 1.5025 g of dry solid (Yield: 42.81%)

Analytical data: HPLC Method 1 (area %): 97.17%. Example 11: Preparation of "(2£)-2-[(5-methoxy-l_J£T-mdol-3-yl)methylene]-iV- pentylhydrazinecarboximidamide" (tegaserod base)

To a 100 niL flask were charged 7.48 g of wet tegaserod hydroiodide (5.00 g of dry product, 0.0116 moles) and 50 niL of deionized water to yield a thick, yellow suspension having a pH of 3.59.

The pH of the resulting suspension was adjusted to 12-13 (actual value 12.99) with 30% aqueous sodium hydroxide (4 mL). The suspension was stirred at 20-25° C for 30 minutes. The resulting solid was filtered and washed twice with 10 mL of water to yield 6.30 g of wet solid (3.55 g of dry product, according to loss on drying data, partial yield: 101.14%, HPLC Method 1 (area %): 97.20 %).

To the same flask of the above step were charged the wet solid and 50 mL of water. The suspension was stirred at 20-25° C for 30 minutes. The resulting solid was filtered and washed twice with 5 mL of water to yield 6.51 g of wet solid (3.17 g of dry product, according to loss on drying data, partial yield 89.23%; Global yield: 90.25%).

Analytical data: HPLC Method 1 (area %): 99.18%; XRD (2θ)(wet): Substantially identical to Figure 3.

Example 12: Preparation of "(2£)-2-[(5-methoxy-llRndol-3-yl)methylene]-iV- pentylhydrazinecarboximidamide" (tegaserod base)

To a 500 mL flask were charged 27.83 g of wet tegaserod hydroiodide (27.00 g of dry product, 0.0629 moles) and 270 mL of deionized water to yield a thick, yellow suspension having a pH of 3.88.

The pH of the resulting suspension was adjusted to 12-13 (actual value 12.80) with 50% aqueous sodium hydroxide (15 mL). The suspension is stirred at 20-25° C for 1 hour. The resulting solid was filtered and washed twice with 25 mL of water to yield 36.18 g of wet solid (17.74 g of dry product, according to loss on drying data, partial yield: 93.57, HPLC Method 1 (area %): 98.34%).

To the same flask of the above step, were charged the wet solid and 270 mL of water. The suspension was stirred at 20-25° C for 30 minutes. The resulting solid was filtered and washed twice with 25 niL of water to yield 24.73 g of wet solid (17.08 g of dry product, according to loss on drying data, partial yield 96.26%, HPLC Method 1 (area %): 99.53%).

To the same flask of the above step were charged the wet solid and 136.7 mL of MIBK (methyl isobutyl ketone). The suspension was stirred at 20-25° C for 2 hours. The resulting solid was filtered and washed twice with MIBK to yield 10.93 g of wet solid. The obtained solid was dried at 40° C under vacuum to yield 8.97 g of dry product (partial yield 52.51%; Global yield: 47.30%).

Analytical data: HPLC Method 1 (area %): 99.78%.

Example 13: Preparation of "(2£)-2-[(5-methoxy-l_JH^r-indol-3-yl)methylene]-iV- pentylhydrazinecarboximidamide" (tegaserod base)

To a 500 mL flask were charged 208.93 g of wet tegaserod hydroiodide (160.63 g of dry product, 0.3742 moles) and 1606 mL of deionized water to yield a yellow suspension having a pH of 2.95.

The pH of the resulting suspension was adjusted to 11-11.5 (actual value 11.30) with 30 mL sodium hydroxide (50% aqueous solution). The suspension was then stirred at 20-25° C for 2 hours, and the pH was adjusted as necessary with sodium hydroxide (15 mL). The solution was filtered, and the solid was washed twice with 100 mL of water to yield 187.55 g of wet solid (91.37 g of dry product, according to loss on drying data, partial yield: 81.02%, HPLC Method 1 (area %): 95.74%).

To the same flask of the above step were charged the wet solid and 1124 mL of water. The suspension was heated at 40-50° C and stirred at this temperature for 30 minutes. The solution was filtered and the solid was washed twice with 100 mL of water to yield 192.38 g of wet solid (88.84 g of dry product, according to loss on drying data, partial yield 97.23%, HPLC Method 1 (area %): 96.77%).

To the same flask of the above step were charged the wet solid and 1124 mL of water. The suspension was heated at 40-50° C and stirred at this temperature for 30 minutes. The solution was filtered and the solid was washed twice with 100 mL of water to yield 180.21 g of wet solid (83.85 g of dry product, according to loss on drying data, partial yield 96.30%, HPLC Method 1 (area %): 97.20%).

To the same flask of the above step were charged the wet solid and 335.4 niL of acetonitrile. The suspension was stirred at reflux temperature for 10 minutes, cooled to 20- 25° C and stirred for 2 hours at this temperature. The solution was filtered, and the resulting solid was washed twice with 3 mL of acetonitrile. The solid was dried at 40° C under vacuum to yield 58.42 g of dry product (Partial yield 69.67%; Global yield: 52.85%)

Analytical data: HPLC Method 1 (area %): 99.801 %.

Example 14: Preparation of ^M(2jE)-2-[(5-methoxy-LH-indol-3-yl)methylene]-iV- pentylhydrazinecarboximidamide" (tegaserod base monohydrate)

To a 500 mL flask were charged 20.85 g of wet tegaserod hydroiodide (15 g of dry product, 0.0349 moles) and 150 mL of deionized water to yield a thick, yellow suspension having a pH of 4.08.

The pH of the resulting suspension was adjusted to 11-11.5 (actual value 11.48) with diethylamine (2.1 mL). The suspension was stirred at 20-25° C for 2 hours, and the pH was adjusted if necessary (7.8 mL more of diethylamine were added). The resulting solid was filtered and washed twice with 20 mL of water to yield 24.82 g of wet solid (11.10 g of dry product, according to loss on drying data, partial yield: 105.53 %, HPLC Method 1 (area %): 95.74 %).

To the same flask of the above step, there were charged the wet solid and 150 mL of water. The suspension was heated at 40-50° C and stirred at this temperature for 30 minutes. The resulting solid was filtered and washed twice with 10 mL of water to yield 12.16 g of wet solid (8.84 g of dry product, according to loss on drying data, partial yield 79.63%, HPLC Method 1 (area %): 93.92%).

To the same flask of the above step were charged the wet solid and 35.37 mL of acetonitrile. The suspension was stirred at reflux temperature for 15 minutes, and the solution obtained was filtered at 30° C. The solution was then cooled to 20-25° C, stirred for 30 minutes at this temperature, further cooled to 0-10° C and stirred for 1 hour at this temperature. The solution was filtered and washed twice with 4 mL of acetonitrile to yield 6.96 g of wet solid (6.06 g of dry product, according to loss on drying data, partial yield 68.59%; Global yield: 57.64%).

Analytical data: HPLC Method 1 (area %): 99.74%; XRD (2θ)(wet): Substantially identical to Figure 3; XRD (2θ)(dry): Substantially identical to Figure 3; IR: Substantially identical to Figure 4; Water content of dried product (KF method): 5.91 %.

Example 15: Preparation of "(2E)-2-[(5-methoxy-lJϊ-indol-3-yI)methylene]-iV- pentylhydrazinecarboximidamide maleate" (tegaserod maleate)

To a 2 L flask are charged 80.47 g of 5-methoxy-l/f-indole-3-carbaldehyde (0.4593 moles, 1.0 molar equivalent) and 604.70 mL of ethyl acetate. The suspension was stirred at 20-25° C. To the suspension was added 15O g of N-pentylhydrazinecarboximidamide hydroiodide (0.5512 moles, 1.200 molar equivalents, quality 1) dissolved in 200 mL of ethyl acetate added over 5 to 10 minutes to yield an orange suspension having a pH of 7.10.

The pH of the resulting suspension was adjusted to 3-3.5 (actual value 2.98) with glacial acetic acid (17 mL, 0.65 molar equivalents) at 20-25° C. The suspension was heated to reflux and maintained at this temperature for 1 hour. The thick yellow suspension obtained was cooled. The reaction mixture was monitored by TLC, stirred for approximately 1 hour at 20- 25° C and filtered to yield 233.14 g of wet tegaserod hydroiodide (174.08 g of dry product, according to loss on drying data, partial yield: 88.28%, HPLC Method 1 (area %): 98.46%).

In the same flask of the above step, there were charged the wet solid and 1740.8 mL of deionized water to yield a yellow suspension with a pH of 4.44.

The pH of the resulting suspension was adjusted to 11-11.5 (actual value 11.12) with diethylamine (74.6 mL). The suspension was stirred at 20-25° C for 2 hours, and the pH was adjusted as needed with diethylamine (54.7 mL). The suspension was filtered and washed twice with 174 mL of water to yield 172.39 g of wet solid (119.67 g of dry product, according to loss on drying data, partial yield: 97.91%, HPLC Method 1 (area %): 96.28 %).

To the same flask of the above step were charged the wet solid and 1740.8 mL of water. The suspension was heated at 40-50° C and stirred at this temperature for 30 minutes. The suspension was then filtered washed twice with 174 mL of water to yield 156.78 g of wet solid (117.35 g of dry product, according to loss on drying data, partial yield 98.06%, HPLC Method 1 (area %): 98.77 %).

To the same flask of the above step were charged the wet solid, 1173.5 niL of water and 5.86 g of sodium metabisulfite. The suspension was heated at 40-45° C and stirred at this temperature for 30 minutes. The suspension was then filtered and washed twice with 72.4 mL of water to yield 201.91 g of wet solid (113.98 g of dry product, according to loss on drying data, partial yield 97.13 %, HPLC Method 1 (area %): 96.76 %).

To the same flask of the above step were charged the wet solid and 455.92 mL of acetonitrile. The suspension was stirred at reflux temperature for 10 minutes, cooled at 20-25° C and stirred for 2 hours at this temperature. The suspension was then filtered and washed twice with 45.6 mL of acetonitrile to yield 121.37 g of wet solid (86.12 g of dry product, according to loss on drying data, partial yield 75.57 %, global yield: 62.21%, HPLC Method 1 (area %): 99.59%).

To a 1 L flask were charged the wet solid of the above step and 688.96 mL of isopropanol. The suspension was heated at 60-65° C and stirred at this temperature until near total dissolution is observed. The solution was then cooled to 50° C and filtered.

Over the resulting clear and hot filtrate were added a dissolution of 34.44 g of maleic acid and 187.91 mL of isopropanol over about 30-45 minutes. Once the addition was completed, the temperature was about 20-25° C. A thick suspension was observed at the beginning of the addition which became more fluid during the additions. The suspension obtained was stirred at 20-25° C for 1 hour and then at 0-10° C for one additional hour. The suspension was filtered and then washed twice with 56.36 mL of isopropanol to obtain 243.82 g of wet solid. The solid was dried at 40° C under vacuum to yield 98.01 g of final product (Partial yield: 81.15 %; Global yield: 50.48 %).

Analytical data: HPLC Method 1 (area %): 99.72%; Melting point: 179.2-181.1° C; Residual solvents: not detected (< 100 ppm of isopropanol); Heavy metals: < 20 ppm;

Residue on ignition: < 0.1%; Water content (KF method): 0.63 %; Loss on drying: 0.14 %. Example 16: Preparation of "(2£)-2-[(5-methoxy-lH-indol-3-yI)methylene]-Λ^r- pentylhydrazinecarboximidamide" (tegaserod base)

To a 1 L flask were charged 58.25 g of N-pentylhydrazinecarboximidamide hydroiodide (0.21 moles, 1.25 molar equivalents, HPLC Method 1 (area %): 94.8%), 30 g of 5-methoxy-li/~indole-3-carbaldehyde (0.17 moles, 1.0 molar equivalent, HPLC Method 1 (area %): 99.9%) and 300 niL of ethyl acetate. The suspension was stirred at 20-25° C for 10 minutes to yield an orange suspension having a pH of 7.50.

The pH of the resulting suspension was adjusted to 3—3.5 (actual value 3.35) with glacial acetic acid (25 mL, 2.55 molar equivalents of acid), which was added at 20-25° C. The suspension was then heated to reflux and maintained at this temperature for 1 hour. The resulting thick yellow suspension was then cooled, and the reaction mixture was monitored by TLC analysis and stirred for an additional 1 hour at 20-25° C. The solution was then filtered and washed twice with 30 mL of ethyl acetate to yield 67.06 g of wet crude tegaserod hydroiodide (66.74 g of dry product, according to loss on drying data, partial yield: 90.79%, HPLC Method 1 (area %): mam product: 98.89% , impurity A: 0.11 %).

To the same flask used in the above step were charged the wet solid, 200 mL of methanol, 200 mL of acetonitrile and 5.34 g of activated charcoal. The suspension was stirred at 20-25° C for 30 minutes, filtered over three filter papers, and the residue was washed twice with 15 mL of a mixture of methanol/acetonitrile (1:1) to yield an orange clear solution.

To a clean and dry 2L flask was charged the orange clear solution to which was added

667 mL of deionized water over 30 minute to yield a white suspension. The suspension was then stirred for 1 hour at 20-25° C and for 2 additional hours at 0-10° C. The resulting solid was filtered and washed twice with 62 mL of deionized water to yield 70.56 g of wet tegaserod hydroiodide (54.73 g of dry product, according to loss on drying data, partial yield 82.01%, HPLC Method 1 (area %): main product 99.61%, impurity A 0.09%).

To the same flask used in the above step were charged the wet tegaserod hydroiodide and 548 mL of deionized water to yield a white suspension having a pH of 6.56. The obtained suspension was then seeded with the desired polymorphic form of tegaserod base. The pH of the resulting suspension was adjusted to 11.5-12 (actual value 11.54) with diethylamine (35 mL). Next, the suspension was stirred at 20-25° C for 2 hours (no more diethylamine was needed to maintain the pH). The suspension was then filtered, and the solid was washed twice with 59 mL of water to yield 67.37 g of wet solid (39.98 g of dry product, according to loss on drying data, HPLC Method 1 (area %): main product 99.12%, impurity A 0.09%).

To the same flask used in the above step were charged the wet solid and 548 mL of water. The resulting suspension was heated at 40-50° C and maintained at this temperature for 30 minutes. The suspension was then filtered, and the solid was washed twice with 47 mL of water to yield 57.89 g of wet solid (36.66 g of dry product, according to loss on drying data). Partial Yield: 91.71%; Global yield: 95.46%.

Analytical data: HPLC Method 1 (area %): main product: 99.89%, impurity A:

0.09%; IR (wet): substantially identical to Figure 4.

Example 17: Preparation of "(2E)-2-[(5-methoxy-lH^r-indol-3-yl)methyIene]-Λ^L pentylhydrazinecarboximidamide maleate" (tegaserod maleate)

To a 2 L flask were charged 50 g of 5-methoxy-lH-indole-3-carbaldehyde (0.28 moles, 1.0 molar equivalent, HPLC Method 1 (area %): 99.5%) and 370 mL of ethyl acetate. The resulting suspension was stirred at 20-25° C, and 97.08 g of ]V-pentylhydrazine carboximidamide hydroiodide (0.36 moles, 1.25 molar equivalents, HPLC Method l(area %): 95.3%), which had been dissolved in 130 mL of ethyl acetate over 5 to 10 minutes, was added to yield an orange suspension having a pH of 7.66.

The pH of the resulting suspension was adjusted to 3-3.5 (actual value 3.31) with glacial acetic acid (40 mL) added at 20-25° C. The suspension was then heated to reflux and maintained at this temperature for 1 hour. The resulting yellow suspension was then cooled, and the reaction mixture was monitored by TLC and stirred for an additional hour at 20-25° C. The suspension was then filtered and washed with 50 mL of ethyl acetate to yield 144.57 g of wet crude tegaserod hydroiodide (109.95 g of dry product, according to loss on drying data, partial yield: 89.74%, HPLC Method 1 (area %): main product: 98.98 %, impurity A: 0.11%).

To the same flask used in the above step were charged the wet solid, 330 mL of methanol, 330 mL of acetonitrile and 8.80 g of activated charcoal. The suspension was then stirred at 20-25° C for 30 minutes, filtered over three filter papers, and the residue was washed twice with 16 mL of a mixture of methanol/acetonitrile (1 : 1) to yield an orange clear solution.

To a clean and dry 2L flask was charged the orange clear solution and 1100 mL of deionized water were added over 30 minute to yield a white suspension. The suspension was then stirred for 1 hour at 20-25° C and for 2 additional hours at 0-10° C. The suspension was then filtered and the obtained solid was washed twice with 103 mL of deionized water to yield 100.32 g of wet tegaserod hydroiodide (84.06 g of dry product, according to loss on drying data, partial yield 76.46%, HPLC Method 1 (area %): main product: 99.87%, impurity A: 0.08%; HPLC method 2 (area %): main product: 99.86%, impurity A: 0.08%, impurity B: not detected).

To the same flask used in the above step were charged the wet solid and 840 mL of deionized water to yield a white suspension having a pH of 6.00. The pH of the resulting suspension was then adjusted to 11-11.5 (actual value 11.23) with diethylamine (27 mL). The suspension was then stirred at 20-25° C for 2 hours, and the pH was adjusted as necessary with diethylamine (8 mL). Next, the suspension was filtered, and the solid was washed twice with 76 mL of water to yield 71.84 g of wet solid (57.42 g of dry product, according to loss on drying data, partial yield: 97.31%, HPLC Method 1 (area %): main product: 99.81%, impurity A: 0.08%).

To the same flask used in the above step were charged the wet solid and 840 mL of water. The obtained suspension was heated at 40-50° C and stirred at this temperature for 30 minutes. The suspension was then filtered, and the obtained solid was washed twice with 76 mL of water to yield 64.53 g of wet solid (54.80 g of dry product, according to loss on drying data, partial yield 95.44%, HPLC Method 1 (area %): main product: 99.81%, impurity A: 0.08%; HPLC method 2 (area %): main product: 99.78%, impurity A: 0.08%, impurity B: 0.05%).

To a 1 L flask were charged the wet solid and 438 mL of isopropanol. The resulting suspension was heated at 70-80° C and stirred at this temperature until near total dissolution was observed. The solution was then filtered, and the clear and hot filtrate solution was seeded with the desired polymorphic form of tegaserod maleate. Over approximately 30-45 minutes, a filtered dissolution of 21. H g of maleic acid and 148 mL of isopropanol was added to the resulting suspension. A thick suspension was observed at the beginning of the addition, which became more fluid during the process. Once the addition was completed, the suspension was cooled to 20-25° C, maintained at this temperature for 1 hour and then at 0-10° C for an additional 1 hour and 30 minutes. Next the suspension was filtered, and the obtained solid was washed twice with 51 mL of isopropanol to yield 154.04 g of wet solid. The solid was then dried at 40° C under vacuum to yield 72.06 g of final product. Partial Yield: 94.93%; Global Yield: 60.49%.

Analytical data: HPLC Method 1 (area %): main product 99.77%, impurity A: 0.08%; Melting point: 181.0-181.6° C; Residual solvents: not detected (< 100 ppm of isopropanol); Heavy metals: < 20 ppm; Residue on ignition: < 0.1%; Water content (KF method): 0.23 %; Loss on drying: 0.20 %; Particle size (method 1 PS): D₁₀ (v): 1.3 μm; D₅₀ (v): 6.3 μm; D₉₀ (v): 14.5 μm; Specific surface area (method 1 SS): 12.3423 ± 0.0534 ni²/g.

By following the above-described procedures, additional samples of tegaserod maleate were prepared as illustrated in the following additional examples. Particle size and specific surface area results for these examples are shown in Table 1, below.

Table 1

By following the above-described procedures, additional samples of tegaserod hydroiodide, tegaserod base and tegaserod maleate were prepared as illustrated in the following additional examples and analyzed using the HPLC Method 2 described above. HPLC results for these examples are shown in Table 2, below.

Table 2

Example 35: Preparation of "(2i^-2-[(5-methoxy-lJ7-indoI-3-yl)methylene]-JV- pentylhydrazinecarboximidamide hydroiodide" (tegaserod hydroiodide)

As shown in this example, the quality of the N-pentyl-N'-aminoguanidine hydroiodide used to produce tegaserod hydroiodide has an important effect on the yield of the reaction. Li Example 1 above , the N-pentyl-N'-aminoguanidine hydroiodide (i.e., N- pentylhydrazinecarboximidamide hydroiodide) used had an HPLC purity (area %) of about 95% when analyzed by HPLC Method 1 ("Quality 1"). In this example, the N-pentyl-N'- aminoguanidine hydroiodide (i.e., N-pentylhydrazine carboximidamide hydroiodide) has used an HPLC purity (area %) of about 91% when analyzed by HPLC Method 1 ("Quality 2"). Thus, the only difference between this example and Example 1 is the quality of the N-pentyl-N'- aminoguanidine hydroiodide used.

In a 500 niL flask are charged 15.0O g of 5-methoxy-lH-indole-3-carbaldehyde (0.0856 moles, 1.0 molar equivalent) and 100 niL of ethyl acetate. The suspension was stirred at 20-25° C. To the suspension was added N-pentylhydrazinecarboximidamide hydroiodide Quality 2 (i.e., N-pentyl-N'-aminoguanidine hydroiodide Quality 2) (24.49 g, 0.090 moles, 1.050 molar equivalents) dissolved in 50 mL of ethyl acetate over 5-10 minutes to yield an orange suspension having a pH of 7.10.

The pH of the resulting suspension was adjusted to 2.5 - 3.5 (actual value 3.04) with glacial acetic acid (11 mL, 2.24 molar equivalents of acid) added at 20-25° C. The suspension was then heated to reflux and maintained at this temperature for 2 hours. The resulting yellow suspension was then cooled. The reaction mixture is monitored by TLC and stirred for 20 minutes at 20-25° C. The solution was then filtered to yield 13.58 g of wet tegaserod hydroiodide (13.55 g of dry product; Yield: 36.86%).

Analytical data: HPLC Method 1 (area %): 95.4%; Potentiometric Assay using HClO₄: 112.75%; Potentiometric Assay using Tetra n-butyl ammonium hydroxide: 112.55%; Melting point : 203.3-204.4° C.

Example 36 : Preparation of ''(2E)-I- [(5-methoxy-liϊ-indol-3-yl)methylene] -N- pentylhydrazinecarboximidamide" (tegaserod base)

This example illustrates Example 2a of U.S. Patent No. 5,510,353 for obtaining tegaserod base without using chromatography purification.

In a 100 mL flask are charged 2.22 g of 5-methoxy-lH-indole-3-carbaldehyde (0.0127 moles, 1.0 molar equivalent), 80 mL of methanol and a solution of 4.35 g of VV-pentyl hydrazinecarboximidamide hydroiodide (0.016 moles, 1.260 molar equivalents, quality 1) dissolved in 20 mL of methanol. An orange suspension having a pH of 8.88 is obtained.

The reaction mixture was cooled at 5° C, and the pH of the resulting suspension is adjusted to 3 (actual value 3.06) with a mixture of MeOH/HCl (2 mL of a solution 0.85 N, 0.134 molar equivalents of acid were needed). The suspension was maintained at 3-5° C for 2 hours during which it became more fluid with stirring and became an orange solution. The reaction mixture was then evaporated to dryness to yield 6.16 g of a brown-orange powder (HPLC Method 1 (area %): 95.37%).

The resulting solid and 129.68 mL of ethyl acetate were then combined in a 250 mL to yield a yellow suspension. The yellow suspension was then stirred for 15 minutes and had a pH of 1.68. To the suspension was added 129.68 mL of a 2N Na₂CO₃ solution, which caused dissolution of the solid. The mixture was then stirred for 30 minutes and had a final pH of 8.84. Next, the mixture was permitted to separate into two phases. The resulting product in the organic phase was dried with sodium sulphate anhydride and then evaporated to dryness to yield 3.96 g of a thick, brown oil (Yield: 72.79%, HPLC Method 1 (area %): 91.09%).

Example 37: Preparation of "βEJ-l-KS-methoxy-lH→ndoI-S-ytymetliylenel-iV'-

Klir^S-methyl-lif^ndol-S-ylJmethylenelhydrazinecarboximidohydrazide maleate" (impurity B maleate)

In a 1 L flask, 47.43 g of 5-methoxy-lH-indole-3-carbaldehyde (0.271 moles, 2.0 molar equivalents), 17 g of hydrazinecarboximidohydrazide hydrochloride (0.135 moles, 1.0 molar equivalent) and 474 niL of ethyl acetate are combined to yield a light brown suspension with a pH of 5.37.

The pH of the resulting suspension was adjusted to 3 — 3.5 (actual value 3.33) with glacial acetic acid at 20-25° C (9 mL, 1.16 molar equivalents of acid were needed). The suspension was then heated to reflux and maintained at this temperature for 1 hour. Next, 474 mL of methanol was added to the reaction mixture and the fluid suspension obtained was stirred at 20-25 ° C for about 24 hours. During mixing, the reaction mixture was monitored by TLC. The resulting green-yellow suspension was filtered to yield 55.93 g of wet impurity B hydrochloride (41.43 g, according to loss on drying data, partial yield: 69.57%, HPLC Method 1 (area %): 99.473%).

In the same flask, the obtained wet solid and 469.02 mL of deionised water were combined to yield a thick, crude suspension having a pH of 3.89. The pH of the resulting suspension was then adjusted to 11.5-12 (actual value 11.62) with diethylamine (44.04 mL are needed), and the suspension was stirred at 20-25° C for 2 hours (the pH was adjusted as needed with 11.01 mL more of diethylamine). The suspension was then filtered and the obtained solid was washed twice with 55.05 mL of water to yield 19.96 g of wet solid (36.30 g of dry product, according to loss on drying data, partial yield: 95.53%, HPLC Method 1 (area %): 99.76%).

In the same flask, the resulting solid was combined with 413.97 mL of water. The suspension was then heated at 40-50° C, stirred at this temperature for 30 minutes. Next, the suspension was filtered and the resulting solid was washed twice with 55.05 mL of water to yield 109.68 g of wet Impurity B base (34.61 g of dry product, according to loss on drying data, partial yield 95.34%, HPLC Method 1: 99.73 area %).

The obtained wet solid and 277 niL of isopropanol were combined in a 500 niL flask. The suspension was then heated at reflux temperature, stirred at this temperature for 10 minutes, and cooled at 75° C. To the resulting suspension, a solution of 10.48 g of maleic acid and 73.31 mL of isopropanol was added over about 15-30 minutes while maintaining the temperature at 70-80° C. Once the addition was completed, the reaction mixture was allowed to cool to 20-25° C over about 1 hour. The obtained suspension was then stirred at 20-25° C for 1 hour, at 0-10° C for an additional one and a half hours. The solution was the filtered and the resulting solid was washed twice with 36.50 mL of isopropanol to yield 51.10 g of wet solid which was then dried at 40° C under vacuum to yield 38.05 g of impurity B maleate (Partial Yield 85.38%; Global Yield: 54.10%).

Analytical data: Assay (HClO₄): 96.47%; HPLC Method 1 (% area): 99.40%; HPLC Method 2 (area %): 98.59%; Melting point: 183.8-185.2° C; Water content (KF method): 3.42%; Loss on drying: 1.84%.

Although the invention has been described and illustrated with a certain degree of particularity, it is understood that the present disclosure has been made only by way of example, and that numerous changes in the conditions and order of steps can be resorted to by those skilled in the art without departing from the spirit and scope of the invention.

Claims

CLAIMSWhat is claimed is:

1. 3-(5-methoxy-lH-indol-3-ylmethylene)-N-pentylcarbazimidamide hydroiodide (tegaserod hydroiodide).

2. The tegaserod hydroiodide of claim 1 , wherein said tegaserod hydroiodide has a purity higher than approximately 95% when analyzed by reverse phase HPLC.

3. The tegaserod hydroiodide of claim 2, wherein said tegaserod hydroiodide has a purity higher than approximately 98% when analyzed by reverse phase HPLC.

4. The tegaserod hydroiodide of claim 3, wherein said tegaserod hydroiodide has a purity higher than approximately 99% when analyzed by reverse phase HPLC.

5. The tegaserod hydroiodide of claim 4, wherein said tegaserod hydroiodide has a purity higher than approximately 99.5% when analyzed by reverse phase HPLC.

6. The tegaserod hydroiodide of claim 1, wherein said tegaserod hydroiodide has an X- ray diffraction pattern (2Θ) having characteristics peaks at approximately 5.10, 5.24, 13.96, 18.21, 18.54, 20.90, 21.68, 22.98, 24.40, 26.12, 28.68 and 32.23 degrees.

7. The tegaserod hydroiodide of claim 1 , wherein said tegaserod hydroiodide is crystalline.

8. 3-(5-methoxy-lH-indol-3-ylmethylene)-N-pentylcarbazimidamide (tegaserod free base), wherein said tegaserod free base is derived from tegaserod hydroiodide.

9. The tegaserod free base of claim 8, wherein said tegaserod free base has a purity higher than approximately 95% when analyzed by reverse phase HPLC.

10. The tegaserod free base of claim 9, wherein said tegaserod free base has a purity higher than approximately 98% when analyzed by reverse phase HPLC.

11. The tegaserod free base of claim 10, wherein said tegaserod free base has a purity higher than approximately 99% when analyzed by reverse phase HPLC.

12. The tegaserod free base of claim 11, wherein said tegaserod free base has a purity higher than approximately 99.5% when analyzed by reverse phase HPLC.

13. The tegaserod free base of claim 8, wherein said tegaserod free base has an X-ray diffraction pattern (2Θ) having characteristics peaks at approximately 7.66, 9.00, 15.34, 17.38, 18.05, 19.25, 20.90, 21.96, 22.27, 22.48, 23.98, 28.43, 30.34, 30.98 degrees.

14. The tegaserod free base of claim 8, wherein said tegaserod free base is crystalline.

15. Tegaserod free base monohydrate.

16. The tegaserod free base of claim 15, wherein said tegaserod free base is prepared from tegaserod hydroiodide.

17. 3-(5-methoxy-lH-indol-3-ylmethylene)-N-pentylcarbazimid amide hydrogen maleate (tegaserod maleate), wherein said tegaserod free base is derived from said tegaserod hydroiodide of claim 1.

18. The tegaserod maleate of claim 17, wherein said tegaserod maleate has a purity higher than approximately 95% when analyzed by reverse phase HPLC.

19. The tegaserod maleate of claim 18, wherein said tegaserod maleate has a purity higher than approximately 98% when analyzed by reverse phase HPLC.

20. The tegaserod maleate of claim 19, wherein said tegaserod maleate has a purity higher than approximately 99% when analyzed by reverse phase HPLC.

21. The tegaserod maleate of claim 20, wherein said tegaserod maleate has a purity higher than 99.5% when analyzed by reverse phase HPLC.

22. A process for preparing tegaserod hydroiodide comprising reacting 5-methoxy-lϋ- indole-3-carbaldehyde with N-pentylhydrazinecarboximidamide hydroiodide.

23. The process of claim 22, wherein said N-pentylhydrazinecarboximidamide hydroiodide has a purity higher than approximately 95% when analyzed by HPLC.

24. The process of claim 22, further comprising reacting said 5-methoxy-lH^"-indole-3- carbaldehyde with said N-pentylhydrazinecarboximidarnide hydroiodide in at least one polar solvent.

25. The process of claim 24, wherein said at least one polar solvent is at least one of ethyl acetate, acetonitrile, water and combinations thereof.

26. The process of claim 22, further comprising reacting said 5-methoxy-lH-indole-3- carbaldehyde with said N-pentylhydrazinecarboximidamide hydroiodide in the presence of at least one organic acid.

27. The process of claim 26, wherein said at least one organic acid is at least one of glacial acetic acid, aqueous acetic acid and combinations thereof.

28. The process of claim 26, wherein the amount of said at least one organic acid is an amount sufficient to adjust the pH of the reaction to between approximately 2 to approximately 4.

29. The process of claim 22, wherein said reacting of said 5-methoxy-l/f-indole-3- carbaldehyde with said N-pentylhydrazinecarboxiniidamide hydroiodide is performed at a temperature of approximately 0° C.

30. The process of claim 22, further comprising at least one purification step.

31. The process of claim 30, wherein said at least one purification step is at least one of contacting said tegaserod hydroioide with a solvent system, treating a solution containing said tegaserod hydroiodide with a decolorizing agent and treating a solution of said tegaserod hydroiodide with a reducing agent.

32. The process of claim 31 , wherein said decolorizing agent is at least one of activated charcoal, silica gel, ambosol and mixtures thereof.

33. The process of claim 31, wherein said reducing agent is at least one of sodium metabisulfite, sodium hydrosulfite and sodium thiosulfate (pentahydrate) and mixtures thereof.

34. The process of claim 31, wherein said solvent system comprises at least one alcoholic solvent and acetonitrile.

35. The process of claim 34, wherein said at least one alcoholic solvent is at least one of methanol, ethanol, isopropanol, n-butanol and mixtures thereof.

36. A process for preparing tegaserod free base and hydrates thereof comprising converting tegaserod hydroiodide to said tegaserod free base and hydrates thereof.

37. The process of claim 36, wherein said step of converting said tegaserod hydroiodide to said tegaserod free base and hydrates thereof comprises contacting said tegaserod hydroiodide with at least one inert solvent and at least one base.

38. The process of claim 37, wherein said inert solvent is deionized water.

39. The process of claim 37, wherein said at least one base is an organic base, an inorganic and combinations thereof.

40. The process of claim 39, wherein said organic base is at least one of an alkyl amine, an aryl amine and combinations thereof.

41. The process of claim 39, wherein said organic base is at least one of diethylamine, triethylamine and combinations thereof.

42. The process of claim 37, wherein said inorganic base is at least one of a metal alkaline base, an earth metal base and combinations thereof.

43. The process of claim 39, wherein said at least one inorganic base is potassium hydroxide, sodium hydroxide and mixtures thereof.

44. The process of claim 37, wherein the amount of said at least one base is an amount sufficient to adjust the pH of the reaction to between approximately 9 and approximately 13.

45. The process of claim 37, further comprising the step of seeding the reaction with at least one polymorphic form of tegaserod base.

46. The process of claim 37, wherein said reaction is performed at a temperature between approximately 0° C and approximately 60° C.

47. A process for preparing tegaserod maleate comprising i. preparing tegaserod hydroiodide; ii. converting said tegaserod hydroiodide to tegaserod base; and iii. converting said tegaserod base to said tegaserod maleate.

48. The process of claim 47, wherein said tegaserod maleate has a purity higher than 95% when analyzed by reverse phase HPLC.

49. The process of claim 48, wherein said tegaserod maleate has a purity higher than 98% when analyzed by reverse phase HPLC.

50. The process of claim 49, wherein said tegaserod maleate has a purity higher than 99% when analyzed by reverse phase HPLC.

51. The process of claim 50 wherein said tegaserod maleate has a purity higher than 99.5% when analyzed by reverse phase HPLC.

52. A process for preparing tegaserod maleate comprising i. preparing tegaserod hydroiodide; ii. converting said tegaserod hydroiodide to tegaserod base; and iii. converting said tegaserod base to said tegaserod maleate; wherein said tegaserod hydroiodide is prepared according to the process of claim 22.

53. A process for preparing tegaserod maleate comprising i. preparing tegaserod hydroiodide; ii. converting said tegaserod hydroiodide to tegaserod base; and iii. converting said tegaserod base to said tegaserod maleate; wherein said tegaserod base is prepared according to the process of claim 37.

54. Impurity A having an HPLC RRT (relative retention time) of approximately 0.93.

55. Impurity A having an HPLC RRT (relative retention time) of approximately 0.58.

56. Tegaserod hydroioide according to claim 1 having less than approximately 0.1% as area percentage HPLC of impurity A

57. Tegaserod base according to claim 8 having less than approximately 0.1% as area percentage HPLC of impurity A.

58. The tegaserod maleate made by the process of claim 46, wherein said tegaserod maleate has less than approximately 0.1% as area percentage HPLC of impurity A.

59. The process of claim 47, wherein said tegaserod maleate has less than approximately 0.1% as area percentage HPLC of impurity A.

60. The process of claim 47, wherein said tegaserod hydroioide has less than approximately 0.1% as area percentage HPLC of impurity A and said tegaserod base has less than approximately 0.1% as area percentage HPLC of impurity A.

61. A process for preparing tegaserod maleate comprising converting at least one of tegaserod base having less than approximately 0.1% as area percentage HPLC of impurity A and tegaserod hydroioide having less than approximately 0.1% as area percentage HPLC of impurity A into tegaserod maleate.

62. Impurity B having the following structure:

63. Impurity B characterized as having an HPLC RRT of approximately 1.10.

64. Tegaserod hydroioide according to claim 1 having less than approximately 0.1% as area percentage HPLC of impurity B

65. Tegaserod base according to claim 8 having less than approximately 0.1% as area percentage HPLC of impurity B.

66. The tegaserod maleate made by the process of claim 47, wherein said tegaserod maleate has less than approximately 0.1% as area percentage HPLC of impurity B.

67. The process of claim 47, wherein said tegaserod maleate has less than approximately 0.1% as area percentage HPLC of impurity B.

68. The process of claim 47, wherein said tegaserod hydroioide has less than approximately 0.1% as area percentage HPLC of impurity B and said tegaserod base has less than approximately 0.1% as area percentage HPLC of impurity B.

69. A process for preparing tegaserod maleate comprising converting at least one of tegaserod base having less than approximately 0.1% as area percentage HPLC of impurity B and tegaserod hydroioide having less than approximately 0.1% as area percentage HPLC of impurity B into tegaserod maleate.

70. A process for preparing tegaserod maleate comprising contacting tegaserod base with at least one inert solvent and maleic acid to obtain a solution.

71. The process of claim 70, further comprising purifying said tegaserod base prior to adding said maleic acid.

72. The process of claim 70, further comprising seeding said solution with at least one polymorphic form of tegaserod maleate.

73. The process of claim 71, wherein said purifying comprises treating said solution with at least one of a decolorizing agent, a reducing agent and combinations thereof.

74. The process of claim 73, wherein said decolorizing agent is at least one of activated charcoal, silica gel, ambosol and combinations thereof.

75. The process of claim 73, wherein said reducing agent is at least one of sodium metabisulfite, sodium bisulfite, sodium hydrosulfite and sodium thiosulfate (pentahydrate) and combinations thereof.

76. The process of claim 70, wherein the molar quantitity of said maleic acid is between approximately 0.9 to approximately 1.5 moles per mole of said tegaserod base.

77. The process of claim 76, wherein the molar quality of said maleic acid is between approximately 1.0 to approximately 1.2 moles per mole of said tegaserod base.

78. The process of claim 70, wherein said at least one inert solvent is isopropanol.

79. Tegaserod maleate prepared by the process of claim 70, wherein said tegaserod maleate has a particle size distribution wherein approximately 10% of the total volume comprises particles having a diameter less than approximately 3 μm.

80. Tegaserod maleate prepared by the process of claim 70, wherein said tegaserod maleate has a particle size distribution wherein approximately 50% of the total volume comprises particles having a diameter less than approximately 10 μm.

81. Tegaserod maleate prepared by the process of claim 70, wherein said tegaserod maleate has a particle size distribution wherein approximately 90% of the total volume comprises particles having a diameter less than approximately 20 μm.

82. Tegaserod maleate prepared by the process of claim 70, wherein said tegaserod maleate has a surface area of approximately 5 to approximately 20 m Ig.

83. Tegaserod maleate prepared by the process of claim 70, wherein said tegaserod maleate has a surface area of approximately 8 to approximately 13 m²/g.

84. A pharmaceutical composition comprising the tegaserod maleate of any of claims 79- 81.

85. A process for purifying tegaserod hydroiodide comprising: contacting said tegaserod hydroioide with a solvent system to obtain a solution; and contacting said solution with water to precipitate said tegaserod hydroiodide, wherein said solvent system comprises acetonitrile.

86. The process of claim 85, wherein said solvent system further comprises at least one alcohol solvent.

87. The process of claim 86, wherein said at least one alcohol solvent is at least one of methanol, ethanol, isopropanol and n-butanol and combinations thereof.

88. The process of claim 85, further comprising treating said solution with at least one of a decolorizing agent, a reducing agent and combinations thereof.

89. The process of claim 88, wherein said decolorizing agent is at least one of activated charcoal, silica gel, ambosol and combinations thereof.

90. The process of claim 88, wherein said reducing agent is at least one of sodium bisulfite, sodium hydrosulfite and sodium thiosulfate (pentahydrate) and combinations thereof.