KR20070030962A - Processes for preparing novel crystal forms of ondansetron - Google Patents

Abstract

Ondansetron crystalline forms A and B are useful for the treatment of nausea and vomiting. Form B has a uniquely high melting point of about 244 ° C., and both forms are stable to thermally induced polymorphic transitions at temperatures of 30 ° C. to below melting point.

Ondansetron

Description

Production method of novel ondansetron crystal form {PROCESSES FOR PREPARING NOVEL CRYSTAL FORMS OF ONDANSETRON}

1 is a differential scanning calorimetry thermogram of ondansetron form B. FIG.

2 is a characteristic powder X-ray diffraction pattern of ondansetron Form B.

3 is a differential scanning calorimeter thermal analysis diagram of ondansetron Form A. FIG.

4 is a characteristic powder X-ray diffraction pattern of ondansetron Form A. FIG.

This application claims the rights under 35 U.S.C. §1.119 (e) to Provisional Application No. 60 / 376,395, filed April 30, 2002, which application is incorporated herein by reference.

The present invention provides (±) 1,2,3,9-tetrahydro-9-methyl-3- [2-methyl-1h-imidazol-1-yl) -methyl] -4h-carbazol-4-one ( Ondansetron). In particular, the present invention relates to newly discovered high melting point ondansetron crystal forms, newly discovered second crystal forms, methods for preparing these new forms, pharmaceutical compositions containing these crystal forms, nausea using them and To a method of treating vomiting.

(±) 1,2,3,9-tetrahydro-9-methyl-3- [2-methyl-1H-imidazol-1-yl) having the above molecular structure and formula C ₁₈ H ₁₉ N ₃ O Methyl] -4H-carbazol-4-one is a selective 5-HT ₃ receptor antagonist. It is a nitrogen containing compound which may be present in free base and salt form. The free base is known by the general name ondansetron. Ondansetron is useful for reducing nausea in patients receiving chemotherapy treatment (Grunberg, SM ,; Hesketh, PJ "Control of Chemotherapy-Induced Emesis" N. Engl. J. Med . 1993 , 329, 1790-96 ). Ondansetron has been approved by the US Food and Drug Administration (FDA) for the prophylactic treatment of nausea and vomiting associated with some cancer chemotherapy, radiotherapy and postoperative nausea and / or vomiting. Ondansetron under the trade name Zofran® ODT is commercially available as orally disintegrating tablets.

The present invention relates to the physical properties of the solid state of ondansetron. Merck According to Index (12th ed., Merck & Co: Whitehouse Station, NJ1996), ondansetron has a melting point in the range of 231 to 232 ° C.

U.S. Patent 4,695,578 discloses several preparations of ondansetron. Co-acquired and co-pending US patent application (atty.ref. No. 2664/55602) also discloses an ondan setron preparation. The above-mentioned US patent '578 and patent application [2664/55602] are incorporated herein by reference in their entirety, in particular to teach a method for synthesizing ondansetron from commercially available and readily accessible starting materials. have.

In Example 4 of US Pat. No. 578, 1,2,3,9-tetrahydro-9-methyl-3- [2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazole- 4-one was methylated with dimethylsulfate in N, N-dimethylformamide at the 9-N position of the carbazole-4-one ring system. Ondansetron is formed as a solid in the reaction mixture. This separated solid decomposes at 223-224 ° C.

In Example 7 of US Pat. No. 578, ondansetron is dimethyl from 3-[(dimethylamino) methyl] -1,2,3,9-tetrahydro-9-methyl-4H-carbazol-4-one in water. Prepared by substituting an amine with 2-methylimidazole (however, the mechanism of the reaction need not be a simple substitution). The precipitated crude product having a melting point of 221-221.5 ° C. was recrystallized from methanol to give ondansetron having a melting point of 231-232 ° C.

In Example 8 of US Pat. No. 578, ondansetron was prepared by the process of Michael, 2-methylimidazole in 1,2,3,9-tetrahydro-9-methyl-3-methylene-4H-carbazol-4-one. Michael) was added by the type addition method. The product was recrystallized from methanol to give ondansetron having a melting point of 232-234 ° C.

In Example 18 (ii) of U.S. Patent '578, 2-methylimidazolo 3- (chloromethyl) -1,2,3,9-tetrahydro-9-methyl-4H-carbazol-4-one Chloride in water was substituted and then subjected to column chromatography to prepare ondansetron having a melting point of 228 to 229 ° C.

In Example 19 of US Pat. No. 578, 2,3,4,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl) methyl] -1H-carbazole The maleate was DDQ oxidized and then subjected to column chromatography to prepare ondansetron having a melting point of 227-228.5 占 폚.

In Example 20 of US Pat. No. 578, 2,3,4,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl) methyl] -1H-carbazole The 4-ol was DDQ oxidized and then subjected to column chromatography to prepare ondansetron having a melting point of 232 to 234 ° C.

In US Pat. Nos. 4,983,621, 4,783,478 and 4,835,173, ondansetron was prepared as described in Example 7 of US Pat. No. 4,695,578, to produce a recrystallized crude ondansetron having the same melting point range.

In US Pat. No. 4,957,609, palladium 3- [2-iodophenyl) methylamino] -6-[(2-methyl-1H-imidazol-1-yl) methyl] -2-cyclohexen-1-one Ondansetron was prepared by intramolecular coupling (intramolecular palladium catalyzed coupling) followed by column chromatography under a catalyst. The product was decomposed at 215 ~ 216 ° C.

In US Pat. No. 4,739,072, 6-[(2-methyl-1H-imidazol-1-yl) methyl] -3- (2-methyl-2-phenylhydrazino) -2-cyclohexen-1-one Ondansetron was prepared by a reaction involving zinc catalyzed cyclization. Treatment by column chromatography yielded a product having a melting point of 216-218 占 폚. The chromatographed product was recrystallized from methanol to give ondansetron having a melting point in the range of 227.5-228.5 ° C.

As can be clearly seen from the summary of some of the above known methods for preparing ondansetron, the reported melting point of ondansetron does not involve decomposition, from 215 ° C. with degradation, depending on how to prepare and separate ondansetron. Varying over a wide range up to 234 ° C. Ondansetron crystallized from methanol in the past, according to these reports, melts in a narrower and more consistent temperature range (227-234 ° C) than chromatographic materials that appear to have a melting point dispersed over a wide range (215-234 ° C). Seems to be.

The inventors have discovered and characterized a novel high melting point ondansetron crystal form and a second crystalline form that melts at the more typical temperatures of ondansetron prepared by conventional methods.

There is a need for new ondansetron crystal forms. The discovery of new crystalline forms of pharmaceutical compounds offers the opportunity to improve the performance properties of pharmaceutical products. This expands the list of substances that formulation researchers can use to design pharmaceutical formulations of drugs, such as those with targeted directed release profiles or other desirable properties.

A first aspect of the invention relates to crystalline Form B of ondansetron. Ondansetron Form B has a uniquely high melting point of 244 ± 2 ° C. and is stable to thermally induced polymorphic transitions between 30 ° C. and 180 ° C. Form B can be identified not only by its thermal properties but also by powder X-ray crystallography. Form B can be prepared by precipitation from certain alcohol solvents under controlled conditions.

A second aspect of the invention relates to crystalline Form A of ondansetron, which is readily discernible from its powder X-ray diffraction pattern. Ondansetron Form A is also stable against thermally induced polymorphic transitions between 30 ° C and 180 ° C. Form A may be prepared by precipitation from selected organic solvents, and mixtures of these organic solvents and water, under controlled conditions.

The invention also provides a pharmaceutical composition comprising ondansetron form A, ondansetron form B and mixtures thereof.

The present invention also provides methods for treating and / or preventing nausea and vomiting with ondansetron form A and ondansetron form B. In particular, ondansetron forms A and B are useful for treating and / or preventing nausea and vomiting associated with surgery, vomiting-induced cancer chemotherapy and radiotherapy.

Detailed description of the invention

In a first aspect, the present invention provides a novel thermally stable ondansetron crystal form represented by Form B. Form B is characterized by thermal methods including differential scanning calorimetry (“DSC”) and thermogravimetric analysis (“TGA”), powder X-ray diffraction (“PXRD”) analysis. PXRD patterns and differential thermal analyzes are provided in the figures. In the relevant section, TGA results are discussed in the above section.

Referring to FIG. 1, the differential scanning calorimetry analysis diagram of ondansetron form B shows the unique thermal stability of this crystal form. 1 has a sharp melting point endotherm with a maximum at 244 ° C. The change in maximum melting point endothermic temperature obtained from a similar sample of Form B analyzed on another commercial calorimeter using the same heating rate should be significantly less than ± 2 ° C. However, capillary melting points are usually not measured or recorded at precisely defined heating rates. Different heating rates in combination with thermal inertia can cause the capillary melting point to deviate from the true melting point of the sample. Thus, ondansetron, which exhibits melting at 244 ± 2 ° C., such as measured melting points, maximum melt endotherms, inflection points in the heat absorption curve, and the like, is considered to be identical in form B to its identity. The magnitude of the melting endotherm is estimated to be 140.11 Jg ⁻¹ , but the exact heat of fusion could not be measured due to overlap with other endotherms.

Over and above the melt endotherm there is a wide endotherm attributable to the volatilization or chemical decomposition of ondansetron. At temperatures below the endotherm of the melt, the differential scanning calorimetry thermogram is flat. This feature is consistent with the absence of polymorphic transitions before melting. Thus, although detectable and neither endothermic transitions may occur to detectably, Form B appears to be stable to thermally induced polymorphic transitions between 30 ° C and 180 ° C. The thermal analysis was performed under a dry inert atmosphere. Thus, it is also not excluded that Form B is susceptible to solvent induced transitions, including vapor induced transitions in this temperature range.

Differential scanning calorimetry was performed using the Mettler Toledo 821 STAR ^e system. Samples of 3-5 mg were analyzed in loosely fitted aluminum crucibles. Injection was performed at 30-300 ° C. at a ramp rate of 10 ° C./min under a nitrogen purge of 40.0 mL / min flow rate. The sample showing the regenerated thermal analysis in Figure 1 was 5.05 mg in weight.

The PXRD pattern of ondansetron Form B (FIG. 2) is unique. Form B can be characterized by the PXRD characteristics shown in Table 1 that distinguish this form from Form A.

Peak position (° 2θ) ^a 11.0 11.2 14.9 15.5 15.9 16.5 20.6 21.4 23.1 23.5 24.2 24.7 24.8 25.8 26.9 28.1

^a expected change between devices: ± 1.0 °

PXRD patterns were made on a Scintag X-ray powder diffractometer model X'TRA equipped with a copper cathode tube and a solid state detector. Samples were prepared gently and sufficiently polished in agate mortar to reduce preferential orientation. No crystalline damage was observed in the samples prepared by grinding. The powdered sample was poured into a round cavity of the sample holder and pressed with a glass plate to form a smooth surface. Continuous scanning was performed to 2-40 degrees two (theta) at 3 degrees / min. Reported peak positions are considered accurate within ± 0.05 °. Those skilled in the art of X-ray crystallography will understand that the peak positions determined in other devices may vary by ± 1 °.

Dry loss of ondansetron Form B (“LOD”) was found to be about 2%, calculated for hypothetical hemi-hydrate (or C ₁ -C ₃ alcohol 1/2 solvate). It is believed to be consistent with the unsolvated ondansetron, which is less than one amount and has adsorptive moisture. LOD was measured by TGA using Mettler TG50, sample weight 7-15 mg, heating rate 10 ° C./min. Standard alumina crucibles were used.

Ondansetron Form B was prepared under controlled conditions. Only a method of successfully calculating Form B can be described. Other conditions for producing ondansetron Form B can be found through routine experimentation.

Ondansetron Form B can be prepared by crystallizing ondansetron from solutions in C ₁ -C ₃ alcohols, in particular methanol, ethanol, propan-1-ol, propan-2-ol and mixtures thereof. Ondansetron is dissolved in C ₁ -C ₃ alcohol, preferably in an amount sufficient to produce a solution of about 50 mM to about 300 mM, more preferably about 85 mM to about 150 mM. Ondansetron has limited solubility in these alcohols at room temperature. Therefore, it may be necessary to heat the mixture in order to sufficiently dissolve the ondansetron. Preferably, the mixture is refluxed until the mixture is a clear solution. The solution is preferably free of solid ondansetron, which may potentially seed the mixture to cause the ondansetron to precipitate in a crystalline form other than Form B, or to allow Form B to co-crystallize with other forms. Can be. Preferably, Form B obtained by crystallization from the alcohol solution contains up to about 5% of other ondansetron crystal forms, and more preferably, Form B contains up to about 1% of other ondansetron crystal forms.

Crystallization of Form B from this solution can occur spontaneously when left at room temperature. If the mixture is heated, cooling the solution may cause supersaturation leading to crystallization of Form B. Crystallization can also be induced by seeding with crystals of ondansetron form B. Maximum recovery of ondansetron Form B is obtained by cooling the mixture to a temperature below room temperature, such as from about 20 ° C to about 0 ° C. Another means of increasing the yield of Form B is to evaporate some of the alcohol after the starting ondansetron is completely dissolved. Examples are provided below showing the use of a combination of techniques to optimally recover Form B. It should be noted that the preferred solution concentration is dilute. This is due to the poor dissolution of ondansetron in the lower alcohol from which Form B is obtained. Although cooling of the solvent and / or partial evaporation is not critical to the practice of the present invention, cooling and / or partial evaporation of the solvent is wound in order to maximize recovery of traces of dissolved ondansetron in solution after partial crystallization.

If the crystallization is considered to be sufficiently complete, the crystals are separated from the alcohol by conventional means such as filtration, decantation, centrifugation and the like. These crystals can be washed with a solvent such as cold methanol and dried under drying conditions such as 65 ° C. under suction pump or oil pump vacuum. Yields in the range of 70-90% are typical, but may be larger or smaller.

Ondansetron Form B can be obtained with good polymorphic purity by carrying out the preferred embodiments of the foregoing process. Preferably, the ondansetron form B prepared by the above process contains up to about 5% of other ondansetron crystal forms, more preferably up to about 1% of other ondansetron crystal forms. Less Preferred Methods Embodiments or other methods can yield poor ondansetron Form B, particularly if other polymorphic seeds are present. Mixtures containing small amounts of ondansetron form B, such as 25% or less, may exhibit improved properties due to the presence of form B, and therefore such mixtures are improved by the present invention and are considered to be within the scope of the present invention. Of course, as a secondary component, ondansetron form B, found in admixture with other substances such as pharmaceutical excipients, is of particular note as a substance encompassed by ondansetron form B, which produces a thermal analysis showing a melting point of 224 ± 2 ° C.

In a second aspect of the invention, the invention provides ondansetron Form A. Form A is characterized by PXRD, DSC, and TGA using the same equipment and sample preparations used to characterize Form B.

Referring to FIG. 3, the differential thermal analysis of Form A has a melting endotherm with a maximum at 230 ° C. FIG. At temperatures higher than 230 ° C., there is a wide endotherm that overlaps with the melt endotherm, which contributes to the volatilization of ondansetron. When Form A was heated in an "open pan", this overlapping broad endotherm was not observed. However, when Form B was heated in an open pan, its DSC thermal analysis was the same as the thermal analysis observed when Form B was heated in a closed pan. DSC thermal analysis of Form A was performed on the same equipment as used for Form B and using the same procedure (except for some differences mentioned). The sample that produced the thermal analysis of FIG. 3 weighed 4.75 mg.

The PXRD pattern of ondansetron Form A clearly distinguishes Form A from Form B. The characteristic peak positions in the PXRD pattern of Form A are shown in Table 2.

Peak position (° 2θ) ^a 11.0 11.2 14.8 15.4 16.4 20.6 21.4 23.2 24.1 24.7 25.4 25.9 26.7 27.8

^a expected change between devices: ± 1.0 °

Starting with the PXRD features common to Form A and Form B, there are strong peaks at 7.0, 11.0, and 11.2 ± 1.0 ° 2θ, and other common peaks at 14.8, 15.4, 16.5, 20.6, 21.4, and 24.2 ± 1.0 ° 2θ. have.

Significant differences between Form A and Form B are found in the 22-28 ° range of the pattern. Form A produces a peak at 25.4 ° 2θ. The peak closest to 25.4 ° 2θ in the Form B pattern is at 25.8 ° 2θ. Form A also has only one peak at 23.2 ° 2θ in the range of 22-24 °. Form B produces two peaks at 23.1 and 23.5 ° 2θ in this region. Also, the peaks at 26.7 and 27.8 ° 2θ in the Form A pattern do not have corresponding portions in the Form B pattern.

Finally, in the Form A pattern, the peak at 15.9 ° 2θ does not have a corresponding portion in the Form B pattern, and the peak at 25.9 ° 2θ of the Form B pattern does not have a corresponding portion in the Form A pattern.

Like Form B, the sample of Form A was found to have about 2% LOD.

Form A was prepared under controlled conditions. This can only explain ways of successfully calculating Form A. Other conditions for producing ondansetron Form A can be found through routine experimentation.

Form A can be prepared by crystallization from a wide range of organic solvents and mixtures of organic solvents and water. Suitable organic solvents are C ₄ The above monohydroxy, dihydroxyl and polyhydroxyl alcohols; Liquid aromatic compounds such as benzene and toluene; Acetic acid esters such as ethyl acetate and butyl acetate; Polar aprotic solvents such as N, N-dimethylformamide (“DMF”). Preferred solvents are 1-butanol, ethyl acetate, butyl acetate, DMF and DMF-water mixtures. Particularly preferred solvents are 1-butanol and DMF.

Ondansetron is preferably dissolved completely in solvent before attempting to separate Form A as a precipitate. Ondansetron solubility in solvents is a factor that affects the relative amounts of ondansetron and solvent bound. While the polarity of the solvent from which Form A crystallizes to some extent, the ratio of ondansetron to solvent varies significantly depending on the solvent selection. When using one of the particularly preferred solvents, ondansetron is preferably added to the solvent in an amount sufficient to form a 50 mM to about 300 mM solution once fully dissolved.

In order to accelerate dissolution and increase solubility, it is preferable to heat the mixture of ondansetron and a solvent. More preferably, the mixture is heated to the reflux temperature of the solvent. Crystallization of Form A can occur spontaneously or can be induced, for example, by cooling, evaporation or seeding of the solvent. The heated solution may be cooled to ambient temperature and the heated or ambient temperature solution may be cooled to a low temperature such as 20 ° C. to 0 ° C.

After crystallization of Form A is deemed sufficient, the crystals are separated from the solvent by conventional methods such as filtration, decantation, centrifugation and the like. The crystals can be washed with a suitable solvent and dried by conventional techniques.

Ondansetron Form A can be obtained with good polymorphic purity by carrying out the preferred embodiments of the aforementioned method. Preferably, the ondansetron form A prepared by the method contains up to about 5% of other ondansetron crystal forms, more preferably up to about 1% of other ondansetron crystal forms. Less Preferred Methods Embodiments or other methods can yield ondansetron Form A with less purity, especially when other polymorphic seeds are present. Mixtures containing small amounts of ondansetron Form A, such as 25% or less, may exhibit improved properties due to the presence of Form A, and therefore such mixtures are improved by the present invention and are considered to be within the scope of the present invention. . Of course, as a secondary component, ondansetron form A found in the mixture with other substances such as pharmaceutical excipients is in particular of particular interest as the substance encompassed by ondansetron form A.

Ondansetron forms A and B have use as active agents in pharmaceutical compositions and formulations for preventing nausea and vomiting associated with surgery, vomiting-induced cancer chemotherapy and radiotherapy. Ondansetron forms A and B are useful for preparing salts and solvates of ondansetron, such as hydrochloride dihydrate, currently prescribed to patients in the United States. Such salts and solvates are contemplated to be within the scope of the present invention to the extent that salt formation or solvation does not significantly change the atomic position and molecular conformation of the ondansetron.

Ondansetron forms A and B can be incorporated into pharmaceutical products for administration to humans or other mammals in need of inhibiting vomiting. The pharmaceutical compositions and formulations may be formulated for transdermal delivery, gut delivery or parenteral delivery. The most appropriate route in any given situation depends on the nature and severity of the condition being treated and on other situations as assessed by the physician. Pharmaceutical compositions for digestive tract delivery can be processed into liquid solutions, suspensions, syrups and elixirs, as well as tablets, powders, capsules, suppositories, cachets, troches, and lozenges. .

Many excipients that can be included in enteric formulations and are known in the pharmaceutical art include microcrystalline cellulose, lactose, starch, calcium carbonate, sugars, dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin, maltodextrin and mannitol Diluents such as; Acacia, alginic acid, carbomer, carboxymethylcellulose sodium, ethyl cellulose, gelatin, guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, maltodextrin, methylcellulose, polymethacrylate, povidone and alginic acid Binders such as sodium salts; Disintegrants such as pregelled starch, alginic acid, carboxymethyl cellulose calcium, croscarmellose sodium, crospovidone and sodium starch glycorate; Chelating agents and antioxidants such as alcohols, sodium benzoate, butylated hydroxy toluene, butylated hydroxyanisole and ethylenediamine tetraacetic acid; Antibacterial agents such as methylparaben and propylparaben, gluconic acid, lactic acid, citric acid or buffers such as acetic acid, sodium gluconate, sodium lactate, sodium citrate or sodium acetate, and colorants such as titanium dioxide, ferrous oxide and ferric oxide, and sucrose , Sweeteners and spices such as aspartame and strawberry flavors.

Pharmaceutical compositions containing ondansetron forms A and B may optionally contain a viscosity modifier such as corn syrup; Antibacterial agents such as sodium benzoate; Buffers such as citric acid and sodium citrate; And oral suspensions in which ondansetron is dispersed in a liquid vehicle together with spices such as strawberry flavor.

Such pharmaceutical products further comprise an injectable suspension in which ondansetron is optionally suspended in an aqueous or oily medium with an antimicrobial agent and packaged in a single or multiple dose container.

Particularly preferred pharmaceutical formulations of ondansetron Form A and / or Form B are oral disintegrating tablets. Oral disintegrating tablets may be formulated according to methods known in the art using pharmaceutical excipients that are dispersed or dissolved in saliva but do not contain the drug in solid form. Such excipients include gelatin and mannitol, and may further include antimicrobial agents such as methylparaben and propylparaben, sweeteners and spices such as aspartame and strawberry flavor.

The pharmaceutical compositions and formulations of the present invention may be administered to a patient in such a way that known ondansetron containing compositions are administered for the purpose of preventing nausea and vomiting associated with chemotherapy and postoperative nausea or vomiting. For this purpose, ondansetron Form A and / or Form B are preferably administered in an amount of about 10 to about 50 mg / day, more preferably about 24 mg / day.

While the invention has been described in connection with some preferred embodiments, the invention is described in greater detail below with reference to the following examples.

EXAMPLE

Ondansetron  Preparation of Form A

Example  One

Ondansetron (2 g) was added to N, N-dimethylformamide (80 mL). This mixture was heated to dissolve completely. The formed clear solution was cooled to 20 ° C. and placed in a 2-8 ° C. refrigerator overnight. The next day, the crystals were filtered and dried in vacuo at 60 ° C. for one day to give ondansetron Form A (0.81 g, 41%).

Example  2

Ondansetron (2 g) was added to 1-butanol (30 mL). This mixture was heated to reflux. The resulting solution was cooled to 20 ° C. and then placed in a 2-8 ° C. refrigerator overnight. The next day, the crystals were filtered and dried in vacuo at 60 ° C. for one day to give ondansetron Form A (1.26 g, 63%).

Ondansetron  Preparation of Form B

Example  3

Ondansetron (2 g) was added to ethanol (45 mL). This mixture was heated to reflux. The formed clear solution was cooled to 20 ° C. and then placed in a 2-8 ° C. refrigerator overnight. The next day, the crystals were filtered and dried in vacuo at 60 ° C. for one day to give ondansetron Form B (1.76 g, 88%).

Example  4

Ondansetron (1.5 kg) was added to methanol (60 L). This mixture was heated to reflux. This clear hot solution was filtered through carbon (Norti-SX-1). About 1/4 of the methanol volume was distilled off. Next, the solution was cooled to 0-5 degreeC over 4 hours. The crystals were then filtered, washed with methanol and dried in vacuo at 65 ° C. for one day to give ondansetron Form B (1.1 kg, 73%).

The present invention provides ondansetron crystal forms A and B useful for the treatment of nausea and vomiting. In particular, Form B has a uniquely high melting point of about 244 ° C., and Forms A and B are stable to thermally induced polymorphic transitions at temperatures of 30 ° C. up to the melting point.

Claims (19)

Differential scanning calorimetry thermograms with strong intensity peaks at 15.9, 23.1, 23.5, 25.8, 26.9 and 28.1 ± 1.0 ° 2θ of the powder X-ray diffraction pattern, medium intensity peaks at 25.8 and 26.9 ± 1.0 ° 2θ A method for producing a high melting point ondansetron crystal of Form B, characterized in that the melting endotherm has a maximum value at 244 ± 2 ° C. in a differential scanning calorimetry thermogram. (a) dissolving ondansetron in an alcohol selected from the group consisting of ethanol, propan-1-ol and propan-2-ol to form a solution, (b) crystallizing the ondansetron crystals of Form B from the solution by making the ondansetron concentration in the solution from about 50 mM to about 300 mM, and (c) separating the ondansetron crystals of Form B from the solution Method for producing a high melting point ondansetron crystal of Form B comprising a. The method of claim 1, wherein the step (a) solution is a clear solution. The method of claim 1, wherein separating ondansetron crystals from the solution comprises a filtration process and a drying process in which the loss of drying is about 2% by weight. The method of claim 1, wherein the solution of step (a) is heated to produce a solution having ondansetron at a concentration of about 50 mmol to about 300 mmol per liter of alcohol. The method of claim 1, further comprising drying the ondansetron. The method of claim 1, wherein the crystallization step comprises cooling the ondansetron solution. The method of claim 6, wherein the solution is cooled to about 0 ° C. to about 20 ° C. 7. The method of claim 1, wherein the crystallization step comprises evaporating a sufficient amount of alcohol from the ondansetron solution to induce crystallization of ondansetron. Differential scanning calorimetry thermograms with strong intensity peaks at 15.9, 23.1, 23.5, 25.8, 26.9 and 28.1 ± 1.0 ° 2θ of the powder X-ray diffraction pattern, medium intensity peaks at 25.8 and 26.9 ± 1.0 ° 2θ A method for producing a high melting point ondansetron crystal of Form B, characterized in that the melting endotherm has a maximum value at 244 ± 2 ° C. in a differential scanning calorimetry thermogram. (a) mixing ondansetron with an alcohol selected from the group consisting of ethanol, propan-1-ol and propan-2-ol to form a mixture having an ondansetron concentration of about 85 mM to about 150 mM ondansetron per liter of alcohol, (b) heating the mixture to form a solution, (c) cooling the solution to about 0 ° C. to about 20 ° C. to crystallize ondansetron crystals of Form B from the solution, (d) separating ondansetron crystals of Form B from the solution, and (e) drying the ondansetron crystals of Form B Method for producing a high melting point ondansetron crystal of Form B comprising a. 10. The method of claim 9, wherein the solution of step (b) is free of visible suspended solids. It has strong intensity peaks at 23.2, 25.9 and 27.8 ± 1.0 ° 2θ of the powder X-ray diffraction pattern, has a medium intensity peak at 25.4 and 26.7 ± 1.0 ° 2θ, and has a melting point endotherm of 230 ± 2 on the differential scanning calorimetry thermogram. A process for producing ondansetron crystals of form A characterized by having a maximum at ° C, (a) an organic solvent selected from the group consisting of monohydroxy, dihydroxyl and polyhydroxyl alcohols containing at least 4 carbon atoms, liquid aromatic compounds, acetic acid esters and polar aprotic solvents and these organic solvents Dissolving ondansetron in a solvent system selected from the group consisting of a mixture of water and water to form a solution, (b) crystallizing ondansetron crystals of Form A from this solution, and (c) separating the ondansetron crystal of Form A from the solution A method for producing ondansetron crystals of Form A comprising a. The method of claim 11, wherein the organic solvent is selected from the group consisting of 1-butanol, benzene, toluene, ethyl acetate, butyl acetate, and N, N-dimethylformamide. The method of claim 12, wherein the organic solvent is selected from the group consisting of 1-butanol and N, N-dimethylformamide. The method of claim 11, wherein step (a) produces a clear solution. The method of claim 14, wherein the concentration of ondansetron in the solution is about 50 mM to about 300 mM. The method of claim 11, wherein said dissolving step comprises heating a mixture of ondansetron and said solvent system. The method of claim 11, wherein the crystallization step comprises cooling the ondansetron solution. The method of claim 11, wherein the crystallization step comprises evaporating a sufficient amount of organic solvent from the ondansetron solution to induce crystallization of ondansetron. The method of claim 11, wherein the crystallization step comprises seeding the ondansetron solution with ondansetron crystals.

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