KR20060127892A - New polymorphic forms of ondansetron, processes for preparing them, pharmaceutical compositions containing them and their use as antiemetics - Google Patents

Abstract

This invention relates to new polymorphs of (±)1,2,3,9-tetrahydro-9- methyl-3-[(2-methyl-1H-imidazol-1-il)methyl]-4H-carbazol-4-one, known under the INN of ondansetron, to processes for preparing said polymorphs, to pharmaceutical compositions containing them and to their use in the treatment and prophylaxis of nausea and vomiting. The invention provides new stable polymorphic forms of ondansetron and processes for manufacturing them at an industrial scale.

Description

New polymorphic forms of ondansetron, processes for preparing them, pharmaceutical compositions containing them and their use as antiemetics

Field of invention

The present invention relates to (±) 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl) methyl] -4H, known as INN of ondansetron It relates to a novel polymorph of carbazol-4-one.

The present invention also relates to methods of preparing the polymorphs, pharmaceutical compositions comprising them and their use for the treatment and prevention of nausea and vomiting.

Background of the Invention

Compound (±) 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one is an ondansetron Known as INN, it has the following structure:

Ondansetron is a selective antagonist of the 5-HT ₃ receptor marketed as an antiemetic agent.

GB 2153821 describes ondansetron, salts and solvates thereof. In particular, the preparation of basic ondansetron is described in some examples. Thus, in Example 4, the preparation of basic ondansetron was methylated in dimethylformamide with dimethyl sulfate; The product obtained is described as melting with decomposition at 223 to 224 ° C. In Example 7, the basic ondansetron comprises 3-[(dimethylamine) methyl] -1,2,3,9-tetrahydro-9-methyl-4H-carbazol-4-one hydrochloride 2-methylimidazole And on water to obtain ondansetron having a melting point of 221 to 221.5 ° C., followed by recrystallization in methanol to obtain a melting point of 231 to 232 ° C. In Example 8, preparation of the basic ondansetron was carried out by treating 1,2,3,9-tetrahydro-9-methyl-3-methylene-4H-carbazol-4-one in 2-methylimidazole and water It is described to obtain ondansetron having a melting point of 232 to 234 ° C. which is recrystallized in methanol to decompose. In Example 18, the preparation of the basic ondansetron involved 3- (chloromethyl) -1,2,3,9-tetrahydro-9-methyl-4H-carbazol-4-one with 2-methyl-imidazole and DMF ( Dimethylformamide) and then purified by column chromatography to give ondansetron having a melting point of 228 to 229 ° C. In Example 19, the preparation of the basic ondansetron was performed with 2,3,4,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl) methyl] -1H-carbazole male Eate was oxidized in THF (tetrahydrofuran) with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone and then purified by column chromatography to give ondansetron having a melting point of 227 to 228.5 ° C. It is described. In Example 20, the preparation of the basic ondansetron was performed using 2,3,4,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl) methyl] -1H-carbazole- It is described that 4-ols are oxidized in THF with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone and then purified by column chromatography to give ondansetron at melting points 227.5 to 229 ° C. .

GB 2220352, EP 385517 and EP 276559 also describe the preparation of ondansetron according to example 7 of the patent, which shows the same melting point as mentioned in the example above.

Another method also describes the preparation of ondansetron for obtaining ondansetron having a melting point in the following document: in EP 221629, after purification by column chromatography, it is decomposed at 215 to 216 ° C .; In EP 219929, after purification by column chromatography, it is melted at 216 to 218 ° C., and after recrystallization in methanol, it is melted at 227.5 to 228.5 ° C .; Finally, in ES 2043535 it is melted at 227-228.5 ° C. after recrystallization in methanol.

That is, all of the references mentioned above describe ondansetrons having a wide variety of melting points in the range of 215-234 ° C. Following purification by column chromatography, they remain variously at 215 to 229 ° C., and after recrystallization in methanol the melting point is raised and is about 230 ° C. (227 to 234 ° C.).

WO 03093260 describes two crystalline forms of basic ondansetron, referred to as Form A and Form B, respectively, including those having a melting point similar to those described in the references above and having a higher melting point. Form B has a powder X-ray diffraction pattern characterized by a melting point of 244 ± 2 ° C. and the following peaks: 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 ° 2θ. Its process is described as dissolving the basic ondansetron in ethanol or methanol at reflux and subsequently cooling. Form A is characterized by a powder X-ray diffraction pattern present with the following peaks: 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 ° 2θ.

The process for preparing Form A is described as recrystallization of ondansetron in N, N-dimethylformamide and recrystallization in 1-butanol.

The described examples alone describe a process for preparing polymorphic forms of ondansetron up to several grams or up to 1.1 kg. In addition, even if a small amount of the product is obtained, the volume of solvent to be used is very high (necessary to produce a maximum amount of 60 L of solvent, ie 1.1 kg), thus hindering its large-scale production.

Therefore, a novel stable polymorphic form of ondansetron and its preparation method for producing the product on an industrial scale are recommended.

Description of the Invention

The invention provides (±) 1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazole known as INN of ondansetron Three different polymorphic forms of 4-one are provided.

Thus, a first aspect of the invention relates to a novel polymorphic form of ondansetron, hereinafter referred to as Form C, which is characterized by exhibiting a powder X-ray diffraction pattern using Kα ₁ radiation of Cu according to FIG. do.

A second aspect of the invention relates to a novel polymorphic form of ondansetron, hereinafter referred to as Form D, which is characterized by exhibiting a powder X-ray diffraction pattern using Kα ₁ radiation of Cu according to FIG. 2.

A third aspect of the invention relates to a novel polymorphic form of ondansetron, hereinafter referred to as Form E, which is characterized by exhibiting a powder X-ray diffraction pattern using Kα ₁ radiation of Cu according to FIG. 3.

The subject of the invention is also a process for the preparation of novel polymorphic forms of ondansetron referred to as forms C, D and E.

Another aspect of the invention is a pharmaceutical composition comprising a novel polymorphic form of ondansetron referred to as forms C, D and E.

Another aspect of the invention is the use of the novel polymorphic form of ondansetron referred to as forms C, D and E for the manufacture of a medicament for the treatment and prevention of nausea and vomiting.

A further aspect of an aspect of the present invention is a therapeutic method for treating and preventing postoperative nausea and vomiting and for inhibiting nausea and vomiting induced by radiotherapy and cytotoxic chemotherapy.

1 shows a powder X-ray diffraction pattern of Form C. The y-axis represents intensity (total) and the x-axis represents 2 theta each.

2 shows the powder X-ray diffraction pattern of Form D.

3 shows a powder X-ray diffraction pattern of Form E. FIG.

4 shows low frequency Raman spectra of Forms C, D and E. FIG. The y-axis represents Raman intensity (A.U., in arbitrary units) and the x-axis is frequency.

Three polymorphic forms of ondansetron, the subject of the present invention, can be identified by their powder X-ray diffraction pattern.

Form C according to the first aspect of the present invention is characterized by a powder X-ray diffraction pattern having two inherent peaks at 14.97 and 20.86 ° 2θ and no peak below 6.5 ° 2θ. In the lower range, the phase is also characterized by a peak of 25.50 ° 2θ. The diffraction pattern of Form C also has a number of lower peaks at each interval of 5 to 30 ° 2θ in relation to the other two polymorphic diffraction patterns that are the subject of the present invention. Table 1 shows the peaks observed in the powder X-ray diffraction pattern of Form C using the conditions for providing the diffraction pattern described below. Table 1 further includes the relative intensity values of the peaks as further information.

Form C shows a powder X-ray diffraction pattern using Kα ₁ emission of Cu according to FIG. 1.

Form D in accordance with a second aspect of the present invention is 11.29 °; 14.58 °; 17.16 °; 18.89 °; 20.28 °; 21.22 °; It is characterized by a powder X-ray diffraction pattern showing peaks at 25.06 ° and 27.49 ° 2θ. Table 2 shows the peaks observed in the powder X-ray diffraction pattern of Form D. Table 2 further includes the relative intensity values of the peaks as further information.

Form D shows a powder X-ray diffraction pattern using Kα ₁ emission of Cu according to FIG. 2.

Form E associated with the third aspect of the invention is 6.29 °; 11.09 °; 11.88 °; 12.69 °; It is characterized by powder X-ray diffraction which shows a peak at 14.97 ° (the last peak is also present in the diffraction pattern of Form C) and double (24.96 °; 25.17 °) 2θ. Table 3 below shows the peaks observed in the powder X-ray diffraction pattern of Form E. Table 3 further includes the relative intensity values of the peaks as further information.

Form E shows a powder X-ray diffraction pattern using Kα ₁ emission of Cu according to FIG. 3.

Advantageously, Form E can also be prepared in a way that can be recycled on an industrial scale, thereby making the optimal crystalline form of ondansetron and therefore the preferred form for market trading.

Powder X-ray diffraction patterns are obtained with Kα ₁ radiation of Cu in a transfer geometry using a Lindemann glass capillary of 0.5 mm diameter using an INEL CPS-120 device with a Ge base monochromator. When measuring the position of the peak, the error is evaluated to ± 0.05 ° 2θ.

The difference between the three polymorphic forms C, D and E is also recognized in the low frequency region 15-150 cm ⁻¹ of the Raman spectra as shown in FIG. 4. The Raman spectra of Forms C and D are similar to each other, but they show a clear spectral difference for Form E. Thus, the Raman technique can distinguish Form E from these two forms, but is not suitable for distinguishing Forms C and D from each other.

Raman spectra are obtained using a Jobin-Yvon T64000 device using an argon laser and the measurements are performed using excitation waves of 514.5 nm and laser power between 30 and 35 mW.

Three polymorphic forms of the present invention exhibit a melting point in the range of 240 to 247 ° C. The melting point can be measured by DSC using an aluminum crucible with perforated lid at a heating rate of 10 ° C./min based on the melting peak. The melting points of the three polymorphs of the present invention are similar, and considering that the basic ondansetron melt-decomposes to release 2-methylimidazole, the melting temperature is a unique value that allows the three forms of the present invention to distinguish from each other. no.

In the following, the preparation method of the three polymorphs referred to as forms C, D and E of the present invention will be described in detail.

Thus, Form C can be obtained by adding a solvent precipitated in a saturated solution of basic ondansetron at room temperature. More specifically, Form C

a) a saturated solution of basic ondansetron in dichloromethane is prepared at room temperature;

b) C ₅ -C ₇ alkanes are added to precipitate the crystalline form;

c) can be prepared by a method comprising recovering the crystalline form.

Preferably, the C ₅ -C ₇ alkanes are selected from n-hexane or n-pentane.

Form D is

a) dissolving the basic ondansetron in reflux in C ₁ -C ₄ alcohol;

b) t-butyl-methyl-ether is added and then cooled;

c) by a method comprising recovering the crystalline form.

Preferably, the C ₁ -C ₄ alcohol is methanol.

The present invention also provides a method of preparing Form E. The method

a) dissolving ondansetron hydrochloride in a mixture of C ₁ -C ₃ alcohol and water;

b) basic ondansetron is precipitated by basic solution;

c) the solid is filtered off, washed with water;

d) the water-wet solid obtained in step c) is suspended with methanol under reflux with stirring;

e) recovering the crystalline form.

Preferably, the C ₁ -C ₃ alcohol is methanol.

The basicization of step b) can be carried out by adding a solution of sodium hydroxide, potassium hydroxide or aqueous ammonia. Preferably, the basicization of step b) is carried out by addition of an aqueous ammonia solution. Advantageously, basification with aqueous ammonia produces ammonium chloride as a residue, which dissolves better in water and alcohol than sodium chloride or potassium chloride and is therefore easier to remove.

Advantageously, this process makes it possible to obtain Form E in a way that is completely recycled on an industrial scale. In addition, since it is not necessary to completely dissolve the basic ondansetron in alcohol, which is a very insoluble solvent, a larger amount of product can be obtained with a smaller amount of solvent compared to the prior art.

Form E also

a) dissolving the base ondansetron in reflux with C ₁ -C ₄ alcohol;

b) ethyl acetate is added, then cooled and concentrated by slow evaporation at room temperature;

c) can be prepared on an experimental scale by a method comprising recovering the crystalline form.

Preferably, the C ₁ -C ₄ alcohol is methanol.

Recovery of the polymorphic form of the present invention is carried out by filtration of the solid and drying using conventional methods.

In the present invention, "C ₁ -C ₄ alcohol" means methanol, ethanol, n-propanol, isopropyl alcohol, n-butanol.

In the present invention, "C ₅ -C ₇ alkanes" means n-pentane, n-hexane, n-heptane.

Basic ondansetron and ondansetron hydrochloride used as starting materials for preparing the polymorphic forms of the present invention can be prepared by the methods described in the literature. Preferably, they are obtained according to the general method described in ES 2043535, the industrial application of which is carried out in a mixture of isopropyl alcohol and water as solvent using hydrochloric acid as the acid catalyst, and ondansetron directly in the form of hydrochloride To be separated. Basic ondansetron can be obtained, in turn, by basifying a solution of the hydrochloride.

Subject of the invention is also a pharmaceutical composition comprising a therapeutically active amount of a novel polymorphic form of ondansetron, referred to as Form C, D or E, with a suitable amount of one or more excipients.

The composition prepared by the present invention can be administered by any suitable route, but the oral or parenteral route is preferred.

Compositions for parenteral or topical administration may be in the form of injectable solutions, intravenous solutions, infusions, suppositories, or transdermal systems. Pharmaceutical compositions for oral administration include solids such as tablets or capsules prepared by conventional methods with pharmaceutically acceptable excipients, or aqueous or oily solvents prepared by conventional methods with pharmaceutically acceptable additives, Liquids such as syrups, elixirs, emulsifiers or suspending agents.

Tablets and injectable solutions or intravenous solutions are the preferred oral and parenteral dosage forms, respectively.

Particularly preferred pharmaceutical dosage forms for forms C, D and E of ondansetron are oral disintegrating tablets (also referred to as oral dispersibility). Buccodispersable tablets mean non-encapsulated tablets that have the advantage of staying in the mouth and disintegrating quickly before swallowing. Various forms of technology have been described for preparing these types of tablets, which are known to those skilled in the art. Especially preferably, it is what is described in WO 03103629.

Such pharmaceutical forms include dosages of forms C, D and E, preferably from 2 to 10 mg.

According to conventional pharmaceutical practice, excipients for tablet forms may include diluents, disintegrants, wetting agents, lubricants, colorants, flavoring agents or other conventional adjuvants. Thus, conventional tablet excipients include, for example, lactose, microcrystalline cellulose, corn starch, hypromellose, magnesium stearate, macrogol, polyvinylpyrrolidone, mannitol.

Injectable formulations according to the invention preferably comprise aqueous solutions with conventional excipients for injectable formulations comprising sodium citrate, citric acid, sodium chloride, together with water for injection.

Also subject of the present invention is the use of Forms C, D and E for the treatment and prevention of postoperative nausea and vomiting and for the preparation of a medicament for the inhibition of nausea and vomiting caused by radiotherapy and cytotoxic chemotherapy. .

In addition, the subject of the present invention is directed to the treatment and prevention of postoperative nausea and vomiting, consisting in administering to a patient in need thereof a therapeutically effective amount of Form C, D or E, preferably 2 to 10 mg. And for the inhibition of nausea and vomiting caused by radiotherapy and cytotoxic chemotherapy.

Experimental part

The following examples illustrate the invention in a non-limiting manner.

Synthesis Example

Example 1 Preparation of Basic Ondansetron Form C

492 mg of basic ondansetron is dissolved in 35 mL of dichloromethane. When 18 mL of n-hexane is added, crystals precipitate out. The resulting suspension is stirred for 10 minutes and filtered. The white solid obtained is dried at 40 ° C. to maintain weight. 137 mg of basic ondansetron Form C (28%) are obtained.

Example 2 Preparation of Basic Ondansetron Form C

When 146 mL of n-pentane is added to a stirred solution of 4 g of basic ondansetron in 284 mL of dichloromethane at 20-22 ° C., crystals appear precipitated. The resulting solution is stirred for 10 minutes and filtered. The white solid obtained is dried at 40 ° C. to maintain weight. 2 g of basic ondansetron Form C (50%) are obtained.

Example 3 Preparation of Basic Ondansetron Form D

A stirred solution of 4 g of basic ondansetron in 178 mL of methanol is heated to complete dissolution under reflux. 509 mL of t-butyl-methyl-ether is slowly added, then the heater is switched off and the mixture is allowed to cool slowly to 20-22 ° C. with standing and stirring. The suspension obtained is filtered and the white solid obtained is dried at 40 ° C. to maintain weight. 2.4 g of basic ondansetron Form D (60%) are obtained.

Example 4 Preparation of Basic Ondansetron Form E (Laboratory Method)

The stirred solution of 4 g of basic ondansetron in 200 mL of methanol is heated to complete dissolution under reflux. 480 mL of ethyl acetate is slowly added, then the heater is switched off and the mixture is allowed to cool slowly to 20-22 ° C. with stirring. The stirring is stopped, the mixture is left to stand, the flask is slowly concentrated, filtered and dried at 40 ° C. until crystals form for 20-30 days. 1 g of ondansetron Form E (25%) is obtained.

Example 5 Preparation of Basic Ondansetron Form E (Industrial Plant Method)

A stirred suspension of 16 kg of ondansetron hydrochloride in 80 L of methanol and 80 L of water is heated at 30 ° C. until complete dissolution. 6 L of 25% aqueous ammonia is added for 2 hours until pH 9 is reached. Once the basic ondansetron precipitates, the obtained suspension is heated to 35 ° C. and stirred at this temperature for 1 hour. It is then cooled to 22-25 ° C. and the suspension is centrifuged. The cake obtained is washed with water (2 x 40 L) and suspended again in 60 L of water. The suspension is stirred at 35 ° C. for 30 minutes, cooled to 22-25 ° C., centrifuged again and finally washed with water (2 × 40 L). The water-wet solid is suspended in 180 L of methanol and the mixture is refluxed with stirring for 1 hour. The suspension fluidizes but does not dissolve. Cool to 20-22 ° C. and stir for 30 minutes. Cool to 0-5 ° C. and stir the suspension at this temperature for 1 hour. The suspension is centrifuged and the cake washed with 20 L of cold methanol. The product is dried at 60 ° C. under vacuum for 15 hours. 10.8 kg of basic ondansetron Form E (84%) are obtained.

Claims (18)

C. Polymorphic Form C of Basic Ondansetron, characterized in that the powder X-ray diffraction pattern is inherent peak at 14.97 and 20.86 ° 2θ and no peak below 6.5 ° 2θ. A powder X-ray diffraction pattern was 11.29 °; 14.58 °; 17.16 °; 18.89 °; 20.28 °; 21.22 °; Polymorphic form D of basic ondansetron, characterized by the presence of an inherent peak at 25.06 ° and 27.49 ° 2θ. The powder X-ray diffraction pattern was 6.29 °; 11.09 °; 11.88 °; 12.69 °; Polymorphic form E of the basic ondansetron, characterized by the inherent peak at 14.97 ° and the inherent peak in double at 2θ (24.96 °; 25.17 °). The polymorphic form of claim 1, wherein the powder X-ray diffraction pattern also has a peak at 25.50 ° 2θ. The polymorphic form of claim 4, wherein a powder X-ray diffraction pattern is present at the next peak.

6. Polymorphic form according to claim 5, characterized in that there is a powder X-ray diffraction pattern according to FIG. 3. The polymorphic form of claim 2 wherein the powder X-ray diffraction pattern is at the next peak.

8. Polymorphic form according to claim 7, wherein there is a powder X-ray diffraction pattern according to FIG. 4. The polymorphic form of claim 3, wherein the powder X-ray diffraction pattern is at the next peak.

10. Polymorphic form according to claim 9, characterized in that there is a powder X-ray diffraction pattern according to FIG. a) a saturated solution of basic ondansetron in dichloromethane is prepared at room temperature; b) C ₅ -C ₇ alkanes are added to precipitate the crystalline form; c) A process for producing a polymorphic form according to claim 1 comprising recovering the crystalline form. The method of claim 11, wherein the C ₅ -C ₇ alkanes are n-hexane or n-pentane. a) dissolving the basic ondansetron in reflux in C ₁ -C ₄ alcohol; b) t-butyl-methyl-ether is added and then cooled; c) A process for producing a polymorphic form according to claim 2 comprising recovering the crystalline form. a) dissolving ondansetron hydrochloride in a mixture of C ₁ -C ₃ alcohol and water; b) basic ondansetron is precipitated by basic solution; c) the solid is filtered off, washed with water; d) the water-wet solid obtained in step c) is suspended with methanol under reflux with stirring; e) A process for producing a polymorphic form according to claim 3 comprising recovering the crystalline form. The method according to claim 13 or 14, wherein the alcohol is methanol. The process of claim 14, wherein the basicization of step b) is carried out by adding an aqueous ammonia solution. A pharmaceutical composition comprising a polymorphic form according to any one of claims 1 to 10 together with one or more excipients in a therapeutically active amount. The method according to any one of claims 1 to 10, which is used to prepare a medicament for the treatment and prevention of postoperative nausea and vomiting, and to inhibit nausea and vomiting induced by radiotherapy and cytotoxic chemotherapy. Polymorphic form.

Images