ES2238001B1 - NEW POLYMORPHIC FORMS OF ONDANSETRON, PROCEDURES FOR THEIR PREPARATION, PHARMACEUTICAL COMPOSITIONS CONTAINING THEM AND THEIR USE AS ANANTIMETICS. - Google Patents

Abstract

New polymorphic forms of ondansetron, procedure for its preparation, pharmaceutical compositions containing them and their use as antiemetics. The present invention relates to novel polymorphs of the (+ -) 1,2,3,9-tetrahydro-9-methyl-3 - [(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazole -4-one, known under the DCI of ondansetron to the procedures for obtaining said polymorphs, to pharmaceutical compositions containing them and their use in the treatment and prophylaxis of nausea and vomiting. The invention provides new stable polymorphic forms of ondansetron and processes for manufacturing on an industrial scale.

Description

New polymorphic forms of ondansetron, procedures for its preparation, pharmaceutical compositions that they contain them and their use as antiemetics.

Field of the Invention

The present invention relates to new polymorphs of the (±) 1,2,3,9-tetrahydro-9-methyl-3 - [(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one, known under the ICD of ondansetron.

The present invention also relates to procedures for obtaining said polymorphs, to pharmaceutical compositions containing them and for use in the treatment and prophylaxis of nausea and vomiting.

Background of the invention

The compound (±) 1,2,3,9-tetrahydro-9-methyl-3- [2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one It is known under the ICD of ondansetron and has the following structure:

one

Ondansetron is a selective antagonist of 5-HT3 receptor, which is marketed as antiemetic.

Patent GB 2153821 describes ondansetron, its salts and solvates. In particular, obtaining ondansetron base is described in several examples. Thus, in example 4, describes obtaining the base ondansetron by methylation with dimethyl sulfate in dimethylformamide; the product obtained melts with decomposition at 223 ° C - 224 ° C. In example 7, you get Ondansetron base by hydrochloride treatment 3- [dimethylamino) methyl] -1,2,3,9-tetrahydro-9-methyl-4H-carbazol-4-one with 2-methylimidazole in water, to yield ondansetron with a melting point of 221ºC - 221.5ºC that after Recrystallization from methanol gives a melting point of 231-232 ° C. In example 8, the obtaining of ondansetron base is described by treatment of 1,2,3,9-tetrahydro-9-methyl-3-methylene-4H-carbazol-4-one with 2-methylimidazole in water followed by recrystallization in methanol, to yield ondansetron with a dot melting of 232º-234ºC with decomposition. In example 18, describes the obtaining of ondansetron base by reaction of the 3- (chloromethyl) -1,2,3,9-tetrahydro-9-methyl-4H-carbazol-4-one with 2-methylimidazole in DMF (dimethylformamide), which after purification by column chromatography yields ondansetron with a melting point of 228º-229ºC. Example 19 describes obtaining ondansetron base by oxidation of maleate 2,3,4,9-tetrahydro-9-methyl-3 - [(2-methyl-1H-imidazol-1-yl) methyl] -1H-carbazole with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone in THF (tetrahydrofuran) which after purification by chromatography of column yields ondansetron with a melting point of 227 ° C-228.5 ° C. Example 20 describes the obtaining ondansetron base by oxidation of 2,3,4,9-tetrahydro-9-methyl-3 - [(2-methyl-1H-imidazol-1-yl) methyl] -1H-carbazol-4-ol  with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone in THF which after purification by column chromatography yields ondansetron with a melting point of 227.5-229 ° C.

In GB 2220352, EP 385517 and EP 276559 the obtaining of ondansetron according to the Example 7 of the patent cited above, giving a point of merger that matches the one mentioned in that example.

Other procedures of obtaining ondansetron, which yield ondansetron with the following melting points: in EP 221629, after unification by column chromatography, decomposes at 215-216 ° C; in ES 219929, after purification by chromatography of column, melts at 216-218 ° C and, after recrystallization in methanol, at 227.5-228.5 ° C; and finally in the Patent ES 2043535, after recrystallization from methanol, melts 227-228.5 ° C.

That is, all the references mentioned above describe ondansetron with very variable melting points that They range from 215ºC to 234ºC. After purification by chromatography of column remain variable, from 215 to 229 ° C, and after recrystallization in methanol rise and focus on 230 ° C (227-234 ° C).

In the international patent application WC 03093260 two crystalline forms of ondansetron base are described, one with a melting point similar to that described in the references previous and another with a higher melting point, called, respectively, Form A Form B. Form B has a point of melting of 244 ± 2 ° C a powder X-ray diffractogram that characterized by 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; 28.1º 2 \ theta. Its preparation by ondansetron solution is described base in ethanol or methanol at reflux temperature and later cooling. Form A is characterized by a diffractogram of X-ray powder that has 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; 27.8º 2? Describes the obtaining of Form A by ondansetron recrystallization in N, N-dimethylformamide by recrystallization in 1-butanol.

The examples described describe obtaining polymorphic forms of ondansetron only on a few scale grams or maximum of 1.1 kg. Moreover, despite the small number of quantities of product obtained, the necessary volume of solvent used is very high (to obtain maximum described quantity, 1.1 kg, 60 L of solvent is required) which difficult to obtain on a large scale.

It is advisable to have new ways Stable polymorphs of ondansetron and procedures for its manufacturing that allow obtaining it on an industrial scale.

Description of the invention

It is the object of the present invention to provide three different polymorphic forms of the (±) 1,2,3,9-tetrahydro-9-methyl-3 - [(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one, known under the ICD of ondansetron.

Thus, a first aspect of the invention relates to to a new polymorphic form of ondansetron called, now hereinafter, Form C characterized by presenting a X-ray powder diffractogram, using radiation K? 1 of Cu, according to Figure 1.

A second aspect of the invention relates to a new polymorphic form of ondansetron called, now in ahead, Form D characterized by presenting a diffractogram X-ray powder, using Kα1 {Cu} radiation, from according to Figure 2.

A third aspect of the invention relates to a new polymorphic form of ondansetron called, now in Go ahead, Form E characterized by presenting a diffractogram X-ray powder, using Kα1 {Cu} radiation, from according to Figure 3.

They are also object of the present invention procedures for obtaining the new polymorphic forms of ondansetron called Form C, D and E.

Another aspect of the present invention is a pharmaceutical composition containing any of the new polymorphic forms of ondansetron, called Form C, D and E.

Yet another aspect of the invention is the use of the new polymorphic forms of ondansetron called Form C, D and E for the manufacture of a medicine intended for treatment and prophylaxis of nausea and vomiting.

And a further aspect of the invention is a therapeutic method for the treatment and prophylaxis of nausea and postoperative vomiting as well as for the control of nausea and vomiting induced by radiotherapy cytotoxic chemotherapy.

Description of the figures

Figure 1 shows the X-ray diffractogram powder of Form C. The ordinate axis represents the intensity (in beads) and in that of abscissa the angle 2 Theta.

Figure 2 shows the X-ray diffractogram Form D powder.

Figure 3 shows the X-ray diffractogram Form E powder.

Figure 4 shows the Raman spectrum of low frequency of Forms C, D and E. On the ordinate axis, represents the Raman intensity (in U.A., arbitrary units) and in the one of abcisas the frequency.

Detailed description of the invention

The three polymorphic forms of ondansetron, object of the present invention, are identifiable by their X-ray powder diffractogram.

Form C, to which the first aspect refers of the invention, is characterized by an X-ray diffractogram in powder that has two characteristic peaks at 14.97 and 20.86º 2 the and has no peaks below 6.5 2 the. In the 25.50º peak also characterizes the phase 2 \ theta. The diffractogram of Form C presents, in relation to that of the other two polymorphs, also object of the present invention, lower number of peaks in the angular range 5 - 30 ° 2 \ theta. Table 1 shows the peaks observed in a X-ray powder diffractogram of Form C using the Conditions for obtaining the diffractogram described below. This table 1 also includes the relative intensity values.  of these peaks, as additional information.

TABLE 1

2

Form C presents an X-ray diffractogram powder, using Kα1 Cu radiation, according with Figure 1.

Form D, to which the second refers aspect of the invention, is characterized by a diffractogram of X-ray powder that has peaks at 11.29º; 14.58º; 17.16; 18.89º; 20.28º; 21.22º; 25.06º and 27.49º 2?. Table 2 shows show the peaks observed on an x-ray diffractogram in Form D powder. Said table 2 also includes values of the relative intensity of these peaks, as information additional.

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TABLE 2

3

Form D presents an X-ray diffractogram powder, using Kα1 Cu radiation, according with Figure 2.

Form E, to which the third aspect refers of the invention, is characterized by an X-ray diffractogram in powder that has peaks at 6.29 °; 11.09º; 11.88º; 12.69º; 14.97º (This last peak is also present in the diffractogram of the Form C) and a doublet (24.96 °; 25.17 °) 2 the. In table 3 that follow the peaks observed in a ray diffractogram X powder of Form E. It is also indicated in the table as additional information, the relative intensity of these peaks.

TABLE 3

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4

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Form E presents an X-ray diffractogram powder, using Kα1 Cu radiation, according with Figure 3.

Advantageously, Form E can be obtained from reproducible form on an industrial scale, which makes it the Optimal ondansetron crystal form for marketing and, therefore, the preferred one.

X-ray powder diffraction diagrams were obtained with Kα1 radiation from Cu, by means of a INEL CPS-120 equipment with primary monochromator from Ge and in transmission geometry with the samples inside 0.5 mm diameter Lindemann glass capillaries. The error in the determination of the position of the peaks can be estimated at ± 0.05 ° 2?.

There are also differences between the three polymorphic forms C, D and E, in the low frequency region (between 15 and 150 cm -1) of the Raman spectra, shown in Figure 4. The Raman spectra of Forms C and D are more similar to each other while presenting a clear difference spectral with respect to Form E. Therefore, the Raman technique it is not adequate to distinguish Forms C and D from each other, although it allows to distinguish between both forms and Form E.

Raman spectra were obtained with a device Jobin-Yvon T64000 with an argon laser and the determination was made with an excitation wave of 514.5 nm, and a laser power between 30 and 35 mW.

The three polymorphic forms of this invention have melting points in a range of 240-247 ° C. Melting points were determined by DSC, from the melting peak, using an aluminum crucible with perforated lid at a heating rate of 10 ° C / min. Given that the melting temperatures of the three polymorphs of the invention are similar and since ondansetron base melts with decomposition releasing 2-methylimidazole, the melting temperature is not considered as a characteristic that allows distinguishing between Three forms of the invention.

The following will describe in detail the procedures for obtaining the three polymorphs called Form C, D and E of the invention.

Thus, Form C can be obtained by adding a precipitating solvent on a saturated solution of Ondansetron base at room temperature. Specifically, Form C It can be obtained by a procedure comprising:

to)

preparation of a saturated solution of ondansetron based at room temperature in dichloromethane- no;

b)

precipitation of the crystalline form by the addition of a C 5 -C 7 alkane; Y

C)

form recovery crystalline

Preferably said alkane C_ {5} -C_ {7} is selected from n-hexane or n-pentane.

Form D can be obtained by procedure comprising:

to)

Ondansetron base solution in a C 1 -C 4 alcohol at reflux;

b)

addition of t-butyl methyl ether followed by cooling; Y

C)

form recovery crystalline

Preferably said alcohol C 1 -C 4 is methanol.

The present invention also provides a procedure for the manufacture of Form E. Said procedure comprises:

to)

hydrochloride solution ondansetron in a mixture of an alcohol C 1 -C 3 and water;

b)

base wave precipitation by basification of the solution;

C)

solid filtration and washing with Water;

d)

water wet solid suspension obtained in step c) with reflux methanol with stirring; Y

and)

form recovery crystalline

Preferably said alcohol C 1 -C 3 is methanol.

The basification of stage b) can lead to carried out by adding a solution of sodium hydroxide, potassium hydroxide or aqueous ammonia. Preferably, the Basification of step b) is carried out by adding a aqueous ammonia solution. Advantageously, the basification with aqueous ammonia produces as a residue ammonium chloride which is very much more soluble in water and alcohols than sodium or potassium chloride and therefore it is much more easily removable.

Advantageously, said procedure allows get Form E perfectly reproducible in scale industrial. In addition, not requiring the complete dissolution of the Ondansetron base in an alcohol, solvent in which it is little soluble, allows to obtain higher quantities of product with much lower volumes of solvent compared to the technique previous.

Form E can also be obtained at the scale of laboratory using a procedure that includes:

to)

dissolve ondansetron base in an alcohol C 1 -C 4 at reflux;

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b)

addition of ethyl acetate followed by cooling and concentration by slow evaporation at temperature environment and

C)

form recovery crystalline

Preferably said alcohol C 1 -C 4 is methanol.

The recovery of any of the ways Polymorphic of the present invention is carried out by filtration of the solid and dried, according to conventional methods.

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

In the present invention by "an alkane C_ {5} -C_ {7} "means n-pentane, n-hexane, n-heptane.

Ondansetron base and hydrochloride ondansetron used as a starting product to obtain the Polymorphic forms of the present invention can be obtained by any of the procedures described in the literature. Preferably, they are obtained according to the general procedure described in patent ES 2043535, whose industrial application is carried out with hydrochloric acid as an acid catalyst, in a mixture of isopropyl alcohol and water as solvent, which allows to directly isolate ondansetron in the form of hydrochloride. The base ondansetron can be obtained in turn by basification of a solution of said hydrochloride.

Also object of the present invention is a pharmaceutical composition containing any of the new polymorphic forms of ondansetron called Form C, D or E in a therapeutically active amount and an adequate amount of at Less an excipient.

The compositions provided herein invention can be administered by any appropriate retailer but, preferably, orally or parenterally.

Compositions for parenteral administration or topical they can be presented in the form of injectable solutions, intravenous, infusions, or suppositories or transdermal systems. Pharmaceutical compositions for oral administration may be solid, such as tablets or capsules prepared by  conventional media with pharmaceutically excipients acceptable, or liquids such as, for example, aqueous solutions or oily, syrups, elixirs, prepared emulsions or suspensions by conventional means with pharmaceutically additives acceptable.

They are preferred forms of oral administration and parental tablets and injectable solutions and intravenous, respectively.

An especially preferred pharmaceutical form for the administration of Forms C, D and E of ondansetron are the oral disintegration tablets also called orodispersible). By orodispersible tablets are understood as uncoated tablets to be placed in the mouth and that they have the advantage that they disintegrate quickly before being swallowed Different types of technologies have been described for get tablets of this type, which are known to an expert in the matter. Especially preferred are those described in International Patent Application WO 03103629.

Such pharmaceutical forms may contain a dose of any of Forms C, D and E preferably between 2-10 mg

According to the pharmaceutical practice conventional, excipients for tablet forms can comprise diluents, disintegrants, wetting agents, lubricants, dyes, aromas or other conventional adjuvants. Thus, typical tablet excipients comprise, for example, lactose, microcrystalline cellulose, corn starch, hypromellose, magnesium stearate, macrogol, polyvinylpyrrolidone, mannitol.

Injectable formulations according to the The invention preferably comprises aqueous solutions. And how Conventional excipients typical of injectable formulations they comprise sodium citrate, citric acid, sodium chloride, in addition to water for injections.

The use of any of Forms C, D and E for the manufacture of a medicine intended for the treatment and prophylaxis of nausea and postoperative vomiting as well as the control of nausea and vomiting induced by radiotherapy and cytotoxic chemotherapy.

An object of the present invention is also a therapeutic method for the treatment and prophylaxis of nausea and postoperative vomiting as well as the control of nausea and vomiting induced by radiotherapy and cytotoxic chemotherapy comprising administer to patients who require an amount therapeutically effective of any of Forms C, D or E, preferably between 2-10 mg.

Experimental Part

Next and by way of explanation although limiting the invention the following examples are set forth.

Synthesis Examples Example 1 Preparation of ondansetron base form C

492 mg of ondansetron base is dissolved in 35 mL of dichloromethane. 18 mL of n-hexane are added, observing the precipitation of crystals. The resulting suspension Stir for 10 minutes and filter. The white solid obtained dried at 40 ° C until constant weight. 137 mg of Ondansetron base Form C (28%).

Example 2 Preparation of ondansetron base form C

At a stirred solution of 4 g of ondansetron base in 284 mL of dichloromethane at 20-22 ° C are added 146 mL of n-pentane, observing the precipitation of crystals. The resulting suspension is stirred for 10 minutes and It leaks. The white solid obtained is dried at 40 ° C to weight constant. 2 g of ondansetron base Form C (50%) are obtained.

Example 3 Preparation of ondansetron base form D

A stirred suspension of 4 is heated to reflux g of ondansetron base in 178 mL of methanol until dissolution is obtained total. Slowly add 509 mL of t-butyl methyl ether and the heating, allowing the mixture to cool slowly with stirring up to 20-22 ° C. The resulting suspension is filtered and The white solid obtained is dried at 40 ° C until constant weight. they obtain 2.4 g of ondansetron base Form D (60%).

Example 4 Preparation of ondansetron base form E (Methodical laboratory)

A stirred suspension of 4 is heated to reflux g of ondansetron base in 200 mL of methanol until obtaining total dissolution 480 mL of acetate are slowly added ethyl and the heating is turned off, allowing the mixture to cool slowly with stirring to 20-22 ° C. It stops stirring and let it concentrate slowly with the flask open over 20-30 days until the appearance of crystals, which are filtered and dried at 40 ° C. 1 g of ondansetron Form E. (25%).

Example 5 Preparation of ondansetron base form E (Plant methodics industrial)

A stirred suspension of 16 is heated at 30 ° C Kg of ondansetron hydrochloride in 80 L of methanol and 80 L of water until complete dissolution. 6 L of 25% aqueous ammonia are added over 2 hours, until reaching pH 9. Ondansetron precipitates base and the resulting suspension is heated to 35 ° C and stirred at that temperature for 1 hour. It is cooled to 22-25 ° C and the suspension is centrifuged. The resulting cake is washed with water (2 x 40 L) and suspended again in 60 L of water. Stir the suspension at 35 ° C for 30 min., cooled to 22-25 ° C and centrifuged again, finally washing with water (2 x 40 L). The wet water solid is suspended in 180 L of methanol and the mixture is refluxed with stirring for 1 hour. The suspension fluidizes but does not reach dissolution. Be cool to 20-22 ° C and stir the suspension 30 min. Be cool to 0-5 ° C and stir the suspension 1 hour at that temperature The suspension is centrifuged and the cake is washed with 20 L cold methanol. The product is dried at 60 ° C under vacuum for 15 hours. 10.8 kg of ondansetron form E base (84%) are obtained.

Claims (18)

1. Polymorphic C form of ondansetron base, characterized by the fact that its powder X-ray diffractogram has characteristic peaks at 14.97 and 20.86 ° 2 ta and does not present peaks below 6.5 ° 2 ta. 2. Polymorphic D shape of the base ondansetron, characterized by the fact that its powder X-ray diffractogram has characteristic peaks at 11.29º; 14.58º; 17.16; 18.89º; 20.28º; 21.22º; 25.06º and 27.49º 2?. 3. Polymorphic form E of ondansetron base, characterized by the fact that its powder X-ray diffractogram has characteristic peaks at 6.29 °; 11.09º; 11.88º; 12.69º; 14.97º and a doublet at (24.96º; 25.17º) 2 the. 4. Polymorphic form according to claim 1, characterized in that its powder X-ray diffractogram also has a peak at 25.50 ° 2?. 5. Polymorphic form according to claim 4, characterized in that its powder X-ray diffractogram has the following peaks:

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5

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6. Polymorphic form according to claim 5, characterized in that it has a powder X-ray diffractogram according to Figure 1. 7. Polymorphic form according to claim 2, characterized in that its powder X-ray diffractogram has the following peaks:

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7

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8. Polymorphic form according to claim 7, characterized in that it has a powder X-ray diffractogram according to Figure 2. 9. Polymorphic form according to claim 3, characterized in that its powder X-ray diffractogram has the following peaks: 9 10. Polymorphic form according to claim 9, characterized in that it has a powder X-ray diffractogram according to Figure 3. 11. Method for obtaining the polymorphic form according to claim 1, characterized in that it comprises:

to)

preparation of a saturated solution of ondansetron based at room temperature in dichloromethane;

b)

precipitation of the crystalline form by the addition of a C 5 -C 7 alkane; Y

C)

form recovery crystalline

12. Method according to claim 11, characterized in that said C5-C7 alkane is n-hexane or n-pentane. 13. Method for obtaining the polymorphic form according to claim 2, characterized in that it comprises:

to)

Ondansetron base solution in a C 1 -C 4 alcohol at reflux;

b)

addition of t -butyl methyl ether followed by cooling; Y

C)

form recovery crystalline

14. Method for obtaining the polymorphic form according to claim 3, characterized in that it comprises:

to)

hydrochloride solution ondansetron in a mixture of an alcohol C 1 -C 3 and water;

b)

base wave precipitation by basification of the solution;

C)

solid filtration and washing with Water;

d)

water wet solid suspension obtained in step c) with reflux methanol with stirring; Y

and)

form recovery crystalline

15. Method according to any of claims 13 or 14, characterized in that said alcohol is methanol. 16. Method according to claim 14, characterized in that the basification of step b) is carried out by adding an aqueous ammonia solution. 17. Pharmaceutical composition comprising a polymorphic form according to any one of claims 1 to 10, in a therapeutically active amount and an adequate amount of At least one excipient. 18. Polymorphic form according to any of the claims 1 to 10 for use in the manufacture of a medicine intended for the treatment and prophylaxis of nausea and postoperative vomiting as well as the control of nausea and vomiting induced by radiotherapy and cytotoxic chemotherapy.