MX2007003719A - Tadalafil crystal forms and processes for preparing them - Google Patents

Abstract

The present invention provides tadalafil crystal forms II, III, IV, VI, VII, and VIII, and processes for preparing these forms. The present invention also provides processes for preparing tadalafil forms I and V.

Description

CRYSTAL FORMS OF TADALAFIL AND PROCESSES TO PREPARE THEM BACKGROUND OF THE INVENTION The invention relates to crystalline forms of tadalafil with methods of its synthesis.

BACKGROUND OF THE INVENTION Tadalafil, (6R-trans) -6- (1, 3-benodioxol-5-yl) -2, 3, 6, 7, 12, 12 hexahydro-2-methyl-pyrazino) [1,2 ': 1, 6 ] pyrido [3, -b] -indol-1,4-dione, is a white crystalline powder (CAS No. 171596-29-5).

Tadalafil is currently marketed as Cialis. Cialis was developed by Eli Lilly as a treatment for impotence. In this character, tadalafil is reported to work by inhibiting the formation of cyclic guanosine monophosphate-like phosphodiesterase type 5 (PDE5) specific (cGMP). Inhibition of PDE5 presumably decreases impotence by increasing the amount of cGMP, which results in smooth muscle relaxation and increased blood flow.

Polymorphism, the appearance of different crystalline forms, is a property of some molecules and molecular complexes. A single molecule, such as Tadalafil, can give rise to a variety of crystalline forms that have distinct crystal structures and physical properties such as melting point, X-ray diffraction pattern, digital impression of infrared radiation absorption, and spectrum of solid state NMR. A crystalline form can give rise to thermal behavior different from that of another crystalline form. The thermal behavior can be measured in the laboratory by techniques such as capillary melting point, thermogravimetric analysis ("TGA") and differential scanning calorimetry ("DSC"), which have been used to distinguish polymorphic forms.

The difference in the physical properties of different crystalline forms derives from the orientation and intermolecular interactions of adjacent or complex molecules in the global solid. Accordingly, polymorphs are distinguishable solids that share the same molecular formula that still has distinguishable advantageous physical properties compared to other crystalline forms of the same compound or complex.

One of the most important physical properties of pharmaceutical compounds is their solubility in aqueous solution, particularly their solubility in a patient's gastric juices. For example, when absorption through the gastrointestinal tract is slow, it is often desirable for a drug to be unstable under conditions in the stomach or intestine of the patient to dissolve slowly such that it does not accumulate in a harmful environment. Different crystalline or polymorphic forms of the same pharmaceutical compounds may have and are reported to have different aqueous solubilities.

The discovery of novel polymorphic forms of a pharmaceutically useful compound provides a new opportunity to improve the performance characteristics of a pharmaceutical product. It broadens the repertoire of materials that a formulation scientist has at his or her disposal to designate, for example, a pharmaceutical dosage form of a drug with. a desired release profile or other desired characteristic. There is a need in the art for polymorphic forms of tadalafil.

The repetition of the procedure described in US 5,859,006 derives in form I of crystalline anhydrous tadalafil (using MeOH). Form I of crystalline anhydrous tadalafil is characterized by at least one of: an X-ray diffraction pattern with characteristic reflections at 7.3 °, 10.6 °, 12.6 °, 14.6 °, 18.5 ° , 21.8 °, and 24.3 ° + 0.2 ° 2T, or a DSC thermogram with a single endotherm at 300 ° C.

The repetition of the procedure described in WO 04/011463 derives in the form V of crystalline anhydrous tadalafil (using acetic acid). Form V of crystalline anhydrous tadalafil is characterized by an X-ray diffraction pattern with characteristic reflections at 8.3 °, 15.1 °, 18.8 °, 19.2 ° and 20.3 ° ± 0.2 ° 2T. The crystalline form can also be characterized by a DSC thermogram with two endotherms at 110 ° C and 300 ° C. Form V of tadalafil can also be characterized by TGA, which shows a weight loss of 13% at a temperature between 25 ° C and 150 ° C. Form V of tadalafil can also be characterized by Karl-Fischer, which shows a water content of less than 1%. The weight loss corresponds to the theoretical value of tadalafil acetic acid of 4: 1.

Extract of the invention In one aspect, the present invention provides a method of preparing Form I crystalline anhydrous tadalafil by crystallizing it from a solvent selected from the group consisting of 2-methoxyethanol, absolute ethanol, acetonitrile, 1-propanol, isopropanol, ethyl acetate, dimethyl sulfoxide, toluene ("DMSO"), n-butanol, chloroform, tetrahydrofuran ("THF") and mixtures thereof.

In still another aspect, the present invention provides a method of preparing Form I crystalline anhydrous tadalafil including the steps of dissolving tadalafil in a solvent selected from the group consisting of chloroform, methylene chloride, THF, and acetone; combining this isolation with an organic antisolvent selected from the group consisting of petroleum ether, exano cycle, toluene, xylenes, benzene and methyl tert-butyl ether ("MTBE") to obtain a precipitate; and isolate the precipitate.

In another aspect, the present invention provides an anti-solvent crystallization method of preparing Form I of crystalline anhydrous tadalafil comprising the steps of dissolving tadalafil in THF; combining the solution with an antisolvent selected from the group consisting of petroleum ether, heptane and hexane; add an antisolvent that is methanol until a precipitate is obtained; and isolate the precipitate.

In another aspect, the present invention provides a thorough drying process for preparing Form I of anhydrous crystalline tadalafil comprising dissolving crystalline tadalafil in an aliphatic ketone selected from the group consisting of methyl ethyl ketone, isobutyl ketone and acetone; cool the solution to obtain a precipitate; isolate the precipitate; and exhaustively dry tadalafil at a temperature of 45 ° C to 90 ° C to obtain the crystalline form.

In still another aspect, the present invention provides a process for preparing Form I crystalline anhydrous tadalafil by dissolving tadalafil in an aliphatic ketone selected from the group consisting of methylethyl ketone and acetone; cool the solution to obtain a precipitate; isolate the precipitate; and expose it to high humidity to obtain the crystalline form. In one aspect, the present invention provides a crystalline form of Form II tadalafil by an X-ray diffraction pattern with reflections at 7.6 °, 14.0 °, 15.2 °, 18.0 °, and 22 , 8 ° ± 2o 2T.

In another aspect, the present invention provides a process for preparing Form I of anhydrous crystalline tadalafil which comprises exposing one of the group consisting of the methylvathyl ketone solvate of Form II crystalline tadalafil and the acetone solvate of Form II crystalline tadalafil at high humidity to obtain the crystalline form.

In one aspect, the present invention provides Form III crystalline tadalafil, characterized by an X-ray diffraction pattern with reflections at 8.3 °, 13.5 °, 7.7 °, and 18.4 ° ± 2 °. 2T.

In another aspect, the present invention provides a process for preparing Form I of anhydrous crystalline tadalafil which comprises exposing one of the group consisting of the methyl ethyl ketone solvate of Form III crystalline tadalafil and the acetone solvate of Form III crystalline tadalafil a high humidity to obtain the crystalline form.

In another aspect, the present invention provides a thorough drying process for preparing a mixture of Form I and form III of tadalafil, which comprises exhaustively drying crystalline tadalafil selected from the group consisting of the methyl ethyl ketone solvate of Form II crystalline tadalafil and Form II crystalline tadalafil at a temperature between 50 ° C and 75 ° C.

In one aspect, the present invention provides a crystalline form of Form IV of tadalafil, characterized by an X-ray diffraction pattern with reflections at 7.6 °, 10.6 °, 15.2 °, 18.4 °, and 22.7 ° ± 2o 2T.

In yet another embodiment, the present invention provides a method of preparing Form V crystalline tadalafil, which includes the steps of providing a solution of tadalafil in acetic acid; cool the solution until a precipitate is obtained; and isolate the precipitate.

In yet another aspect, the present invention provides a crystalline form of Form VI of tadalafil, characterized by one of: an X-ray diffraction pattern with reflections at 7.1 °, 9.3 °, 11.4 °, 13 , 5 °, 17.8 °, 19.2 °, 21.2 ° 2T, or by an exotherm in DSC at 200 ° C and a fusion endotherm at 300 ° C. In another aspect, the present invention provides a crystalline form of Form VII tadalafil, characterized by at least one of: an X-ray diffraction pattern with reflections at 7.0 °, 13.1 °, 17.6 ° , 19.0 °, 20.9 °, 24.6 ° 2T, or by two endotherms in DSC: a wide endotherm at 170 ° C and a fusion endotherm at 300 ° C.

In another aspect, the present invention provides Form VIII crystalline tadalafil, characterized by an X-ray diffraction pattern with reflections at 7.2 °, 7.6 °, 8.2 °, 13.5 °, 17, 6 °, 18.2 °, 22, 6o ± 2o 2T.

In another aspect, the present invention provides a method of preparing Form VIII crystalline tadalafil by performing one of the following: heating form IV of crystalline tadalafil at a temperature of between 50 ° C to 70 ° C to obtain Form VIII of crystalline tadalafil; . or heat Form IV crystalline tadalafil, at a temperature of between 40 ° C and 70 ° C to obtain a mixture of the forms of crystalline tadalafil, where the crystalline forms are Form VIII and Form I.

In still another aspect, the present invention provides a method of preparing Form I crystalline tadalafil by heating Form IV crystalline tadalafil at a temperature between 40 ° C and 80 ° C to obtain a mixture of Form VIII and I of crystalline tadalafil.

Brief Description of the Figures Figure 1 illustrates an X-ray diffraction diagram of Form I of anhydrous crystalline tadalafil.

Figure 2 illustrates an X-ray diffraction diagram of Form II crystalline tadalafil.

Figure 3 illustrates an X-ray diffraction diagram of Form III crystalline tadalafil.

Figure 4 illustrates an X-ray diffraction diagram of Form IV crystalline tadalafil.

Figure 5 illustrates a diagram of X-ray diffraction of Form V crystalline tadalafil.

Figure 6 illustrates an X-ray diffraction diagram of Form VI crystalline tadalafil.

Figure 7 illustrates an X-ray diffraction diagram of Form VII crystalline tadalafil.

Figure 8 illustrates an X-ray diffraction diagram of Form VIII crystalline tadalafil.

Figure 9 illustrates a DSC thermogram of Form I anhydrous crystalline tadalafil.

Figure 10 illustrates a DSC thermogram of Form II crystalline tadalafil, methylethyl ketone solvate.

Figure 11 illustrates a DSC thermogram of Form II crystalline tadalafil, acetone solvate.

Figure 12 illustrates a DSC thermogram of Form III crystalline tadalafil, methylethyl ketone solvate.

Figure 13 illustrates a DSC thermogram of Form III crystalline tadalafil, acetone solvate.

Figure 14 illustrates a DSC thermogram of Form IV crystalline tadalafil.

Figure 15 illustrates a DSC thermogram of Form V crystalline tadalafil.

Figure 16 illustrates a DSC thermogram of Form VI crystalline tadalafil.

Figure 17 illustrates a DSC thermogram of Form VII crystalline tadalafil.

Figure 18 illustrates a DSC thermogram of Form VIII crystalline tadalafil.

Figure 19 illustrates a TGA thermogram of Form II crystalline tadalafil, methylethyl ketone solvate.

Figure 20 illustrates a TGA thermogram of Form II crystalline tadalafil, acetone solvate.

Figure 21 illustrates a TGA thermogram of Form III crystalline tadalafil, methyl ethyl ketone solvate.

Figure 22 illustrates a TGA thermogram of Form III crystalline tadalafil, acetone solvate.

Figure 23 illustrates a TGA thermogram of crystalline Form IV crystallite.

Figure 24 illustrates a TGA thermogram of Form V crystalline tadalafil.

Figure 25 illustrates a TGA thermogram of Form VI crystalline tadalafil.

Figure 26 illustrates a TGA thermogram of Form VII crystalline tadalafil.

Figure 27 illustrates a TGA thermogram of Form VIII crystalline tadalafil.

Detailed description of the invention The invention provides novel crystalline forms of (6R-trans) -6- (1,3-benzodioxol-5-yl) -2, 3, 6, 7, 12, 12a-hexahydro-2-methyl-pyrazino [1, 2 ': 1, 6] pyrido [3, 4b] indole-1,4-dione. The novel crystalline forms of tadalafil have been called Forms II, III, IV, V, VII and VIII. The present invention also provides methods of making each crystalline form and methods of reworking the I and V forms of tadalafil.

Through the crystalline processes of this invention, each of the novel crystalline forms of tadalafil can be obtained substantially free of other crystalline forms. This invention also provides crystallization processes, especially in the case of Form III with respect to Forms II and III, and Forms I and III where a mixture of two forms in crystallization can be obtained.

The term "anti-solvent" means a liquid which, when added to a solution of tadalafil in a solvent, induces the precipitation of tadalafil. The precipitation of tadalafil is induced with the antisolvent when the addition of the antisolvent causes the tadalafil to precipitate from the solution more rapidly or to a greater extent than what tadalafil precipitates from a solution containing an equal concentration of tadalafil in the same solvent when the The solution is kept under the same conditions for the same period of time but without adding the antisolvent. In other words, the solubility, at a particular temperature, of tadalafil in the combination of the solvent and the antisolvent is lower than in the solvent alone. Precipitation can be perceived by the naked eye as a turbidity of the solution the formation of distinguishable particles of tadalafil suspended or on the surface of the solution, or collected on the walls or at the bottom of the container containing the solution.

The term "lower alcohol" refers to an alcohol containing three or fewer carbons.

The term "% final volume" as used with reference to antisolvents means the liquid volume of the antisolvent added to the tadalafil solution compared to the total liquid volume of the solvent and the antisolvent, or in the case of the addition of a primer and second antisolvent, the volume of the second antisolvent compared to the total liquid volume of the solvent, the first antisolvent and the second antisolvent.

The term "room temperature" refers to an ambient temperature of 10 ° C to 30 ° C, preferably 18 ° C to 28 ° C, more preferably 20 ° C to 25 ° C, more preferably 21 ° C to 23 ° C. ° C.

The term "hot" refers to the temperature of at least 20 ° C from the starting temperature of the reaction mixture.

As used herein, the term "exhaustively dry" as used in the description of processes to obtain Form I crystalline tadalafil, refers to drying a sample of crystalline tadalafil for a sufficient time to effect the conversion of the form crystalline to form I, generally at least 3 hours and preferably for 24 hours.

As used herein, the terms "exhaustively drying" and "exhaustively drying" refer both to a process for obtaining Form I crystalline tadalafil, thoroughly drying Form II or Form III crystalline tadalafil obtained previously, and also to a Additional step in the process to obtain Form II or Form III crystalline tadalafil, which can be performed to obtain Form I crystalline tadalafil.

As used herein, the term "suspension" refers to a thin mixture of a liquid and a finely divided substance, such as any form of crystalline tadalafil.

As used herein, the term "high humidity" refers to an atmosphere in which the relative humidity is not less than 80% and is preferably 100%.

As used herein, the term "relative humidity" refers to the ratio of the amount of water vapor in air at a specific temperature to the maximum amount that air can contain at that temperature, expressed as a percentage.

As used herein, the term "aliphatic ketone" refers to an organic chemical compound having the general structure RiC (0) R2 wherein Rx and R2 are, independently, branched linear alkyl groups having from one to four atoms of carbon.

As used herein, the term "exposure time" refers to a period of time sufficient to effect the conversion of crystalline tadalafil to Form I crystalline tadalafil. The exposure time is generally a period of at least three days, and preferably a period of seven days.

As used herein, the term "substantially free of", with reference to crystalline forms II, III, IV, VI, VII and VIII, refers to crystalline forms having a purity greater than 95%, preferably higher than 99% In one embodiment of the invention, Form I crystalline tadalafil can be prepared by a single solvent crystallization method, or by an anti-solvent crystallization method. In the first step of each method, a tadalafil solution is provided. The tadalafil solution can be provided by any convenient means, for example, by adding tadalafil with solvent to a suitable container, as determined by one skilled in the art, and heating. Possible methods of heating include sand baths, oil baths, and preferably water baths.

In one embodiment, the present invention provides a method of preparing Form I crystalline anhydrous tadalafil by crystallizing it from a solvent selected from the group consisting of 2-methoxyethanol, absolute ethanol, acetonitrile, 1-propanol, isopropanol, ethyl acetate, toluene containing dimethyl sulfoxide ("D SO"), n-butanol, chloroform, tetrahydrofuran ("THF") and mixtures thereof.

In another embodiment, the present invention provides a single method of crystallizing a single solvent to obtain Form I crystalline anhydrous tadalafil, comprising the steps of dissolving tadalafil in a solvent selected from the group consisting of absolute ethanol, 1-propanol, isopropanol , 2-methoxyethanol, acetonitrile and mixtures thereof, at a temperature of 60 ° C to 120 ° C; cool the solution until a precipitate is obtained; and isolate the precipitate. Preferably, the tadalafil is dissolved at a temperature of 83 ° C. Preferably, the solution is cooled to a temperature below 30 ° C and above 10 ° C, more preferably at room temperature.

Depending on the concentration of the concentration provided and the crystallization temperature of the solution, a retention time, or a time of crystallization, which is the time during which the precipitate is obtained, can be used. Preferably, the retention time is 24 hours or more. The cooling may optionally be carried out in steps, for example, by cooling the tadalafil solution at room temperature and then further cooling to 10 ° C. Suitable methods of isolating the precipitate include centrifugation and decantation and preferably filtration.

In another embodiment, the present invention provides a crystallization method of a single solvent to obtain Form I crystalline anhydrous tadalafil comprising the steps of dissolving tadalafil in a solvent selected from the group comprising ethyl acetate, toluene containing DMSO, n -butanol, methanol, chloroform, THF and mixtures thereof; cool the solution until a precipitate is obtained; and isolate the precipitate. Preferably, when the solvent is DMSO, its concentration is from 0.5% to 5% by volume. Preferably, the tadalafil is dissolved at reflux temperature. Preferably, the solution is cooled to a temperature between 0 ° C to room temperature. The cooling may optionally be carried out in steps, for example, by cooling the solution to room temperature and then cooling it again at 0 ° C in an ice bath for 1 hour to complete the precipitation.

In another embodiment, the present invention provides a process for preparing Form I of anhydrous tadalafil by an anti-solvent crystallization method. The method comprises dissolving tadalafil in an organic solvent selected from the group consisting of chloroform, methylene chloride, THF, and acetone, combining the solution with an organic antisolvent selected from the group consisting of petroleum ether, cyclohexane, toluene, xylene, benzene, hexane , heptane, octane and MTBE, to obtain a precipitate; and isolate the precipitate. Preferred solvent and antisolvent combinations include chloroform and one of the groups consisting of petroleum ether, preferably 40% of the final volume, toluene, preferably 73% of the final volume, xylenes, preferably 70% of the final volume or benzene, preferably 70% of the final volume. Additional preferable combinations of solvent and antisolvent include methylene chloride and cyclohexane, preferably 40% of the final volume, and hot acetone and MTBE, preferably 50% of the final volume.

In another embodiment, the present invention provides a process for preparing Form I crystalline anhydrous tadalafil by an anti-solvent crystallization method using a combination of the first and second antisolvent. The process comprises dissolving tadalafil in THF; combining the solution with an antisolvent selected from the group consisting of petroleum ether, heptane and hexane; add an antisolvent that methanol until obtaining a precipitate; and isolate the precipitate. Preferably, the insulation is by filtration. Preferably, after the combination, the petroleum ether is 96% by volume. Preferably, the final volume of methanol is 23%.

In another embodiment, Form I crystalline anhydrous tadalafil can be produced by a thorough drying method. The method comprises dissolving tadalafil in an aliphatic ketone selected from the group consisting of methyl ethyl ketone, isobutyl ketone or acetone; cool the solution to obtain a precipitate; isolate the precipitate; and dry it thoroughly at a temperature of 45 ° C to 90 ° C to obtain the crystalline form. Preferably, the solution is cooled to room temperature, and optionally it can be further cooled to a temperature of not less than 10 ° C, to complete the precipitation. Preferably, the precipitated crystalline tadalafil is isolated by filtration. Preferably, the drying occurs at a temperature of 65 ° C. Preferably, drying is for 24 hours. Preferably, the drying is under atmospheric pressure.

In yet another embodiment, Form I crystalline anhydrous tadalafil can be produced in a high humidity atmosphere. The process comprises providing a tadalafil solution in an aliphatic ketone selected from the group consisting of ketone and acetone; cool the solution to obtain a precipitate; isolate the precipitate; and exposing the precipitate to high humidity to obtain the crystalline form. Preferably, the solution is cooled to room temperature, and optionally it can be further cooled to a temperature of not less than 10 ° C, to complete the precipitation. Preferably, the precipitated crystalline tadalafil is isolated by filtration. Preferably, the high humidity is a relative humidity greater than 80%, more preferably a relative humidity of 100%. Preferably, the precipitate is exposed to high humidity at room temperature.

In another embodiment, the present invention provides novel crystalline forms of tadalafil that may exist as ketones. Form II of crystalline tadalafil and Form III of crystalline tadalafil can exist as ketones, wherein the ketone can be, for example, acetone or methylethyl ketone.

In another embodiment, the present invention provides a novel crystalline form of Form II of tadalafil characterized by an X-ray diffraction pattern with characteristic reflections at 7 ° C., 6 °, 14.0 °, 15.2 °, 18.0 °, and 22.8 ° + 2 ° 2T. The crystalline form can be a solvate ketone. The solvate ketone may be methyl ethyl ketone solvate or acetone solvate. The crystalline form can also be characterized by two endotherms in DSC at 105 ° C-115 ° C and 300 ° C. Methylethyl ketone solvate form tadalafil form II can be characterized by TGA, which shows a weight loss of 15% -16% at a temperature of 100 ° C. The methyl ethyl ketone solvate of form II of tadalafil can also be characterized by Kart-Fisher, which shows a water content of less than 1%. The acetone solvate of form II of tadalafil can also be characterized by TGA, which shows a weight loss of 10% -15% at a temperature lower than 120 ° C. The weight losses correspond to the theoretical value of the methyl ethyl ketone solvate of tadalafil and to the acetone solvate of tadalafil at a ratio of 1: 1. Figure 2 illustrates a characteristic X-ray diffraction pattern of Form II crystalline tadalafil. The X-ray diffraction pattern of Form II is insensitive to the identity of the ketone that forms the ketone solvate. Figures 10 and 19 illustrate DSC and TGA thermograms corresponding to the methyl ethyl ketone solvate of Form II crystalline tadalafil, respectively. Figures 11 and 20 illustrate DSC and TGA thermograms corresponding to the acetone solvate of Form II crystalline tadalafil, respectively.

In another embodiment, the present invention provides a process for preparing Form II crystalline tadalafil by a single solvent crystallization method. The method comprises dissolving tadalafil in a ketone solvent selected from the group consisting of methylethyl ketone or acetone at a temperature of 45 ° C to 83 ° C; cool the solution until a precipitate is obtained; and isolate the precipitate. Preferably, the tadalafil is dissolved at a temperature of 83 ° C. Preferably, the solution is cooled to a temperature between 0 ° C and 25 ° C, more preferably at a temperature of 10 ° C.

A retention time can be used during cooling. Depending on the concentration of the solution provided and the crystallization temperature of the solution, a retention time, or a time of crystallization, which is the time at which the precipitate is obtained, can be used. Preferably, the retention time is 24 hours or more. The cooling may optionally be carried out in steps, for example, by cooling the tadalafil solution to room temperature and then cooling to 10 ° C.

In another embodiment, the present invention provides a process for preparing Form II crystalline tadalafil using an antisolvent crystallization method. The method comprises dissolving tadalafil in methylethyl ketone, combining the solution with an antisolvent selected from the group consisting of petroleum ether, cyclohexane, or MTBE, until a precipitate is obtained, and isolating the precipitate. Preferably, the antisolvent comprises 50% of the final volume.

Form I of tadalafil can also be obtained by drying the solvate ketone of Form II crystalline Tadalafil at a temperature between 40 ° C and 90 ° C. Preferably, the drying is at a temperature of 50 ° C. Preferably, drying is at least 2 days. Preferably, the drying is under atmospheric pressure.

In yet another embodiment, Form II crystalline tadalafil, methylethyl ketone sulfate or Form II crystalline tadalafil, acetone solvate, can be used to produce Form I crystalline anhydrous tadalafil in a high humidity atmosphere. The method comprises exposing the crystalline tadalafil selected from the group formed by Form II crystalline tadalafil, methylethyl ketone solvate and Form II crystalline tadalafil, acetone solvate at high humidity until the crystalline form is obtained.

Preferably, the high humidity is a relative humidity greater than 80%, more preferably a relative humidity of 100%. Preferably, the exposure is at room temperature.

In another embodiment, the present invention provides a novel crystalline form of Tadalafil Form II, solvate ketone characterized by an X-ray diffraction pattern with characteristic reflections at 8.3 °, 13.5 °, 7.7 ° and 18 °. , 4 ° + 2 ° 2T. The crystalline form can also be characterized by two DSC endotherms at 80 ° C-90 ° C and 300 ° C. The crystalline form can be a ketone solvate. The ketone solvate may be methyl ethyl ketone solvate or acetone solvate. The methyl ethyl ketone of form III of tadalafil can also be characterized by TGA, which shows a weight loss of 4% -5% at a temperature of 80 ° C. The methyl ethyl ketone solvate of form II of tadalafil can also be characterized by Karl-Fisher, which shows the water content of less than 1%. The weight loss corresponds to the theoretical value of the methyl ethyl ketone solvate of tadalafil at a ratio of 4: 1. The acetone solvate of form III of tadalafil can also be characterized by TGA, which shows a weight loss of 2% -3% at a temperature between 25 ° C and 140 ° C. The acetone solvate of form III of tadalafil can also be characterized by Karl-Fisher, which shows the water content of less than 1%. The weight loss corresponds to the theoretical value of acetone solvate of tadalafil of the ratio of 5: 1. Figure 3 illustrates an X-ray diffraction pattern representative of Form III crystalline tadalafil. The X-ray diffraction pattern of Form III is insensitive to the identity of the ketone that forms the ketone solvate. Figures 12 and 21 illustrate DSC and TGA thermograms representative of the methyl ethyl ketone solvate of crystalline tadalafil form III, respectively. Figures 13 and 22 illustrate the DSC and TGA thermograms representative of the acetone solvate of Form III crystalline tadalafil, respectively.

In another embodiment, the present invention provides a process for preparing a mixture of Form II and Form III of tadalafil, ketone solvates by drying Form II of tadalafil, ketone solvate at a temperature of 50 ° C to 80 ° C for 0, 5 to 6 hours. Preferably, the crystalline form is dried under vacuum. Preferably, the crystalline form is dried at a temperature of 65 ° C. Preferably, the crystalline form is dried for 3 hours. A mixture of the methyl ethyl ketone solvate of Form II and Form II of tadalafil can also be obtained by drying Form II of tadalafi, methylethyl ketone solvate at a temperature of 45 ° C to 70 ° C for 0.5 to 5 hours. Preferably, the crystalline form is dried at a temperature of 65 ° C. Preferably, the crystalline form is dried under vacuum. Preferably, the crystalline form is dried for 2 hours.

In a preferred embodiment, Form III crystalline tadalafil, acetone solvate can be obtained by drying Form II crystalline tadalafil, acetone solvate at a temperature of 45 ° C to 70 ° C for 0.5 to 5 hours. Preferably, the crystalline form is dried at a temperature of 65 ° C. Preferably, the crystalline form is dried under vacuum. Preferably, the crystalline form is dried for 3 hours.

The drying of the solvate ketone of Form II of tadalafil is correctly controlled to obtain the desired crystalline form. The drying of Form II of the Tadalafil Cetone solvate by vacuum gives Form III, while drying under atmospheric pressure results in the formation of Form I. The drying time must be sufficient for the complete conversion to the crystalline form desired.

In yet another embodiment, Form III crystalline tadalafil, methyl ethyl ketone solvate or Form II crystalline tadalafil, acetone solvate can be used to produce Form I crystalline anhydrous tadalafil in a high humidity atmosphere. The method comprises exposing the crystalline tadalafil of the group formed by Form III crystalline tadalafil, methylethyl ketone solvate and Form III crystalline tadalafil, acetone solvate at high humidity. Preferably, the high humidity is a relative humidity greater than 80%, more preferably a relative humidity of 100%. Preferably, the exposure is at room temperature.

In another embodiment, Form II crystalline tadalafil, methylethyl ketone solvate or Form II crystalline tadalafil, acetone solvate can be used to produce a mixture of Form I crystalline anhydrous tadalafil and form III crystalline tadalafil by a method of exhaustive drying. The method comprises drying the crystalline tadalafil selected from the group consisting of Form II crystalline tadalafil, methylethyl ketone solvate and Form II crystalline tadalafil, acetone solvate, at a temperature between 50 ° C and 75 ° C. Preferably, the drying is under atmospheric pressure. Preferably, the drying is at a temperature of 65 ° C. Preferably, the drying is for at least 24 hours.

In another embodiment, the present invention provides a novel crystalline form of Form IV of tadalafil, characterized by an X-ray diffraction pattern with characteristic reflections at 7.6 °, 10.6 °, 15.2 °, 18.4 ° and 22.7 ° ± 2o 2T. The crystalline form can also be characterized by two DSC endotherms at 110 ° C-115 ° C and 300 ° C. Form IV of tadalafil can also be characterized by TGA, which shows a weight loss of 11% -16% at a temperature between 25 ° C and 130 ° C. Figure 4 illustrates a characteristic X-ray diffraction pattern of Form IV crystalline tadalafil. Figures 14 and 23 illustrate DSC and TGA thermograms characteristic of Form IV crystalline tadalafil, respectively.

In another embodiment, the present invention provides a process for preparing Form IV crystalline tadalafil by a single solvent crystallization method, comprising the steps of dissolving tadalafil in methylene chloride; cool the solution until a precipitate is obtained; and isolate the precipitate. Preferably, the step of dissolving is at reflux temperature. Preferably, the solution is cooled to a temperature between 0 ° C and room temperature. Preferably, the solution is first cooled to room temperature and then cooled to 0 ° C in an ice bath for 1 hour to complete the precipitation.

In another embodiment, the present invention provides a process for preparing Form IV crystalline tadalafil, by an antisolvent crystallization process. The process comprises providing a solution of tadalafil in methylene chloride; combining the solution with an antisolvent that is petroleum ether until a precipitate is obtained; and isolate the precipitate. Preferably, the step of dissolving is at reflux temperature. Preferably, the petroleum ether is 30% of the final volume.

Form II, form III and form IV of tadalafil are all characterized by an endothermic peak by DSC at 80 ° C-120 ° C, and by a fusion endotherm at 300 ° C.

In another embodiment, the present invention provides a process for preparing Form V crystalline tadalafil by a single solvent crystallization method. The process comprises dissolving tadalafil in acetic acid; cool the solution until a precipitate is obtained; and isolate the precipitate. Preferably, the tadalafil is dissolved at reflux temperature. Preferably the cooling is at a temperature between room temperature to 0 ° C. Preferably, the solution is first cooled to room temperature and then cooled to 0 ° C in an ice bath for 1 hour to complete the precipitation.

In another embodiment, the present invention provides a crystalline anhydrous form of Form VI of tadalafil, characterized by at least one of: an X-ray diffraction pattern with reflections at 7.1 °, 9.3 °, 11.4 ° , 13.5 °, 17.8 °, 19.2 °, 21.2 ° 2T, or by an exotherm in DSC at 200 ° C and a melting point at 300 ° C. Form VI of tadalafil is also characterized by TGA, which shows a weight loss of less than 1%. Figure 6 illustrates an X-ray diffraction pattern representative of Form VI crystalline tadalafil. Figures 16 and 28 illustrate DSC and TGA thermograms representative of Form VI crystalline tadalafil, respectively.

In another embodiment, the present invention provides a process for preparing Form VI crystalline anhydrous tadalafil using a single solvent method. The method comprises suspending methanol and Form IV of tadalafil until a precipitate is obtained; and isolate the precipitate. Preferably, tadalafil is isolated by filtration. Preferably, the isolated precipitate is dried at a temperature of 40 ° C to 70 ° C, more preferably at a temperature of 65 ° C, under vacuum, for 3 hours.

In another embodiment, the present invention provides a crystalline form of Form VII of tadalafil, toluene solvate characterized by at least one of: an X-ray diffraction pattern with reflections at 7.0 °, 13.1 °, 17, 6 °, 19.0 °, 20.9 °, 24.6 ° 2T, or by two endotherms in DSC; a wide endotherm at 170 ° C and a fusion endotherm at 300 ° C. The crystalline form can be a toluene solvate. Form VII of tadalafil can also be characterized by TGA, which shows a weight loss of 5% -6% at a temperature of 80 ° C. Form VII of tadalafil can also be characterized by Karl-Fisher, which shows a water content of less than 1%. Figure 7 illustrates an X-ray diffraction pattern representative of Form VII crystalline tadalafil. Figures 17 and 26 illustrate DSC and TGA thermograms representative of Form VII crystalline tadalafil, respectively.

In yet another aspect, the present invention provides a method of preparing Form VII crystalline tadalafil which includes the steps of providing a suspension of toluene and tadalafil, wherein tadalafil is selected from the group consisting of the group of crystalline forms comprising Form IV of crystalline tadalafil, Form V of crystalline tadalafil, and Form II of crystalline tadalafil until a precipitate is obtained; and isolate the precipitate. Preferably, the insulation is by filtration. Preferably, the isolated precipitate is dried at 65 ° C.

In another embodiment, the present invention provides Form VIII crystalline tadalafil, dichloromethane solvate, characterized by an X-ray diffraction pattern with reflections at 7.2 °, 7.6 °, 8.2 °, 13.3 °, 17.6 °, 18.2 °, 22.6 ° ± 2 ° 2T. The crystalline form can be dichloromethane solvate. The crystalline form can also be characterized by two endotherms at 100 ° C and 300 ° C. Form VII of tadalafil can also be characterized by TGA, which shows a weight loss of 7% -9%. Figure 8 illustrates an X-ray diffraction pattern representative of Form VIII crystalline tadalafil. Figures 18 and 27 illustrate DSC and TGA thermograms, respectively, of Form VIII crystalline tadafil.

In another embodiment, the present invention provides a process for preparing the form VIII of crystalline tadalafil, dichloromethane solvate by heating. In this method, Form IV crystalline tadalafil can be heated to a temperature between 50 ° C and 70 ° C, preferably at 65 ° C, preferably under vacuum, to obtain Form VIII crystalline tadalafil, dichloromethane solvate, or heating at temperatures between 40 ° C and 70 ° C, preferably at 60 ° C, preferably under atmospheric pressure, to obtain a mixture of the crystalline tadalafil forms, wherein the forms are Form I of crystalline anhydrous tadalafil and the Form VIII of crystalline tadalafil, dichloromethane solvate.

In yet another embodiment, the present invention provides a method of preparing Form I crystalline tadalafil, by heating Form I crystalline tadalafil, by heating Form IV crystalline tadalafil to a mixture of the forms of crystalline tadalafil, wherein the crystallines are Form VIII and Form I. Preferably, the heating is under atmospheric pressure.

Another embodiment of the invention comprises the crystalline forms II, III, IV, VI, VII and VIII tadalafil substantially free of crystalline form I.

The crystalline forms II, III, IV, VI, VII and VIII of tadalafil can be obtained with a particle size distribution having d (0.9), 200 μ or 600 μ. The particle size distribution of the crystalline forms of Tadalafil of the present invention can be varied by changing experimental parameters, such as the cooling speed, and the stirring speed.

The particle size distribution of Form I can be from 200 μ to 600 μ after grinding.

The X-ray diffraction data were obtained with a Scintag variable goniometer, Cu tube, solid state detector, using a standard circular aluminum sample holder with zero circular background. Scan parameters: Range 2 ° -40 ° 2T: continuous scanning at a speed of 3 ° / min.

The DSC data were obtained with a DSC821e, Metteler Toledo. The weight of the sample was 3 mg and the heating rate (exploration) was 10 ° C / minute. The lid of the crucible had 3 holes in it.

The TGA data was obtained using a Mettler TG50 using a standard aluminum vessel. The weight of the sample was 7-15 mg, and the heating rate (scan) was 10 ° / minute. A cold environment with a thermostat of 10 ° C to 30 ° C was used in several of the following samples. The temperature was changed according to the needs and objectives of the experiment.

EXAMPLES Preparation of Tadalafil Crystalline Form I Example 1 Tadalafil (5.01 g) was added to an Erlenmeyer flask with 2-methoxyethanol (104 ml) and heated in a water bath at 83 ° C until dissolved. The solution was cooled to room temperature, and after 24 hours, it was cooled again in a cold environment for 24 hours. The precipitate was collected by filtration and dried in a vacuum oven for 3 hours at 65 ° C. Form I of tadalafil was obtained. The loss in drying ("LOD") by TGA was 0.6%.

Example 2 Tadalafil (5.07 g) was added to an Erlenmeyer flask with absolute ethanol (550 ml) and heated in a water bath at 83 ° C until dissolved. The solution was cooled to room temperature, and after 24 hours, it was cooled again in a cold environment for 24 hours. The precipitate was cooled by filtration and dried in a vacuum oven for 3 hours at 65 ° C. Form I of tadalafil was obtained. LOD by TGA was 0.3%.

Example 3 Tadalafil (5.07 g) was added to an Erlenmeyer flask with acetonitrile (250 ml) and heated in a water bath at 83 ° C until dissolved. The solution was cooled to room temperature, and after 24 hours, it was further cooled in a cold environment for 24 hours. The precipitate was collected by filtration and dried in a vacuum oven for 3 hours at 65 ° C. Form I of tadalafil was obtained.

Example 4 Tadalafil (5.14 g) was added to an Erlenmeyer flask with 1-propanol (1 L) and heated in a water bath at 83 ° C until dissolved. The solution was cooled to room temperature, and after 24 hours, it was further cooled in a cold environment for 24 hours. The precipitate was collected by filtration and dried in a vacuum oven for 3 hours at 65 ° C.

Example 5 Tadalafil (4.18 g) was added to an Erlenmeyer flask with isopropanol (1 L) and heated in a water bath at 83 ° C until dissolved. The solution was cooled to room temperature and after 24 hours, it was further cooled in a cold environment for 24 hours. The precipitate was collected by filtration and dried in a vacuum oven for 3 hours at 65 ° C.

Example 6 Tadalafil (5.0 g) was stirred in ethyl acetate (950 ml) and heated to reflux temperature. The solution was allowed to crystallize overnight and was further cooled in an ice bath for 1 hour. The precipitate was then cooled by filtration.

Example 7 Tadalafil (5.0 g) was stirred in toluene (160 ml) and DMSO (4 ml) and heated to reflux temperature. The solution was allowed to crystallize overnight, and was further cooled in an ice bath for 1 hour. The precipitate was then collected by filtration.

Example 8 Tadalafil (5.0 g) was stirred in n-butanol (300 ml) and heated to reflux temperature. The solution was allowed to crystallize overnight and was further cooled in an ice bath for 1 hour. The precipitate was then collected by filtration.

Example 9 Tadalafil (5.0 g) was stirred in methanol (850 ml) and heated to reflux temperature. The solution was allowed to crystallize overnight, and was further cooled in an ice bath for 1 hour. The precipitate was then collected by filtration.

Example 10 Tadalafil (5.0 g) was stirred in chloroform (225 ml) and heated to reflux temperature. The solution was allowed to crystallize overnight, and was further cooled in an ice bath for 1 hour. The precipitate was then collected by filtration.

Example 11 Tadalafil (5.0 g) was stirred in THF (150 ml) and heated to reflux temperature. The solution was allowed to crystallize overnight, and was further cooled in an ice bath for 1 hour. The precipitate was then collected by filtration.

Example 12 Tadalafil (5.0 g) was dissolved in chloroform (300 ml). Petroleum ether 40-60 (200 ml) was added to the solution, and the resulting precipitate was collected by filtration.

Example 13 Tadalafil (5.0 g) was dissolved in methylene chloride (300 ml). Cyclohexane (200 ml) was added to the solution, and the resulting precipitate was collected by filtration.

Example 14 Tadalafil (5.0 g) was dissolved in THF (20 ml). Petroleum ether 40-60 (500 ml) was added to the solution, and then methanol (150 ml) was added. The resulting precipitate was then collected by filtration.

Example 15 Tadalafil (5.0 g) was dissolved in chloroform (300 ml). Then toluene (800 ml) was added to the solution and the resulting precipitate was collected by filtration.

Example 16 Tadalafil (5.0 g) was dissolved in chloroform (300 ml). Then a mixture of Xylenes (620 ml) was added to the solution, and the resulting precipitate was collected by filtration.

Example 17 Tadalafil (5.0 g) was dissolved in chloroform (300 ml). Then benzene (700 ml) was added to the solution and the resulting precipitate was collected by filtration.

Example 18 Tadalafil (5.0 g) was dissolved in acetone (400 ml) at 55 ° C. MTBE (400 mL) was added to the solution, and the resulting precipitate was collected by filtration.

Example 19 Tadalafil (5.0 g) was dissolved in methylethyl ketone (400 ml) at 80 ° C. Petroleum ether 40-60 (400 ml) was added to the solution, and the resulting precipitate was collected by filtration. The sample was then dried at 65 ° C overnight under atmospheric pressure to give a mixture of Form I and Solvated Form II.

Example 20 Methyl ethyl ketone (750 ml) was added to a 1 L Erlenmeyer flask and heated to 80 ° C in a water bath. Tadalafil (12, 4 g) was added slowly. An additional amount of methylethyl ketone was added to ensure total dissolution. The solution was removed from the heating bath. It crystallized, was stirred overnight, and was filtered the next day. The sample was then dried at 65 ° C overnight under atmospheric pressure to give a mixture of Form I and Solvated Form II.

Example 21 Tadalafil (5.0 g) was dissolved in hot methylethyl ketone (400 ml). Petroleum ether 40-60 (400 mL) was added and the resulting precipitate was filtered. The sample was kept at 50 ° C for 7 days to give form I.

Example 22 Tadalafil (5.0 g) was dissolved in hot methylethyl ketone (400 ml). Petroleum ether 40-60 (400 ml) was added to the solution, and the resulting precipitate was filtered. The sample was analyzed by XRD and by TGA and found to contain the methyl ethyl ketone solvate form II of Tadalafil. The sample was kept at room temperature at 100% humidity for 7 days to form Form I.

Example 23 Methyl ethyl ketone (750 ml) was added to an Erlenmeyer flask and heated in a water bath. Slowly tadalafil (12.4 g) was added. A small additional amount of methylethyl ketone was added to ensure total dissolution. The solution was removed from the heating bath. It crystallized, was stirred overnight, and was filtered the next day. The sample was identified by XRD and by TGA analysis containing methylethyl ketone solvate form tadalafil form II. The sample was kept at room temperature at 100% relative humidity for 7 days to form Form I.

Example 24 Tadalafil (5.09 g) was heated with acetone (326 ml) at 83 ° C in a water bath until the solution was complete. The solution was removed from the water bath and cooled to room temperature. After 24 hours of rest, the sample was placed in a cold environment for 24 hours, filtered and dried at 65 ° C for 24 hours.

Example 25 Tadalafil (5.09 g) was heated with acetone (326 ml) at 83 ° C in a water bath until the solution was complete. The solution was removed from the water bath and cooled to room temperature. After 24 hours of rest, the sample was placed in a cold environment for 24 hours, and then filtered. The sample was kept for 3 days at room temperature at 100% relative humidity to give Form I.

Preparation of Tadalafil Crystalline Form II Example 26 Tadalafil (5.14 g) was added to an Erlenmeyer flask with methylethyl ketone (346 ml) and heated in a water bath at 83 ° C until dissolved. The solution was cooled to room temperature, and after 24 hours, it was further cooled to room temperature for 24 hours. The resulting precipitate was collected by filtration. The water content by Karl Fischer ("KF") was 0.46%. Form II of tadalafil was obtained.

Example 27 Tadalafil (5.09 g) was added to an Erlenmeyer flask with acetone (326 ml) and heated in a water bath at 83 ° C until dissolved. The solution was cooled to room temperature, and after 24 hours it was further cooled in a cold environment at 10 ° C-30 ° C for 24 hours. The resulting precipitate was collected by filtration. Form II of tadalafil was obtained.

Example 28 Tadalafil (5.0 g) was dissolved in methylethyl ketone (400 ml) at 80 ° C. Petrolatum ether (400 ml) was added to the solution, and the resulting precipitate was collected by filtration. Form II of tadalafil was obtained.

Example 29 Tadalafil (5.0 g) was dissolved in hot methylethyl ketone (400 ml). Cyclohexane (400 ml) was added to the solution, and the resulting precipitate was collected by filtration. Form II of tadalafil was obtained.

Example 30 Tadalafil (5.0 g) was dissolved in hot methylethyl ketone (400 ml). TBE (400 ml) was added to the solution, and the resulting precipitate was collected by filtration. Form II of tadalafil was obtained. The water content by KF was 0.11%.

Preparation of the crystalline form III of tadalafil Example 31 Tadalafil prepared according to example 26 was dried at 65 ° C under vacuum for 3 hours, and derived into a mixture of forms II and III.

Example 32 Tadalafil prepared according to example 27 was dried at 65 ° C under vacuum for 3 hours and derived in a mixture of forms II and III.

Example 33 Form II of tadalafil solvate methyl ethyl ketone was heated at atmospheric pressure at 65 ° C for 2 hours, and derived into a mixture of forms I and III.

EXAMPLE 34 Form II of tadalafil solvate ketone was heated at 65 ° C under vacuum for 3 hours, and derived into form III tadalafil. The water content by KF was 0.4%.

Preparation of the crystalline form VI of tadalafil Example 35 Tadalafil (5.0 g) was stirred in methylene chloride (450 ml) and heated to reflux temperature. It was allowed to crystallize overnight, and then further cooled in an ice bath for 1 hour to complete the precipitation. The precipitate was then filtered. Form IV of tadalafil was obtained. The water content by KF was 0.21%.

Example 36 Tadalafil (5.0 g) was dissolved in methylene chloride (700 ml). Petroleum ether 40-60 (300 ml) was added to the solution, and the resulting precipitate was collected by filtration. Form IV of tadalafil was obtained. The water content by KF was 0.38%.

Preparation of the crystalline form V of tadalafil Example 37 Tadalafil (5.0 g) was stirred in acetic acid (50 ml) and heated to reflux temperature. It was allowed to crystallize overnight, and then further cooled in an ice bath for 1 hour. The resulting precipitate was collected by filtration. The water content by KF was 0.20%. Form V of tadalafil was obtained. See the TGA thermogram in Figure 24.

Preparation of the crystalline form VI of tadalafil Example 38 Form IV of Tadalafil (2.0 g) was suspended overnight in methanol (15 ml) and filtered the next day. The sample was dried at 65 ° C under vacuum for 3 hours. Form VI of tadalafil was obtained. The water content by KF was less than 1%.

Preparation of the crystalline form VI of tadalafil Example 39 Form VI of tadalafil (2, Og) was suspended overnight in toluene (20 ml) and filtered the next day. The sample was dried at 65 ° C under vacuum for 3 hours. Form VII of tadalafil was obtained.

Example 40 Form V of tadalafil (2.0 g) was suspended in toluene (20 ml) overnight, and filtered the next day. The sample was dried at 65 ° C under vacuum for 3 hours. Form VII of tadalafil was obtained. Example 1 Form II of tadalafil (2.0 g) was suspended overnight in toluene (20 ml) and filtered the next day. The sample was dried at 65 ° C under vacuum for 3 hours. Form VII of tadalafil was obtained.

Preparation of crystalline form VIII of tadalafil Example 42 Form IV of dichloromethane solvate of tadalafil (2.0 g) was heated at 65 ° C under vacuum. Form VIII of tadalafil was obtained.

Example 43 Form IV of dichloromethane solvate of tadalafil (0.5 g) was heated at 65 ° C under atmospheric pressure to obtain a mixture of the crystalline forms of tadalafil Form I and Form VIII.

Claims (91)

1. A process for preparing form I of crystalline tadalafil comprising crystallizing it from a solvent selected from the group consisting of 2-methoxyethanol, absolute ethanol, acetonitrile, 1-propanol, isopropanol, ethyl acetate, toluene and dimethyl sulfoxide ("DMSO") , n-butanol, chloroform, tetrahydrofuran ("THF") and mixtures thereof.

2. A process for preparing Form I crystalline tadalafil, comprising the steps of: (a) dissolving tadalafil in a solvent selected from the group consisting of 2-methoxyethanol, absolute ethanol, acetonitrile, 1-propanol, isopropanol, and mixtures thereof, at a temperature of at least 60 ° C to 120 ° C to obtain a solution; (b) cooling the tadalafil solution from step a) until a precipitate is obtained; and (c) isolating the precipitate from step b).

3. The process according to claim 1, wherein the solution of step b) is cooled to a temperature lower than 30 ° C and higher than 10 ° C.

4. The process according to claim 1, wherein the solution of step b) is cooled to room temperature.

5. A process for preparing Form I crystalline tadalafil, comprising the steps of: (a) dissolving tadalafil in a solvent selected from the group consisting of ethyl acetate, toluene containing DMSO, n-butanol, methanol, chloroform, THF and mixtures of them to obtain a solution; (b) cooling the solution resulting from step a) until a precipitate is obtained; (c) isolating the precipitate from step b) to obtain crystalline tadalafil.

6. The process according to claim 1, wherein the tadalafil of step a) is dissolved at reflux temperature.

7. The process according to claim 5, wherein the solution of step b) is cooled to a temperature below room temperature and above 0 ° C.

8. A process for preparing form I of crystalline tadalafil, comprising the steps of: a) dissolving tadalafil in a solvent selected from the group consisting of chloroform, methylene chloride, THF and acetone to obtain a solution; b) combining the solution of step a) with an antisolvent selected from the group consisting of petroleum ether, cyclohexane, toluene, xylene, benzene, hexane, heptane, octane, and MTBE, and a precipitate is obtained; and c) isolating the precipitate from step b) to obtain crystalline tadalafil.

9. The process according to claim 8, wherein the solvent of step a) is chloroform and the antisolvent of step b) is selected from the group consisting of petroleum ether, wherein the petroleum ether is 40% of the final volume, toluene, where toluene is 73% of the final volume, xylenes, where xylenes are 70% of the final volume, and benzene, where benzene is 70% of the final volume.

10. The process according to claim 8, wherein the solvent of step a) is THF and the antisolvent comprises first and second antisolvents, wherein the first antisolvent is petroleum ether, wherein the petroleum ether is 96% by volume after the combination with the tadalafil solution, and where the second antisolvent is methanol, where the methanol is 23% of the final volume.

11. The process according to claim 8, wherein the solvent of step a) is methylene chloride and the antisolvent of step b) is cyclohexane, wherein the cyclohexane is 40% of the final volume.

12. The process according to claim 8, wherein the solvent of step a) is acetone and the antisolvent of step b9 is MTBE, wherein the MTBE is 50% of the final volume.

13. A process for preparing form I of crystalline tadalafil, comprising the steps of: a) dissolving tadalafil in THF to obtain a solution; b) combining the solution of step a) with an antisolvent selected from the group consisting of petroleum ether, heptane and hexane; c) adding an antisolvent that is methanol until a precipitate is obtained; d) Isolate the precipitate from step c) to obtain crystalline tadalafil.

14. A process for preparing form I of crystalline tadalafil, comprising the steps of: a) dissolving tadalafil in an aliphatic ketone selected from the group consisting of methylethyl ketone, isobutyl ketone or acetone to obtain a solution; b) cooling the solution until a precipitate is obtained; and c) drying the precipitate from step c) at a temperature of 45 ° C to 90 ° C to obtain crystalline tadalafil.

15. The process according to claim 14, wherein the solution is cooled to room temperature.

16. The process according to claim 15, wherein the solution is further cooled to a temperature below 10 ° C.

17. The process according to claim 14, wherein the precipitate from step c) is dried at 65 ° C.

18. The process according to claim 14, wherein the precipitate of step c) is dried under atmospheric pressure.

19. A process for preparing form I of crystalline tadalafil, comprising the steps of: a) dissolving tadalafil in an aliphatic ketone selected from the group consisting of methylethyl ketone and acetone to obtain a solution; b) cooling the solution until a precipitate is obtained; c) isolating the precipitate; and d) exposing the precipitate to high humidity to obtain crystalline tadalafil.

20. The process according to claim 19, wherein the solution of step b) is cooled to room temperature.

21. The process according to claim 20, wherein the solution is further cooled to a temperature below 10 ° C.

22. A crystalline form of tadalafil (form II) characterized by X-ray reflections at 7.6 °, 14.0 °, 15.2 °, 18.0 °, and 22.8 ° + 2 ° 2T.

23. The crystalline tadalafil according to claim 22, which has an X-ray diffraction diagram that is substantially illustrated in Figure 2.

24. The crystalline form according to claim 22, characterized by two DSC endotherms at 105 ° C-115 ° C and 300 ° C.

25. The crystalline form according to claim 22, characterized by TGA, which shows a weight loss of 10% -15% at a temperature lower than 120 ° C.

26. The crystalline tadalafil according to claim 22, wherein the crystalline tadalafil is a ketone solvate.

27. The crystalline tadalafil according to claim 26, wherein the ketone solvate is methyl ethyl ketone solvate.

28. The crystalline tadalafil according to claim 26, wherein the ketone solvate is acetone solvate.

29. A process for preparing the crystalline form of tadalafil according to claim 22, comprising the steps of: a) providing a solution of tadalafil in a solvent selected from the group consisting of methylethyl ketone and acetone, at a temperature of 45 ° C to 83 ° C; b) cooling the solution from step a) until a precipitate is obtained; and c) isolating the precipitate from step b) to obtain the crystalline tadalafil according to claim 22.

30. The process according to claim 29, wherein tadalafil from step a) is provided at 83 ° C.

31. The process according to claim 29, wherein the solution of step b) is cooled to a temperature below 0 ° C and above 25 ° C.

32. The process according to claim 31, wherein the solution of step b) is cooled to 10 ° C.

33. A process for preparing the crystalline form of tadalafil according to claim 22, comprising the steps of: a) dissolving tadalafil in methylethyl ketone to obtain a solution; b) combining the solution of step a) with an antisolvent selected from the group consisting of petroleum ether, cyclohexane, and MTBE, until a precipitate is obtained; and c) isolating the precipitate from step b) to obtain crystalline tadalafil.

34. A process for preparing form I of crystalline tadalafil comprising the steps of drying the solvate ketone of crystalline tadalafil form II at a temperature of 40 ° C to 90 ° C.

35. The process according to claim 34, wherein the drying is for at least 2 days.

36. The process according to claim 34, wherein the drying is under atmospheric pressure.

37. The process according to claim 34, wherein the drying is at a temperature of 50 ° C.

38. A process for preparing form I of crystalline tadalafil comprising the steps of exposing crystalline tadalafil selected from the group consisting of form II of crystalline tadalafil, methyl ethyl ketone solvate and form II of crystalline tadalafil, acetone solvate at high humidity.

39. A crystalline form of tadalafil (Form IIII) characterized by X-ray reflections at 8.9 °, 13.5 °, 7.7 °, and 18.4 ° ± 2 ° 2T.

40. The crystalline form of tadalafil according to claim 39, which has an X-ray diffraction diagram that is substantially illustrated in Figure 3.

41. The crystalline form of tadalafil according to claim 39, characterized by two endotherms in DSC at 80 ° C-90 ° C and at 300 ° C.

42. The crystalline form of tadalafil according to claim 39, characterized by TGA, which shows a weight loss of 4% -5% at a temperature of 80 ° C.

43. The crystalline tadalafil according to claim 39, wherein the crystalline tadalafil is a solvate ketone.

44. The crystalline tadalafil according to claim 43, wherein the ketone solvate is methyl ethyl ketone solvate.

45. The crystalline tadalafil according to claim 43, wherein the ketone solvate is acetone solvate.

46. On process for preparing the crystalline form of tadalafil according to claim 39, comprising one of the following: a) drying crystalline tadalafil form II at a temperature of 50 ° C to 80 ° C under vacuum for 0.5 to 6 hours until a mixture of form II and form III of crystalline tadalafil is obtained; or b) drying form II of methalythyl ketone solvate of tadalafil, at a temperature of 45 ° C to 70 ° C under vacuum for 0.5 to 5 hours to obtain a mixture of form II and form III of crystalline tadalafil; or c) drying form II acetone solvate of tadalafil at a temperature of 45 ° C to 70 ° C under vacuum for 0.5 to 5 hours to obtain crystalline tadalafil, termed form III.

47. The process according to claim 46, wherein the drying in a), b) or c) is at a temperature of 65 ° C.

48. The process according to claim 46, wherein the drying in a), b) or c) is under vacuum.

49. A process for preparing crystalline tadalafil form I comprising exposing crystalline tadalafil selected from the group consisting of form III of crystalline tadalafil, methyl ethyl ketone solvate and form III of crystalline tadalafil, acetone solvate at high humidity.

50. A process for preparing a mixture of crystalline tadalafil form I and crystalline tadalafil form II comprising the steps of drying the crystalline tadalafil selected from the group consisting of form II crystalline tadalafil, methyl ethyl ketone solvate and form II tadalafil crystalline, acetone solvate, at a temperature between 50 ° C and 75 ° C.

51. The process according to claim 50, wherein the drying is under atmospheric pressure.

52. The process according to claim 50, wherein the drying is at a temperature of 65 ° C.

53. A crystalline form of tadalafil (form IV) characterized by X-ray reflections at 7.6 °, 10.6 °, 15.2 °, 18.4 ° and 22.7 ° ± 2 ° 2T.

54. The crystalline form of tadalafil according to claim 53, having an X-ray diffraction diagram that is substantially illustrated in Figure 4.

55. The crystalline form of tadalafil according to claim 53, characterized by two DSC endotherms at 110 ° C-115 ° C and 300 ° C.

56. The crystalline form of tadalafil according to claim 53, characterized by TGA, which shows a weight loss of 11% -16%.

57. A process for preparing the crystalline form of tadalafil according to claim 53, comprising the steps of: a) dissolving tadalafil in methylene chloride to obtain a solution; b) cooling the solution from step a), until a precipitate is obtained; and c) isolating the precipitate from step c) to obtain the crystalline tadalafil.

58. The process according to claim 57, wherein the dissolution in step a) is at the reflux temperature.

59. The process according to claim 57, wherein the solution of step b) is cooled to a temperature between 0 ° C and room temperature.

60. A process for preparing the crystalline form of tadalafil according to claim 53, comprising the steps of: a) dissolving tadalafil in methylene chloride to obtain a solution; b) combine the solution of step a) with petroleum ether; and c) isolating the precipitate from step b) to obtain crystalline tadalafil.

61. The process according to claim 60, wherein the dissolution in step a) is at reflux temperature.

62. A process for preparing the crystalline form V of tadalafil comprising the steps of: a) dissolving tadalafil in acetic acid to obtain a solution; b) cooling the solution of step a) to obtain a precipitate; and c) isolating the precipitate from step b) to obtain crystalline tadalafil.

63. The process according to claim 62, wherein the dissolution of step a) is at reflux temperature.

64. The process according to claim 62, wherein the cooling of step b) is at a temperature between room temperature and 0 ° C.

65. A crystalline form of tadalafil (Form VI) characterized by at least one of: a) X-ray reflections at 7.1, 9.3, 11.4, 13.5, 17.8, 19, 2 °, 21.2 ° 2T, or b) an exotherm in DSC at 200 ° C, and a fusion endotherm at 300 ° C.

66. The crystalline form of tadalafil according to claim 65, which has an X-ray diffraction pattern that is substantially as illustrated in Figure 6.

67. The crystalline form of tadalafil according to claim 65, having a DSC thermogram substantially illustrated in Figure 16.

68. The crystalline form of tadalafil according to claim 65, characterized by TGA, which shows a weight loss of less than 1%.

69. A process for preparing the crystalline form of tadalafil according to claim 65, comprising the steps of: a) providing a suspension of methanol and form IV of crystalline tadalafil; and b) isolating the tadalafil from step a) to obtain the crystalline tadalafil.

70. The process according to claim 69, wherein the isolated form is further dried at a temperature of 40 ° C to 70 ° C under vacuum.

71. The process according to claim 70, wherein the isolated crystalline tadalafil is dried at a temperature of 65 ° C.

72. The process according to claim 69, wherein the drying is for 3 hours.

73. A crystalline form of tadalafil (Form VII) characterized by at least one of the following: a) X-ray reflections at 7.0 °, 13.1 °, 17.6 °, 19.0 °, 20.9 °, 24.6 ° 2T; or b) two DSC endotherms at 170 ° C and 300 ° C.

74. The crystalline form of tadalafil according to claim 71, which has an X-ray diffraction diagram substantially illustrated in Figure 7.

75. The crystalline form of tadalafil according to claim 73, having a DSC thermogram substantially illustrated in Figure 17.

76. The crystalline form of tadalafil according to claim 73, wherein the crystalline form is a toluene solvate.

77. A process for preparing the crystalline form of tadalafil according to claim 73, comprising the steps of: a) suspending tadalafil in toluene, wherein the tadalafil is selected from a group of crystalline forms comprising: Form IV, Form V and Form II, until a precipitate is obtained; and b) isolating the precipitate from step a) to obtain crystalline tadalafil.

78. The process according to claim 77, wherein the isolated form is further dried at 65 ° C under vacuum.

79. The process according to claim 78, wherein the drying is for 3 hours.

80. A crystalline form of tadalafil (Form VIII) characterized by x-ray reflections at 7.2 °, 7.6 °, 8.2 °, 13.3 °, 17.6 °, 18.2 °, 22, 6o + 2nd 2T.

81. The crystalline form of tadalafil according to claim 80, which has an X-ray diffraction diagram substantially illustrated in Figure 8.

82. The crystalline form according to claim 80, characterized by two DSC endotherms at 100 ° C and 300 ° C.

83. The crystalline form of tadalafil according to claim 80, wherein the crystalline form is dichloromethane solvate.

84. A process for preparing the crystalline form of tadalafil according to claim 80, comprising one of the following steps: a) heating the IV form of crystalline tadalafil at a temperature of 50 ° C to 70 ° C, or b) heating the form IV of crystalline tadalafil at a temperature of 40 ° C to 70 ° C to obtain a mixture of Form I and Form VIII of crystalline tadalafil.

85. The process according to claim 84, wherein the IV form of crystalline tadalafil of a) is heated to a temperature of 65 ° C.

86. The process according to claim 84, wherein the heating of a) is under vacuum.

87. The process according to claim 84, wherein the IV form of crystalline tadalafil from b) is heated to a temperature of 60 ° C.

88. The process according to claim 84, wherein the heating of b) is under atmospheric pressure.

89. A process to prepare Form I crystalline anhydrous tadalafil, where the form IV of crystalline tadalafil is heated to a temperature between 40 ° C and 80 ° C, to obtain a mixture of the forms of crystalline tadalafil, where the forms Crystalline substances are called Form I and Form VIII.

90. The process according to claim 89, wherein the heating is at a temperature of 60 ° C.

91. The process according to claim 89, wherein the heating is under atmospheric pressure.