LT4100B - Paroxetine hydrochloride anhydrate and process for preparing thereof - Google Patents

Abstract

Invention relates to paroxetyne hydrochloride anhydrate, with no attached propane dipropanol, in its several forms, its production method, and new intermediate substances, used to obtain the mentioned compound.

Description

The present invention relates to paroxetine hydrochloride having the formula:

anhydrate, its method of administration and its use in medicine.

EP-B-223403 describes paroxetine hydrochloride semi-hydrate and its use in the treatment of certain disorders of the body. Example 8 of this document describes the preparation of paroxetine hydrochloride anhydrate by crystallization from a water-containing solvent in the form of wafer crystals having a melting point of 118 ° C and an IR spectrum at 890, 1200, 1490, 3400 and 3640 cm ^-1 . This material is hereinafter referred to as the "Z" form. Subsequently, repetition of the procedure described in Example 8 failed to obtain any type of paroxetine hydrochloride anhydrate, and there is no clear indication elsewhere in this document or any other route or modification of this method to obtain the anhydrate.

International Journal of Pharmaceutics, 42 (1988) p. 135-143, published by Elsevier, also describes paroxetine hydrochloride anhydrate. This anhydrate is said to be obtained by crystallization of paroxetine hydrochloride from anhydrous propan-2-ol. Subsequently, by repeating this procedure, a solvate of paroxetine hydrochloride with propan-2-ol, m.p. propan-2-ol is bound to the product. This bound propan-2-ol cannot be removed by conventional drying, such as vacuum drying.

Paroxetine hydrochloride anhydrate without propan-2-ol bound has not been described in the literature; nor is the method described which, as a single product, would yield such a compound. A process for the preparation of paroxetine hydrochloride anhydrate free of bound propan-2-ol was found in this work. In addition, four new forms of paroxetine hydrochloride anhydrate were unexpectedly identified and described. These forms continue

Brief description of the figures

FIG. IR spectra of Form A paroxetine hydrochloride anhydrate FIG. 1B. IR spectrum of paroxetine hydrochloride anhydrate form A Figure 2A. IR spectrum of paroxetine hydrochloride anhydrate form B Figure 2B. IR spectrum of paroxetine hydrochloride anhydrate form B Figure 3A. IR spectrum of C-form paroxetine hydrochloride anhydrate Figure 3B. IR spectrum of C-form paroxetine hydrochloride anhydrate Fig.4. X-ray diffraction pattern of paroxetine hydrochloride anhydrate form A.

FIG. X-ray diffraction pattern of paroxetine hydrochloride anhydrate form B.

Fig.6 X-ray diffraction pattern of paroxetine hydrochloride anhydrate form C

FIG. A forms paroxetine hydrochloride anhydrate solid phases ¹³ C NMR spectrum FIG. B forms paroxetine hydrochloride anhydrate solid phases ^I3 C NMR spectrum FIG. C forms paroxetine hydrochloride anhydrate solid phases ¹³ c NMR

spectrum

10OA. IR spectrum of paroxetine hydrochloride solvate with toluene FIG. IR spectrum of paroxetine hydrochloride solvate with toluene FIG. 11 A. IR spectrum of D-form paroxetine hydrochloride anhydrate FIG. IR spectrum of D-form paroxetine hydrochloride anhydrate

The present invention describes a paroxetine hydrochloride anhydrate which is free of bound propan-2-ol.

The present invention also describes paroxetine hydrochloride anhydrate, which is free of bound organic solvent.

The present invention describes a paroxetine hydrochloride anhydrate which does not contain propan-2-ol other than Form Z.

The term "non-bound organic solvent" means less than the amount of propan-2-ol remaining in the solvate, i.e. in a crystal lattice of the product under normal vacuum oven conditions.

The present invention also describes paroxetine hydrochloride solvates other than propan-2-ol solvents as starting materials for the preparation of paroxetine hydrochloride anhydrates without bound organic solvent. Examples of such solvates include solvates with other alcohols such as propan-1-ol and ethanol (except propan-2-ol), solvates with organic acids such as acetic acid, solvates with organic bases such as pyridine, solvates with ketones, such as acetone, solvates with ethers such as tetrahydrofuran, and solvates with chlorinated hydrocarbons such as chloroform, and solvates with hydrocarbons such as toluene.

It is desirable that the paroxetine hydrochloride anhydrate is free from propan-2-ol bound in pure form. A fully suitable paroxetine hydrochloride anhydrate free of bound propan-2-ol is one having a purity of greater than 50%, preferably greater than 60%, more preferably greater than 70%, and more preferably greater than 80%. and preferably at greater than 90%. Most preferably, paroxetine hydrochloride anhydrate is obtained in a completely pure form, i.e. the content of paroxetine hydrochloride anhydrate, free of bound propan-2-ol, is greater than 95%.

It will be appreciated that the paroxetine hydrochloride anhydrate of the present invention, free of bound propan-2-ol, may contain unbound water, i. water that is different from the crystallization water.

Typically, the weight of the bound organic solvent should be less than 2.0% by weight, preferably less than 1.8%, more preferably less than 1.5%, particularly less than 1.0%, even better, less than 0.5% and most preferably less than 0.1%.

In general, all percentages herein are by weight unless otherwise indicated.

Preference is given to forms of paroxetine hydrochloride anhydrate free from bound propan-2-ol or other organic solvent:

1) Form A paroxetine hydrochloride anhydrate (hereinafter designated);

2) paroxetine hydrochloride anhydrate form B (hereinafter designated);

3) Form C paroxetine hydrochloride anhydrate (hereinafter designated);

4) Form D paroxetine hydrochloride anhydrate (hereinafter designated).

The forms of paroxetine hydrochloride anhydrate and the resulting material may be separated from one another by the methods described in EP-B-0223403 and International Journal of Pharmaceutics 42 (1988), 135-143, by crystal form, by solvent analysis, or by methods such as IR spectra, melting point, X-ray diffraction, NMR spectra, differential scanning calorimetry (DSK), microscopy, and any other method of analysis that separates one form from another.

For example, Form A, which is free from organic solvent, may be distinguished from other forms by the following analytical data: Form A has a melting point of about 123-125 ° C, provided that Form is of a similar purity to that described in Example 1; it can be identified by conventional methods such as high performance liquid chromatography (ASSCh) and by the intense IR spectral (Fig. 1) bands at 513, 538, 571, 592, 613, 665, 722, 761, 783, 806, 818, 839, 888, 906, 924, 947, 966, 982, 1006, 1034, 1068, 1091, 1134, 1194, 1221, 1248, 1286, 1340, 1387, 1493, 1513, 1562, 1604, 3402, 3631 cm ^-1 .

DSK exotherm measured at 10 ° C / mm. has a maximum of about 126 ° C for an open dish and about 128 ° C for a closed dish. The A-shaped X-ray diffraction pattern is very similar to that shown in Fig.4, for example, having characteristic maxima at 6.6, 8.0, 11.2, 13.2 at 20 degrees, and very similar to the solid in Fig. 7. The NMR spectrum, for example, has characteristic maxima at

154,3,149,3,141,6,138,5 da.s.

Form B, free from organic solvent, may be distinguished from other forms by the following analytical data: it has a melting point of about 138 ° C, provided that form is of a similar purity to that described in Example 7; it can be identified by conventional methods such as high performance liquid chromatography (ASSCh) and by the intense IR spectral (Fig.2) bands at 538, 574, 614, 675, 722, 762, 782, 815, 833, 884, 925, 938, 970, 986, 1006, 1039, 1069, 1094, 1114, 1142, 1182, 1230, 1274, 1304, 1488, 1510, 1574, 1604, 1631 cm @ ^-1 .

The DSK exotherm, measured at a rate of 10 ⁽ 'C / min.), Has a maximum of about 137 ° C, and an open and closed dish. The B-shaped X-ray diffraction pattern is very similar to that shown in Fig. 5, for example.

5.7, 11.3, 12.4, 14.3, 20 degrees, and the very similar solid state NMR spectrum shown in Fig. 8, for example, has characteristic peaks at 154.6, 148.3, 150.1, 141.7, 142.7, 139.0 md

Form C, free from organic solvent, can be distinguished from other forms by the following analytical data: it has a melting point of about 164 ° C, provided that form is of a similar purity to that described in Example 8; it can be identified by conventional methods such as high performance liquid chromatography (ASSCh) and by the intense IR spectral (Fig.3) bands at 540, 574, 615, 674, 720, 760, 779, 802, 829, 840, 886, 935, 965, 984, 1007, 1034, 1092, 1109, 1139, 1183, 1218, 1240, 1263, 1280, 1507, 1540, 1558, 1598, 1652 cm ^-1 .

DSK exotherm measured at 10 ° C / min. has a maximum of about 161 ° C in both the open and closed pan.

The C-shaped X-ray diffraction pattern is very similar to that shown in Fig.6, for example, having characteristic maxima at 10.1, 12.1, 13.1 14.3 degrees 20, and very similar to the solid state NMR spectrum shown in Fig.7, for example, have characteristic peaks at 154.0, 148.5, 143.4, 140.4 md

Form D may be distinguished from the others by the following analytical data: It is a semi-crystalline solid having a melting point of about 125 ° C, provided that it is of a similar purity to that described in Example 14; it can be identified by conventional methods such as ASSCh.

Form D may also be characterized in that it exhibits substantially similar physical properties when obtained from a toluene solvate as the starting material using the general procedures described herein; said solvate with toluene has intense IR bands at 1631, 1603, 1555, 1513, 1503, 1489, 1340, 1275, 1240, 1221, 1185, 1168, 1140, 1113, 1101, 1076, 1037, 1007, 986, 968, 935 , 924, 885, 841, 818, 783, 760, 742, 720, 698, 672, 612, 572, 537 and 465 cm ^-1 , with characteristic X-ray diffraction maxima at 7.2,

9.3,12.7 and 14.3 20-degree.

A person skilled in the art will readily determine which form is to be assigned to a particular sample using conventional techniques based on the data given above and in the examples and other conventional techniques.

Mostly, forms A and B are needle-shaped crystals, while form C is needles or prisms.

The present invention also encompasses a process for the preparation of paroxetine hydrochloride anhydrate, propane-2-ol free, comprising crystallization of paroxetine hydrochloride from:

(1) an organic solvent or mixture of organic solvents to form solvates of paroxetine hydrochloride which do not remove the solvent by conventional drying techniques; or

(2) an organic solvent or mixture of organic solvents, free from paroxetine hydrochloride solvate, which may be removed by vacuum drying;

then, in the case of 1, the solvent or solvents are ejected using a ejection agent, o

In the case of 2, the solvent is removed.

The present invention also encompasses a process for the preparation of paroxetine hydrochloride solvates other than propan-2-ol wherein the paroxetine hydrochloride is crystallized from an organic solvent or mixture of organic solvents to form paroxetine hydrochloride solvates which are not removed by conventional drying techniques.

The present invention also encompasses a process for preparing paroxetine hydrochloride anhydrate which is free of bound organic solvent, wherein the solvent or solvents bound to paroxetine hydrochloride are displaced from the paroxetine hydrochloride solvate using a displacement agent.

In one preferred embodiment of the invention, the crystallization of paroxetine hydrochloride anhydrate is achieved by treating the free base paroxetine solution in an organic solvent or solvents with dry gaseous hydrogen chloride.

Alternatively, water may be removed by aceotropic distillation before crystallization of paroxetine hydrochloride. Suitable solvents for this purpose are those which form an aceotrope with water, such as pyridine and propan-2-ol. It should also be noted that solvent mixtures may be used to aid in the removal of water by aceotropic distillation.

In another aspect of the invention, paroxetine hydrochloride anhydrate is crystallized by dissolving paroxetine hydrochloride semi-hydrate in a dry solvent which forms an aceotropic with water. Such solvent is distilled off and dry solvent is added again until the water is completely removed.

The paroxetine hydrochloride semi-hydrate or its free base may be prepared according to the procedures described in EP-B-0223403.

The organic solvent must be very dry, i.e. its water content must be less than that needed to form paroxetine hydrochloride semi-hydrate. Very dry organic solvents may be prepared by known methods. They may be dried using conventional techniques such as molecular mesh drying or may use dry commercial solvents.

Factors that determine the form of the resulting product are the organic solvent or solvents used; choosing the solvent gives the product in the desired form.

It should be noted that the formation of the desired form also depends on the method of solvent removal.

It should also be noted that according to Embodiment 1, the organic solvent or solvents which form the crystalline solvate of paroxetine hydrochloride, from which the solvent is not removed by conventional drying techniques, may be selected experimentally. Such organic solvents include alcohols, especially alkanols such as propan-2-ol; organic acids such as acetic acid; organic bases such as pyridine; nitriles such as acetonitrile; ketones such as acetone; ethers such as tetrahydrofuran and chlorinated hydrocarbons such as chloroform. It is understood that other organic solvents may be present.

The paroxetine hydrochloride solvate obtained in Option 1 is readily isolated and dried using conventional drying techniques, such as vacuum drying, where some or all of the free or unbound solvent is removed. The bound solvent is then displaced using a displacement agent such as water or dry carbon dioxide. Other ejection agents, which can be selected experimentally, can also be used.

The preferred ejection agent is water or water vapor. It is important that the paroxetine hydrochloride solvate is in contact with the amount of water and for such time as to displace the solvent but not to form the hydrochloride semi-hydrate.

The amount of water, the physical state of the water (liquid or vapor), and the duration of contact of paroxetine hydrochloride with water vary for different solvates. Mostly it depends on the solubility of the particular solvate.

Specific ratios of solvate to water of paroxetine hydrochloride are given in the following examples (Examples 1, 4-6, 9-11, 13 and 15). It should be noted that the pyridine solvate is apparently more water soluble than, for example, the propan-2-ol solvate. Thus, the use of a total ionic effect when diluted hydrochloric acid is used can prevent the solvate from dissolving and thereby converting it to the hydrochloride semi-hydrate.

After contact with water, which removes the solvent bound to the product, the product is well dried, for example, in a vacuum at elevated temperature. Water-absorbent materials such as phosphorus pentoxide can also be dried.

When carbon dioxide is used, care should be taken to ensure that the carbon dioxide stream, temperature and pressure are optimized for the removal of solvent from paroxetine hydrochloride. High carbon pressure, such as about 2500 psi, is usually required. It is best to carry out the process at higher temperatures, such as 50-80 ° C, more preferably 55-75 ° C.

Option 1 is best suited to obtain Form A.

It is desirable to add a small amount of crystallization centers of the solvate as the starting material for the preparation of paroxetine hydrochloride anhydrate form A to form crystallization centers of crystals of such solvate.

Another way to facilitate the crystallization of the starting solvate is by adding crystals of paroxetine hydrochloride anhydrate form A.

According to Embodiment 2, the organic solvent or mixture of organic solvents which do not form solvates with paroxetine hydrochloride and which are removed by conventional drying in a vacuum oven may be selected experimentally.

An example of a solvent that forms a bound solvate with paroxetine hydrochloride but is removed by conventional vacuum oven drying is toluene.

Preferably, toluene is used to obtain the D form.

To facilitate the crystallization of the solvates, which are the starting material for the preparation of paroxetine hydrochloride anhydrate form D, a small amount of such a solvate crystal must be added to form crystallization centers. For this purpose, D-form paroxetine hydrochloride anhydrate crystals may also be used.

Examples of solvents which do not form bound solvates with paroxetine hydrochloride and which are removed by conventional vacuum oven drying include butan-1-ol and ethyl acetate.

For Form B, it is best to use butan-1-ol and for Form C, butan-1-ol or ethyl acetate.

If Form B is required, it can be produced using the procedure described in Example 7.

To facilitate B-crystallization, it is best to add a small amount of B-crystal to form the crystallization centers.

If Form C is required, it can be prepared according to the procedures described in Examples 8 and 12.

It should also be noted that to facilitate crystallization of the C form, C crystals must be used to form the crystallization centers.

Form A, B, C and D crystals to form crystallization centers may be prepared according to the procedures described below or may be obtained on request from Corporate Intellectual Property, Smith, Beecham plc, New Frontiers Science Park, Third Avenue, Harlow, Essex, CM 19 5AW , United Kingdom. Form A is BRL 29060F, Form B is BRL 29060G; Form C is BRL29060H; Form D is BRL 29060H. Examples of Forms A, B, C, and D are also available from NCIMB, 23 St. Machor Drive, Aberdeen, AB2 IR Y, Scotland, United Kingdom.

Paroxetine hydrochloride anhydrate, propan-2-ol and forms A, B, C, and D (all of which are referred to hereinafter as the "products of the invention") can be used to treat and prevent the following conditions: alcoholism, anxiety, depression, obsessive neurosis, panic, chronic pain, obesity, senile dementia, migraine, bulimia, anorexia, social phobia, premenstrual syndrome, depression in the adolescent, trichothilomania, dysthymia, drug abuse.

These disorders are referred to as "diseases".

The present invention also encompasses a pharmaceutical composition for the treatment or prophylaxis of a disorder, wherein the product of the invention is mixed with a pharmaceutically acceptable carrier.

The present invention also encompasses products of the invention for the treatment and / or prophylaxis of disorders.

The present invention also encompasses the use of the products of the invention in the manufacture of a medicament for the treatment and / or prophylaxis of ailments.

The products are best suited for the treatment and / or prevention of depression, obsessive neuroses and panic.

The compositions of the present invention are generally adapted for oral administration, but the present invention also encompasses solution-form compositions for parenteral administration.

Said formulations are usually dosage formulations containing from 1 to 200 mg of active ingredient, based on the free base, usually from 5 to 100 mg, for example from 10 to 50 mg, such as 10, 12.5, 15, 25, 30 or 40 mg per person. The preferred unit dose is 20 mg of active ingredient, calculated on the free base. Such a composition is usually administered 1 to 6 times daily, for example 2, 3 or 4 times, such that the total amount of active ingredient used is from 5 to 400 mg, based on the free base. It is best to take the unit dose once a day.

The preferred dosage forms are tablets or capsules.

The compositions of the present invention may be prepared by conventional mixing techniques such as mixing, filling and pressing.

Suitable carriers for the compositions of the present invention include diluents, binders, disintegrants, paints, flavor enhancers and / or preservatives. These agents can be used in conventional ways, such as those commonly used in the manufacture of industrial antidepressants.

Specific examples of pharmaceutical compositions include those described in EP-B0223403 and US 4007196, wherein the product of the present invention is used as an active ingredient.

The present invention is illustrated by the following examples:

example

Crystalline paroxetine hydrochloride anhydrate, propane-2-ol free (form A)

A solvate of paroxetine hydrochloride with propan-2-ol

Paroxetine hydrochloride semi-hydrate (150 g), propan-2-ol (1000 ml) and toluene (300 ml) were stirred and refluxed. The solvent is distilled off with the addition of propan-2-ol to maintain the same volume until the boiling point reaches about 82 ° C, indicating no water left.

The mixture is left to cool to about 50 ° C and then crystallizes immediately. The contents of the flask quickly turn into a thick mass; it is diluted with propan-2-ol (about 500 ml) and stirred vigorously. The resulting suspension was allowed to cool to about 30 ° C, filtered under vacuum, protected from atmospheric moisture. The filtered wet substance is dried under high vacuum over phosphorus pentoxide.

The yield of the solvated paroxetine hydrochloride was 151 g and the propan-2-ol content was 13.0% (by NMR).

The IR spectrum (suspension in petroleum jelly oil), among other bands, has a characteristic band at 667 cm < ^{1 &} gt ;.

2. Paroxetine hydrochloride anhydrate (form A)

The paroxetine hydrochloride solvate with propan-2-ol (110 g, propan-2-ol content 13.0%) was stirred in a glass with water (275 mL) for 20 minutes. The mixture is filtered under vacuum and the wet solid is dried under vacuum over phosphorus pentoxide to constant weight.

The yield of paroxetine hydrochloride form A was 91.0 g.

Water content 0.13% (KF), propan-2-ol content 0.05% (by NMR).

Lyd. mp: 123-125 ° C.

The DSK exotherm measured at 10 ° C / min has a maximum of about 126 ° C for an open dish and 121 ° C for a closed dish.

IR spectrum (suspension vaseline oil), in addition to other bands are characteristic bands at 665, 3631 and 3402 ^cm-1 (see. FIG).

Elemental Analysis:

Calculated for Paroxetine Hydrochloride Anhydrate: C, 62.38; H, 5.79; N, 3.83%.

Found: C, 62.10; H, 5.89; N, 3.67%

X-ray powder diffraction (see Fig. 4) and solid state ¹³ C NMR (see Fig. 7) of this sample were investigated. Example ²

Solvate of paroxetine hydrochloride with propan-2-ol

The free paroxetine base (42.09 g) is dissolved in propan-2-ol (Fisons SLR grade, 210 ml). Into a refrigerated flask containing propan-2-ol (157 g) was added gaseous hydrogen chloride until 20.8 g of hydrogen chloride were absorbed. 39 g of this solution (containing about 4.6 g of hydrochloric acid) are quickly added to the paroxetine solution and the mixture is stirred vigorously. After about 1 minute, the crystallization begins and the mixture becomes an immiscible slurry which is left to stand for one hour. The product was filtered off, washed with propan-2-ol (50 mL) and dried in vacuo at room temperature to constant weight in a phosphorus pentoxide desiccator. The sample is analyzed by NMR spectroscopy; it was found to contain about 6% by weight of propan-2-ol. Part of the material is placed in a vacuum oven at 50 ° C and dried again to constant weight. It takes 4 days. NMR spectra indicate that the material contains about 2% propan-2-ol.

example

Solvate of paroxetine hydrochloride with propan-2-ol

The free base of paroxetine (52.37 g) is dissolved in dry propan-2-ol (250 ml) and, with vigorous stirring, a solution of gaseous hydrogen chloride in dry propan-2-ol (50 g of a solution containing about 5.8 g of hydrogen) is added rapidly. chloride). After about 30 seconds, crystallization begins and the mixture is stirred for another 30 minutes at room temperature to completely crystallize the material. The product is isolated by vacuum filtration, washed with 25 ml of dry propan-2-ol and dried in a desiccator containing phosphorus pentoxide at room temperature in vacuo.

After 3 days, the material was analyzed by NMR; it was found to contain 10.5% propan-2-ol. The remaining material was dried for another 3 days to constant weight in a desiccator containing fresh phosphorus pentoxide. NMR analysis shows 5.7% propan-2-ol in the product.

example

Crystalline paroxetine hydrochloride anhydrate, free from bound pyridine (Form A)

1. Preparation of a solvate of paroxetine hydrochloride with pyridine

Paroxetine hydrochloride, containing about 2% propan-2-ol, (20.0 g) was dissolved in hot pyridine (200 mL) and some solvent was distilled off. Stopper the flask and allow to cool; a reddish solution crystallizes. The slurry is well stirred, filtered to avoid atmospheric moisture, and the solid is washed with pyridine (25 mL) on the filter. The product is dried under high vacuum over phosphorus pentoxide.

Yield 22 g.

Microscopic examination shows the product to be needle-like crystals and NMR analysis indicates that it contains 15.2% pyridine (1: 1 theory corresponds to 17.77%). The IR spectrum of the pyridine solvate (suspension in petroleum jelly) differs from both the semi-hydrate and the A-form anhydrate and also has no intense bands in the 3000 cm @ ^-1 range. The pyridine solvate also has a different X-ray powder diffraction pattern.

2. Preparation of paroxetine hydrochloride anhydrate (form A)

The paroxetine hydrochloride solvate with pyridine (5.00 g) was added to 5M hydrochloric acid (25 mL) in a beaker and stirred for 5 minutes. The mixture is filtered, the crystals are well dried and washed with water (15 ml). Dry under high vacuum over phosphorus pentoxide.

Yield 4.00 g.

The IR spectrum (suspension in petroleum jelly) is in agreement with that of paroxetine hydrochloride anhydrate, and no pyridine is found by NMR. Example ⁵

Paroxetine hydrochloride anhydrate, free from bound acetic acid (form A)

1. Preparation of a paroxetine hydrochloride solvate with acetic acid

Paroxetine hydrochloride containing about 2% propan-2-ol (30.0 g) was dissolved in hot glacial acetic acid (120 mL) and part of the solvent was distilled off. Stopper the flask and allow to cool overnight. A few crystals of form A paroxetine hydrochloride anhydrate are added to the clear, slightly yellow solution to form crystallization centers, sonicated and stirred at room temperature for several hours. The mixture was left to stand for 24 hours, filtered, and the product dried in a good vacuum desiccator containing potassium hydroxide.

Yield 17.29 g.

NMR analysis indicates that the product contains 13.5% acetic acid (according to the theory, a 1: 1 solvate corresponds to 14.10%). The IR spectrum (suspension in petroleum jelly oil) of the solvate with acetic acid differs from that of paroxetine hydrochloride semi-hydrate and form A anhydrate, and has an intense band at 1705 cm ^-1 , indicating no acetic acid bound cm ' ^{1 in the} area. The powder X-ray diffraction pattern of the solvate with acetic acid also differs.

2. Preparation of paroxetine hydrochloride anhydrate (form A)

Paroxetine hydrochloride solvate with acetic acid (1.00 g) was treated with 5M hydrochloric acid (5 mL) and stirred for 5 minutes. The mixture is filtered, the solid is well dried and the crystals are dried in a good vacuum desiccator containing phosphorus pentoxide.

Yield 0.80 g.

The IR spectrum (suspension in petroleum jelly oil) confirms that the product is anhydrate form A paroxetine hydrochloride. NMR analysis indicates that the material contains about 0.4% acetic acid. Microscopic examination revealed that the material was needle-like crystal fragments.

example

Paroxetine hydrochloride anhydrate free from bound acetonitrile (form A)

1. Preparation of a paroxetine hydrochloride solvate with acetonitrile

Paroxetine hydrochloride anhydrate form A obtained in Example 1 (10.8 g) was dissolved in warm dry acetonitrile (40 ml) in a conical flask, stoppered and refrigerated for 1 hour; during this time several crystals fall out. The mixture is sonicated, placed in the refrigerator again and left overnight. The contents of the flask turn into a thick mass. The next morning, the mass is disintegrated by vigorous stirring and sonication, and the mixture is filtered. The product is dried in a good vacuum desiccator containing phosphorus pentoxide.

Yield 9.30 g, 2.5% acetonitrile (by NMR).

2. Preparation of paroxetine hydrochloride anhydrate (form A)

The paroxetine hydrochloride solvate with acetonitrile (4.23 g) was stirred in water (20.6 g) for 10 minutes. The solid is filtered off with suction, washed on the filter with water (10 mL) and dried in a vacuum oven containing phosphorus pentoxide at 50 ° C.

Yield: 3.75 g.

The IR spectrum indicates that the product is Form A paroxetine hydrochloride anhydrate.

The sample contains about 0.5% acetonitrile (by NMR)

Paroxetine hydrochloride anhydrate (Form B)

The free base paroxetine (10.0 g) was dissolved in butan-1-ol (25 mL) at room temperature and a solution of hydrogen chloride gas (1.25 g) in butan-1-ol (15 mL) was added. The clear reddish-brown solution is stoppered and kept in the refrigerator overnight. A small amount of crystalline material forms on the bottom of the flask. Ultrasonic processing is used to induce mass crystallization. The mixture was again refrigerated overnight, allowed to warm to room temperature and filtered. The product is dried in a good vacuum desiccator containing phosphorus pentoxide.

Microscopic analysis under a polarizing microscope shows that the product crystals are feather-shaped.

Melting point: 137-138 ° C.

NMR spectrum (CDCl3) is consistent with that of a standard paroxetine hydrochloride sample.

Elemental analysis corresponds to anhydrous paroxetine hydrochloride:

Calcd. For C19H21NCIFO3: C, 62.38; H, 5.79; N, 3.83;

Found: C, 62.08; H, 5.75; N, 3.81; C, 19.62%

The powder X-ray diffractogram of the material confirms that the sample is crystalline (see Figure 5). The diffractogram differs from that of the semi-hydrate as well as that of the A-form anhydrate.

The IR spectrum (suspension in petroleum jelly oil) is also different from that of the semi-hydrate and form A anhydrate (see Figure 2).

DSK exotherm measured at 10 ° C / min. has a maximum at 137 ° C in both open and closed dishes.

The ¹³ C NMR spectrum of the solid was also recorded (see Fig.8).

example

Paroxetine hydrochloride anhydrate (form C)

Paroxetine hydrochloride semi-hydrate (300 g) and toluene (1200 ml) were refluxed and the water was removed by the Din and Stark apparatus. When no more water is collected, the toluene is distilled off and anhydrous butan-1-ol is added. Distill until the distillate has a vapor temperature of 117 ° C, indicating that no toluene is present. The mixture was diluted to about 1200 ml with butan-l-ol and allowed to cool. At about 42 ° C, several crystals of Form B paroxetine hydrochloride anhydrate crystals are added to form crystallization centers. Although this causes crystallization, it has been observed that the product crystallizes in the form of nicely formed prisms, which indicates that the product crystallizes in a different form from the attached crystals.

The mixture was left overnight, then filtered. The crystals are washed on the filter with butan-1-ol, dried in vacuo at 50 ° C over phosphorus pentoxide.

Yield 250 g.

Melting point: 162-164 ° C.

NMR (CDC1 ₃₎ confirms that the product is paroxetine hydrochloride, and shows that it contains butan-l-ol in trace amounts (about 0.1%). The IR spectrum (suspension in petroleum jelly) differs from both the A and B forms (see Figure 3).

Water content 0.06% (KF).

Elemental analysis corresponds to anhydrous paroxetine hydrochloride:

Calculated for C ₁₉ H ₂ iNC ₁ FOR: C 62.38 H 5.79 N 3.83 C19.69%

Found: C, 62.23; H, 5.67; N, 3.83; C, 19.74%

DSK exotherm measured at 10 ° C / min. has a maximum at 161 ° C in both open and closed dishes.

The powder X-ray diffractogram of the material confirms that the sample is a crystalline material (see Figure 6). The diffractogram differs from the diffractograms for both Form A and Form B anhydrates.

The ¹³ C NMR spectrum of the solid was also recorded (see Fig.9).

example

Paroxetine hydrochloride anhydrate free from bound acetone (Form A)

A solvate of paroxetine hydrochloride with acetone

The free base of paroxetine (10.51 g) was dissolved in acetone (40 mL, dried on 4A molecular mesh) and a solution of gaseous hydrogen chloride (1.3 g) in dry acetone (10 mL) was added with stirring. Within one minute, self-crystallization begins and the mixture quickly becomes immiscible. After about half an hour, the product is filtered off, placed in a phosphorus pentoxide desiccator and dried at room temperature overnight.

Product weight: 11.24 g. Acetone content (by NMR) is 4%. The IR spectrum observes a characteristic band at 667 cm @ ^-1 .

About half of the product is placed in a vacuum oven at 50 ° C and further dried to constant weight. NMR analysis of the product obtained shows 1.2% acetone.

2. Paroxetine hydrochloride anhydrate (form A)

A sample of the solvate (5.18 g) in acetone was stirred in water (20 mL) for 10 min, filtered and dried in a vacuum oven with phosphorus pentoxide at 50 ° C.

Product weight: 4.63 g. NMR analysis indicates 0.6% acetone. The IR spectrum corresponds to that of paroxetine hydrochloride Form A anhydrate and has a characteristic band at 665 cm @ ^-1 .

example

Paroxetine hydrochloride anhydrate, free from bound ethanol (form A)

A solvate of paroxetine hydrochloride with ethanol

The free base of paroxetine (11.25 g) was dissolved in absolute ethanol (40 ml) and a solution of hydrogen chloride gas (1.9 g) in absolute ethanol (20 ml) was added with stirring. After 10 min of crystallization, no crystalline crystals were added to form the clear solution of paroxetine hydrochloride anhydrate form A to form crystallization centers. After 30 minutes crystallization still did not begin. Then half the solution is evaporated under reduced pressure and the same crystals are added again. Slow crystallization is now observed and the mixture is left to stand for another hour. The resulting crystalline mass is dried at room temperature in a vacuum desiccator containing phosphorus pentoxide.

Product weight: 11.87 g. The ethanol content (by NMR) is 4%. The IR spectrum has a characteristic band at 667 cm ^-1 .

A small sample was placed in a vacuum oven at 50 ° C and further dried. NMR analysis of the product obtained indicates 0.7% ethanol. The IR spectrum corresponds to that of Form A paroxetine hydrochloride anhydrate and has a characteristic band at 665 cm @ ^-1 .

2. Paroxetine hydrochloride anhydrate (form A)

A sample of the solvate (5.3 g) in ethanol was stirred in water (20 mL) for 10 minutes, filtered and dried overnight at room temperature in a phosphorus pentoxide desiccator.

Product weight: 4.56 g. NMR analysis indicates that it contains less than 0.4% ethanol. The IR spectrum is consistent with that of paroxetine hydrochloride anhydrate form A and has a characteristic band at 665 cm @ ^-1 .

example

Paroxetine hydrochloride anhydrate free from bound chloroform (Form A)

A solvate of paroxetine hydrochloride with chloroform

The free base of paroxetine (8.54 g) is dissolved in chloroform, and a solution of gaseous hydrogen chloride (1.05 g) in chloroform (10 ml) is added with stirring. After 5 minutes of crystallization, no small amount of crystalline crystals of form A paroxetine hydrochloride anhydrate is added to the clear solution. After 15 minutes, crystallization still does not begin. Then hydrogen chloride gas is added to the solution until the orange color disappears. After one hour very slow crystallization can be observed and large, visible, needle-like crystals are formed. The mixture was left to crystallize in a stoppered flask for an additional hour, then filtered and dried at room temperature in a vacuum desiccator containing phosphorus pentoxide.

Product weight: 5.65 g. Chloroform content (by NMR) is 12.5%. The IR spectrum has a characteristic band at 667 cm ^-1 .

Place a small sample in a vacuum oven at 50 ° C and continue to dry. NMR analysis of the product obtained shows 3.4% chloroform.

2. Paroxetine hydrochloride anhydrate (form A)

A sample of chloroform solvate (2.0 g) containing 12.5% chloroform was stirred in water (8 ml) for 10 minutes, filtered and dried overnight in a vacuum oven at 50 ° C.

Product weight: 1.09 g. NMR analysis indicates that it contains about 0.8% chloroform. The IR spectrum is consistent with that of paroxetine hydrochloride anhydrate form A and has a characteristic band at 665 cm @ ^-1 .

example

Paroxetine hydrochloride anhydrate (form C)

Dissolve the free base of paroxetine (8.5 g) in ethyl acetate (40 ml) and add gaseous hydrogen chloride until the weight of the solution flask is 1.1 g. After 15 minutes, crystallization is not observed, and so form A crystals of paroxetine hydrochloride form A are added to the clear solution to form crystallization centers. After stirring for another hour, signs of very slow crystallization may be observed. After stirring the mixture overnight in a sealed flask, the product crystallized, then filtered and dried at room temperature in a vacuum desiccator containing phosphorus pentoxide.

Product weight: 7.56 g. The ethyl acetate content (by NMR) is 0.4%. The IR spectrum differs from that of paroxetine hydrochloride semi-hydrate and form A anhydrate and is consistent with that of Example 8.

example

Paroxetine hydrochloride anhydrate, propane-1-ol free (form A)

1. Preparation of a paroxetine hydrochloride solvate with propan-1-ol

The free base of paroxetine (10.6 g) was dissolved in propan-1-ol (30 ml) and hydrogen chloride gas (1.25 g) was added to the solution. The warm solution is added to form crystallization centers of paroxetine hydrochloride anhydrate form B crystals and sonicated; the pink solution rapidly crystallizes out. The slurry was diluted with propan-1-ol (25 mL), filtered, avoiding contact with atmospheric humidity, and dried in vacuo over phosphorus pentoxide.

Yield: 10.3 g.

NMR analysis indicates that the product contains about 7% propan-1-ol. The IR spectrum (suspension in petroleum jelly) indicates that the product is not in the form B and that the solvated compound has a characteristic band at 667 cm @ ^-1 . The X-ray diffraction pattern of the solvate with propan-1-ol powder is different.

2. Preparation of paroxetine hydrochloride anhydrate (form A)

Paroxetine hydrochloride solvate with propan-1-ol (5.24 g) was stirred in water (25 mL) for 10 min. The mixture was filtered and the product was washed with water (10 mL). The crystals were dried under high vacuum over phosphorus pentoxide at 50 ° C.

Yield 4.35 g.

The IR spectrum (suspension in petroleum jelly) confirms that the product is an anhydrate form A, NMR analysis indicates that it contains about 0.25% propan-1-ol.

example

Paroxetine hydrochloride anhydrate (form D)

1. Preparation of a solvate of paroxetine hydrochloride with toluene

Paroxetine hydrochloride semi-hydrate (100 g) was stirred and refluxed in toluene (1000 mL) and the water removed using a Din and Stark apparatus. The solution is allowed to cool, added to form crystallization centers of paroxetine hydrochloride anhydrate form A, and sonicated. Crystallization does not begin, but after stirring at room temperature for 40 minutes, the contents of the flask suddenly turn into a thick mass. The product is filtered off and dried under vacuum over phosphorus pentoxide.

Product NMR analysis indicates that it contains about 10% toluene. The toluene solvate gives a different IR spectrum with a characteristic band at 672 cm @ ^-1 .

This procedure was repeated by adding a solvate with toluene to form crystallization centers and the product was dried under vacuum over phosphorus pentoxide.

The yield of the solvate with toluene was 106.7 g.

Product NMR analysis indicates that it contains about 10% toluene. The product powder gives a different X-ray diffractogram.

2. Desolvation of toluene-containing solvate

The solvate with toluene (20.0 g) was heated at 80 ° C for 18 hours under vacuum over phosphorus pentoxide. NMR analysis indicates that the product contains about 0.3% toluene.

Water content: 0.08% (KF).

Melting point: about 125 ° C.

example

Paroxetine hydrochloride anhydrate, free from bound tetrahydrofuran (Form A)

A solvate of paroxetine hydrochloride with tetrahydrofuran

The free base of paroxetine (10.26 g) was dissolved in dry tetrahydrofuran (35 mL) and a solution of gaseous hydrogen chloride (1.3 g) in dry tetrahydrofuran (15 mL) was added with vigorous stirring. After a short time, the solution remains clear, followed by rapid crystallization, and within minutes the solution becomes immiscible. After another half hour, the product is filtered off and dried at room temperature in a vacuum desiccator containing phosphorus pentoxide.

Product weight: 12.31 g. The tetrahydrofuran content (by NMR) is 11.4%. The characteristic spectrum of the solvate at 667 cm ^{-1 is} observed in the IR spectrum.

Place a small sample in a vacuum oven at 50 ° C and dry over the weekend. NMR analysis of the resulting product shows that it contains 1.3% tetrahydrofuran.

2. Paroxetine hydrochloride anhydrate (form A)

A sample (5.0 g) of the solvate with tetrahydrofuran containing 11.4% tetrahydrofuran was stirred in water (20 ml) for 10 minutes, filtered and dried in a vacuum oven at 50 ° C.

Product weight: 3.79 g. NMR analysis indicates that it contains about 0.02% tetrahydrofuran. The IR spectrum is consistent with that of paroxetine hydrochloride anhydrate form A and has a characteristic band at 665 cm @ ^-1 .

example

Paroxetine hydrochloride anhydrate, propane-2-ol free (form A)

Paroxetine hydrochloride solvate with propan-2-ol (70 mg, containing 11.6% propan-2-ol) (Examples 2 or 3) was treated with a stream of carbon dioxide (3 mL / min, 55 ° C and 2500 psi). After 30 minutes, the propan-2-ol content is reduced to 5.2%, and after a further 120 minutes, it is further reduced to 0.4%. The temperature is then raised to 75 ° C and the propan-2-ol content found after 30 minutes is 0.13%. After another 60 minutes at 75 ° C, propan-2-ol was 0.07%.

In a separate experiment, 70 mg of the propan-2-ol solvate was exposed to carbon dioxide (3 mL / min, 75 ° C and 2500 psi). After 150 minutes, the propan-2-ol content is 0.19%.

The experiment was repeated with a larger sample of the solvate (350 mg) under the same conditions and after 150 min. the propan-2-ol content was found to be 0.16%.

example

Crystallization of C-form paroxetine hydrochloride anhydrate from 2-butanone with addition of crystallization centers

Paroxetine hydrochloride anhydrate form C (7.0 g) is heated to boiling in anhydrous 2-butanone (40 ml) and the solution is allowed to cool to about 40 ° C. A small amount of C-shaped crystals is added to form the crystallization centers, and the stirred mixture is allowed to cool to room temperature. The product was filtered off, washed with anhydrous 2-butanone (20 mL) and dried in an oven at 100 ° C.

Weight of dried product 5.95 g.

Melting point: 162-163 ° C.

The IR spectrum (suspension in petroleum jelly oil) is in agreement with that of the C-form paroxetine hydrochloride anhydrate.

example

Crystallization of paroxetine hydrochloride from toluene with addition of material to form crystallization centers

Dissolve the form C paroxetine hydrochloride anhydrate (20.0 g) in boiling toluene (200 ml) and transfer the solution into approximately 50 ml in a 4-conical flask. Reheat each flask to boiling point, allowing a certain amount of toluene to evaporate to remove crystalline particles. Immediately stopper the flask 1 and allow to cool. The remaining flasks are covered with foil, allowed to cool slightly and added to form crystallization centers:

to flask 2, paroxetine hydrochloride solvate with toluene; to flask 3, paroxetine hydrochloride anhydrate form B; to flask 4, form C paroxetine hydrochloride anhydrate.

The added crystals remain undissolved. Stopper the flasks, mix gently for several seconds and allow to cool. It is observed that in flask 2 crystallization proceeds very fast and in flasks 3 and 4 it is much slower. At the same time, the solution of the flask 1 remains completely clear. All 4 flasks are left at room temperature overnight. The next morning, flask 1 contains only a few crystals, whereas flasks 2, 3, and 4 contain many crystals.

Stir flask 1 gently for several hours; during this time most of the paroxetine hydrochloride is crystallized.

The product of each flask was filtered and dried at 50 ° C under vacuum.

Flask 1 a (not added to form crystallization centers):

Product weight: 4.25 g;

Appearance: short needles / sticks;

IR spectrum: coincides with spectrum of paroxetine hydrochloride anhydrate form C;

Lyd. mp: 161-162 ° C.

Flask 2- a (crystals of solvate with toluene added):

Product weight: 3.80 g;

Appearance: long thin needles;

IR spectrum: coincides with that of paroxetine hydrochloride solvate with toluene;

Solvent content: 11% toluene (by NMR);

Lyd. temp .: initially melts at about 70 ° C, then hardens and melts again at 161-162 ° C.

Flask 3a (anhydrate crystals of form B added):

Product weight: 4.20 g;

Appearance: Needles;

IR spectrum: coincides with the spectrum of paroxetine hydrochloride anhydrate form B;

Solvent content: 0.8% toluene (by NMR);

Lyd. 138-140 ° C.

Flask 4 (anhydrate crystals of form C added):

Product Weight: 4.93 g;

Appearance: Needles;

IR spectrum: coincides with spectrum of paroxetine hydrochloride anhydrate form C;

Solvent content: 0.8% toluene (by NMR);

Lyd. mp: 161-162 ° C.

example

Crystalline paroxetine hydrochloride anhydrate, propane-2-ol free (form A)

A solution of paroxetine hydrochloride with propan-2-ol in 2.6% propan-2-ol and dried in a vacuum oven (1 g) was placed in a glass tube. Immerse the tube in a waterbath at 50 ° C and pass through the sample with nitrogen saturated with water vapor at 40 ° C. After 10 hours, a small amount of material was removed and analyzed by NMR, which showed a propan-2-ol reduction to 2.0%. The temperature of the bath surrounding the tube is increased to 80 ° C and the temperature of the gas introduced through the sample is raised to 70 ° C. After 10 hours, a sample is withdrawn from the tube and analyzed by NMR, which indicates that the propan-2-ol content has further decreased to 1.0%.

example

Paroxetine hydrochloride anhydrate free from bound acetone (Form A)

1. Preparation of a paroxetine hydrochloride solvate with acetone

A suspension of form C (prism) paroxetine hydrochloride anhydrate (5.0 g) in acetone (75 mL) is heated to reflux and many fine needles are formed. Stopper the flask and leave at room temperature overnight. The solvent was evaporated at low temperature on a rotary evaporator and hexane (100 mL) was added. The solvent was evaporated again at low temperature to give a crystalline solvate with acetone. NMR analysis indicates that it contains acetone (12.2%) and the IR spectrum (suspension in petroleum jelly) shows characteristic bands at 667 and 1714 cm ^-1 .

2. Preparation of paroxetine hydrochloride anhydrate (form A) from a solvate with acetone

Form C paroxetine hydrochloride (5.3 g) is converted into solvates with acetone according to the procedure described above. Water (50 mL) is added and the resulting suspension is gently shaken for 10 minutes. The white solid was filtered off, well dried and dried in a vacuum oven at 50 ° C. Yield 4.60 g. The acetone content is 0.1% (by NMR). The IR spectrum (suspension in petroleum jelly) is in agreement with that of the standard sample of paroxetine hydrochloride anhydrate, form A.

example

Paroxetine hydrochloride anhydrate (form D)

1. Preparation of a solvate of paroxetine hydrochloride with toluene

The anhydrous paroxetine hydrochloride solution in toluene is prepared by refluxing a mixture of paroxetine hydrochloride semi-hydrate and toluene in a Din and Stark apparatus until no more water is collected. This solution is cooled and crystalline crystallization centers of paroxetine hydrochloride solvate with toluene are added. The product is filtered off, washed with toluene and dried in a vacuum oven at 50 ° C. NMR analysis indicates that it contains 18% toluene. IR spectra recorded at 22 ° C on a Perkin-Elmer 1720Χ FT-IR spectrometer coupled to a Spectra-Tech IRPlan microscope are shown in Fig. 10A and 10B.

2. Preparation of paroxetine hydrochloride anhydrate form D

A small sample of paroxetine hydrochloride solvate with toluene (18% toluene) is heated at 80 ° C and the resulting paroxetine hydrochloride anhydrate form D is analyzed by IR-microspectrometry using a Perkin-Elmer 1720Χ FT-IR spectrometer coupled to a Spectra-Tec IR-Plan microscope. The IR spectra obtained are shown in Figures IIIA and 11B.

Claims (2)

Definition of the Invention 1. Paroxetine hydrochloride anhydrate, free from propan-2-ol bound. 2. Paroxetine hydrochloride anhydrate, free of bound organic solvent. 3. Paroxetine hydrochloride anhydrate, free from bound propan-2-ol, characterized in that it is other than Form Z. 4. Solvates of paroxetine hydrochloride except for the solvate with propan-2-ol. 5. The solvates of paroxetine hydrochloride according to claim 4, wherein the bonded solvents are selected from the group consisting of alcohols (except propan-2-ol), organic acids, organic bases, nitriles, ketones, ethers, chlorinated hydrocarbons and hydrocarbons. 6. The paroxetine hydrochloride solvate of claim 4, wherein the coupled solvent is selected from the group consisting of propan-1-ol, ethanol, acetic acid, pyridine, acetonitrile, acetone, tetrahydrofuran, chloroform, and toluene. 7. Paroxetine hydrochloride anhydrate free from bound propan-2-ol according to claim 1, characterized in that it is completely pure. 8. Paroxetine hydrochloride anhydrate according to claim 1, characterized in that it is in the form of A, characterized in that it has a melting point of 123125 ° C; has intense IR spectral bands at 513, 538, 571, 592, 613, 665, 722, 761, 783, 806, 818, 839, 888, 906, 924, 947, 966, 982, 1006, 1034, 1068, 1091 , 1134, 1194, 1221, 1248, 1286, 1340, 1387, 1493, 1513, 1562, 1604, 3402, 3631 cm ^-1 ; her DSK exotherm measured at 10 ° C / min. has a maximum at 126 ° C for an open dish and 121 ° C for a closed dish; its X-ray diffractogram has characteristic peaks at 6.6, 8.0, 11.2, 13.1 at 20 degrees, and the solid-phase NMR spectrum has characteristic peaks at 154,3,149,3,141,6, 138.5 md 9. Paroxetine hydrochloride anhydrate according to claim 1, characterized in that it is in the form B, characterized in that it has a melting point of about 138 ° C; has intense IR bands at 538, 574, 614, 675, 722, 762, 782, 815, 833, 884, 925, 938, 970, 986, 1006, 1039, 1069, 1094, 1114, 1142, 1182, 1230, 1274 , 1304, 1488, 1510, 1574, 1604, 1631 cm ^-1 ; her DSK exotherm measured at 10 ° C / min. has a maximum at 137 ° C in both open and closed panes; its X-ray diffractogram has characteristic peaks at 5.7, 11.3, 12.4, 14.3 at 20 degrees, and the solid-phase NMR spectrum has characteristic peaks at 154,6,148,3,150,1,141,7,142,7,139,0 md 10. Paroxetine hydrochloride anhydrate according to claim 1, characterized in that it is in the form of C, characterized in that it has a melting point of about 164 ° C; has intense IR bands at 540, 574, 615, 674, 720, 760, 779, 802, 829, 840, 886, 935, 965, 984, 1007, 1034, 1092, 1109, 1139, 1183, 1218, 1240, 1263 , 1280, 1304, 1507, 1540, 1558, 1598, 1652 cm ^-1 ; her DSK exotherm measured at 10 ° C / min. has a maximum at 161 ° C in both open and closed panes; its X-ray diffraction pattern has characteristic maxima at 10.1, 12.1 13.1 14.3 at 20 degrees, and the solid-phase NMR spectrum has characteristic peaks at 154,0,148,5,143,4,140,4 md 11. Paroxetine hydrochloride anhydrate according to claim 1, characterized in that it is in the form of D, characterized in that it is a semi-crystalline solid with a melting point of about 125 ° C when made from a solvate with toluene as starting material that has intense bands in the IR spectrum at 1631, 1603, 1555, 1513, 1503, 1489, 1340, 1275, 1240, 1221, 1185, 1168, 1140, 1113, 1101, 1076, 1037, 1007, 986, 968, 935, 924, 885, 841, 818, 783, 760, 742, 720, 698, 672, 612, 572, 537 and 465 cm ^-1 and characteristic X-ray diffraction peaks at 7.2, 9.3, 12.7 and 14.3 20 degrees. 12. Paroxetine hydrochloride anhydrate according to claim 8, characterized in that it is a needle-like crystal. 13. Paroxetine hydrochloride anhydrate according to claim 9, characterized in that it is a needle-like crystal. 14. Paroxetine hydrochloride anhydrate according to claim 10, characterized in that it is in the form of needles or prisms. A compound according to any one of claims 1 to 3 wherein it is selected from the group consisting of: crystalline paroxetine hydrochloride anhydrate free from bound pyridine (form A), paroxetine hydrochloride anhydrate free from bound acetic acid (form A), paroxetine hydrochloride anhydrate free from bound acetonitrile (form A), paroxetine hydrochloride anhydrate (form B), paroxetine hydrochloride anhydrate (form C), paroxetine hydrochloride anhydrate free from bound acetone (form A), paroxetine hydrochloride anhydrate free from ethanol bound (form A) ), paroxetine hydrochloride anhydrate free from bound chloroform (form A), paroxetine hydrochloride anhydrate free from bound propan-1-ol (form A), paroxetine hydrochloride anhydrate (form D), and paroxetine hydrochloride anhydrate free from bound tetrahydrofuran (form A). 16. A process for the preparation of paroxetine hydrochloride anhydrate, free from propan-2-ol, comprising the crystallization of paroxetine hydrochloride from: (1) an organic solvent or mixture of organic solvents which forms a solvate with paroxetine hydrochloride and which is not removed by conventional drying techniques; or 2) an organic solvent or mixture of organic solvents, whether or not forming a solvate with paroxetine hydrochloride, but which is removed by conventional vacuum oven drying; then, in the first case, the bound solvent or solvents are ejected using the ejection agent, and in the second case, the solvent is removed. 17. A process for the preparation of solvates of paroxetine hydrochloride, except for the solvate with propan-2-ol, characterized in that the paroxetine hydrochloride is crystallized from an organic solvent or mixture of solvents which forms a solvate with paroxetine hydrochloride which is not removed by conventional drying techniques. 18. A process for preparing paroxetine hydrochloride anhydrate which is free of bound organic solvent by removing the bound solvent or solvents from the paroxetine hydrochloride solvate using a displacement agent.