ITMI20132114A1 - A CRYSTAL SHAPE OF POSACONAZOLO - Google Patents

Description

Title: "A crystalline form of Posaconazole"

Description

The subject of the present invention is a new crystalline form of Posaconazole, called Form A having new and distinctive chemical-physical characteristics described herein, as well as a pharmaceutical composition that includes it. A further object of the present invention is a process for the preparation of said Posaconazole, Form A. Posaconazole is also claimed, an amorphous solid obtained from Posaconazole, Form A.

State of the art

Posaconazole (CAS Registry Number 171228-49-2), represented by the formula (I) below, is known as an antifungal agent.

Chemical name of Posaconazole of formula (I) is 2,5-anhydrous-1,3,4-trideoxy-2-C- (2,4-difluorophenyl) -4 - [[4- [4- [4- [1 - [(1S, 2S) -1-ethyl-2-hydroxypropyl] -1,5-dihydro-5-oxo-4H-1,2,4-triazol-4-yl] phenyl] -1piperazinyl] phenoxy] methyl] -1- (1H-1,2,4-triazol-1-yl) -D-threo-pentitol.

WO95 / 17407 and WO 96/38443 describe a compound of formula (I) and its use in the treatment of fungal infections.

Three polymorphic forms of Posaconazole, Form I, II and III are described and characterized in WO 99/18097.

WO 10/000668 describes a further crystalline form, Posaconazole, Form IV.

A further form of Posaconazole, Form V, is described in WO 11/158248.

There is a need for alternative forms of Posaconazole which are more stable when used in pharmaceutical compositions and / or which have advantageous properties for their preparation and storage.

The physical properties of an active substance in the solid state are fundamental for the management of the material during transformation into a pharmaceutical product. The flow properties are highlighted in particular, as well as the dissolution rate in an aqueous liquid. Dissolution in water is particularly critical for Posaconazole, being a strongly lipophilic base. The dissolution rate in aqueous liquid influences the dissolution rate of the active ingredient in the stomach of a patient with evident therapeutic consequences. The dissolution rate must also be taken into strong consideration in the formulation of syrups, elixirs and other liquid medicaments. These and other physical characteristics are influenced by the conformation and orientation of the molecules in the unit cell, which defines a particular polymorphic form of a substance. The polymorphic form can give rise to a different thermal behavior from that of the amorphous material or another polymorphic form. The thermal behavior is measured in the laboratory with techniques such as the capillary melting point, thermo gravimetric analysis (TGA) and differential scanning calorimetry (DSC) and can be used to distinguish some polymorphic forms from others. A particular polymorphic form can also give rise to distinct spectroscopic properties, detectable with X-ray crystallography, NMR spectrometry and infrared spectrometry.

The discovery of new forms of Posaconazole provides a new opportunity to improve the synthesis process of the active pharmaceutical ingredient (API), leading to a form of Posaconazole with improved characteristics, for example in terms of fluidity and solubility, which are noticeable. in the state of the art.

Here a new crystalline form of Posaconazole, having distinctive and advantageous chemical-physical characteristics, Posaconazole Form A, is prepared, described and characterized for the first time.

Description of the invention

The purpose of the present invention is to make available a new crystalline form of Posaconazole.

A more complete understanding of the present invention can be obtained by referring to the summary tables of some chemical-physical characteristics of Posaconazole, Form A reported below.

The main peaks of X-ray diffraction, the main bands and characteristics of the FT-IR spectrum, differential scanning thermal analysis (DSC), thermo gravimetric analysis, evolved gas analysis (EGA), absorption measurements are reported. / desorption of moisture administered by gas flow (DVS).

The X-ray powder diffractogram (XRPD) was obtained using the X'Pert PRO PANalytical instrument equipped with X'Celerator detector and X-ray tube (Cu LFF PW3373 / 00 DK312503) with 40mA current intensity and 40kV voltage. The sample is placed on a support and analyzed using the following parameters:

- Scanning range (°): 3.0010-39.9997

- Step size (°): 0.0167

- Scan mode: continuous

- Counting time (s): 12,700

- Soller slot (rad): 0.04

- Diverging slot: 1/4

- Antiscatter slot: 1/2

The FT-IR spectrum (Fourier transform IR spectroscopy) was recorded using the Nicolet FT-IR 6700 (ThermoFischer) apparatus equipped with a KBr splitter and a DTGS KBr detector. The spectrum was acquired in 16 scans at a resolution of 4 cm <-1>.

The DSC analyzes were obtained by using a DSC 200 F3 Maia® differential scanning calorimeter. The samples were loaded on aluminum crucibles and heated to 350 ° C at one. heating rate of 10K / min.

Sensor: heat flow system.

Measurement range from 0 mW to ± 600 mW.

Temperature accuracy: 0.1K

Enthalpy accuracy: generally <1%

Cooling options: forced air (down to room temperature), liquid nitrogen (down to -170 ° C) Purge gas flow: 60ml / min

The thermograms were obtained using a Mettler Toledo Stare System thermobalance. The samples were loaded on aluminum crucibles and heated to 460 ° C at a heating rate of 10 K / min.

Temperature accuracy ± 1 K.

Temperature accuracy ± 0.4 K.

Cooling time 20 min (1100 to 100 º C).

Sample volume ≤ 100 l.

Description of the figures

Figure 1: XRPD spectrum of Posaconazole, Form A.

Figure 2: FT-IR spectrum of Posaconazole, Form A.

Figure 3: DSC analysis of Posaconazole, Form A.

Figure 4: TGA analysis of Posaconazole, Form A.

Figure 5: EGA analysis of Posaconazole, Form A.

Figure 6: comparison between the absorption profile of the gas released at about 50 ° C by Posaconazole, Form A and the water profile as available in the database.

Figure 7: DVS analysis of Posaconazole, Form A.

Figure 8: XRPD analysis of the powder obtained after DVS analysis compared with Posaconazole Form A and Form I.

Figure 9: XRPD analysis of the wet and dry sample.

Figure 10: XRPD analysis of the wet and dry sample.

Figure 11: XRPD analysis of the wet and dry sample.

Figure 12: XRPD analysis of the wet and dry sample.

Figure 13: XRPD analysis of the wet and dry sample.

Figure 14: XRPD analysis of the wet and dry sample.

Figure 15: XRPD analysis of the wet and dry sample.

Figure 16: XRPD analysis of the wet and dry sample.

Figure 17: XRPD analysis of the wet and dry sample.

Figure 18: comparison between the XRPD patterns of the samples obtained in examples A to I and the reference Form A.

Figure 19: XRPD spectrum of Posaconazole, low crystallinity form.

Figure 20: XRPD spectrum of Posaconazole, amorphous solid. Detailed description of the invention:

Posaconazole Form A of the present invention is characterized by the following chemical-physical parameters.

The XRPD analysis leads to obtaining the characteristic spectrum shown in Figure 1. The main peaks at 2theta / - 0.3 degrees are: 4.3, 6.3, 9.3, 12.7, 15.4, 16 , 8, 17.8, 18.1, 18.7, 20.7, 23.1, 26.4. Table 1 below shows the significant peaks of the spectrum.

Table 1:

FT-IR analysis gives the spectrum shown in Figure 2. Said FT-IR spectrum is characterized by the peaks shown in Table 2 below.

Table 2:

The DSC analysis, shown in Figure 3, highlights a first endothermic event at about 50 ° C, associated with the loss of water, an endothermic peak at about 98 ° C corresponding to the melting point, an exothermic peak at about 117 ° C. associated with a recrystallization event, a second endothermic peak at about 170 ° C associated with the melting.

The thermogram shown in Figure 4 shows a weight loss of about 3.6% at about 50 ° C which corresponds to the loss of water, as confirmed by the EGA analysis described below. There is also a continuous weight loss passing from about 400 ° C to about 450 ° C. The characteristic events of the measured weight loss are best observed on the DTG curve, shown on the same graph. The DTG curve represents the derivative of the thermogram and allows to observe events at about 170 ° C and about 410 ° C, associated with the degradation of the sample following heating.

To better characterize the events observed with the thermo-gravimetric analysis, an analysis of evolved gases (EGA) was carried out, the results of which are shown in Figure 5. Comparing the absorbance of the gas emitted by the EGA analysis at the weight loss observed at about 50 ° C with the absorbance profile of water as available in the database, see Figure 6, it is confirmed that the weight loss observed at about 50 ° C for Posaconazole, Form A is attributable to water loss.

Finally, DVS analysis was conducted. A sample of Posaconazole, Form A was introduced into a DVS chamber at 25 ° C and subjected to gradual hydration from 40 to 90% RH. The sample, as shown in Figure 7, shows a hydration phenomenon with about 1.75% weight variation at 90% RH, 25 ° C. Water is lost dropping from 90 to 9% RH and only partially regained when the system returns from 0 to 40%. The XRPD analysis shows that the powder is a mixture of Form A (hydrated) and form I (anhydrous), as shown in Figure 8.

Said crystalline form claimed herein is obtained starting from Posaconazole Form I, as described in WO9918097A1.

A further object of the present invention is the process for the preparation of said Form A of Posaconazole. Said process provides for the use of Posaconazole, Form I, as described in the state of the art referred to in the above description, and includes a precipitation mediated by the addition of antisolvent at a temperature above the ambient temperature followed by cooling and short shaking. In particular, said process comprises: i) resuspending Posaconazole Form I in a suitable solvent;

ii) heating while stirring at a suitable temperature until a clear solution is obtained;

iii) adding a suitable antisolvent in a suitable ratio with said solvent;

iv) cooling, while stirring, the solution obtained in iii) to room temperature;

v) stirring the solution obtained in iv) at a suitable temperature and time;

vi) filtering the mixture obtained in iv) so as to isolate the precipitate;

vii) drying the precipitate at a suitable temperature.

In a preferred embodiment, said step ii) occurs at a temperature of about 35-40 ° C and said solvent is acetone. In said step iii), said antisolvent is water and the water / acetone ratio is 3/1 volume / volume. In said step v), the suspension is kept under stirring for about 1 hour, preferably at room temperature.

The product obtained is Posaconazole, Form A claimed in the present invention.

A further object of the present invention is the process for obtaining Posaconazole, an amorphous solid, starting from said Posaconazole, Form A.

This process includes:

i) keep in vacuum at room temperature for at least 3 hours, or for 6 hours, or for about 18 hours Posaconazole, Form A;

ii) bring the product resulting from step i) to a temperature between 35 and 50 ° C, or between 37 and 45 ° C, or between 38 and 43 ° C, preferably at about 40 ° C under vacuum, where said conditions are maintained for at least 30 minutes, or for at least 60 minutes, preferably for about 90 minutes.

The resulting product is Posaconazole, an amorphous solid having the XRPD spectrum shown in Figure 20. Table 3 below shows the significant peaks of the spectrum.

Table 3:

Said crystalline form and said amorphous solid of Posaconazole can find application in pharmaceutical compositions. The pharmaceutical composition that includes said crystalline form and / or said amorphous solid may contain additives such as sweeteners, flavors, coating substances, inert diluents such as lactose and talc, binders such as starch, hydroxyethyl cellulose, hydroxypropyl cellulose and analogues. Any conventional technique can be used for the preparation of pharmaceutical formulations according to the present invention.

EXAMPLES

Example 1: Preparation of Posaconazole, Form A, laboratory scale.

378 mg of Posaconazole, Form I was loaded into a flask. Increasing quantities of acetone were added under stirring at room temperature until complete dissolution of the solid to check the saturation concentration. A total amount of 16.5ml was added, which corresponds to a concentration of approximately 23g / l.

16.5 ml of water was added as antisolvent (1/1 v / v) under stirring in about 10 seconds. The formation of the precipitate was almost immediate. The suspension was filtered under vacuum, washed with 10 ml of water and then the solid was analyzed by XRPD. The analysis led to the diffraction pattern of Form A (Figure 9). The solid on the filter was allowed to dry at room temperature and pressure for about 3 hours. About 350 g of hydrate were obtained.

Example 2: Preparation of Posaconazole, Form A.

2.3 g of Posaconazole, Form I was loaded into a 250 ml reactor with 100 ml of acetone. The suspension was kept under stirring (150 rpm) at 25 ° C. After an hour the powder was not completely dissolved. The reactor was heated to 35 ° C thus obtaining complete dissolution. 100 ml of water were added as antisolvent (1/1 v / v) under stirring in about 2 minutes (3 L / h). The formation of the precipitate was almost immediate. In a few seconds the reactor was packed with the solid, for this reason the stirring was brought to 200 rpm. The suspension was cooled to 20 ° C in one hour: the stirring was not able to move the solid present in the upper portion of the reactor. The reactor was then discharged of the suspension and washed three times with water using 100 ml at each wash. The suspension was filtered under vacuum for 10 minutes. The solid was analyzed by XRPD immediately after filtration (“wet”) and after drying at ambient temperature and pressure (“dry”). The analysis led to the diffraction pattern shown in Figure 10. About 2.4 g of hydrate were obtained.

Example 3: Preparation of Posaconazole, Form A.

1.5 g of Posaconazole, Form I was loaded into a 250 ml reactor with 100 ml of acetone. The suspension was kept under stirring (150 rpm) at 25 ° C. After an hour the solution was completely clear. 100 ml of water were added as antisolvent (1/1 v / v) under stirring in about 2 minutes (3 L / h). The formation of the precipitate was almost immediate. The suspension was left under stirring for about an hour at 25 ° C, after which the reactor was discharged of the suspension by washing with 50 ml of water. The suspension was filtered under vacuum for 10 minutes. The solid was analyzed by XRPD immediately after filtration (“wet”) and after drying at ambient temperature and pressure (“dry”). The analysis led to the diffraction pattern shown in Figure 11. About 1.46 g of hydrate were obtained.

Example 4: Preparation of Posaconazole, Form A.

The experiment reported in example 3 was repeated maintaining the same conditions reported in example 3, except for the reactor washing, carried out here with 70 ml of water instead of 50 ml. The solid was analyzed by XRPD immediately after filtration (“wet”) and after drying at ambient temperature and pressure (“dry”). The analysis led to the diffraction pattern shown in Figure 12. About 1.3 g of hydrate were obtained.

Example 5: Preparation of Posaconazole, Form A.

The experiment reported in example 3 was repeated maintaining the same conditions reported in example 3, varying here the speed of adding the antisolvent. 100 ml of water were added under stirring in about 30 seconds (about 12 L / h).

The solid was analyzed by XRPD immediately after filtration (“wet”) and after drying at ambient temperature and pressure (“dry”). The analysis led to the diffraction pattern shown in Figure 13. About 1.3 g of hydrate were obtained.

Example 6: Preparation of Posaconazole, Form A, scale up.

15 g of Posaconazole, Form I was loaded into a 2 L reactor with 1 L of acetone. The suspension was kept under stirring (150 rpm) at 25 ° C. After 15 min the solution was completely clear. 1 L of water was added as antisolvent (1/1 v / v) under stirring in about 20 minutes (3 L / h). The formation of the precipitate was almost immediate. The suspension was left under stirring for about an hour at 25 ° C, after which the reactor was discharged of the suspension by washing with 200 ml of water. The suspension was filtered under vacuum for one hour. The solid was analyzed by XRPD immediately after filtration (“wet”) and after drying at ambient temperature and pressure (“dry”). The analysis led to the diffraction pattern shown in Figure 14. About 13.8 g of hydrate were obtained.

Example 7: Preparation of Posaconazole, Form A, process optimization.

1.5 g of Posaconazole, Form I was loaded into a 250 ml reactor with 50 ml of acetone. The reactor was heated to 35 ° C so as to obtain a complete dissolution, maintaining a stirring of 150 rpm. 150 ml of water were added as antisolvent (3/1 v / v) under stirring in about 3 minutes (3 L / h). After the addition, the formation of the precipitate was observed and the stirring was brought to 200 rpm. The suspension was cooled to 25 ° C in 20 minutes (0.17 ° C / min) and kept under stirring for about one hour, after which the reactor was drained of the suspension by washing twice using 50 ml of water for each wash. . The suspension was filtered under vacuum for 10 minutes. The solid was analyzed by XRPD immediately after filtration (“wet”) and after drying at ambient temperature and pressure (“dry”). The analysis led to the diffraction pattern shown in Figure 15. About 1.5 g of hydrate were obtained.

Example 8: Preparation of Posaconazole, Form A, scale up process optimized.

15 g of Posaconazole, Form I was loaded into a 2 L reactor with 500 ml of acetone. The reactor was heated to 40 ° C so as to obtain a complete dissolution. 1500 ml of water were added as antisolvent (3/1 v / v) under stirring in about 6 minutes (15 L / h). After the addition, the formation of the precipitate was observed and the stirring was brought to 200 rpm. The suspension was cooled to 25 ° C in 90 minutes (0.17 ° C / min) and kept under stirring for about 2 hours, after which the reactor was discharged of the suspension by washing with 500 ml of water. The suspension was filtered under vacuum for 30 minutes. The solid was analyzed by XRPD immediately after filtration (“wet”) and after drying at ambient temperature and pressure (“dry”). The analysis led to the diffraction pattern shown in Figure 16. About 15.4 g of hydrate were obtained.

Example 9: Preparation of Posaconazole, Form A, optimized scale up process.

30 g of Posaconazole, Form I was loaded into a 5 L reactor with 1000 ml of acetone. The reactor was heated to 40 ° C so as to obtain a complete dissolution. 3000 ml of water were added as antisolvent (3/1 v / v) under stirring in about 12 minutes (15 L / h). After the addition, the formation of the precipitate was observed. The suspension was cooled to 25 ° C in 90 minutes (0.17 ° C / min) and kept under stirring for about 2 hours, after which the reactor was discharged of the suspension by washing with 1000 ml of water. The suspension was filtered under vacuum for 30 minutes. The solid was analyzed by XRPD immediately after filtration (“wet”) and after drying at ambient temperature and pressure (“dry”). The analysis led to the diffraction pattern shown in Figure 17. Approximately 31.7 g of hydrate were obtained.

Summary examples 1-9

As demonstrated by the examples above, the drying process at room temperature does not induce phase transition in the samples: the weak enlargement observed suggests a slight harmophization of the sample. The speed of adding the antisolvent does not affect the crystallization process and is therefore not to be considered a critical parameter.

On the other hand, the concentration of Posaconazole, Form I, although not to be considered problematic for the polymorphism, has been observed to heavily affect the workability of the suspension, given the formation of a sticky solid during precipitation. The results are summarized in Table 4 below.

Table 4:

As reported in Figure 18, all experiments conducted using the conditions claimed here resulted in the precipitation of the desired form, Posaconazole, Form A.

Example 10: Drying Posaconazole, Form A Posaconazole, Form A was kept at room temperature under vacuum. At subsequent times, the XRPD analysis was conducted in order to evaluate the degree of crystallinity. As shown in table 5 below, after 3 hours of exposure under the indicated conditions, a product with a low degree of crystallinity is obtained.

Table 5

RT = ambient temperature

SV = under vacuum

ND = not proven

The XRPD spectrum of the product obtained by maintaining Posaconazole, Form A for 18 hours at room temperature is shown in Figure 19. The peaks of the XRPD spectrum are shown in Table 6.

Table 6

Example 11: Preparation of Posaconazole, amorphous solid, starting from Posaconazole, Form A.

Posaconazole, Form A of the present invention is maintained for 18 hours under vacuum at room temperature. The product obtained has a low crystallinity, as evidenced by the XRPD spectrum in Figure 19.

The low crystallinity product is then heated to a temperature of 40 ° C and maintained at this temperature under vacuum for 90 minutes. The product obtained at the end of the further drying step is Posaconazole, an amorphous solid, characterized by the XRPD spectrum of Figure 20.

Posaconazole, Form A of the present invention is a particularly stable form, the production process of which has been implemented on a large scale while maintaining the chemical-physical characteristics of the obtained product unaltered. Therefore, Posaconazole Form A described and claimed herein is an advantageous form of Posaconazole due to the stability characteristics demonstrated. Posaconazole, Form A of the present invention also leads to the obtainment of Posaconazole, an amorphous solid when exposed to the drying conditions described and claimed herein.

Claims (11)

CLAIMS 1. A crystalline form of Posaconazole, Posaconazole Form A which has a melting point of approximately 170 ° C, characterized by the XRPD diffractogram which gives the following main peaks at 2theta / - 0.3 degrees: 4.3, 6.3 , 9.3, 12.7, 15.4, 16.8, 17.8, 18.1, 18.7, 20.7, 23.1, 26.4. 2. The crystalline form according to claim 1, characterized by the following XRPD diffractogram: The crystalline form according to one of claims 1 or 2, which is obtained from Posaconazole, Form I by precipitation mediated by the addition of antisolvent at a temperature above ambient followed by cooling and short stirring 4. A process for preparing a crystalline form of Posaconazole crystalline form which includes: i) resuspend Posaconazole Form I in a suitable solvent; ii) heating while stirring at a suitable temperature until a clear solution is obtained; iii) adding a suitable antisolvent in a suitable ratio with said solvent; iv) cooling, while stirring, the solution obtained in iii) to room temperature; v) stirring the solution obtained in iv) at a suitable temperature and time; vi) filtering the mixture obtained in iv) so as to isolate the precipitate; vii) drying the precipitate at a suitable temperature. 5. The process according to claim 4, where said step ii) takes place at a temperature of about 35-40 ° C and said solvent is acetone. 6. The process according to claim 5, where in said step iii) said antisolvent is water and the water / acetone ratio is 3/1 volume / volume. 7. The process according to claim 5, where in said step v) said stirring is maintained for about 1 hour, preferably at room temperature. 8. Process for obtaining Posaconazole, an amorphous solid, which includes: i) keep in vacuum at room temperature for at least 3 hours, or for 6 hours, or for about 18 hours Posaconazole, Form A; ii) bring the product resulting from step i) to a temperature between 35 and 50 ° C, or between 37 and 45 ° C, or between 38 and 43 ° C, under vacuum, where these conditions are maintained for at least 30 minutes, or for at least 60 minutes, preferably for about 90 minutes. 9. Posaconazole, amorphous solid, obtained according to the process of claim 8 characterized by the following XRPD spectrum: 10. Pharmaceutical compositions which comprise as the active ingredient the crystalline form of Posaconazole of any one of claims 1 to 3. 11. Pharmaceutical compositions comprising as active ingredient Posaconazole, amorphous solid of claim 9.