PROCESS FOR PREPARING DROSPIRENONE IN THE FORM OF A FINE POWDER BY DOUBLE CHANGE OF CRYSTALLINE FORM

Abstract

The present invention relates to a process for the industrial-scale preparation of γ-lactone of 17β-hydroxy-6β,7β;15β,16β-dimethylene-3-oxo-17α-pregn-4-ene-21-carboxylic acid, commonly known as drospirenone, in the form of a fine powder without using mechanical grinding or micronization techniques, but by exploiting a double change of crystalline form, from crystalline form I to crystalline form II and from crystalline form II to crystalline form I. The invention further relates to the new crystalline form II of drospirenone obtained in the process.

Description

Description Title of the invention: Process for preparing drospirenone SUB FORM of fine powder through double change of shape CRYSTALLUINE

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[0002] — The present invention relates to the field of active pharmaceutical ingredients and in particular to an industrial-scale process for the preparation of γ-lactone acid 17B-hydroxy-6p,7B;15p,16f-dimethylene-3-oxo-17a-pregn-4-ene-21-carboxylic, known by the common name drospirenone, in the form of a fine powder without using mechanical grinding or micronization techniques, but by exploiting the formation of a new solid form. The invention further relates to the new solid form of drospirenoc obtained by this process. Prior art

[0003] — Drospirenone is a steroid widely used in oral contraceptives combined (COC) and in postmenopausal hormone replacement therapy in combination with 17-P-estradiol as a progestin.

[0004] — The structural formula of drospirenone is as follows:

[0005] [Chem.1] ñ

[0006] — Drospirenone has been known in the literature since the late 1980s (J Steroid Biochem, 19(1), 771-76, 1983). To date, drospirenone is known under a unique crystalline form which presents with an octahedral habit, as shown Figure 1, and which will be defined in the following description as 'drospirenone in the form crystalline I”; the only other known solid form of the compound is the amorphous form, as indicated in Italian patent no. 1357209 B1 in the name of the present applicant.

[0007] — The advantage of using drospirenone under EP 1214076 B1 is known from EP 1214076 B1 micronized form in pharmaceutical compositions. Pharmaceutical Development and Technology vol. 9, No. 1, pages 1-13 (2004) discusses various techniques for reducing the particle size of an active pharmaceutical ingredient (API) that can be used in pharmaceutical compositions. These techniques range from mechanical milling to spray drying, crystallization with supercritical fluids, and precipitation by solvent change. The most widely used and practical technique in the pharmaceutical field is the mechanical grinding of APIs, which, however, presents a number of drawbacks, as clearly explained on page 3 of the Pharmaceutical Development and Technology article cited above. The main problem is the partial or total alteration of the crystalline structure (amorphization, transformation into different solid forms) due to the mechanical stress to which the powders are subjected during grinding / micronization.These uncontrolled changes in crystalline form are undesirable for pharmaceutical industry processes because they lead to problems of uniformity of API content in the dosage form (typically tablets) due to unpredictable mechanical interactions with excipients or the possible return over time to the initial crystalline form (when this is more thermodynamically stable), and generally to an alteration of the bioavailability of the API. The objective of the present invention is to provide a method for reducing the particle size of crystalline drospirenone in crystalline form 1 without using mechanical grinding methods. Summary of the invention This objective is achieved with the present invention, which in its first aspect consists of a process for the direct production of fine-grained drospirenone by means of a double change in crystalline form: 1) from crystalline form I to crystalline form II; and 2) from crystalline form II to crystalline form I, which includes the following steps: a) preparation of a suspension of a solid form of drospirenone in crystalline form I in a mixture of acetone and diisopropyl ether; b) cooling the suspension to a temperature equal to or less than -5 °C; c) agitation of the suspension at the temperature of point b) until the formation of acicular crystals of crystalline form II is observed; d) filtration of the suspension at a temperature equal to or less than -5 °C; e) drying of the crystalline solid obtained at a temperature above +5 °C for to obtain drospirenone in crystalline form I and with fine particle size. In a preferred embodiment, the process includes adding to the suspension in step c) a crystalline form II primer of drospirenone. In its second aspect, the invention relates to the new crystalline form II of drospirenone, produced by means of the process described above. Description of the figures The invention will be described with reference to the figures, in which: figure 1 - Figure 1 shows two photographs at different magnifications obtained by scanning electron microscopy (SEM) of drospirenone crystals of crystalline form I according to the known technique; [Fig. 2] - The [Fig. 2] shows two photographs obtained with the Particle View V19 probe, first of drospirenone ([Fig.2a]) and then ([Fig.2b]) of the transformation of crystalline form I into crystalline form II; [Fig.3] - The [Fig.3] shows the XRPD spectrum on drospirenone powder in crystalline form I; [Fig.4] - The [Fig.4] shows the XRPD spectrum on drospirenone powder in crystalline form II; [Fig.5] - The [Fig.5] shows a scanning electron microscope (SEM) photograph of drospirenone crystals in the final form of the invention, crystalline form I, after retransformation from crystalline form II; [Fig.6] - [Fig.6] shows enlarged details of [Fig.5]; [Fig.7] - [Fig.7] shows enlarged details of [Fig.5]; [Fig.8] - [Fig.8] shows enlarged details of [Fig.5]; [Fig.9] - The [Fig.9] shows a dimensional distribution graph of drospirenone powders in the final form of the invention, crystalline form I, after retransformation from crystalline form II; [Fig. 10] - Figure 10 shows a dimensional distribution graph of drospirenone powders of crystalline form I obtained according to comparative example 3. Detailed description of the invention As is known in crystallography, crystalline solids are characterized by a lattice or crystalline structure which describes the geometry of the elementary cell of the crystal and the arrangement of atoms in the cell, and by a crystalline habit which, on the other hand, describes the external morphology of the crystal. In the remainder of the description and in the claims, the definitions “crystal form I” and “crystal form IT” are used to define the crystal structures of the different drospirenone forms of the process of the invention, and the definitions “octahedral habitus” and “acicular habitus” are used to define the external appearance of crystals but, as we know, there is no certain one-to-one relationship between crystal structure and crystal habitus. In the present case, the acicular habitus is not an indication of the presence of the crystalline form I or IL. Crystalline form I is characterized by the presence, in an X-ray powder diffraction (XRPD) spectrum, of two intense peaks at angles 26 of 12.30° and 17.35° ([Fig.3]), while crystalline form II is characterized by the presence in an XRPD spectrum of three intense peaks at angles 20 of 8.90°, 16.75° and 18.56° ( [Fig.4]); all these angles, as well as those reported below, are understood with the usual approximation of + 0.2° 26 typical of this technique. In this text, moreover, the terms “fine powder” or “fine particle size” refer to a powder of X,, less than 50 µm; in a cumulative volumetric distribution, Xo indicates the value of the equivalent spherical diameter which defines the 90th percentile of the total volume of the particles which constitute the sample. In its first aspect, the invention consists of a process for the direct production of fine-grained drospirenone by means of a double change in crystalline form: 1) from crystalline form I to crystalline form II; and 2) from crystalline form II to crystalline form I. In detail, the process consists of the steps described below. Step a) can be carried out according to two possible operating methods, a1) and a2). According to procedure a1), a suspension is prepared by mixing powders of a solid form of drospirenone with a mixture of acetone and diisopropyl ether (commonly called isopropyl ether) at a temperature between 0 and 45 °C. This starting solid form consists of powders of the API crystalline form I; this known form of drospirenone generally exhibits a characteristic octahedral habit, illustrated at two different magnifications in the two SEM images in Figure 1. The drospirenone used is pharmaceutical grade, while the acetone and isopropyl ether are standard grade, with a purity greater than 99%, and are preferably filtered before use to remove any physical impurities that may be present. The suspension is preferably stirred to separate the powder particles and disperse them in the solvent. In an alternative embodiment, the suspension can be prepared according to procedure a2) by dissolving and recrystallizing a solid form of drospirenone (in this case, amorphous drospirenone can also be used as the starting material). According to this alternative procedure, the solid drospirenone is dissolved in acetone by heating under reflux; the resulting solution is then cooled to a temperature between 40 and 45 °C; to this cooled solution, is then added isopropyl ether, this addition determining the crystallization of drospirenone in crystalline form I with formation of the suspension of point a); the whole procedure is carried out under agitation. Preparing the suspension by dissolving and recrystallizing API results in a suspension with grains of more homogeneous dimensions, which accelerates the transition to the IT crystalline form. In step b), the suspension obtained as described above is cooled, according to one of the two operating methods of step a), to a temperature < -5 °C. In step c), the suspension from step b) is kept under stirring at the indicated temperature, until the change in the morphology of the crystals from octahedral to acicular is observed, which has been shown to be accompanied by the transformation of the crystal structure from crystalline form I to crystalline form II, which is confirmed by XRPD analysis. This step can be done according to two possible operating methods, cl) and c2). According to procedure 11), this step is carried out by allowing spontaneous transformation into crystalline form II, which occurs within a period of 0.5 to 48 hours. Preferably, according to this procedure, the suspension is maintained under stirring at a temperature between -10 and -5 °C for a period of 0.5 to 24 hours. In the preferred embodiment of the process, step c) is carried out according to procedure c2) by adding to the suspension a small amount of drospirenone in crystalline form II, obtained in a previous preparation, which acts as a initiator of the desired transformation; under these conditions, and operating at a temperature between -10 and -5 °C under stirring, the transformation typically ends in a period of between 0.5 and 2 hours. In this preferred embodiment, in step c2) an optional addition of isopropyl ether to the suspension can then be carried out. The transformation of the initial powders (both in the case where it follows operating mode cl as in the case of operating mode c2) can be monitored with specific automatic instruments available commercially, for example the Particle View V19 probe (Mettler Toledo) and the associated iC PVM image acquisition and processing software (Mettler Toledo); this probe is connected to a high magnification microcamera with the ability to record images continuously, and it allows the formation and transformation of crystals in solution to be observed in real time. At the same time, it is possible to confirm that the change in crystalline form has taken place by analyzing the wet solid using XPRD analysis. Figure 2 shows two photographs obtained using the Particle View V19 probe, first of drospirenone (Fig. 2a) and then (Fig. 2b) the transformation from crystal form I to crystal form II, which takes place during step c). The upper part of the figure shows the initial drospirenone, in crystal form I (octahedral habit), while the lower part of the figure illustrates the appearance of the crystals with an acicular habit that are produced in this step. Once the transformation of the suspended crystals is complete, they are recovered in step d), which consists of filtering the suspension at a temperature equal to or less than -5 °C, preferably between -10 and -5 °C. An XRPD analysis of these still-moist crystals confirmed that they are of crystalline form II. In the last step of the process, e), the resulting crystalline solid product is dried at a temperature above +5 °C, preferably at a temperature of 40 to 50 °C, operating under a pressure lower than ambient. The drying of step e) results in the solid-solid transformation of drospirenone, which returns from crystalline form II to crystalline form I but retaining the acicular habitus. With the change in crystalline form that takes place in this step, from crystalline form II to crystalline form I, a spontaneous fragmentation of the crystals is observed with a reduction in their dimensions and the production of API particles with a granulometry suitable for use in drug administration formulations, without the need for grinding. In its second aspect, the invention relates to the crystalline form II of drospirenone produced as an intermediate of the process. The industrial utility of this new crystalline form, as described above, is that it allows obtaining drospirenone of crystalline form I with a granulometry smaller than that obtained with the processes of the known technique, and which is already adapted to the production of pharmaceutical formulations without requiring mechanical treatments to reduce dimensions. Figures 3 and 4 respectively reproduce a powder X-ray diffraction (XRPD) spectrum of drospirenone of known crystalline form I and of crystalline form II of the present invention (the spectrum of crystalline form I is shown for comparison). The powder spectrum of crystalline form II was derived from wet powders obtained after step d) of the process because, as mentioned, said drying re- transforms this form into the known crystalline form I. The table below summarizes the values ​​of the main peaks of the XRPD spectra of the two crystalline forms with their relative intensities. The angular positions of the diffraction peaks are given with an uncertainty of +0.220°. [Table 1] By exploiting the double change in crystal form, from crystal form I to crystal form II and again from crystal form II to crystal form I, microfractures are generated in the crystals, making additional mechanical treatments to reduce particle size unnecessary. This phenomenon is illustrated in Figures 5 to 8. Figure 5 shows a scanning electron microscope (SEM) image of drospirenone crystals in crystal form I after retransformation from crystal form II; Figures 6, 7, and 8 show electron microscope images of individual crystals from Figure 5, obtained at higher magnification, which highlight the presence of fracture lines. The invention will be illustrated in more detail by the following examples. Materials, methods and experimental conditions Images of drospirenone crystals during crystallization were acquired using the Particle View V19 probe (Mettler Toledo) and the associated iC PVM image acquisition and processing software (Mettler Toledo). XRD analyses were performed using a Bruker D2 Phaser diffractometer (2nd ed.) operating with a copper-anode X-ray source (λ = Ka, λ = 1.54184 Å). Kb radiation was eliminated using a nickel filter. The X-ray detector was a LINXEYE linear solid-state detector. Samples were loaded as thin films onto a silicon zero-background sample holder and analyzed in the range of 7 to 35°20' with increments of 0.02°20' and an acquisition time of 4 s / °20', rotating the sample holder during the analysis. Electron microscopy images were acquired using a JSM-IT200 SEM microscope (Jeol) operating under high vacuum at 20 kV and equipped with a SED detector. Samples were deposited onto the SEM support using a double-sided, conductive carbon adhesive film and were metallized with gold prior to analysis. The particle size distribution of the powders was measured using a Helos laser particle size analyzer equipped with a Quixel disperser (device and disperser manufactured and marketed by Sympatec GmbH of Clausthal-Zellerfeld, Germany), using milli-Q ultrapure water as the dispersing medium. The sample was first dispersed in milli-Q water with the addition of a few drops of Tween® 80 (polyethylene glycol sorbitan monooleate, marketed by Merck) and placed in an ultrasonic bath for 5 minutes. The resulting suspension was then added to the dispersing medium in the instrument until an optical density (OD) of 4 to 15% was achieved. The measurement (30 s background + 30 s measurement) was performed under continuous sonication with the recirculation pump set at 20%. Unless otherwise stated, the water used to carry out the experimental tests (except for the measurement of particle size) is pure water. Unless otherwise stated, the organic solvents used in the tests are of “technical” grade. Unless otherwise stated, the reagents and catalysts used in the tests are commercial grade. Example 1 This example relates to the process of the invention in its most general embodiment (without the addition of a drospirenone primer in crystalline IT form). 250 g of drospirenone in crystalline form I and 1700 ml of acetone are loaded into a 3 litre double jacketed reactor with anchor stirrer, reflux, temperature probe and liquid heating and cooling system. The mixture is stirred, heated under reflux, and kept under stirring until the solid is completely dissolved. The solution is cooled to 40-45 °C and then 600 ml of isopropyl ether is added. The formation of octahedral crystals is observed. The mixture is left to stir for 10 minutes and then cooled to -5 °C. The suspension is left to stir. After observing, after 22 hours, the transformation of the octahedral crystals into acicular ones, the mixture is left to stir at -5 °C for another 24 hours. The suspension is filtered under vacuum, the drospirenone (white solid) in crystalline form II is recovered (XRD analysis performed on the wet sample), and it is stored at T <S5°C. The XRD spectrum of drospirenone in crystalline form II obtained in this example is shown in [Fig.4] and is characterized by diffraction peaks at the following angular positions: 8.9°, 11.6°, 13.5°, 14.5°, 15.2°, 16.8°, 17.0°, 17.4°, 17.6°, 18.4°, 18.6°, 19.8°, 21.2°, 22.1°, 23.19°, 23.3°, 24.4°, 25.3°, 25.6°, 27.2°, 27.3°, 28.9°, 29.4°, 29.8°, 31.3°, 31.9° and 32.5° + 0.2° 20. Example 2 This example relates to the process of the invention carried out by adding a drospirenone primer of crystalline form II to a suspension obtained by adding powders of crystalline form I to the solvent (step sequence a1 > b > c2—+d > e). In a 100 ml reactor, at a temperature between 20 and 25 °C, 5 g of drospirenone in crystalline form 1, 27.5 ml of acetone and 35.0 ml of isopropyl ether are loaded. The resulting suspension is stirred and cooled to -5 °C for 10 minutes. 50 mg of drospirenone in crystalline form II obtained in example 1 is added and the suspension is kept under stirring for 2 hours at -5 °C. The suspension is filtered and the drospirenone (white solid) is recovered. The moist solid is dried under vacuum at 50°C for 16 hours. The XRPD diffractogram of the obtained solid (shown in [Fig. 3]) corresponds to that of the known crystal form I, with peaks in the angular positions indicated previously, while the crystal habit corresponds to the acicular habit of crystal form II Example 3 This example relates to the process of the invention carried out by adding a drospirenone primer of crystalline form II to a suspension of crystalline form I obtained by crystallization from a solution (step sequence aa >b +2 +de). 100 g of drospirenone in crystalline form I and 550 ml of acetone are loaded into a 3 litre double jacketed reactor with anchor stirrer, reflux, temperature probe and liquid heating and cooling system. The suspension is stirred and heated under reflux while continuing to stir until the solid is completely dissolved. The solution is cooled to 40-45 °C and then 240 ml of isopropyl ether is added. The formation of octahedral crystals is observed. The suspension thus obtained is cooled to -5 °C, left under stirring for 10 minutes, then 1.0 g of drospirenone in crystalline form II (obtained in example 1) is added and stirring is continued for 30 minutes. An additional 1160 ml of isopropyl ether is added (keeping the temperature of the mixture constantly < 3 °C) and the suspension is stirred for 2 hours while maintaining the internal temperature between -5 °C and -10 °C. The suspension is filtered, and drospirenone (white solid) is recovered. The XRPD spectrum of the just filtered wet solid corresponds to that obtained in example 1 ([Fig.4]). The moist solid is dried under vacuum at 50°C for 6 hours. The solid obtained is again subjected to XRD analysis; the spectrum corresponds to that of drospirenone in crystalline form I but the powder retains the crystalline habit of the crystalline form IT, as shown by the comparison of [Fig.2b] and [Fig.5]. A particle size analysis is performed on this powder; the resulting curve, reproduced in [Fig. 9], demonstrates the production of a fine powder. In particular, the bell curve (to which the vertical scale on the right of the figure refers) shows that the maximum size distribution of the sample particles is between 15 and 20 µm and that all particles have a size less than 110 jm (which is also confirmed by the cumulative curve to which the vertical scale on the left of the figure refers). Example 4 (comparative) In this example, the process of the invention is reproduced only in part and the transformation from crystalline form I to crystalline form II does not take place. 5 g of drospirenone and 27.3 ml of acetone are loaded into a 100 ml EasyMax reactor. The suspension is stirred and heated under reflux until completely dissolved. The solution is cooled to 40-45 °C and then 34.7 ml of isopropyl ether is added. The resulting suspension is cooled to 0 °C, kept under agitation for 10 minutes, and then filtered. The solid is then dried in a vacuum oven at 45°C for 16 hours. The XRPD diffractogram of the solid obtained corresponds to that of the known crystalline form I, with peaks in the angular positions indicated previously. On this powder, a particle size measurement is carried out; the results are shown on the graph in [Fig. 10], which highlights the obtaining of a coarser powder compared to that obtained according to the procedure of example 2, with the peak of the size distribution of the particles of the sample around 70 um and particles having dimensions beyond 150 um.

Claims

Demands

1. . Drospirenone of crystalline form IT, characterized by a diffrac- X-ray togram showing diffraction peaks at angular positions 8.90°, 16.75°, 18.44° and 18.56° + 0.2° 20.

2. . Drospirenone in crystalline form II, according to claim 1, ca- characterized by an X-ray diffractogram that shows peaks of diffraction at angular positions 11.61°, 13.54°, 23.08°, 24.40° and 27.30°+0.2°26.

3. Process for the production of γ-lactone of acid 17B-hydroxy-6p,7(;15p,16B-dimethylene-3-oxo-17a-pregn-4-ene-21-ca rboxivlique (drospirenone) having a fine particle size, characterized by a value of Xy less than 50 µm, by means of a double exchange of crystalline form: 1) from crystalline form I to crystalline form II, characterized by the presence in an XRPD spectrum of peaks at angles 8.90°, 16.75°, 18.44° and 18.56° + 0.2° 20; and 2) from crystalline form II to crystalline form I, characterized by the presence in an XRPD spectrum of peaks at angles 12.30° and 17.35° + 0.2° 20, and in that the process comprises the following steps: a) preparation of a suspension of a solid form of drospirenone crystalline form I in a mixture of acetone and diisopropyl ether; b) cooling of the suspension to an equal or in- less than -5 °C; c) stirring the suspension at the temperature of point b) until observe the formation of crystals of crystalline form II; d) filtration of the suspension at a temperature equal to or lower than 5 >C: e) drying of the crystalline solid obtained at a temperature above +5 °C to obtain drospirenone in crystalline form I having a fine particle size.

4. A production method according to claim 3, wherein step a) is carried out, according to a procedure a1), by suspending crystalline form I powders of drospirenone in a mixture of acetone and diisopropyl ether.

5. A production method according to claim 3, wherein step a) is carried out, according to procedure a2), by dissolution in acetone under reflux conditions of drospirenone powders in the form crystalline or amorphous form, cooling of the solution obtained at a temperature between 40 and 45 °C, and addition of ether diisopropyl to the cooled solution, carrying out the entire procedure under agitation.

6. A production method according to any one of claims 3 to 5, in which step c) is carried out, according to procedure c1), in allowing spontaneous transformation into crystalline form II for a period of between 0.5 and 48 hours.

7. . Production method according to claim 6, wherein step c) according to the operating procedure cl) is carried out at a temperature between between -10 and -5 °C for a period of between 0.5 and 24 hours.

8. . Production method according to any one of claims 3 to 5, in which step c) is carried out, according to procedure c2), in adding to the suspension of step b) a drospirenone primer of crystalline form II.

9. . Production method according to claim 8, wherein step c) according to operating procedure c2) is carried out at a temperature between between -10 and -5 °C for a period of between 0.5 and 2 hours.

10. . Production method according to any one of claims 8 or 9, in which an additional diiso- ether is added propylene suspension.

11. . Production method according to any one of the claims 3 to 10, wherein step e) is carried out at a time temperature between 40 and 50 °C while operating under pressure lower than ambient temperature.