JP6538501B2 - Industrial Production Method of Crystalline Form E Minodronic Acid Hydrate - Google Patents

Description

  The present invention discloses a method for obtaining crystalline Form E of minodronic acid hydrate (I, GAS No. 155648-60-5).

  Applicable to industrial production at various scales, the method uses interparticle friction which is capable of converting a mixture of crystalline form D or crystalline form E into crystalline form E. Friction welding of particles can be triggered by a variety of techniques applicable to industrial scale, such as sieving, micronization, shaking granulation, cyclone crushing, conical mill crushing, and suspension grinding. .

  The method is particularly advantageous in terms of industrial production, yield and reproducibility.

  Minodronic acid hydrate of the formula (I) (1-hydroxy-2-imidazo [1,2-a] pyridin-3-yl) ethane-1,1-diphosphonic acid hydrate: GAS number: 155648-60- 5) is an agent having anti-inflammatory and analgesic / antipyretic activity, and bone resorption inhibitory activity, and is for the treatment of diseases such as Paget's disease, hypercalcemia, carcinoma with bone metastasis and osteoporosis, and Useful for treatment of bone resorption caused by inflammatory joint diseases such as rheumatoid arthritis

  There are different crystalline forms of minodronic acid which differ with respect to the water content and thus the stability under the conditions used for the preparation of the medicament.

  Of the various hydrate forms, the most stable in solid pharmaceutical formulations is the monohydrate form.

  The synthesis of minodronic acid hydrate and various crystal forms are disclosed in patent application EP 0 647 649 A1.

  The document is referred to as a crystalline form, including two types of crystals, designated as crystalline form D and crystalline form E, having the same powder X-ray diffraction (XRPD) spectrum but different dehydration temperatures (TGA or DSC) The physicochemical properties of the monohydrate form, as well as the preparation are described.

  The two crystals, although having identical XRPD spectra, are not included in the usual notion of polymorphic crystals and are described as a novel type of polymorphism.

  EP 0 647 649 A1 (patent document 1) is a method for preparing crude crystals of minodronic acid in an aqueous acid solution, preferably hydrochloric acid, using heating dissolution and precipitation with gradual cooling while gently stirring. It discloses the formation of the two types of crystals caused by the crystals.

  Also disclosed are the operating conditions required to obtain the two crystals individually, Crystalline Form D and Crystalline Form E, with high levels of reproducibility.

  In particular, the preparation of crystalline form D is described as being preferred for industrial scale (Kg scale) synthesis, where agitation is done mechanically. Precipitation occurs with gentle mechanical agitation and gradual cooling.

  The preparation of crystalline form E is preferred in laboratory preparation (on the scale of a gram), in which case gentle magnetic stirring with anchors should not cause vortices on the surface and also use ice bath etc. It is stated that it is necessary to carry out gradual cooling without doing.

  EP 0 647 649 A1 also describes the physicochemical properties of the two hydrate forms, crystalline form D and crystalline form E, describing the X-ray diffraction spectrum as well as the results of the calorimetric measurements.

  The X-ray diffraction of crystal D and crystal E are identical but their thermogravimetric analysis curves are different.

  Crystal D has a dehydration peak falling in the temperature range of 135 ° C. to 149 ° C., while crystal E has a dehydration peak falling in the temperature range of 160 ° C. to 170 ° C.

  EP 0647649 A1 also discloses the physicochemical properties of the two hydrate forms, crystalline form D and crystalline form E, which show that it is preferable to the other crystalline forms of minodronic acid in solid pharmaceutical preparations. ing.

  Applicants have reproduced the conditions described in EP 0 647 649 A1 to confirm that both crystal forms are obtained: crystal form D whose TGA is shown in FIG. 1 by mechanical stirring. By magnetic stirring, crystalline form E whose TGA is shown in FIG. 2 is obtained.

EP0647649A1

  Crystalline form E is thermodynamically more stable because it loses water of crystallization at temperatures higher than crystalline form D, and is thus more interesting in formulations.

  EP 0647649 A1 reports a process for the production of crystalline form E which is only suitable for laboratory scale applications, but it can only be used to make batches of several grams: thus, industrial It is important to find a way to prepare crystalline form E on a physical scale.

  Surprisingly, a large number of techniques applicable to various production scales (from a few grams to a few hundred kilograms) that cause friction between the particles are crystalline form D of minodronic acid hydrate, or with said crystalline form D It has now been found that a mixture of E can be converted to crystalline form E.

FIG. 1 shows the results of TGA-DSC measurement of minodronic acid hydrate of crystalline form D prepared by mechanical stirring. FIG. 2 shows the results of TGA-DSC measurement of minodronic acid hydrate of crystalline form E prepared by magnetic stirring. FIG. 3 shows the results of PSD measurement of Minodronic acid hydrate of crystalline form D of Example 1. FIG. 4 shows the results of TGA measurement of Minodronic acid hydrate of crystalline form E prepared by manual sieving of crystalline form E using a stirrer. FIG. 5 shows the results of measuring the particle size distribution of Minodronic acid hydrate of crystalline form E prepared by manual sieving of crystalline form D using a stirrer. FIG. 6 shows the results of TGA measurement of Minodronic acid hydrate of crystalline form E prepared by micronization of crystalline form D. FIG. 7 shows the results of measurement of the particle size distribution of Minodronic acid hydrate of crystal form E prepared by micronization of crystal form D. FIG. 8 shows the results of TGA measurement of Minodronic acid hydrate of crystalline form E prepared by crushing crystalline form D using a cyclone mill. FIG. 9 shows the results of measurement of particle size distribution of minodronic acid hydrate of crystal form E prepared by crushing of crystal form D using a cyclone type mill. FIG. 10 shows the results of TGA measurement of Minodronic acid hydrate of crystalline form E prepared by crushing crystalline form D using a conical mill. FIG. 11 shows the results of measurement of particle size distribution of Minodronic acid hydrate of crystalline form E prepared by crushing crystalline form D using a conical mill. FIG. 12 shows the results of TGA measurement of minodronic acid hydrate of crystal form E prepared by crushing of crystal form D using a water mill type pulverizer. FIG. 13 shows the results of TGA measurement of Minodronic acid hydrate of crystalline form E prepared by crushing crystalline form D in an ultrasonic bath. FIG. 14 shows the XRPD measurement results of the crystals of Minodronic acid hydrate of crystalline form E prepared by the production method of the present invention.

  For the present invention, all approaches can be used which cause friction between particles of crystalline form D or a mixture of crystalline forms D and E.

  It is possible to use an approach which works in suspension in solvent or in the dry state (i.e. for a mixture of crystalline forms D and E or crystalline form D).

  In one aspect of the present invention, crystalline form E is obtained from crystalline form D, or a mixture of crystalline forms D and E, by manual sieving. The sieve is composed of a metal mesh which is woven with high precision, uniformly spread and has various porosity. The mesh size is variable and has a hole diameter ranging from several hundred μm to only several tens of μm.

  In such an aspect of the invention, an external force is applied to the crystals of crystalline form D by means of a network comprising holes of dimensions smaller than 100 μm, preferably in the range of 30 to 50 μm. As a result, friction is caused not only between the various particles of the article (crystal form D) but also between the particles and the metal network.

  Using this procedure, the conversion of crystalline form D to crystalline form E is complete and crystalline form E is quantitatively recovered without any contamination.

  In another aspect of the present invention, a crusher (micronizer) is used to obtain crystalline form E from crystalline form D or a mixture of crystalline forms D and E. A grinder (micronizer) is a particleizing system capable of obtaining particles having a particle size of several μm. The grinder (micronizer) comprises a hopper for feeding the articles, which is pushed into the atomization chamber by means of a screw. In the atomization chamber, as a result of the thrust of the gas, generally nitrogen, the particles clash and cause friction. The product is then quantitatively recovered in the collection bag.

  The pressure in the atomization chamber, or the speed of the screw, can be varied to improve the incidence and effect of collisions between the various particles.

  The optimum conditions for inducing adequate friction that allow conversion from crystalline form D to crystalline form E are both low screw fade speeds in the range of 5 to 78 rpm, as well as 2 to 8 bars for both fade pressure and grinding pressure Represented by mild pressure in the range of In particular, for laboratory scale millers (micronizers) in kilos, the screw fade speed is in the range of 10 to 50 Hz (5 to 25 rpm), in particular 10 to 20 Hz (5 to 15 rpm), and the pressure is It is in the range of 2 to 5 bar, in particular in the range of 2 to 3 bar. For pilot as well as industrial scale mills (micronizers) the screw fade speed is in the range of 17-78 rpm and the pressure is in the range of 2-8 bar.

  It has been found that excessively high pressure only leads to a crystallizing effect which only reduces the particle size, and it is confirmed that the pressure is not the force necessary to change the crystal form. However, at lower pressures slightly above atmospheric pressure, it has been found that with some linearity crystalline form D is converted to crystalline form E and finally quantitative conversion to the latter is achieved There is.

  In another aspect of the invention, crystalline form E is obtained from crystalline form D, or a mixture of crystalline forms D and E, by crushing in a shaking granulator. Shake-type granulators are operated by a rotor or cylindrical roller, which squeezes the article by means of a sieve with holes of a predetermined size. The mechanism that causes the friction is very similar to that observed in manual sieving. A roller rotating on a sieve with holes of size less than 100 μm breaks up the crystals, rubs together and causes the friction necessary to change the crystal form.

  In another aspect of the invention, crystalline form E is obtained from crystalline form D or a mixture of crystalline forms D and E by crushing in a cyclone mill. Cyclone-type mills are industrial shredding systems that shred articles in a very short time. The articles are fed by a hopper and pushed by a screw into a crushing chamber where they are centrifuged by gas, usually nitrogen, and collected in a collecting bag after passing through a mesh.

  The centrifugal force in the crushing chamber causes a collision between the article and the teeth of the rotor, said collision creating the friction necessary for the quantitative conversion of crystal form D to form E.

  The conditions applied to cause friction are low screw fade speeds in the range of 8 to 70 rpm, in particular in the range of 9 to 30 rpm, as well as mild fades where the pressure is slightly above atmospheric pressure (1-2 bar absolute) Pressure. Once again, product recovery is almost quantitative.

  In another aspect of the invention, crystalline form E is obtained from crystalline form D, or a mixture of crystalline forms D and E, by crushing in a conical mill. A conical mill is usually a crushing apparatus used to break up a mass and consists of a strong cone, inside which a metal mesh with holes of suitable diameter is housed.

  When the articles are introduced into the crushing chamber, the articles are crushed against the surface of the grid by the rotor which rubs the sample onto the holes in the mesh, causing a frictional effect. Product is discharged into the collection bag only when the dimensions of the holes in the grid are reached.

  Some parameters can be varied, for example, the rotor speed is generally in the range of 400-3000 rpm, the rotor-grid gap is about a few mm, generally 0.2-1 mm, and the holes in the mesh are, of course, fed It is necessary to have a diameter smaller than the particle size of the article, generally in the range of 40 to 100 .mu.m.

  All the above mentioned approaches are carried out by dry crushing of the finished article, thus enabling quantitative recovery of the processed product.

  Another aspect of the present invention utilizes a fracturing method that produces friction between particles, which is performed using suspended articles.

  In one of the above embodiments, the crystalline form D, or a mixture of crystalline forms D and E, by disruption in a suspension with solvent, preferably with water or weakly acidic water (pH 2 to 4), Obtain crystal form E.

  The ideal ratio of mass of article to aqueous liquid volume is preferably in the range of 1: 5 to 1:10.

  For the purposes of the present invention, by rotating in the opposite direction to the mill, friction is caused in the presence of cylindrical rollers, or by means of a vigorously stirring stirrer, which causes friction between the various particles, Crushing in suspension can be used.

  In another one of the above embodiments, by sonication of a suspension of crystalline D, or a mixture of crystalline D and E, in a solvent, from crystalline D, or a mixture of crystalline D and E, crystalline Get E Such work is generally performed in an ultrasonic bath. As the solvent, preferably water or weakly acidic water (pH 2 to 4) is used. The ideal ratio of the mass of the article to the aqueous liquid volume is the same as the range applied for crushing in suspension, ie in the range of 1: 5 to 1:10.

  Sonication causes lower friction than kneading systems, and the heat generated is more easily dissipated. Therefore, this method only partially converts crystal form D to crystal form E. Therefore, when it is necessary to increase the ratio of crystal form E in crystal form D or a mixture of crystal forms D and E, this method can be advantageously used.

  Any of the processes that cause friction, either in the dry state or in suspension as described above, can be applied to pure crystalline form D, or a mixture of crystalline forms D and E.

  Unlike the processes described in the literature, where the possibility of obtaining crystalline form E is limited to laboratory scale, the process described above is a mixture of crystalline forms D and E or in an industrial scale process The process described above is particularly advantageous as it is carried out directly from crystalline form D, which is more easily produced. Thus, the process described above can be used for large scale production. The process described above also makes it possible to obtain the product in quantitative yield without loss of its quality.

  The invention will be described in detail in the following examples.

EXAMPLES Abbreviations and equipment used in the following examples are described below.

Abbreviation (Term)
TGA / DSC: Thermal Gravimetric Analysis / Differential Scanning Calorimetry
XRPD: X-ray Powder Diffraction
PSD: Particle-size distribution
Test apparatus For TGA measurement, Malvern apparatus was used for determination of PSD using a Perkin Elmer Pyris 1 TGA apparatus.
XRPD spectra were acquired using an X'Pert Pro MPD instrument.

Example 1: Manual sieving using stirrer A crystalline form D of minodronic acid hydrate (0.5 kg), the PSD of which is shown in Figure 3, is fitted with a network with holes in the range of 30-50 μm After manual sieving with a 20 cm diameter laboratory sieve, the crystalline form E of minodronic acid hydrate (0.498 kg), whose TGA and PSD are shown in FIGS. 4 and 5, respectively, is recovered. Do. The conversion to crystalline form E is quantitative.

Example 2: Micronization Crystallographic form in laboratory scale grinder, at screw feed rates in the range 10-20 Hz (5-10 rpm), under pressure conditions (feed-grinding pressure) in the range 2-3 bar Micronizing Minodronic Acid Hydrate D (3 kg) Crystalline Form E Minodronic Acid Hydrate (2.95 kg), the TGA and PSD of which are shown in FIGS. 6 and 7, respectively, is recovered.

Example 3: Crushing Using a Cyclone-Type Mill Crystals by a cyclone-type mill fitted with a network with 1 mm holes at a screw feed rate of 29 rpm under slightly above atmospheric pressure (1-2 bar) conditions Disrupt type D Minodronic Acid Hydrate (15 kg). 14.8 kg of crystalline Form E minodronic acid hydrate, the TGA and PSD of which are shown in FIGS. 8 and 9, respectively, are recovered.

Example 4: Crushing using a conical mill Minodronic acid hydrate (1 kg) of crystalline form D is crushed in a conical mill with 230 mesh holes (about 60 μm) at 2000 rpm. The microcrystals quantitatively recovered have a TGA (FIG. 10) which exhibits a temperature peak of 150.degree. The PSD is shown in FIG.

Example 5 Crushing in Aqueous Suspension Crystalline form in suspension (250 mL, ratio 1:10) in water or weakly acidic water in a laboratory grinder equipped with a rotating cylindrical roller Mill D Minodronic Acid Hydrate (25 g). The microcrystals, recovered in 80% yield, have TGA (FIG. 12) showing a temperature peak of 150 ° C. (partially crystalline form E).

Example 6: Crushing in an ultrasonic bath Sonication of minodronic acid hydrate (10 g) of crystalline form D in the state of aqueous suspension (100 mL, ratio 1: 10) in a laboratory ultrasonic bath Smash. After sonication for 1 hour, the conversion of crystalline form D to crystalline form E is 50%. 7.5 g of minodronic acid hydrate, the TGA of which is shown in FIG. 13, is recovered as a mixture of crystalline form D and crystalline form E.

  FIG. 14 shows, by way of illustration, XRPD of a crystal of crystalline form E obtained by the production method according to the present invention.

Claims (13)

A process for producing crystalline form E of minodronic acid hydrate, comprising
Starting from crystalline form D of minodronic acid hydrate or a mixture of crystalline forms D and E as a raw material,
It is characterized by producing crystalline form E of minodronic acid hydrate using a method of utilizing friction or friction between particles of crystalline form D or particles of a mixture of crystalline forms D and E. And how to.   The method according to claim 1, characterized in that the method is applied to particles of crystalline form D or particles of a mixture of crystalline forms D and E in the solid state.   It is characterized in that friction or frictional force between the particles is caused in a solid state by sieving, micronization, crushing with a shaking type granulator, crushing with a cyclone type crusher, and grinding with a cone mill. The method according to claim 1 or 2.   A method according to claim 3, characterized in that sieving is used with a mesh having holes with a size of less than 100 μm.   Process according to claim 3, characterized in that a grinder is used, having a screw feed speed in the range 5 to 78 rpm and a feed grinding pressure in the range 2 to 8 bar.   Method according to claim 3, characterized in that a shaking granulator is used, the rollers of which rotate on a sieve with holes of size less than 100 μm.   Process according to claim 3, characterized in that a cyclone-type grinder is used, having a screw feed speed in the range of 9 to 30 rpm and a feed pressure of 1 to 2 bar.   The rotor speed is in the range of 400-3000 rpm, the gap between the rotor and the grid is in the range of 0.2-1.0 mm, and the holes in the mesh have a diameter smaller than the particle size of the articles being fed Process according to claim 3, characterized in that a corn mill is used.   The method according to claim 1, characterized in that the above procedure is applied to a mixture of crystalline forms D and E or crystalline form D in a suspended state.   It is characterized in that friction or frictional force between suspended particles is caused by crushing or sonication of a mixture of crystal forms D and E, or suspension of crystal form D in a solvent. The method according to claim 1 or 9.   Crushing or sonication is carried out in an aqueous solvent, wherein the ratio of the mixture of crystalline forms D and E, or the mass of crystalline form D to the volume of the aqueous solvent, is in the range 1: 5 to 1:10. The method according to claim 10, characterized in that.   The method according to claim 11, characterized in that crushing is carried out in a roll mill.   The method according to claim 11, characterized in that sonication is performed in an ultrasonic bath.