Title of Invention

"METHOD FOR ISOLATING PHARMACEUTICALLY EXPLOITABLE ETIDRONATE DISODIUM"

Abstract

The invention relates to a method for isolating etidronate disodium. According to said method, a liquid-liquid dispersion consisting of an aqueous-organic phase and an aqueous phase containing the etidronate disodium salt is set to a temperature of between 0 °C and 30 °C and is intensively mixed; a coarse-grained fraction is subsequently precipitated out of the liquid-liquid dispersion and in a second, delayed step, a fine-grained fraction is precipitated out of the organic phase. The invention also relates to a novel solid form of etidronate disodium that can be obtained using this method. The invention provides a method for producing etidronate disodium with a particle size in the region of 0.2 to 1.0 mm, good flowability and a high bulk density, coupled with properties that can be pharmaceutically exploited to advantage.

Full Text

The invention relates to a method for isolating pharmaceutically exploitable etridonate disodium by means of precipitation in a liquid-liquid dispersion consisting of an aqueous-organic phase and an aqueous phase of the etidronate disodium salt, and to a novel solid form of etidronete disodium which is obtainable by means of this method. It is known from the technical and patent literature to prepare the disodium salt of hydroxyethane-1,1-diphosphoric acid (HEDP) by means of neutralization with sodium hydroxide solution in the presence of water (DE-A-1 148 551). The disadvantage of the previously known isolation methods for obtaining the solid consists in that the evaporation of the water to the greatest possible extent to give the anhydrous salt can only take place at relatively high temperatures, in that the method of spray drying used for this only affords a hygroscopic product having very low bulk density, a high dust content and poor flowability and is thus not suitable for pharmaceutical processing, in that the method of thin-layer drying at high temperatures to be used alternatively in fact produces compact, but crust-like structures which make an additional grinding process necessary, and in that in the final product an accumulation of the poorly volatile impurities of HEDP, such as phosphorous acid and acetic acid, takes place and therefore require an additional prepurification of the HEDP for pharmaceutical purposes (DD 275 462). It is furthermore known to prepare the disodium salt of HEDP by means of cooling crystallization from a concentrated solution. It is disadvantageous to this solution that the voluminous, needle-shaped crystallizate is separable from the mother liquor with difficulty, that a felt-like filter cake results, that the moist product cakes on drying and the water can be removed from the interior of the agglomerates with great difficulty, and that high mother liquor losses are to be recorded as a result of the good water solubility of the sodium salt. In addition, the patent specification DE-A 1 148 551 describes the conversion of the acids and salts obtained during the acylation of phosphorous acid in crystalline form into corresponding alkali metal salts by means of precipitation by the addition of organic solvents, such as alcohol or acetone, to the aqueous salt solution. The disadvantages of this solution consist in the obtainment of products which are fine-crystalline or needle-shaped to a greater or lesser extent, which are likewise dryable only with difficulty, since they likewise tend to agglomerate and stick together during the drying process, in the high content of firmly bound solvent residues in the final product, for example as solvates, and in the necessity for an additional grinding process of the product. It is moreover known from the technical literature that the addition of the aqueous salt solution to the organic solvent as a rule leads to precipitation of a greasy and sticky aqueous phase, gradually solidifying to give coarse lumps. This is substantiated by the fact that the sodium salt is almost insoluble in all organic solvents. A method for the preparation or isolation of etidronate disodium having technical parameters which guarantee pharmaceutical exploitation is not disclosed in the technical and patent literature. The invention is based on the object of developing a method which makes possible the production of pharmaceutically exploitable etidronate disodium, that is which yields a product of high purity in high yield which has a particle size in the range 0.2 — 1 mm, a bulk density of 0.4 — 0.6 g/cm3 and a good flowability and thus a high pharmaceutical exploitability. This object is achieved according to the invention by a method for isolating etidronate disodium, where a) a liquid-liquid dispersion, consisting of an aqueous-organic phase and an aqueous phase comprising the etidronate disodium salt is adjusted to a temperature of 0°C to 30°C and intensively stirred, b) then a coarse grain fraction is precipitated from the liquid-liquid dispersion, c) in a second, delayed step a fine grain fraction is precipitated from the organic phase. Preferably, the fine grain fraction is separated in a step d) by classification of the coarse grain fraction and fed back into the method. In a further step e), the coarse grain fraction according to step d) can be filtered and dried by means of drying in a moving bed up to a final temperature of 85°C to 100°C. Preferably, the liquid-liquid dispersion has a total water content of 25 to 35% by volume and a total etidronate disodium salt content of 10 to 100 g/kg of dispersion. The liquid-liquid dispersion is preferably adjusted to between 5°C and 10°C. The aqueous-organic phase is preferably an iso-propanol/water phase. In addition, it is preferred according to the invention that, for the liquid-liquid dispersion, an aqueous solution of etidronate disodium is added to a solvent consisting of isopropanol/water. A further subject of the present invention is the etidronate disodium which is obtainable by the method according to the invention. The etidronate disodium according to the invention is obtained as a form free of water of crystallization, is mainly amorphous and is characterized by the X-ray powder diagram shown in figure 1 and the IR spectrum shown in figure 2 . Figure 1 shows an X-ray powder diagram of the etidronate disodium obtainable by the method according to the invention. Figure 2 shows an IR spectrum of the etidronate disodium obtainable by the method according to the invention. A preferred embodiment of the present invention is described by way of example below. In principle, the organic phase can consist of ethanol, methanol, acetone and isopropanol, the most favorable technological and material parameters being achieved Busing isopropanol. The process according to the invention is therefore described below by way of example with the aid of isopropanol as the organic phase. For the preparation of the liquid-liquid dispersion, an aqueous solution of etidronate disodium is added to a solvent consisting of an isopropanol/water mixture, a total water content of 25 to 35% by volume and, in the suspension, a solids content of 10 to 100 g/kg of dispersion is in this case established. Thus, this liquid-liquid dispersion consists of a low-water isopropanol phase and a water-rich salt phase. Between the two phases, a specific distribution equilibrium with respect to water and sodium salt is established. It is crucial for the precipitation process that the organic phase extracts the water from the disperse aqueous phase, but takes up salt only to a small extent. The crystallization then suddenly commences after approximately 7 to 10 mm as a result of high supersaturation. An agglomeration of the crystallizing droplets is superimposed on this crystallization. Relatively large particles are formed, which are split up in the shear field of the stirrer and thus afford the desired particle size distribution. This mechanical comminution is only possible by means of appropriate stirring energy in the course of a few minutes in the transition range from the the still liquid state to the solid state. Somewhat delayed to the coarse grain precipitation just described, a needle-shaped fine grain fraction precipitates in a small amount in the organic phase. Owing to its significantly lower sedimentation rate, it is classified rapidly and without problems before the solid-liquid separation and recirculated to the process. The sandy coarse grain fraction is then filtered and washed. By means of vacuum contact drying in a moving bed and with temperatures raised gradually up to about 85 to 100°C, it is dried to give the anhydrous salt. A significant result of the application of the method according to the invention consists in that a pharmaceutically exploitable etidronate disodium can be prepared using it. The advantages of the solution result from the fact that a method has been developed which makes possible the production of an almost dust-free etidronate disodium from a liquid-liquid dispersion having a total water content of 25 to 35% by volume and a total etidronate disodium salt content of 10 to 100 g/kg of dispersion, the etidronate disodium having a particle size in the range from 0.2 to 1.0 mm, for subsequent tableting having further favorable solid properties, such as, for example, a bulk density of 0.4 - 0.6 g/cm3 and in the granulation of the etidronate disodium at most 10% by weight of all particles being > 1 mm and at most 5% by weight of all particles being which produces an etidronate disodium which corresponds to the pharmaceutical purity requirements according to USP which provides a product which maintains its sandy consistency in the drying process and can be dried without problems to give the anhydrous form. In the drying phase, the release of water of crystallization, this is particularly of crucial importance for a homogeneously dried product. Moreover, the drying process is not burdened by the deposition of large amounts of fine dust from the dried water vapor of the hydrate. Furthermore, this method and the distribution equilibrium in the liquid-liquid dispersion system connected therewith brings about that the contamination of the HEDP (phosphorous acid and acetic acid) to 95% and to 99% respectively in the organic phase and are not, as expected, preferably taken up in the aqueous phase. Thus these impurities are not precipitated in the final product. On account of further advantages, reference can also be made to the description of the working examples. The invention is illustrated with the aid of the following, preferred, nonrestricting examples. Measurement methods: X-ray powder diffractometry (X-ray powder diffraction; XRPD): The data were determined using a Siemens D5000 diffractometer with a Cu anode (resolution of 0.01° between 5° ≤ 29 ≤ 50°) . IR spectroscopy: An ATI Mattson, Genesis FT-IR was used, KBr, 8t, 90 sec . Particle size analysis: A RETSCH screen analysis system was used. Bulk density measurement: The bulk density measurement was carried out by means of a measuring cylinder (unshaken). Water content: The loss on drying was measured using a Mettler Toledo moisture determination apparatus, 200°C, 20 min. Acetic acid The acetic acid content was determined gas- chromatographically (GC Headspace, DBS, 30 m, FID). Isopropanol The isopropanol content was determined gas- chromatographically (GC Headspace, DB wax, 30 m, FID). Phosphite The phosphite content was determined iodometrically by means of titration. Example 1 10.5 1 of isopropanol, precooled to -7°C, having a water content of 25% by volume are introduced into a stirring vessel, equipped with a turbine stirrer and two flow interrupters. With stirring, 1.7 1 of an aqueous solution of the sodium salt having a concentration of 350 g/1 are rapidly added. The solution contains 0.6% by weight of phosphorous acid and 0.6% by weight of acetic acid. After approximately 3 to 4 min, the speed is adjusted to 650 to 700 rpm and stirring is continued at this rate for 10 min. The speed is then lowered to about 250 to 300 rpm and stirring is continued for 10 minutes. After turning off the stirring, the coarse grain fraction sediments within 3 min. The supernatant fine grain suspension is removed and the coarse grain sediment is washed with 7 1 of isopropanol/water mixture (25% by volume of water or clear mother liquors from previous precipitation cycles) by brief stirring and the supernatant suspension is removed again. In this way, the fine grain fraction is separated off almost completely. The fine grain content is about 18 to 19% of the solid. The coarse grain fraction is filtered and partly dried in a stream of air. The moist product is dried in vacuo in a rotary evaporator. After a vacuum of 2 kPa has been reached, the heating bath temperature is gradually increased to 80°C in the course of 3 h. In this phase, the free moisture is essentially dried off under a vacuum of 2 to 3 kPa and from a continuously moving bed. The vapor is condensed. Under a vacuum of less than 2 kPa, a heating bath temperature of 100°C and in a moving bed, the dehydration of the water of crystallization subsequently takes place in the course of 3 h. A final product having the following particle size spectrum is obtained: 0.1 mm 0.07% 0.1-0.2 mm 23.8% 0.2-0.5 mm 27.3% 0.5-0.8 mm 46.2% 0.8-1.0 mm 2.16% 1.0 mm 0.47% The bulk density is 0.48 g/cm3. Further quality parameters achieved were: content: 100% losses on drying 3.5% phosphites: 0.06% isopropanol: 0.01% acetic acid: 0.01% The mother liquor is separated off from the fine grain suspension by sedimentation and removal by distillation and at the end an aqueous solution is obtained which can be employed again for the precipitation. The clear mother liquors, washing mixtures and classification mixtures are in some cases employed again for classification or separated by simple distillation into an isopropanol/water mixture and an aqueous bottom which contains the impurities of the HEDP. The solids yield taking into account the fine grain recycling is 97% of theory. Example 2 Method according to Example 1 with the difference that the water content in the isopropanol employed is 22% by volume. The classified fine grain content is about 14 to 15% of the solid. A final product having the following particle size spectrum is obtained: 0.1 mm 0.0% 0.1-0.2 mm 0.07% 0.2-0.5 mm 19.7% 0.5-0.8 mm 54.9% 0.8-1.0 mm 15.6% 1.0 mm 9.71% The bulk density is 0.51 g/cm3. Example 3 Method according to Example 1 with the difference that a sodium salt solution containing 3% by weight of phosphorous acid is used. A final product having the following quality is achieved: content: 100% loss on drying: 3.5% phosphites: 0.61% isopropanol: 0.01% acetic acid: 0.01% We Claim: 1. A method for isolating etidronate disodium, characterized in that a) a liquid-liquid dispersion which has a total water content of 25 to 35% by volume and a total etidronate disodium salt content of 10 to 100 g/kg of dispersion. an aqueous-organic phase such as herein described and an aqueous phase comprising the etidronate disodium salt is adjusted to a temperature of 0°C to 30°C and intensively stirred, b) then a coarse grain fraction is precipitated from the liquid- liquid dispersion, c) in a second, delayed step a fine grain fraction is precipitated from the organic phase. 2. The method as claimed in claim 1, wherein the fine grain fraction is optionally separated from the coarse grain fraction by classification and fed back into the method. 3. The method as claimed in claim 2, wherein the said coarse grain fraction is filtered and dried by means of drying in a moving bed up to a final temperature of 85°C to 100°C. 4. The method as claimed in one of claims 1 to 3, wherein the liquid- liquid dispersion is preferably adjusted to between 5°C and 10°C. 5 The method as claimed in one of claims 1 to 4, wherein the aqueous-organic phase is an isopropanol/water phase. 6. The method as claimed in one of claims 1 to 5, wherein for the liquid-liquid dispersion, an aqueous solution of etidronate disodium is added to a solvent consisting of isopropanol/water. 7. Etidronate disodium obtainable by a method as claimed in one of claims 1 to 6, having a mainly amorphous solid form and having a particle size of 0.2 - 1 mm with a bulk density of 0.4 - 0.6 g/cm3.

Documents:

545-delnp-2003-abstract.pdf

545-delnp-2003-claims.pdf

545-delnp-2003-complete specification (granted).pdf

545-delnp-2003-correspondence-others.pdf

545-delnp-2003-correspondence-po.pdf

545-delnp-2003-description (complete).pdf

545-delnp-2003-drawings.pdf

545-delnp-2003-form-1.pdf

545-delnp-2003-form-19.pdf

545-delnp-2003-form-2.pdf

545-delnp-2003-form-3.pdf

545-delnp-2003-form-5.pdf

545-delnp-2003-gpa.pdf

545-delnp-2003-pct-210.pdf

545-delnp-2003-pct-301.pdf

545-delnp-2003-pct-304.pdf

545-delnp-2003-pct-306.pdf

545-delnp-2003-pct-318.pdf

545-delnp-2003-pct-338.pdf

545-delnp-2003-pct-409.pdf

545-delnp-2003-petition-137.pdf