Title of Invention	A PROCESS FOR MAKING CRYSTALS OF A 11β-BENZALDOXIM-ESTRA-4,9-DIENE DERIVATIVE
Abstract	What is described is a process for making crystals having a predetermined average particle size in a predetermined size range and a maximum particle size that does not exceed a predetermined maximum value, which includes subjecting a supersaturated solution containing a special 11b-benzaldoxim-estra-4,9-diene to a wet milling by a wet milling apparatus while crystallizing, in order to obtain a primary particle suspension. Crystals obtained according to this process and pharmaceutical preparations containing them are also described.

Title of Invention

A PROCESS FOR MAKING CRYSTALS OF A 11β-BENZALDOXIM-ESTRA-4,9-DIENE DERIVATIVE

Abstract

What is described is a process for making crystals having a predetermined average particle size in a predetermined size range and a maximum particle size that does not exceed a predetermined maximum value, which includes subjecting a supersaturated solution containing a special 11b-benzaldoxim-estra-4,9-diene to a wet milling by a wet milling apparatus while crystallizing, in order to obtain a primary particle suspension. Crystals obtained according to this process and pharmaceutical preparations containing them are also described.

Full Text	A PROCESS FOR MAKING CRYSTALS OF A 11 b -BENZALDOXIM ESTRA- 4,9-DIENE DERIVATIVE The invention relates to a process for production of crystals, whose average particle size is in a predetermined range and whose maximum particle size does not exceed a predetermined value, to the crystals obtained thereby and to the pharmaceutical preparations containing them, especially to low-dosage preparations. EP 0 648 778 A2 discloses 11 (3-benzaldoxim-estra-4,9-diene derivatives. The synthesis and purification of these compounds is described in that reference. However the crystallization and shaping step is not described in that reference. Like most steroids these compounds are crystallized from a suitable solvent. However, a conventional cooling or displacement crystallization produces a coarse-grain crystallizate, which is not further defined. For low dosage preparations, which contain the effective ingredient in only small amounts, for example 0.1 to 2 percent by weight, special requirements are put on the homogeneity of the active ingredient distribution (content uniformity, CUT) and dissolution kinetics. In these low dosage preparations the active ingredient present in very limited amounts is diluted with the other medicinal ingredients to a considerable extent. A certain average particle size should not be exceeded and the scatter or spread of the distribution should not be too great, so that the uniformity of the effective ingredient distribution remains nearly constant. This maximum particle size depends on the dosage and the application form and can be determined statistically. Furthermore with low dosage formulations the fact that smaller particles dissolve more rapidly in the stomach than larger particles must be considered. A certain particle size must not be exceeded in order to meet the requirement in regard to dissolution kinetics (more than 70% of the effective ingredient is dissolved within 45 minutes). Currently crystallizates are micronized in a jet mill according to traditional engineering to obtain the required uniformity of effective-ingredient distribution and dissolution kinetics, especially for low-dosage preparations. Average grain sizes of from 1.5 to 3 urn are obtained. However, there is an enormous increase in surface area as well as a thermodynamic activation of the surface by partial amorphization and/or by considerable destruction or perturbation of lattice structure. These physical changes cause a considerable chemical destabilization of the effective ingredient not only in its pure form, but also and above all, when it is present in a pharmaceutical preparation. The carbamate functional group of the above-mentioned 11b-benzaldoxim-estra-4,9-diene derivative decomposes to form a nitrile by splitting off ethylamine and CO2, The use of a micronizate thus evidently leads to medicinal preparations, in which the effective ingredient is not sufficiently stable under ICH, i.e. (40°C, 70% relative humidity). Lowering the milling pressure of course leads to a slight increase in the average particle size, but also to an undesirable increase in its spread. However a certain minimum pressure is absolutely required for operation of the mill. It has currently been possible to use the form of the solid to obtain better chemical stability through the micronization parameters to an only very limited extent. It is an object of the present invention to provide a process for making crystals which do not have the disadvantages of the known prior art processes and which fulfill the requirements of low-dosage preparations. According to the invention this object is attained by a process for making crystals, whose average grain or particle size is in a predetermined range and whose maximum particle size does not exceed a predetermined value. This process comprises subjecting a supersaturated solution containing the 11b-benzaldoxim-estra-4,9-diene derivative of formula (1) wherein R1 represents hydrogen or an alkyl group with 1 to 6 carbon atoms; R2 represents hydrogen, an alkyl, aryl, aralkyl, or alkylaryl group with 1 to 10 carbon atoms, an acyl group with 1 to 10 carbon atoms or a -CONHR4 group or a -COOR4 group, wherein R4 represents hydrogen, an alkyl, aryl, aralkyl, or alkylaryl group with 1 to 10 carbon atoms; R3 represents hydrogen, an alkyl, aryl, aralkyl, or alkylaryl group with 1 to 10 carbon atoms, or a -(CH2)n-CH2X group, wherein n is 0, 1 or 2, X represents hydrogen, an alkyl, aryl, aralkyl, or alkylaryl group with 1 to 10 carbon atoms, a fluoro group, a chloro group, a bromo group, an iodo group, a cyano group, an azido group, a rhodano group, an -OR5 group or an SR5 group, wherein R5 represents hydrogen, an alkyl, aryl, aralkyl, or alkylaryl group with 1 to 10 carbon atoms, or an acyl group with 1 to 10 carbon atoms; an OR5 group, whherein R5 is as defined above; a -(CH2)0-CH=CH(CH2)p-R6 group, wherein o is 0, 1, 2 or 3 and p is 0, 1 or 2 and R6 represents hydrogen, an alkyl, aryl, aralkyl, or alkylaryl group with 1 to 10 carbon atoms, a hydroxyl group, an alkoxy group, or an acyloxy group with 1 to 10 carbon atoms; a -(CH2)qC=CR7 group, wherein q is 0, 1 or 2 and R7 represents hydrogen, a fluoro group, a chloro group, a bromo group or an iodo group, an alkyl, aryl, aralkyl, or alkylaryl group with 1 to 10 carbon atoms, or an acyl group with 1 to 10 carbon atoms; Z represents hydrogen, an alkyl, aryl, aralkyl, or alkylaryl group with 1 to 10 carbon atoms, an acyl group with 1 to 10 carbon atoms, a -CONHR4 group or a -COOR4 group, wherein R4 represents hydrogen, an alkyl, aryl, aralkyl, or alkylaryl group with 1 to 10 carbon atoms; or an an alkali metal atom or an alkaline earth metal atom, or pharmacologically acceptable salts thereof, to a wet milling by means of a wet milling apparatus while crystallizing, in order to obtain a primary particle suspension. With the process according to the present invention it is surprisingly possible to obtain crystals which are sufficiently stable and which are adjusted in regard to their particle size parameter and thus correct in regard to pharmaceutical requirements for homogeneity of the active ingredient distribution (CUT) and dissolution kinetics for low-dosage formulations. Furthermore the grain size distribution for a certain dosage can be made with a high accuracy and reproducibiiity. Furthermore the process according to the invention can be performed simply, rapidly and in a cost-effective manner. The compound used is 11b-{4-[(ethylamino-carbonyl)oximinomethyl]phenyl}-17b-methoxy-17a- methoxymethyl-estra-4,9-dien-3-one in a preferred embodiment of the process according to the invention. The use of this particular compound in the process according to the invention provides the above-described advantages in a particularly good manner. The invention will now be illustrated in more detail with reference to the accompanying figures in which: FIG. 1 is the IR spectrum of 113-{4-[(ethylaminocarbonyl)oximino-methyl]phenyl}-17p-methoxy- 17a-methoxymethyl-estra-4,9-dien-3-one (J956); FIG. 2 shows nitrile formation as a function of particle size; FIGs. 3 and 4 show the development of the grain size in the crystallization process according to the invention. The average particle size preferably amounts to from 3 pm to 25 urn, especially from 7 urn to 15 mm. The maximum particle size preferably does not exceed 100 pm, more preferably 80 mm. The "maximum particle size" means that no particle has a size that is greater than the stated value. Within these limits for the average particle size and the maximum particle size the particle size distribution is selected in a beneficial way so that the pharmaceutical specifications regarding CUT and dissolution kinetics correspond to those for low-dosage preparations. In the process according to the invention a supersaturated solution of a compound of formula (1) is used. The solution contains the compound of formula (1) as a solute, which is dissolved for that purpose in a solvent. The term "solvent" is understood to also encompass mixtures of different solvents. A supersaturated solution, for example prepared by cooling, used in the process according to the invention contains more dissolved material than it would when the solution is in thermodynamic equilibrium. Supersaturated solutions, in which crystal nuclei spontaneously form, can be used in the process according to the invention. In a preferred embodiment of the process according to the invention the supersaturated solution contains from 10 percent by weight to 30 percent by weight, preferably about 20 percent by weight, of the compound of formula (1), in relation to the supersaturated solution. The above- described advantages of the process according to the invention can be achieved in an especially beneficial manner with these supersaturated solutions. The splvent used to prepare the supersaturated solution is preferably ethyl acetate, which has proven to be particularly good for making supersaturated solutions of the compounds of formula (1). The preparation of the supersaturated solutions can occur in the usual manner. Preferably the supersaturated solution is made by dissolving the compound of formula (1) in a solvent at a temperature below the boiling point and subsequently cooling to a temperature above the freezing point of the solution. If ethyl acetate is used as the solvent for the supersaturated solution, which is preferred, in the process according to the invention, the heating can occur, for example, at about 70°C, until the compound of formula (1) has dissolved in the ethyl acetate and the resulting solution appears to be clear. Cooling can take place during a period from 10 minutes to one hour, preferably 15 minutes to 30 minutes, at about 50 to 10°C, preferably 30 to 35°C. One skilled in the art can easily ascertain the parameters for making a supersaturated solution with another solvent than ethyl acetate. The crystallization is advantageously performed in a vessel, which is equipped with a stirrer. Examples thereof are the crystallization vessels known per se for technical applications. In the process according to the invention wet milling is performed by a wet milling apparatus during crystallization. The crystallization can proceed from the saturated solution, after the wet milling has been started. Suitable apparatus for wet milling are dispersion tools and homogenizers, such as rotor-stator apparatuses, stirring mills, cylinder mills and colloid mills. The manufacture of the crystals according to the invention occurs, as already described above, by crystallization from a solvent or solvent mixture, preferably from a supersaturated ethyl acetate solution prepared by cooling. During the crystallization a wet milling is performed by means of a wet milling apparatus, especially a rotor-stator apparatus or a colloid mill. The wet milling is performed either shortly after crystallization has begun or before it has begun. The apparatus for wet milling can be used immediately as an additional stirring device in the crystallization vessel or in a by-pass loop that goes around the crystallization vessel. If a rotor- stator apparatus is used, the peripheral rotation speed can be 10 m/s to 50 m/s, preferably 20 m/s to 40 m/s. A very high secondary nuclei formation rate is produced by the additional energy input caused by the wet milling, especially by the rotor-stator apparatus. The individual crystal growth is greatly reduced because of that energy input. Also, any agglomerates formed are broken up in narrow gaps. Thus a fine primary particle is the result, whose average particle size is between 3 urn and 5 urn, depending on the setting of supersaturation and peripheral speed of the rotor, and whose maximum particle size is not greater than 25 mm to 60 urn. These particle parameters can already be sufficient for low dose formulations. In order to be able to make crystals that meet the pharmaceutical requirements, even for larger particle sizes, with a definite particle size distribution with suitable accuracy and better reproducibility, the primary suspension is preferably subjected to an oscillatory temperature profile. For that purpose the fine primary particle suspension produced is heated to a temperature Tmax below the solubility limit of the primary particles in the suspension and subsequently cooled slowly to a temperature Tmin, which is above the freezing point of the suspension. On heating the fine-grained fraction of the primary particle suspension is dissolved and precipitated on the coarse particle fraction present during a subsequent cooling process. Because of that a defined shift in the particle size distribution to the larger range occurs. Preferably Tmax is selected so that from 10 to 90, preferably 20 to 50 and more preferably about 30, percent by weight of the primary particles are dissolved in the solvent. The fraction of dissolved primary particles is selected according to the predetermined grain size, which again is determined by the type of low-dosage formulation. If a high proportion of the primary particles dissolve, coarser particles result. In a preferred embodiment of the process according to the invention Tmin is selected so that the dissolved primary particles substantially re-crystallize again. If it is particularly desirable to reduce the losses of the compound of formula (1), nearly all of the dissolved primary particles are re-crystallized on the still remaining primary particles. The cooling from Tmax to Tmin preferably occurs during 1 minute to 10 hours, especially during 0.5 hours to 2 hours. The cooling side of the temperature profile should be controlled so that the fresh nuclei formation is kept as small as possible. The size of this coarsening depends on the amount of the crystallizate dissolved in the heating cycle, which again is determined by the position of both temperatures Tmax and Tmin in relation to the solubility limit and the solid concentration of the suspension. This heating-cooling cycle can be repeated often, preferably 1 to 10 times, until the desired particle size distribution is obtained. The controlling parameters are thus Tmax, Tmin and the number of cycles. The less the desired coarsening, the less Tmax should be. Thus one can approach the desired final particle size with small steps. The development of the dissolved portion of the crystallizate in the heating periods is thus dimensioned so that the maximum particle diameter increases still only to a very small extent and the coarsening occurs in the region of the finer particles. Thus, for example, during dissolution and re-crystallization of 40 percent of the J956 precipitated from a 20 percent by weight ethyl acetate solution, the average particle diameter (x50) increases from 4.9 urn to 7.8 urn while the increase of the maximum particle size (x100) is scarcely measurable. That means that the particle size distribution is considerably narrowed during growth of the average value (x50) of the particle diameter. This effect is especially advantageous for pharmaceutical applications, especially for obtaining suitable CUT values and dissolution properties. After passing through the oscillatory temperature profile the obtained crystal suspension can be filtered and washed with a solvent, since the compound of formula (1) is only soluble to a small extent, for example less than 1 percent by weight. For example, these solvents are methyl-t.- butyl ether, hexane, heptane, water or mixtures of two or more of these solvents. Because of that, in the subsequent drying process, which occurs preferably by a drying gas or in vacuum directly in the filtration unit, bridge formation and agglomeration of the particles are avoided. The drying can occur by convection or vacuum drying in a stirred or moving bed. When a conventional filtration and drying is difficult and leads to impairment of the particle size distribution produced during the crystallization, for example in the case of very fine particle sizes, alternatively the filtered and washed filter cake is suspended with a suspending liquid. The suspending liquid should be a liquid, preferably water, in which the compound of formula (1) is only slightly soluble, for example less than one percent by weight. The obtained suspension can be converted into the dried solid form of the compound of formula (1) by spray drying. The subject matter of the invention also includes crystals of the compound of formula (1), which are obtained by the process according to the invention. Reference is made to the above description in which the process according to the invention has been described in detail. If the steroid 1ip-{4-t(ethylamino-carbonyl)oximinomethyl]phenyl}-17p-methoxy-17a- methoxymethyl-estra-4,9-dien-3-one (referred to hereinafter as J956) is used as the compound of formula (1) in the process according to the invention, the X-ray powder diffraction data shown in Table I below and the IR spectrum shown in FIG. 1 are obtained. Two crystal forms of the compound J956 are known, but only one of these forms is pharmaceutically relevant. The above-described process according to the invention produces this pharmaceutically relevant crystal form and the X-ray powder diffraction data are given in Table 1. Comparison of the observed d-values with the theoretical d-values shows that the deviation is in the range of less than 1%. The present invention also relates to pharmaceutical formulations or preparations, which contain the crystals of the compounds of formula (1). As pharmaceutically effective medicinally effective drug forms, for example hard gelatin capsules or tablets with and without coatings are used, in particular, for peroral administration. The drugs made with the microcrystalline steroid of formula (1) should not impair the chemical and crystalline stability of the microcrystals. This can be achieved by - including a light protective means or agent with the medicinally effective ingredient, for example a colored capsule jacket or applying a colored coating; - not including a surface-increasing adjuvant, such as a highly dispersed silicon dioxide; - using, if possible, no or only water as solvent or auxiliary agent, and/or - keeping the water content of the medicinally effective ingredient low by a sufficient drying. An example of a suitable capsule recipe or formula is provided in Table 2. Table 2: Suitable capsule recipe for composition containing 1 mg of J956 In Table 3 an example of a suitable tablet recipe is provided. Table 3: Suitable capsule recipe for composition containing 1 mg of J956 An essential result of the invention is that microcrystals of the steroid of formula (1) are obtained, which are chemically considerably more stable than currently known micronizates, since first they have a reduced specific surface area and second they have crystalline surfaces that are unperturbed by the crystallization process according to the invention and highly crystalline. In FIG. 2 the stability of the microcrystals regarding nitrile formation under thermal stress (80%, 28% relative humidity) is shown in comparison to micronizates. It shows that the microcrystals with increased particle size in comparison to a micronizate have a considerably improved stability, which results in a reduced generation of nitrile. Another result is that the microcrystals of the steroid of formula (1) obtained by the process according to the invention correspond in terms of their particle size distribution and solubility properties to the pharmaceutical requirements of drugs regarding CUT and dissolution properties. It has been shown that the obtained release values are not inferior to those using micronized solids for comparison (Table 4 and Table 5) for the 1 mg capsule and 1 mg tablet examples. Table 4: J956: Comparative release values for comparison of 1 mg capsule with a micronized effective ingredient to 1 mg capsule with microcrystaltine solids Table 5: J956: CUT value spread for 1 mg capsule with a micronized effective ingredient versus 1 mg capsule with microcrystalline solids Table 6: J956: Comparative release values for comparison of 1 mg tablet with a micronized effective ingredient to 1 mg tablet with microcrystalline solids A further important result is that the pharmaceutically required particle size distribution of the steroid of formula (1) can be produced with high reproducibility and accuracy with the process according to the invention. In FIGS. 3 and 4 the development of the grain size or particle size in the crystallization process is illustrated. The scatter of the particle size distribution is clearly reduced and the maximum grain size is clearly only slightly increased in spite of a multiple increase in the average particle size. This assists in attaining good CUT values, also for low- dosage formulations. Furthermore the grain size distribution produced in the suspension also is maintained in the dried solid body. Finally a pharmaceutical formulation has been found, which provides a chemically stable and pharmaceutically effective medicinal preparation using the microcrystals produced by the process according to the invention. Drugs with the microcrystals according to the invention made of the steroid of formula (1) can advantageously be used for the following applications. Steroids of formula (1), especially J956, are antigestagen-acting substances, which have a considerably reduced antiglucocorticoid activity in comparison to RU 486 (mifeprison), but with the same activity as RU 486 at the progesterone receptor. J956 is designated as "mesoprogestin", whereby it is characterized as a compound, which has both agonistic and also antagonistic activity in vivo at the progesterone receptor (PR). Accordingly functional states can be attained that have gestagen and antigestagen activity. J956 itself is suitable for the following applications: It can be employed, as the case may be, together with an estrogen to make a female contraceptive preparation. It can also be used for treatment and prevention of benign hormone-dependent gynecological maladies, for example for treatment of gynecological conditions, such as endometriosis, uterine fibroids, post-operative peritoneal adhesion, dysfunctional bleeding (metrorrhagia, menorrhagia) and dysmenorrhea, as well as for prevention of gynecological conditions, such as post- operative peritoneal adhesion, dysfunctional uterus bleeding (metrorrhagia, menorrhagia) and dysmenorrhea. The daily dosage of mesoprogestin can be 0.5 mg to 100 mg, preferably 5.0 mg to 50 mg, and at its strongest preferably amounts to 10 mg to 25 mg. J956 can similarly be used together with an estrogen as a pharmaceutical ingredient for making a medicine for hormone replacement therapy (HRT) and treatment of hormone deficiencies and symptoms of hormone irregularities. The following measurement procedures are used to obtain the experimental data. X-Ray Powder Diffractometry (X-Ray Powder Diffraction; XRPD): Data were collected with with a STOE Powder Diffractometer STADIP with a Germanium monochrometer CuKa-)-radiation (X = 1.540598 A) - between 3° IR Spectroscopy: A NICOLET 20 SXB with photoacoustic detector MTEC (KBr, 8t, 90 seconds) was used. Particle size distribution: Sympatec HELOS (H0445), dry dispersion system (RODOS), pressure 2 bar. HPLC: The purity determination took place by the following method: Column: Hypersil ODS, 250 x 4 mm; 5 urn Eluent: acetonitrile-tetrahydofuran mixture (3:1) / water = 4/6 Flow: 1 ml / min Detection UV (299 nm) Evaluation: 100 % surface normalization Headspace for residual solvent: GC-autosystem with HS40 Perkin Elmer, column: DB-wax, 30 m x 0.23 mm, FID. Water determination occurred according to Karl Fischer Content Uniformity Test Content determination according to USP/Ph. Eur. for individual capsules after elution through HPLC with external calibration Column: LiChrosphere 5 u RP-18 encapped, 150 x 3 mm Eluent: acetonitrile / water = 45/55 Flow: 1 ml / min Detection UV (272 nm) Active ingredient release: Active ingredient release in 1000 ml water with 0.3 % sodium dodecyl sulfate, 100 rpm Content determination by HPLC with exteral calibration Column: LiChrosphere 5 u RP-18 encapped, 150 x 3 mm Eluent: acetonitrile / water = 45/55 Flow: 1 ml / min Detection UV (272 nm) The following examples serve to illustrate the invention, but do not limit the broad concept of the invention expressed generally above or in the claims appended below. Example 1 In a glass reactor with an anchor agitator and a double-wall heating/cooling jacket 250 g of carbamate J956 are dissolved in 1100 ml ethyl acetate at 70°C. The clear solution is cooled within 30 minutes to 35°C. A rotor-stator dispersing apparatus is used to prepare this solution. It is operated with a rotation speed of 8000 to 13000 rpm. After 2 to 5 minutes crystallization begins. The Ultra Turrax is operated for an additional 10 minutes and then is shut off. The starting suspension obtained is heated at 55°C and subsequently cooled within an interval of 1 hour 20 minutes to 20cC. This procedure is repeated still twice more. Subsequently the suspension is filtered by a frit and washed with 500 ml of cold MtBE. Subsequently the filter cake is sucked dry with air. Microcrystals are obtained with the following particle size distribution: Example 2 In a sulfonation flask with a blade mixer and a thermostat-equipped heating/cooling bath 50 g of J956 are dissolved in 200 g of ethyl acetate at 70°C. The clear solution is cooled within 15 minutes to 35°C. A rotor-stator dispersing apparatus (Ultra Turrax) is introduced and operated with a rotation speed of 12000 to 16000 rpm. After 2 minutes crystallization begins. The Ultra Turrax is operated for an additional 10 minutes and then is shut off. The starting suspension obtained is heated at 50°C and subsequently cooled within an interval of 1 hour at 20°C. This procedure is repeated still twice more. Subsequently the suspension is filtered by means of a frit and washed with 100 ml MtBE. The filter cake is washed with 1000 ml water very thoroughly and subsequently suspended with 300 g water. The suspension is spray-dried under the following conditions in a laboratory spray-drier with two nozzles (2 mm) (QVF/Yamato): Microcrystals are obtained in the separating filter of the spray-drier with the following particle size distribution: Microcrystalline J956 is mixed with microcrystalline cellulose in a suitable mixer (e.g. container mixer). The magnesium stearate is added and mixed several times. The absence of water in the unit is tested. The mixture is filled in a hard gelatin capsule, size 3, with a suitable capsule filling machine (e.g. Harro Hoeflinger, KFMIIIC). The microcrystalline J956 is mixed with lactose and corn starch in a granulator (e.g. a fluidized bed granulator GPCG 3.1, Glatt Co.). A solution of malto-dextrin in water is sprayed into the mixture. The resulting granulate is then dried (input air temperature 70°C). The granulate is mixed with Na- carboxy-methyl starch and glycerol monobehenate and 150 mg of the resulting mass is pressed to form the tablet core. The tablet core is then sprayed with a suspension of the coating substance in water by means of a suitable coater (e.g. Driacoater 500, Driam). The film arising on the tablet core is then dried (film mass 4 mg, input air temperature 70°C, drying loss of the film tablet 3%). WE CLAIM: 1. A process for making crystals of a 11b-benzaldoxim-estra-4,9-diene derivative, said crystals having an average particle size of from 3 mm to 25 um and a maximum particle size of 100 mm, said process comprising subjecting a supersaturated solution containing said 11b-benzaldoxim-estra-4,9-diene derivative to a wet milling by a wet milling apparatus while crystallizing, in order to obtain a primary particle suspension; wherein said 11b- benzaldoxim-estra-4,9-diene derivative is a compound of formula (I), or a pharmacologically acceptable salt thereof: wherein R1 represents hydrogen or an alkyl group with 1 to 6 carbon atoms; R2 represents hydrogen, an alkyl group with 1 to 10 carbon atoms, an aryl group with 1 to 10 carbon atoms, an aralkyl group with 1 to 10 carbon atoms, an alkylaryl group with 1 to 10 carbon atoms, an acyl group with 1 to 10 carbon atoms or a --CONHR4 group, R3 represents hydrogen, an alkyl group with 1 to 10 carbon atoms, an aryl group with 1 to 10 carbon atoms, an aralkyl group with 1 to 10 carbon atoms, an alkylaryl group with 1 to 10 carbon atoms, or a -(CH2)n-CH2X, an -OR5 group, a -(CH2)o-CH=CH(CH2)p--R6 group or - (CH2)q C=CR7; wherein n is 0, 1 or 2, o is 0, 1, 2 or 3, p is 0, 1 or 2 and q is 0, 1 or 2; wherein X represents hydrogen, a fluoro group, a chloro group, a bromo group, an iodo group, a cyano group, an azido group, a rhodano group, an —OR5 group or an —SR5group; wherein Z represents hydrogen, an alkyl group with 1 to 10 carbon atoms, an aryl group with 1 to 10 carbon atoms, an aralkyl group with 1 to 10 carbon atoms, an alkylaryl group with 1 to 10 carbon atoms, an acyl group with 1 to 10 carbon atoms, a --CONHR4 group, a --COOR4 group, an alkali metal atom or an alkaline earth metal atom; wherein R4 represents an alkyl group with 1 to 10 carbon atoms, an aryl group with 1 to 10 carbon atoms, an aralkyl group with 1 to 10 carbon atoms or an alkylaryl group with 1 to 10 carbon atoms; wherein R5 represents hydrogen, an alkyl group with 1 to 10 carbon atoms, an aryl group with 1 to 10 carbon atoms, an aralkyl group with 1 to 10 carbon atoms, an alkylaryl group with 1 to 10 carbon atoms or an acyl group with 1 to 10 carbon atoms; wherein R6 represents a hydrogen, a hydroxy group, an alkyl group with 1 to 10 carbon atoms, an alkoxy group with 1 to 10 carbon atoms, an aryl group with 1 to 10 carbon atoms, an aralkyl group with 1 to 10 carbon atoms, an alkylaryl group with 1 to 10 carbon atoms, an acyl group with 1 to 10 carbon atoms or an acyloxy group with 1 to 10 carbon atoms; and wherein R7 represents a hydrogen, a fluoro group, a chloro group, a bromo group, an iodo group, an alkyl group with 1 to 10 carbon atoms, an aryl group with 1 to 10 carbon atoms, an aralkyl group with 1 to 10 carbon atoms, an alkylaryl group with 1 to 10 carbon -atoms or an acyl group with 1 to 10 carbon atoms. 2. The process as claimed in claim 1, wherein said 11 P-benzaldoxim-estra-4,9-diene derivative is lip-{4-[(ethylaminocarbonyl)oximinomethyl]phenyl}-7J3-methoxy-17- a- methoxymethyl-estra-4,9-dien-3-one. 3. The process as claimed in claim 1, wherein said supersaturated solution contains from 10 to 30 percent by weight of said compound of said formula (I), based on said supersaturated solution. 4. The process as claimed in claim 3, wherein said supersaturated solution comprises a solvent and said solvent is ethyl acetate. 5. The process as claimed in claim 1, comprising preparing said supersaturated solution by dissolving said compound of formula (I) in a solvent at a temperature below a boiling point of said solvent to form a resulting solution and subsequently cooling said resulting solution to a temperature above a freezing point of the resulting solution. 6. The process as claimed in claim 1, wherein said crystallizing is performed in a vessel or container having a stirring device. 7. The process as claimed in claim 1, wherein said wet milling apparatus is a rotor- stator apparatus, a stirring mill, a roller mill or a colloid mill. 8. The process as claimed in claim 1, comprising heating said primary particle suspension to a temperature (Tmax) below a solubility limit of primary particles of the primary particle suspension and subsequently cooling to a temperature above a freezing point (Tmin) of the primary particle suspension. 9. The process as claimed in claim 8, wherein said supersaturated solution comprises a solvent and said temperature (Tmax) below said solubility limit is selected so that from 10 to 90 percent by weight of said primary particles dissolve in said solvent. 10. The process as claimed in claim 8, wherein said temperature above said freezing point (Tmin) is selected so that dissolved primary particles are substantially re-crystallized. 11. The process as claimed in claim 8, wherein said cooling from said temperature (Tmax) below said solubility limit to said temperature above said freezing point (Tmin) occurs during a time interval of 1 minute to 10 hours. 12. The process as claimed in claim 8, wherein said heating to said temperature (Tmax) below said solubility limit and said cooling to said temperature above said freezing point is performed from 1 to 10 times. 13. Crystals of a 11 P-benzaldoxim-estra-4,9-diene derivative having an average particle size at from 3um to 25um and a maximum particle size of 100mm, wherein said crystals are made by a process comprising subjecting a supersaturated solution containing said 11b- benzald-oxim-estra-4,9-diene derivative to a wet milling by a wet milling apparatus while crystallizing, in order to obtain a primary particle suspension; wherein said 11b- benzaldoxim-estra-4.9-diene derivative is a compound of formula (I), or a pharmacologically acceptable salt thereof: wherein R1 represents hydrogen or an alkyl group with 1 to 6 carbon atoms; R2 represents hydrogen, an alkyl group with 1 to 10 carbon atoms, an aryl group with 1 to 10 carbon atoms, an aralkyl group with 1 to 10 carbon atoms, an alkylaryl group with 1 to 10 carbon atoms, an acyl group with 1 to 10 carbon atoms or a --CONHR4 group, R3 represents hydrogen, an alkyl group with 1 to 10 carbon atoms, an aryl group with 1 to 10 carbon atoms, an aralkyl group with 1 to 10 carbon atoms, an alkylaryl group with 1 to 10 carbon atoms or a --(CH2)n-CH2X, an--OR5 group, a --(CH2)o--CH=CH(CH2)p--R6 group or - (CH2)q C=CR7; wherein n is 0, 1 or 2, o is 0, 1, 2 or 3, p is 0, 1 or 2 and q is 0, 1 or 2; wherein X represents hydrogen, a fluoro group, a chloro group, a bromo group, an iodo group, a cyano group, an azido group, a rhodano group, an --OR5 group or an —SR5 group; wherein Z represents hydrogen, an alkyl group with 1 to 10 carbon atoms, an aryl group with 1 to 10 carbon atoms, an aralkyl group with 1 to 10 carbon atoms, an alkylaryl group with 1 to 10 carbon atoms, an acyl group with 1 to 10 carbon atoms, a --CONHR4 group, a --COOR4 group, an alkali metal atom or an alkaline earth metal atom; wherein R4 represents an alkyl group with 1 to 10 carbon atoms, an aryl group with 1 to 10 carbon atoms, an aralkyl group with 1 to 10 carbon atoms or an alkylaryl group with 1 to 10 carbon atoms; wherein R5 represents hydrogen, an alkyl group with 1 to 10 carbon atoms, an aryl group with 1 to 10 carbon atoms, an aralkyl group with 1 to 10 carbon atoms, an alkylaryl group with 1 to 10 carbon atoms or an acyl group with 1 to 10 carbon atoms; wherein R6 represents a hydrogen, a hydroxy group, an alkyl group with 1 to 10 carbon atoms, an alkoxy group with 1 to 10 carbon atoms, an aryl group with 1 to 10 carbon atoms, an aralkyl group with 1 to 10 carbon atoms, an alkylaryl group with 1 to 10 carbon atoms, an acyl group with 1 to 10 carbon atoms or an acyloxy group with 1 to 10 carbon atoms; and wherein R7 represents a hydrogen, a fluoro group, a chloro group, a bromo group, an iodo group, an alkyl group with 1 to 10 carbon atoms, an aryl group with 1 to 10 carbon atoms, an aralkyl group with 1 to 10 carbon atoms, an alkylaryl group with 1 to 10 carbon atoms or an acyl group with 1 to 10 carbon atoms. 14. The crystals as claimed in claim 13, wherein said 11 P-benzaldoxim-estra-4,9-diene derivative is 11b- {4-[(ethylaminocarbonyl)oximinomethyl]phenyl} -17b-methoxy-1-7a- methoxymethyl-estra-4,9-dien-3-one. 15. The crystals as claimed in claim 13, wherein said supersaturated solution contains from 10 to 30 percent by weight of said 11b-benzaldoxim-estra-4.9-diene derivative, based on said supersaturated solution, and said process comprises preparing said supersaturated solution by dissolving said 11b-benzaldoxim-estra 4,9-diene derivative in a solvent at a temperature below a boiling point of said solvent to form a resulting solution and subsequently cooling said resulting solution to a temperature above a freezing point of the resulting solution. 16. The crystals as claimed in claim 15, wherein said supersaturated solution comprises a solvent and said solvent is ethyl acetate. 17. The crystals as claimed in claim 13, wherein said supersaturated solution comprises a solvent; said process comprises heating said primary particle suspension to a temperature (Tmax) below a solubility limit of primary particles of the primary particle suspension and subsequently cooling to a temperature above a freezing point (Tmax) of the primary particle suspension and wherein said temperature (Tmax) below said solubility limit is selected so that from 10 to 90 percent by weight of said primary particles dissolve in said solvent and said temperature above said freezing point (Tmin) is selected so that dissolved primary particles are substantially re-crystallized, said cooling from said temperature (Tmax) below said solubility limit to said temperature above said freezing point (Tmin) occurs during a time interval of 1 minute to 10 hours. 18. The crystals as claimed in claim 13, wherein said crystallizing is performed in a vessel or container having a stirring device and said wet milling apparatus is a rotor-stator apparatus, a stirring mill, a roller mill or a colloid mill. 19. A pharmaceutical preparation containing crystals of 11b-benzaldoxim-estra-4,9- diene derivative, said crystals having an average particle size of from 3um to 25um and a maximum particle size of 100mm, wherein said crystals are made by a process comprising subjecting a supersaturated solution containing the 11b-benzaldoxim-estra-4,9-diene derivative to a wet milling by a wet milling apparatus while crystallizing, in order to obtain a primary particle suspension; wherein said 11b-benzaldoxim-estra-4,9-diene derivative is a compound of formula (I), or a pharmacologically acceptable salt thereof: wherein R1 represents hydrogen or an alkyl group with 1 to 6 carbon atoms; Rsup 2 represents hydrogen, an alkyl group with 1 to 10 carbon atoms, an aryl group with 1 to 10 carbon atoms, an aralkyl group with 1 to 10 carbon atoms, an alkylaryl group with 1 to 10 carbon atoms, an acyl group with 1 to 10 carbon atoms or a --CONHR4 group, R3 represents hydrogen, an alkyl group with 1 to 10 carbon atoms, an aryl group with 1 to 10 carbon atoms, an aralkyl group with 1 to 10 carbon atoms, an alkylaryl group with 1 to 10 carbon atoms, or a --(CH2)n--CH2x, an -OR5 group, a --(CH2)O--CH=CH(CH2)PR5 group or-(CH2)q C=CR7; wherein n is 0, 1 or 2, o is 0, 1, 2 or 3, p is 0, 1 or 2 and q is 0, 1 or 2; wherein X represents hydrogen, a fluoro group, a chloro group, a bromo group, an iodo group, a cyano group, an azido group, a rhodano group, an -OR5 group or an --SR5 group; wherein Z represents hydrogen, an alkyl group with 1 to 10 carbon atoms, an aryl group with 1 to 10 carbon atoms, an aralkyl group with 1 to 10 carbon atoms, an alkylaryl group with 1 to 10 carbon atoms, an acyl group with 1 to 10 carbon atoms, a --CONHR4 group, a --COOR4 group, an alkali metal atom or an alkaline earth metal atom; wherein R4 represents an alkyl group with 1 to 10 carbon atoms, an aryl group with 1 to 10 carbon atoms, an aralkyl group with 1 to 10 carbon atoms or an alkylaryl group with 1 to 10 carbon atoms; wherein R5 represents hydrogen, an alkyl group with 1 to 10 carbon atoms, an aryl group with 1 to 10 carbon atoms, an aralkyl group with 1 to 10 carbon atoms, art alkylaryl group with 1 to 10 carbon atoms or an acyl group with 1 to 10 carbon atoms; wherein R6 represents a hydrogen, a hydroxy group, an alkyl group with 1 to 10 carbon atoms, an alkoxy group with 1 to 10 carbon atoms, an aryl group with 1 to 10 carbon atoms, an aralkyl group with 1 to 10 carbon atoms, an alkylaryl group with 1 to 10 carbon atoms, an acyl group with 1 to 10 carbon atoms or an acyloxy group with 1 to 10 carbon atoms; and wherein R7 represents a hydrogen, a fluoro group, a chloro group, a bromo group, an iodo group, an alkyl group with 1 to 10 carbon atoms, an aryl group with 1 to 10 carbon atoms, an aralkyl group with 1 to 10 carbon atoms, an alkylaryl group with 1 to 10 carbon atoms or an acyl group with 1 to 10 carbon atoms. 20. The pharmaceutical preparation as claimed in claim 19, wherein said lip.- benzaldoxim-estra-4,9-diene derivative is lip-{4[(ethylaminocarbonyl)-oximino-rnethyl]- phenyl} -17p-methoxy-17a-methoxymethyl-estra-4,9-dien-3 -one. 21. The pharmaceutical preparation as claimed in claim 19, wherein said crystallizing is performed in a vessel or container having a stirring device and said wet milling apparatus is a rotor-stator apparatus, a stirring mill, a roller mill or a colloid mill. 22. The pharmaceutical preparation as claimed in claim 19, wherein said supersaturated solution contains from 10 to 30 percent by weight of said 11 p-benzaldoxim-estra-4,9-diene derivative, based on said supersaturated solution, and said process comprises preparing said supersaturated solution by dissolving said 11 P-benzaldoxim-estra-4,9-diene derivative in a solvent at a temperature below a boiling point of said solvent to form a resulting solution and subsequently cooling said resulting solution to a temperature above a freezing point of the resulting solution. 23. The pharmaceutical preparation as claimed in claim 22, wherein said solvent is ethyl acetate. What is described is a process for making crystals having a predetermined average particle size in a predetermined size range and a maximum particle size that does not exceed a predetermined maximum value, which includes subjecting a supersaturated solution containing a special 11b-benzaldoxim-estra-4,9-diene to a wet milling by a wet milling apparatus while crystallizing, in order to obtain a primary particle suspension. Crystals obtained according to this process and pharmaceutical preparations containing them are also described.

Full Text

A PROCESS FOR MAKING CRYSTALS OF A 11 b -BENZALDOXIM ESTRA-
4,9-DIENE DERIVATIVE
The invention relates to a process for production of crystals, whose average particle size is in a
predetermined range and whose maximum particle size does not exceed a predetermined
value, to the crystals obtained thereby and to the pharmaceutical preparations containing them,
especially to low-dosage preparations.
EP 0 648 778 A2 discloses 11 (3-benzaldoxim-estra-4,9-diene derivatives. The synthesis and
purification of these compounds is described in that reference. However the crystallization and
shaping step is not described in that reference. Like most steroids these compounds are
crystallized from a suitable solvent. However, a conventional cooling or displacement
crystallization produces a coarse-grain crystallizate, which is not further defined.
For low dosage preparations, which contain the effective ingredient in only small amounts, for
example 0.1 to 2 percent by weight, special requirements are put on the homogeneity of the
active ingredient distribution (content uniformity, CUT) and dissolution kinetics. In these low
dosage preparations the active ingredient present in very limited amounts is diluted with the
other medicinal ingredients to a considerable extent. A certain average particle size should not
be exceeded and the scatter or spread of the distribution should not be too great, so that the
uniformity of the effective ingredient distribution remains nearly constant. This maximum particle
size depends on the dosage and the application form and can be determined statistically.
Furthermore with low dosage formulations the fact that smaller particles dissolve more rapidly in
the stomach than larger particles must be considered. A certain particle size must not be
exceeded in order to meet the requirement in regard to dissolution kinetics (more than 70% of
the effective ingredient is dissolved within 45 minutes).
Currently crystallizates are micronized in a jet mill according to traditional engineering to obtain
the required uniformity of effective-ingredient distribution and dissolution kinetics, especially for
low-dosage preparations. Average grain sizes of from 1.5 to 3 urn are obtained. However, there
is an enormous increase in surface area as well as a thermodynamic activation of the surface
by partial amorphization and/or by considerable destruction or perturbation of lattice structure.
These physical changes cause a considerable chemical destabilization of the effective
ingredient not only in its pure form, but also and above all, when it is present in a
pharmaceutical preparation.
The carbamate functional group of the above-mentioned 11b-benzaldoxim-estra-4,9-diene
derivative decomposes to form a nitrile by splitting off ethylamine and CO2, The use of a
micronizate thus evidently leads to medicinal preparations, in which the effective ingredient is
not sufficiently stable under ICH, i.e. (40°C, 70% relative humidity).
Lowering the milling pressure of course leads to a slight increase in the average particle size,
but also to an undesirable increase in its spread. However a certain minimum pressure is
absolutely required for operation of the mill. It has currently been possible to use the form of the
solid to obtain better chemical stability through the micronization parameters to an only very
limited extent.
It is an object of the present invention to provide a process for making crystals which do not
have the disadvantages of the known prior art processes and which fulfill the requirements of
low-dosage preparations.
According to the invention this object is attained by a process for making crystals, whose
average grain or particle size is in a predetermined range and whose maximum particle size
does not exceed a predetermined value. This process comprises subjecting a supersaturated
solution containing the 11b-benzaldoxim-estra-4,9-diene derivative of formula (1)
wherein
R1 represents hydrogen or an alkyl group with 1 to 6 carbon atoms;
R2 represents hydrogen, an alkyl, aryl, aralkyl, or alkylaryl group with 1 to 10 carbon atoms, an
acyl group with 1 to 10 carbon atoms or a -CONHR4 group or a -COOR4 group, wherein R4
represents hydrogen, an alkyl, aryl, aralkyl, or alkylaryl group with 1 to 10 carbon atoms;
R3 represents hydrogen, an alkyl, aryl, aralkyl, or alkylaryl group with 1 to 10 carbon atoms, or a
-(CH2)n-CH2X group, wherein n is 0, 1 or 2, X represents hydrogen, an alkyl, aryl, aralkyl, or
alkylaryl group with 1 to 10 carbon atoms, a fluoro group, a chloro group, a bromo group, an
iodo group, a cyano group, an azido group, a rhodano group, an -OR5 group or an SR5 group,
wherein R5 represents hydrogen, an alkyl, aryl, aralkyl, or alkylaryl group with 1 to 10 carbon
atoms, or an acyl group with 1 to 10 carbon atoms;
an OR5 group, whherein R5 is as defined above;
a -(CH2)0-CH=CH(CH2)p-R6 group, wherein o is 0, 1, 2 or 3 and p is 0, 1 or 2 and R6 represents
hydrogen, an alkyl, aryl, aralkyl, or alkylaryl group with 1 to 10 carbon atoms, a hydroxyl group,
an alkoxy group, or an acyloxy group with 1 to 10 carbon atoms;
a -(CH2)qC=CR7 group, wherein q is 0, 1 or 2 and R7 represents hydrogen, a fluoro group, a
chloro group, a bromo group or an iodo group, an alkyl, aryl, aralkyl, or alkylaryl group with 1 to
10 carbon atoms, or an acyl group with 1 to 10 carbon atoms;
Z represents hydrogen, an alkyl, aryl, aralkyl, or alkylaryl group with 1 to 10 carbon atoms, an
acyl group with 1 to 10 carbon atoms, a -CONHR4 group or a -COOR4 group, wherein R4
represents hydrogen, an alkyl, aryl, aralkyl, or alkylaryl group with 1 to 10 carbon atoms;
or an an alkali metal atom or an alkaline earth metal atom, or pharmacologically acceptable
salts thereof,
to a wet milling by means of a wet milling apparatus while crystallizing, in order to obtain a
primary particle suspension.
With the process according to the present invention it is surprisingly possible to obtain crystals
which are sufficiently stable and which are adjusted in regard to their particle size parameter
and thus correct in regard to pharmaceutical requirements for homogeneity of the active
ingredient distribution (CUT) and dissolution kinetics for low-dosage formulations. Furthermore
the grain size distribution for a certain dosage can be made with a high accuracy and
reproducibiiity. Furthermore the process according to the invention can be performed simply,
rapidly and in a cost-effective manner.
The compound used is 11b-{4-[(ethylamino-carbonyl)oximinomethyl]phenyl}-17b-methoxy-17a-
methoxymethyl-estra-4,9-dien-3-one in a preferred embodiment of the process according to the
invention. The use of this particular compound in the process according to the invention
provides the above-described advantages in a particularly good manner.
The invention will now be illustrated in more detail with reference to the accompanying figures in
which:
FIG. 1 is the IR spectrum of 113-{4-[(ethylaminocarbonyl)oximino-methyl]phenyl}-17p-methoxy-
17a-methoxymethyl-estra-4,9-dien-3-one (J956);
FIG. 2 shows nitrile formation as a function of particle size;
FIGs. 3 and 4 show the development of the grain size in the crystallization process according to
the invention.
The average particle size preferably amounts to from 3 pm to 25 urn, especially from 7 urn to 15
mm. The maximum particle size preferably does not exceed 100 pm, more preferably 80 mm.
The "maximum particle size" means that no particle has a size that is greater than the stated
value. Within these limits for the average particle size and the maximum particle size the
particle size distribution is selected in a beneficial way so that the pharmaceutical specifications
regarding CUT and dissolution kinetics correspond to those for low-dosage preparations.
In the process according to the invention a supersaturated solution of a compound of formula
(1) is used. The solution contains the compound of formula (1) as a solute, which is dissolved
for that purpose in a solvent. The term "solvent" is understood to also encompass mixtures of
different solvents. A supersaturated solution, for example prepared by cooling, used in the
process according to the invention contains more dissolved material than it would when the
solution is in thermodynamic equilibrium. Supersaturated solutions, in which crystal nuclei
spontaneously form, can be used in the process according to the invention.
In a preferred embodiment of the process according to the invention the supersaturated solution
contains from 10 percent by weight to 30 percent by weight, preferably about 20 percent by
weight, of the compound of formula (1), in relation to the supersaturated solution. The above-
described advantages of the process according to the invention can be achieved in an
especially beneficial manner with these supersaturated solutions.
The splvent used to prepare the supersaturated solution is preferably ethyl acetate, which has
proven to be particularly good for making supersaturated solutions of the compounds of formula
(1).
The preparation of the supersaturated solutions can occur in the usual manner. Preferably the
supersaturated solution is made by dissolving the compound of formula (1) in a solvent at a
temperature below the boiling point and subsequently cooling to a temperature above the
freezing point of the solution. If ethyl acetate is used as the solvent for the supersaturated
solution, which is preferred, in the process according to the invention, the heating can occur, for
example, at about 70°C, until the compound of formula (1) has dissolved in the ethyl acetate
and the resulting solution appears to be clear. Cooling can take place during a period from 10
minutes to one hour, preferably 15 minutes to 30 minutes, at about 50 to 10°C, preferably 30 to
35°C. One skilled in the art can easily ascertain the parameters for making a supersaturated
solution with another solvent than ethyl acetate.
The crystallization is advantageously performed in a vessel, which is equipped with a stirrer.
Examples thereof are the crystallization vessels known per se for technical applications.
In the process according to the invention wet milling is performed by a wet milling apparatus
during crystallization. The crystallization can proceed from the saturated solution, after the wet
milling has been started. Suitable apparatus for wet milling are dispersion tools and
homogenizers, such as rotor-stator apparatuses, stirring mills, cylinder mills and colloid mills.
The manufacture of the crystals according to the invention occurs, as already described above,
by crystallization from a solvent or solvent mixture, preferably from a supersaturated ethyl
acetate solution prepared by cooling. During the crystallization a wet milling is performed by
means of a wet milling apparatus, especially a rotor-stator apparatus or a colloid mill. The wet
milling is performed either shortly after crystallization has begun or before it has begun. The
apparatus for wet milling can be used immediately as an additional stirring device in the
crystallization vessel or in a by-pass loop that goes around the crystallization vessel. If a rotor-
stator apparatus is used, the peripheral rotation speed can be 10 m/s to 50 m/s, preferably 20
m/s to 40 m/s. A very high secondary nuclei formation rate is produced by the additional energy
input caused by the wet milling, especially by the rotor-stator apparatus. The individual crystal
growth is greatly reduced because of that energy input. Also, any agglomerates formed are
broken up in narrow gaps. Thus a fine primary particle is the result, whose average particle size
is between 3 urn and 5 urn, depending on the setting of supersaturation and peripheral speed of
the rotor, and whose maximum particle size is not greater than 25 mm to 60 urn. These particle
parameters can already be sufficient for low dose formulations.
In order to be able to make crystals that meet the pharmaceutical requirements, even for larger
particle sizes, with a definite particle size distribution with suitable accuracy and better
reproducibility, the primary suspension is preferably subjected to an oscillatory temperature
profile. For that purpose the fine primary particle suspension produced is heated to a
temperature Tmax below the solubility limit of the primary particles in the suspension and
subsequently cooled slowly to a temperature Tmin, which is above the freezing point of the
suspension. On heating the fine-grained fraction of the primary particle suspension is dissolved
and precipitated on the coarse particle fraction present during a subsequent cooling process.
Because of that a defined shift in the particle size distribution to the larger range occurs.
Preferably Tmax is selected so that from 10 to 90, preferably 20 to 50 and more preferably about
30, percent by weight of the primary particles are dissolved in the solvent. The fraction of
dissolved primary particles is selected according to the predetermined grain size, which again is
determined by the type of low-dosage formulation. If a high proportion of the primary particles
dissolve, coarser particles result.
In a preferred embodiment of the process according to the invention Tmin is selected so that the
dissolved primary particles substantially re-crystallize again. If it is particularly desirable to
reduce the losses of the compound of formula (1), nearly all of the dissolved primary particles
are re-crystallized on the still remaining primary particles.
The cooling from Tmax to Tmin preferably occurs during 1 minute to 10 hours, especially during
0.5 hours to 2 hours.
The cooling side of the temperature profile should be controlled so that the fresh nuclei
formation is kept as small as possible. The size of this coarsening depends on the amount of
the crystallizate dissolved in the heating cycle, which again is determined by the position of both
temperatures Tmax and Tmin in relation to the solubility limit and the solid concentration of the
suspension. This heating-cooling cycle can be repeated often, preferably 1 to 10 times, until the
desired particle size distribution is obtained. The controlling parameters are thus Tmax, Tmin and
the number of cycles. The less the desired coarsening, the less Tmax should be. Thus one can
approach the desired final particle size with small steps. The development of the dissolved
portion of the crystallizate in the heating periods is thus dimensioned so that the maximum
particle diameter increases still only to a very small extent and the coarsening occurs in the
region of the finer particles. Thus, for example, during dissolution and re-crystallization of 40
percent of the J956 precipitated from a 20 percent by weight ethyl acetate solution, the average
particle diameter (x50) increases from 4.9 urn to 7.8 urn while the increase of the maximum
particle size (x100) is scarcely measurable. That means that the particle size distribution is
considerably narrowed during growth of the average value (x50) of the particle diameter. This
effect is especially advantageous for pharmaceutical applications, especially for obtaining
suitable CUT values and dissolution properties.
After passing through the oscillatory temperature profile the obtained crystal suspension can be
filtered and washed with a solvent, since the compound of formula (1) is only soluble to a small
extent, for example less than 1 percent by weight. For example, these solvents are methyl-t.-
butyl ether, hexane, heptane, water or mixtures of two or more of these solvents. Because of
that, in the subsequent drying process, which occurs preferably by a drying gas or in vacuum
directly in the filtration unit, bridge formation and agglomeration of the particles are avoided.
The drying can occur by convection or vacuum drying in a stirred or moving bed.
When a conventional filtration and drying is difficult and leads to impairment of the particle size
distribution produced during the crystallization, for example in the case of very fine particle
sizes, alternatively the filtered and washed filter cake is suspended with a suspending liquid.
The suspending liquid should be a liquid, preferably water, in which the compound of formula
(1) is only slightly soluble, for example less than one percent by weight. The obtained
suspension can be converted into the dried solid form of the compound of formula (1) by spray
drying.
The subject matter of the invention also includes crystals of the compound of formula (1), which
are obtained by the process according to the invention. Reference is made to the above
description in which the process according to the invention has been described in detail.
If the steroid 1ip-{4-t(ethylamino-carbonyl)oximinomethyl]phenyl}-17p-methoxy-17a-
methoxymethyl-estra-4,9-dien-3-one (referred to hereinafter as J956) is used as the compound
of formula (1) in the process according to the invention, the X-ray powder diffraction data shown
in Table I below and the IR spectrum shown in FIG. 1 are obtained.
Two crystal forms of the compound J956 are known, but only one of these forms is
pharmaceutically relevant. The above-described process according to the invention produces
this pharmaceutically relevant crystal form and the X-ray powder diffraction data are given in
Table 1. Comparison of the observed d-values with the theoretical d-values shows that the
deviation is in the range of less than 1%.
The present invention also relates to pharmaceutical formulations or preparations, which
contain the crystals of the compounds of formula (1). As pharmaceutically effective medicinally
effective drug forms, for example hard gelatin capsules or tablets with and without coatings are
used, in particular, for peroral administration. The drugs made with the microcrystalline steroid
of formula (1) should not impair the chemical and crystalline stability of the microcrystals. This
can be achieved by
- including a light protective means or agent with the medicinally effective ingredient, for
example a colored capsule jacket or applying a colored coating;
- not including a surface-increasing adjuvant, such as a highly dispersed silicon dioxide;
- using, if possible, no or only water as solvent or auxiliary agent, and/or
- keeping the water content of the medicinally effective ingredient low by a sufficient drying.
An example of a suitable capsule recipe or formula is provided in Table 2.
Table 2: Suitable capsule recipe for composition containing 1 mg of J956
In Table 3 an example of a suitable tablet recipe is provided.
Table 3: Suitable capsule recipe for composition containing 1 mg of J956
An essential result of the invention is that microcrystals of the steroid of formula (1) are
obtained, which are chemically considerably more stable than currently known micronizates,
since first they have a reduced specific surface area and second they have crystalline surfaces
that are unperturbed by the crystallization process according to the invention and highly
crystalline.
In FIG. 2 the stability of the microcrystals regarding nitrile formation under thermal stress (80%,
28% relative humidity) is shown in comparison to micronizates. It shows that the microcrystals
with increased particle size in comparison to a micronizate have a considerably improved
stability, which results in a reduced generation of nitrile.
Another result is that the microcrystals of the steroid of formula (1) obtained by the process
according to the invention correspond in terms of their particle size distribution and solubility
properties to the pharmaceutical requirements of drugs regarding CUT and dissolution
properties.
It has been shown that the obtained release values are not inferior to those using micronized
solids for comparison (Table 4 and Table 5) for the 1 mg capsule and 1 mg tablet examples.
Table 4: J956: Comparative release values for comparison of 1 mg capsule with a micronized
effective ingredient to 1 mg capsule with microcrystaltine solids
Table 5: J956: CUT value spread for 1 mg capsule with a micronized effective ingredient versus
1 mg capsule with microcrystalline solids
Table 6: J956: Comparative release values for comparison of 1 mg tablet with a micronized
effective ingredient to 1 mg tablet with microcrystalline solids
A further important result is that the pharmaceutically required particle size distribution of the
steroid of formula (1) can be produced with high reproducibility and accuracy with the process
according to the invention. In FIGS. 3 and 4 the development of the grain size or particle size in
the crystallization process is illustrated. The scatter of the particle size distribution is clearly
reduced and the maximum grain size is clearly only slightly increased in spite of a multiple
increase in the average particle size. This assists in attaining good CUT values, also for low-
dosage formulations.
Furthermore the grain size distribution produced in the suspension also is maintained in the
dried solid body.
Finally a pharmaceutical formulation has been found, which provides a chemically stable and
pharmaceutically effective medicinal preparation using the microcrystals produced by the
process according to the invention.
Drugs with the microcrystals according to the invention made of the steroid of formula (1) can
advantageously be used for the following applications. Steroids of formula (1), especially J956,
are antigestagen-acting substances, which have a considerably reduced antiglucocorticoid
activity in comparison to RU 486 (mifeprison), but with the same activity as RU 486 at the
progesterone receptor. J956 is designated as "mesoprogestin", whereby it is characterized as a
compound, which has both agonistic and also antagonistic activity in vivo at the progesterone
receptor (PR). Accordingly functional states can be attained that have gestagen and
antigestagen activity. J956 itself is suitable for the following applications: It can be employed, as
the case may be, together with an estrogen to make a female contraceptive preparation. It can
also be used for treatment and prevention of benign hormone-dependent gynecological
maladies, for example for treatment of gynecological conditions, such as endometriosis, uterine
fibroids, post-operative peritoneal adhesion, dysfunctional bleeding (metrorrhagia, menorrhagia)
and dysmenorrhea, as well as for prevention of gynecological conditions, such as post-
operative peritoneal adhesion, dysfunctional uterus bleeding (metrorrhagia, menorrhagia) and
dysmenorrhea. The daily dosage of mesoprogestin can be 0.5 mg to 100 mg, preferably 5.0 mg
to 50 mg, and at its strongest preferably amounts to 10 mg to 25 mg. J956 can similarly be used
together with an estrogen as a pharmaceutical ingredient for making a medicine for hormone
replacement therapy (HRT) and treatment of hormone deficiencies and symptoms of hormone
irregularities.
The following measurement procedures are used to obtain the experimental data.
X-Ray Powder Diffractometry (X-Ray Powder Diffraction; XRPD):
Data were collected with with a STOE Powder Diffractometer STADIP with a Germanium
monochrometer CuKa-)-radiation (X = 1.540598 A) - between 3° IR Spectroscopy:
A NICOLET 20 SXB with photoacoustic detector MTEC (KBr, 8t, 90 seconds) was used.
Particle size distribution:
Sympatec HELOS (H0445), dry dispersion system (RODOS), pressure 2 bar.
HPLC:
The purity determination took place by the following method:
Column: Hypersil ODS, 250 x 4 mm; 5 urn
Eluent: acetonitrile-tetrahydofuran mixture (3:1) / water = 4/6
Flow: 1 ml / min
Detection UV (299 nm)
Evaluation: 100 % surface normalization
Headspace for residual solvent:
GC-autosystem with HS40 Perkin Elmer, column: DB-wax, 30 m x 0.23 mm, FID.
Water determination occurred according to Karl Fischer
Content Uniformity Test
Content determination according to USP/Ph. Eur. for individual capsules after elution through
HPLC with external calibration
Column: LiChrosphere 5 u RP-18 encapped, 150 x 3 mm
Eluent: acetonitrile / water = 45/55
Flow: 1 ml / min
Detection UV (272 nm)
Active ingredient release:
Active ingredient release in 1000 ml water with 0.3 % sodium dodecyl sulfate, 100 rpm
Content determination by HPLC with exteral calibration
Column: LiChrosphere 5 u RP-18 encapped, 150 x 3 mm
Eluent: acetonitrile / water = 45/55
Flow: 1 ml / min
Detection UV (272 nm)
The following examples serve to illustrate the invention, but do not limit the broad concept of the
invention expressed generally above or in the claims appended below.
Example 1
In a glass reactor with an anchor agitator and a double-wall heating/cooling jacket 250 g of
carbamate J956 are dissolved in 1100 ml ethyl acetate at 70°C. The clear solution is cooled
within 30 minutes to 35°C. A rotor-stator dispersing apparatus is used to prepare this solution. It
is operated with a rotation speed of 8000 to 13000 rpm. After 2 to 5 minutes crystallization
begins. The Ultra Turrax is operated for an additional 10 minutes and then is shut off.
The starting suspension obtained is heated at 55°C and subsequently cooled within an interval
of 1 hour 20 minutes to 20cC. This procedure is repeated still twice more. Subsequently the
suspension is filtered by a frit and washed with 500 ml of cold MtBE.
Subsequently the filter cake is sucked dry with air.
Microcrystals are obtained with the following particle size distribution:
Example 2
In a sulfonation flask with a blade mixer and a thermostat-equipped heating/cooling bath 50 g of
J956 are dissolved in 200 g of ethyl acetate at 70°C. The clear solution is cooled within 15
minutes to 35°C. A rotor-stator dispersing apparatus (Ultra Turrax) is introduced and operated
with a rotation speed of 12000 to 16000 rpm. After 2 minutes crystallization begins. The Ultra
Turrax is operated for an additional 10 minutes and then is shut off.
The starting suspension obtained is heated at 50°C and subsequently cooled within an interval
of 1 hour at 20°C. This procedure is repeated still twice more.
Subsequently the suspension is filtered by means of a frit and washed with 100 ml MtBE. The
filter cake is washed with 1000 ml water very thoroughly and subsequently suspended with 300
g water. The suspension is spray-dried under the following conditions in a laboratory spray-drier
with two nozzles (2 mm) (QVF/Yamato):
Microcrystals are obtained in the separating filter of the spray-drier with the following particle
size distribution:
Microcrystalline J956 is mixed with microcrystalline cellulose in a suitable mixer (e.g. container
mixer). The magnesium stearate is added and mixed several times. The absence of water in the
unit is tested. The mixture is filled in a hard gelatin capsule, size 3, with a suitable capsule filling
machine (e.g. Harro Hoeflinger, KFMIIIC).
The microcrystalline J956 is mixed with lactose and corn starch in a granulator (e.g. a fluidized
bed granulator GPCG 3.1, Glatt Co.). A solution of malto-dextrin in water is sprayed into the
mixture. The resulting granulate is then dried (input air temperature 70°C). The granulate is
mixed with Na- carboxy-methyl starch and glycerol monobehenate and 150 mg of the resulting
mass is pressed to form the tablet core. The tablet core is then sprayed with a suspension of
the coating substance in water by means of a suitable coater (e.g. Driacoater 500, Driam). The
film arising on the tablet core is then dried (film mass 4 mg, input air temperature 70°C, drying
loss of the film tablet 3%).
WE CLAIM:
1. A process for making crystals of a 11b-benzaldoxim-estra-4,9-diene derivative, said
crystals having an average particle size of from 3 mm to 25 um and a maximum particle size
of 100 mm, said process comprising subjecting a supersaturated solution containing said
11b-benzaldoxim-estra-4,9-diene derivative to a wet milling by a wet milling apparatus
while crystallizing, in order to obtain a primary particle suspension; wherein said 11b-
benzaldoxim-estra-4,9-diene derivative is a compound of formula (I), or a
pharmacologically acceptable salt thereof:
wherein R1 represents hydrogen or an alkyl group with 1 to 6 carbon atoms; R2 represents
hydrogen, an alkyl group with 1 to 10 carbon atoms, an aryl group with 1 to 10 carbon
atoms, an aralkyl group with 1 to 10 carbon atoms, an alkylaryl group with 1 to 10 carbon
atoms, an acyl group with 1 to 10 carbon atoms or a --CONHR4 group, R3 represents
hydrogen, an alkyl group with 1 to 10 carbon atoms, an aryl group with 1 to 10 carbon
atoms, an aralkyl group with 1 to 10 carbon atoms, an alkylaryl group with 1 to 10 carbon
atoms, or a -(CH2)n-CH2X, an -OR5 group, a -(CH2)o-CH=CH(CH2)p--R6 group or -
(CH2)q C=CR7; wherein n is 0, 1 or 2, o is 0, 1, 2 or 3, p is 0, 1 or 2 and q is 0, 1 or 2;
wherein X represents hydrogen, a fluoro group, a chloro group, a bromo group, an iodo
group, a cyano group, an azido group, a rhodano group, an —OR5 group or an —SR5group;
wherein Z represents hydrogen, an alkyl group with 1 to 10 carbon atoms, an aryl group
with 1 to 10 carbon atoms, an aralkyl group with 1 to 10 carbon atoms, an alkylaryl group
with 1 to 10 carbon atoms, an acyl group with 1 to 10 carbon atoms, a --CONHR4 group, a
--COOR4 group, an alkali metal atom or an alkaline earth metal atom; wherein R4 represents
an alkyl group with 1 to 10 carbon atoms, an aryl group with 1 to 10 carbon atoms, an
aralkyl group with 1 to 10 carbon atoms or an alkylaryl group with 1 to 10 carbon atoms;
wherein R5 represents hydrogen, an alkyl group with 1 to 10 carbon atoms, an aryl group
with 1 to 10 carbon atoms, an aralkyl group with 1 to 10 carbon atoms, an alkylaryl group
with 1 to 10 carbon atoms or an acyl group with 1 to 10 carbon atoms; wherein R6
represents a hydrogen, a hydroxy group, an alkyl group with 1 to 10 carbon atoms, an
alkoxy group with 1 to 10 carbon atoms, an aryl group with 1 to 10 carbon atoms, an aralkyl
group with 1 to 10 carbon atoms, an alkylaryl group with 1 to 10 carbon atoms, an acyl
group with 1 to 10 carbon atoms or an acyloxy group with 1 to 10 carbon atoms; and
wherein R7 represents a hydrogen, a fluoro group, a chloro group, a bromo group, an
iodo group, an alkyl group with 1 to 10 carbon atoms, an aryl group with 1 to 10 carbon
atoms, an aralkyl group with 1 to 10 carbon atoms, an alkylaryl group with 1 to 10 carbon
-atoms or an acyl group with 1 to 10 carbon atoms.
2. The process as claimed in claim 1, wherein said 11 P-benzaldoxim-estra-4,9-diene
derivative is lip-{4-[(ethylaminocarbonyl)oximinomethyl]phenyl}-7J3-methoxy-17- a-
methoxymethyl-estra-4,9-dien-3-one.
3. The process as claimed in claim 1, wherein said supersaturated solution contains
from 10 to 30 percent by weight of said compound of said formula (I), based on said
supersaturated solution.
4. The process as claimed in claim 3, wherein said supersaturated solution comprises a
solvent and said solvent is ethyl acetate.
5. The process as claimed in claim 1, comprising preparing said supersaturated
solution by dissolving said compound of formula (I) in a solvent at a temperature below a
boiling point of said solvent to form a resulting solution and subsequently cooling said
resulting solution to a temperature above a freezing point of the resulting solution.
6. The process as claimed in claim 1, wherein said crystallizing is performed in a
vessel or container having a stirring device.
7. The process as claimed in claim 1, wherein said wet milling apparatus is a rotor-
stator apparatus, a stirring mill, a roller mill or a colloid mill.
8. The process as claimed in claim 1, comprising heating said primary particle
suspension to a temperature (Tmax) below a solubility limit of primary particles of the
primary particle suspension and subsequently cooling to a temperature above a freezing
point (Tmin) of the primary particle suspension.
9. The process as claimed in claim 8, wherein said supersaturated solution comprises a
solvent and said temperature (Tmax) below said solubility limit is selected so that from 10 to
90 percent by weight of said primary particles dissolve in said solvent.
10. The process as claimed in claim 8, wherein said temperature above said freezing point
(Tmin) is selected so that dissolved primary particles are substantially re-crystallized.
11. The process as claimed in claim 8, wherein said cooling from said temperature
(Tmax) below said solubility limit to said temperature above said freezing point (Tmin) occurs
during a time interval of 1 minute to 10 hours.
12. The process as claimed in claim 8, wherein said heating to said temperature (Tmax)
below said solubility limit and said cooling to said temperature above said freezing point is
performed from 1 to 10 times.
13. Crystals of a 11 P-benzaldoxim-estra-4,9-diene derivative having an average particle
size at from 3um to 25um and a maximum particle size of 100mm, wherein said crystals are
made by a process comprising subjecting a supersaturated solution containing said 11b-
benzald-oxim-estra-4,9-diene derivative to a wet milling by a wet milling apparatus while
crystallizing, in order to obtain a primary particle suspension; wherein said 11b-
benzaldoxim-estra-4.9-diene derivative is a compound of formula (I), or a
pharmacologically acceptable salt thereof:
wherein R1 represents hydrogen or an alkyl group with 1 to 6 carbon atoms; R2 represents
hydrogen, an alkyl group with 1 to 10 carbon atoms, an aryl group with 1 to 10 carbon
atoms, an aralkyl group with 1 to 10 carbon atoms, an alkylaryl group with 1 to 10 carbon
atoms, an acyl group with 1 to 10 carbon atoms or a --CONHR4 group, R3 represents
hydrogen, an alkyl group with 1 to 10 carbon atoms, an aryl group with 1 to 10 carbon
atoms, an aralkyl group with 1 to 10 carbon atoms, an alkylaryl group with 1 to 10 carbon
atoms or a --(CH2)n-CH2X, an--OR5 group, a --(CH2)o--CH=CH(CH2)p--R6 group or -
(CH2)q C=CR7; wherein n is 0, 1 or 2, o is 0, 1, 2 or 3, p is 0, 1 or 2 and q is 0, 1 or 2;
wherein X represents hydrogen, a fluoro group, a chloro group, a bromo group, an iodo
group, a cyano group, an azido group, a rhodano group, an --OR5 group or an —SR5 group;
wherein Z represents hydrogen, an alkyl group with 1 to 10 carbon atoms, an aryl group
with 1 to 10 carbon atoms, an aralkyl group with 1 to 10 carbon atoms, an alkylaryl group
with 1 to 10 carbon atoms, an acyl group with 1 to 10 carbon atoms, a --CONHR4 group, a
--COOR4 group, an alkali metal atom or an alkaline earth metal atom; wherein R4 represents
an alkyl group with 1 to 10 carbon atoms, an aryl group with 1 to 10 carbon atoms, an
aralkyl group with 1 to 10 carbon atoms or an alkylaryl group with 1 to 10 carbon atoms;
wherein R5 represents hydrogen, an alkyl group with 1 to 10 carbon atoms, an aryl group
with 1 to 10 carbon atoms, an aralkyl group with 1 to 10 carbon atoms, an alkylaryl group
with 1 to 10 carbon atoms or an acyl group with 1 to 10 carbon atoms; wherein R6
represents a hydrogen, a hydroxy group, an alkyl group with 1 to 10 carbon atoms, an
alkoxy group with 1 to 10 carbon atoms, an aryl group with 1 to 10 carbon atoms, an
aralkyl group with 1 to 10 carbon atoms, an alkylaryl group with 1 to 10 carbon atoms, an
acyl group with 1 to 10 carbon atoms or an acyloxy group with 1 to 10 carbon atoms; and
wherein R7 represents a hydrogen, a fluoro group, a chloro group, a bromo group, an iodo
group, an alkyl group with 1 to 10 carbon atoms, an aryl group with 1 to 10 carbon atoms,
an aralkyl group with 1 to 10 carbon atoms, an alkylaryl group with 1 to 10 carbon atoms
or an acyl group with 1 to 10 carbon atoms.
14. The crystals as claimed in claim 13, wherein said 11 P-benzaldoxim-estra-4,9-diene
derivative is 11b- {4-[(ethylaminocarbonyl)oximinomethyl]phenyl} -17b-methoxy-1-7a-
methoxymethyl-estra-4,9-dien-3-one.
15. The crystals as claimed in claim 13, wherein said supersaturated solution contains
from 10 to 30 percent by weight of said 11b-benzaldoxim-estra-4.9-diene derivative, based
on said supersaturated solution, and said process comprises preparing said supersaturated
solution by dissolving said 11b-benzaldoxim-estra 4,9-diene derivative in a solvent at a
temperature below a boiling point of said solvent to form a resulting solution and
subsequently cooling said resulting solution to a temperature above a freezing point of the
resulting solution.
16. The crystals as claimed in claim 15, wherein said supersaturated solution comprises
a solvent and said solvent is ethyl acetate.
17. The crystals as claimed in claim 13, wherein said supersaturated solution comprises
a solvent; said process comprises heating said primary particle suspension to a temperature
(Tmax) below a solubility limit of primary particles of the primary particle suspension and
subsequently cooling to a temperature above a freezing point (Tmax) of the primary particle
suspension and wherein said temperature (Tmax) below said solubility limit is selected so
that from 10 to 90 percent by weight of said primary particles dissolve in said solvent and
said temperature above said freezing point (Tmin) is selected so that dissolved primary
particles are substantially re-crystallized, said cooling from said temperature (Tmax) below
said solubility limit to said temperature above said freezing point (Tmin) occurs during a
time interval of 1 minute to 10 hours.
18. The crystals as claimed in claim 13, wherein said crystallizing is performed in a
vessel or container having a stirring device and said wet milling apparatus is a rotor-stator
apparatus, a stirring mill, a roller mill or a colloid mill.
19. A pharmaceutical preparation containing crystals of 11b-benzaldoxim-estra-4,9-
diene derivative, said crystals having an average particle size of from 3um to 25um and a
maximum particle size of 100mm, wherein said crystals are made by a process comprising
subjecting a supersaturated solution containing the 11b-benzaldoxim-estra-4,9-diene
derivative to a wet milling by a wet milling apparatus while crystallizing, in order to obtain
a primary particle suspension; wherein said 11b-benzaldoxim-estra-4,9-diene derivative is
a compound of formula (I), or a pharmacologically acceptable salt thereof:
wherein R1 represents hydrogen or an alkyl group with 1 to 6 carbon atoms; Rsup 2
represents hydrogen, an alkyl group with 1 to 10 carbon atoms, an aryl group with 1 to 10
carbon atoms, an aralkyl group with 1 to 10 carbon atoms, an alkylaryl group with 1 to 10
carbon atoms, an acyl group with 1 to 10 carbon atoms or a --CONHR4 group, R3
represents hydrogen, an alkyl group with 1 to 10 carbon atoms, an aryl group with 1 to 10
carbon atoms, an aralkyl group with 1 to 10 carbon atoms, an alkylaryl group with 1 to 10
carbon atoms, or a --(CH2)n--CH2x, an -OR5 group, a --(CH2)O--CH=CH(CH2)PR5 group
or-(CH2)q C=CR7; wherein n is 0, 1 or 2, o is 0, 1, 2 or 3, p is 0, 1 or 2 and q is 0, 1 or 2;
wherein X represents hydrogen, a fluoro group, a chloro group, a bromo group, an iodo
group, a cyano group, an azido group, a rhodano group, an -OR5 group or an --SR5 group;
wherein Z represents hydrogen, an alkyl group with 1 to 10 carbon atoms, an aryl group
with 1 to 10 carbon atoms, an aralkyl group with 1 to 10 carbon atoms, an alkylaryl group
with 1 to 10 carbon atoms, an acyl group with 1 to 10 carbon atoms, a --CONHR4 group, a
--COOR4 group, an alkali metal atom or an alkaline earth metal atom; wherein R4
represents an alkyl group with 1 to 10 carbon atoms, an aryl group with 1 to 10 carbon
atoms, an aralkyl group with 1 to 10 carbon atoms or an alkylaryl group with 1 to 10
carbon atoms; wherein R5 represents hydrogen, an alkyl group with 1 to 10 carbon atoms,
an aryl group with 1 to 10 carbon atoms, an aralkyl group with 1 to 10 carbon atoms, art
alkylaryl group with 1 to 10 carbon atoms or an acyl group with 1 to 10 carbon atoms;
wherein R6 represents a hydrogen, a hydroxy group, an alkyl group with 1 to 10 carbon
atoms, an alkoxy group with 1 to 10 carbon atoms, an aryl group with 1 to 10 carbon
atoms, an aralkyl group with 1 to 10 carbon atoms, an alkylaryl group with 1 to 10 carbon
atoms, an acyl group with 1 to 10 carbon atoms or an acyloxy group with 1 to 10 carbon
atoms; and wherein R7 represents a hydrogen, a fluoro group, a chloro group, a bromo
group, an iodo group, an alkyl group with 1 to 10 carbon atoms, an aryl group with 1 to 10
carbon atoms, an aralkyl group with 1 to 10 carbon atoms, an alkylaryl group with 1 to 10
carbon atoms or an acyl group with 1 to 10 carbon atoms.
20. The pharmaceutical preparation as claimed in claim 19, wherein said lip.-
benzaldoxim-estra-4,9-diene derivative is lip-{4[(ethylaminocarbonyl)-oximino-rnethyl]-
phenyl} -17p-methoxy-17a-methoxymethyl-estra-4,9-dien-3 -one.
21. The pharmaceutical preparation as claimed in claim 19, wherein said crystallizing is
performed in a vessel or container having a stirring device and said wet milling apparatus is
a rotor-stator apparatus, a stirring mill, a roller mill or a colloid mill.
22. The pharmaceutical preparation as claimed in claim 19, wherein said supersaturated
solution contains from 10 to 30 percent by weight of said 11 p-benzaldoxim-estra-4,9-diene
derivative, based on said supersaturated solution, and said process comprises preparing said
supersaturated solution by dissolving said 11 P-benzaldoxim-estra-4,9-diene derivative in a
solvent at a temperature below a boiling point of said solvent to form a resulting solution
and subsequently cooling said resulting solution to a temperature above a freezing point of
the resulting solution.
23. The pharmaceutical preparation as claimed in claim 22, wherein said solvent is
ethyl acetate.
What is described is a process for making crystals having a predetermined average particle size
in a predetermined size range and a maximum particle size that does not exceed a
predetermined maximum value, which includes subjecting a supersaturated solution containing
a special 11b-benzaldoxim-estra-4,9-diene to a wet milling by a wet milling apparatus while
crystallizing, in order to obtain a primary particle suspension. Crystals obtained according to this
process and pharmaceutical preparations containing them are also described.

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Patent Number

225199

Indian Patent Application Number

01267/KOLNP/2004

PG Journal Number

45/2008

Publication Date

07-Nov-2008

Grant Date

05-Nov-2008

Date of Filing

30-Aug-2004

Name of Patentee

SCHERING AKTIENGESELLSCHAFT

Applicant Address

MULLERSTRASSE 178, 13353 BERLIN

Inventors:

#	Inventor's Name	Inventor's Address
1	GRAWE DETLEF	AM KOTSCHAUER WEG 10, 99510 KLEINROMSTEDT
2	GERECKE HAGEN	ARVID-HARNACK-STRASSE 26, 07743 JENA
3	HOSEL PETER	SCHEIDLER STRASSE 11, 07745 JENA
4	EICHARDT ANNETTE	AM STEINGRABEN 45, 07616 BURGEL
5	GLIESING SABINE	RIEDSTRASSE 2, 07743 JENA
6	MULLER UWE	IM BURGERGARTEN 17, 07747 JENA

PCT International Classification Number

A61K 9/14

PCT International Application Number

PCT/EP03/05102

PCT International Filing date

2003-04-22

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	102 18 109.8	2002-04-23	Germany