Low hygroscopicity arypyprazole medicinal agent and methods for its preparing

FIELD: medicine, pharmacology.

SUBSTANCE: invention relates to arypyprazole anhydrous crystals B showing characteristic peaks in powdered roentgen rays diffraction at 2θ = 11.0°, 16.6°, 19.3°, 20.3° and 22.1°, specific infrared absorption bands at 2945, 2812, 1678, 1627, 1448, 1377, 1173, 960 and 779 cm-1 in IR-spectrum, endothermic peak at 141.5° in thermogravimetric/differential thermic analysis and endothermic peak at 140.7° C in differential scanning calorimetry, arypyprazole A hydrate, to methods for their preparing, pharmaceutical compositions comprising arypyprazole crystals B and methods for their preparing. Invention provides reduced hygroscopicity of arypyprazole crystals B.

EFFECT: improved preparing method.

57 cl, 14 tbl, 24 ex

 

The scope of the invention

The present invention relates to an improved form of aripiprazole, having low hygroscopicity, and methods of producing this improved form.

Background of invention

Aripiprazole, 7-{4-[4-(2,3-dichlorophenyl)-1-piperazinil]butoxy}-3,4-dihydroxybutyl or 7-{4-[4-(2,3-dichlorophenyl)-1-piperazinil]butoxy}-3,4-dihydro-2(1H)-chinoline, is an atypical antipsychotic agent suitable for the treatment of schizophrenia (U.S. patent 4734416 and U.S. patent 5006528). Schizophrenia is a common type of psychosis characterized by delusions, hallucinations and a pronounced avoidance of communication with other people. Onset of schizophrenia usually occurs between the ages of 16 and 25 years, and schizophrenia usually affects 1 out of 100 individuals worldwide. It is more prevalent than Alzheimer's disease, multiple sclerosis, insulin-dependent diabetes and muscular dystrophy. Early diagnosis and treatment can lead to recovery from greatly improved the condition and the result. In addition, early therapeutic intervention can prevent expensive hospitalization.

In accordance with example 1 of Japanese patent laying No. 191256/1990, crystals of anhydrous aripiprazole get, for example, the interaction of 7-(4-bromobutoxy)-3,4-dihydroorotase with 1-(2,3-dichlorophenylamino) and p is the recrystallization of the resulting crude anhydrous aripiprazole with ethanol. In addition, in accordance with the proceedings of the 4th Japanese-Korean Symposium on separation technology (October 6-8, 1996), crystals of anhydrous aripiprazole obtained by heating aripiprazole hydrate at 80°C. However, the crystals of anhydrous aripiprazole obtained above methods have the disadvantage of a significant hygroscopicity.

The hygroscopicity of these crystals makes the hard manual work with them, as should be made expensive and burdensome measurements to be sure that they are not exposed to moisture during their preparation and cooking of them finished the preparative form. Subjected to the action of moisture anhydrous form can absorb water and turn into water form. This creates several difficulties. First, aquatic forms of aripiprazole have the disadvantage lesser bioavailability and a lower solubility than the anhydrous form of aripiprazole. Secondly, the change in the number of water aripiprazole compared with anhydrous aripiprazole medicinal substance from batch to batch may not meet the specifications established by the organizations that regulate the dose of medicines. Thirdly, the grinding may cause adhesion of medicinal substance, conventional anhydrous aripiprazole, production is nomu equipment which can further lead to slower process, more frequent involvement of the operator in the process, high cost, high maintenance and a lower product yield. Fourth, in addition to the problems caused by the introduction of moisture during processing of these hygroscopic anhydrous forms, the ability to absorb moisture during storage and handling of these forms may have an adverse effect on the solubility aripiprazole medicinal substance. Thus, the shelf life of the product can be greatly reduced and/or can significantly increase the cost of packing. It would be highly desirable to find a form of aripiprazole, which has a low hygroscopicity, in order thereby to facilitate the operation of pharmaceutical processing and cooking of ready preparative forms required to obtain a uniform dosage forms aripiprazole medicinal product with increased shelf life, suitable solubility and appropriate bioavailability.

Additionally, in proceedings of the 4th Japanese-Korean Symposium on separation technology (October 6-8, 1996) indicated that the crystals of anhydrous aripiprazole exist as crystals of type I and type crystals II; crystals of type I of anhydrous aripiprazole can be obtained by recrystallization of aripiprazole and the solution in ethanol, or by heating aripiprazole hydrate at 80° With; and the crystals of type II anhydrous aripiprazole can be obtained by heating crystals of type I of anhydrous aripiprazole at a temperature of from 130 to 140°C for 15 hours.

The above methods crystals of type II anhydrous aripiprazole with high purity, cannot easily obtain on an industrial scale with good reproducibility.

SUMMARY of the INVENTION

Thus, in accordance with the present invention provides a form of aripiprazole, which has a low hygroscopicity and which is amenable to pharmaceutical processing and cooking from it ready preparative form. It was found that this form of aripiprazole with low hygroscopicity is a crystalline substance, defined here as the crystals of anhydrous aripiprazole. Was also open specific way to obtain this anhydrous crystalline substance, it is another aspect of the present invention. In particular, as part of the present invention, it was found that to obtain crystals of anhydrous aripiprazole, which has the desired pharmaceutical properties and for which use the most effective way, the intermediate product may be a hydrate as defined here above. It was also discovered that a particular letter is the sequence of the process flow should be so, to form the hydrate A. it Was found that obtaining hydrate And requiring milling, is defined here as getting a regular hydrate. Then hydrate And can be turned into crystals of anhydrous aripiprazole by suitable heating, as here defined. Oddly enough, if the normal hydrate is first heated and then grind, this leads to a serious agglomeration that make the process commercially unsuitable.

The purpose of this invention is the provision of new crystals of anhydrous aripiprazole.

In addition, another objective of the present invention is to provide crystals of anhydrous aripiprazole, which do not degrade easily in the hydrate, do not reduce significantly the original solubility even when a pharmaceutical composition comprising anhydrous aripiprazole, retain for a long period of time.

The next objective of the present invention is to provide methods of obtaining crystals of anhydrous aripiprazole with high purity on an industrial scale with good reproducibility.

Research was carried out, designed to achieve the above objectives. During the research discovered that the required crystals of anhydrous aripiprazole can be obtained when the good is known about the anhydrous aripiprazole is heated at a certain temperature. In addition, we discovered that the desired crystals of anhydrous aripiprazole can be obtained by recrystallization well-known anhydrous aripiprazole using specific solvents. In addition, we discovered that the desired crystals of anhydrous aripiprazole can be obtained by suspendirovanie well-known anhydrous aripiprazole in a solvent and heating the thus obtained suspension.

The present invention thus created on the basis of these discoveries and knowledge.

BRIEF DESCRIPTION of DRAWINGS

Figure 1 represents a thermogravimetric/differential thermogram hydrate a of aripiprazole obtained in example 1.

The figure 2 shows the1H NMR spectrum (DMSO-d6, TMC) hydrate a of aripiprazole obtained in example 1.

The figure 3 shows a chart of powdered x-ray diffraction hydrate a of aripiprazole obtained in example 1.

The figure 4 shows1H NMR spectrum (DMSO-d6, TMC) crystals of anhydrous aripiprazole obtained in example 2.

Figure 5 shows a chart of powdered x-ray diffraction of crystals of anhydrous aripiprazole obtained in example 2.

Figure 6 represents a thermogravimetric/differential thermogram of aripiprazole hydrate obtained in reference example 3.

The piano is the Gur 7 shows a chart of powdered x-ray diffraction of the aripiprazole hydrate, obtained in reference example 3.

The figure 8 shows the endothermic curve of thermogravimetric/differential thermal analysis of a-type crystals With anhydrous aripiprazole obtained in example 11.

The figure 9 shows1H NMR spectrum (DMSO-d6, TMC) type crystals With anhydrous aripiprazole obtained in example 11.

The figure 10 shows the spectrum of the powder x-ray diffraction of crystals of the type With anhydrous aripiprazole obtained in example 11.

The figure 11 shows the IR spectrum of the crystal type With anhydrous aripiprazole obtained in example 11.

The figure 12 shows13From the NMR spectrum of a-type crystals With anhydrous aripiprazole (range aripiprazole removed in the solid state)obtained in example 11.

The figure 13 shows the endothermic curve of thermogravimetric/differential thermal analysis of the type D crystals of anhydrous aripiprazole obtained in example 12 or example 13.

The figure 14 shows1H NMR spectrum (DMSO-d6, TMC) of the type D crystals of anhydrous aripiprazole obtained in example 12 or example 13.

The figure 15 shows the spectrum of the powder x-ray diffraction of crystals of type D of anhydrous aripiprazole obtained in example 12 or example 13.

The figure 16 shows the infrared spectrum of the type D crystals of anhydrous aripiprazole, Paul is obtained in example 12 or example 13.

The figure 17 shows13With the NMR-spectrum of the type D crystals of anhydrous aripiprazole (spectra aripiprazole removed in the solid state), obtained in example 12 or example 13.

Figure 18 shows an endothermic curve of thermogravimetric/differential thermal analysis of crystals of the type E of anhydrous aripiprazole obtained in example 14.

The figure 19 shows1H NMR spectrum (DMSO-d6, TMC) crystals of type E anhydrous aripiprazole obtained in example 14.

The figure 20 shows the spectrum of the powder x-ray diffraction of crystals of type E anhydrous aripiprazole obtained in example 14.

The figure 21 shows the IR spectrum of the crystals of type E anhydrous aripiprazole obtained in example 14.

The figure 22 shows the endothermic curve of thermogravimetric/differential thermal analysis of the type F crystals of anhydrous aripiprazole obtained in example 15.

The figure 23 shows1H NMR spectrum (DMSO-d6, TMS) of the type F crystals of anhydrous aripiprazole obtained in example 15.

The figure 24 shows the spectrum of the powder x-ray diffraction of the type F crystals of anhydrous aripiprazole obtained in example 15.

The figure 25 shows the IR spectrum of the type F crystals of anhydrous aripiprazole obtained in example 15.

The figure 26 shows endothermy the mini curve of thermogravimetric/differential thermal analysis of the type G crystals of anhydrous aripiprazole, obtained in example 16-(b).

The figure 27 shows1H NMR spectrum (DMSO-d6, TMS) of the type G crystals of anhydrous aripiprazole obtained in example 16-(b).

The figure 28 shows the spectrum of the powder x-ray diffraction of the type G crystals of anhydrous aripiprazole obtained in example 16-(b).

The figure 29 shows the infrared spectrum of the type G crystals of anhydrous aripiprazole obtained in example 16-(b).

The figure 30 shows an endothermic curve of thermogravimetric/differential thermal analysis of the vitreous form of anhydrous aripiprazole obtained in example 16-a).

The figure 31 shows the spectrum of the powder x-ray diffraction of the vitreous form of anhydrous aripiprazole obtained in example 16-a).

DETAILED description of the INVENTION

In accordance with the first embodiment of the first aspect of the present invention is provided hydrate a of aripiprazole where specified hydrate has a range of powder x-ray diffraction, which is essentially the same as the spectrum of the powder x-ray diffraction, are shown in figure 3.

In accordance with another embodiment of the first aspect of the present invention is proposed hydrate a of aripiprazole where specified hydrate has characteristic peaks in the powder x-ray diffraction PR is 2θ =12,6°, 15,4°, 17,3°, 18,0°, 18,6°, 22,5° and 24.8°.

In accordance with another embodiment of the first aspect of the present invention is proposed hydrate a of aripiprazole where specified hydrate has a characteristic infrared absorption band at 2951, 2822, 1692, 1577, 1447, 1378, 1187, 963 and 784 cm-1in the IR spectrum (KBR).

In accordance with another embodiment of the first aspect of the present invention is proposed hydrate a of aripiprazole where specified hydrate has1H NMR spectrum, which is essentially the same as1H NMR spectrum (DMSO-d6, TMS)shown in figure 2.

In accordance with another embodiment of the first aspect of the present invention is proposed hydrate a of aripiprazole where specified hydrate has1H NMR spectrum (DMSO-d6, TMS)having characteristic peaks at 1.55V-to 1.63 ppm (m, 2H), 1,68-of 1.78 ppm (m, 2H), 2,35 is 2.46 ppm (m, 4H), 2,48-of 2.56 ppm (m, 4H+DMSO), 2,78 ppm (t, J=7.4 Hz, 2H), 2,97 ppm (shirt, J=4.6 Hz, 4H), to 3.92 ppm (t, J=6, 3 Hz, 2H), to 6.43 ppm (d, J=2,4 Hz, 1H), of 6.49 ppm (DD, J=8,4 Hz, J=2.4 Hz, 1H),? 7.04 baby mortality ppm (d, J=8,1 Hz, 1H), 7,11-7,17 ppm (m, 1H), 7,28-to 7.32 ppm (m, 2H) and 10.00 ppm (s, 1H).

In accordance with another embodiment of the first aspect of the present invention is proposed hydrate a of aripiprazole, where specified, the hydrate has an endothermic curve which is essentially the same as the endothermic curve thermogravimetry the definition/differential thermal analysis (heating rate 5° C/min), shown in figure 1.

In accordance with another embodiment of the first aspect of the present invention is proposed hydrate a of aripiprazole, where specified, the hydrate has an average particle size of 50 μm or less.

In accordance with another embodiment of the first aspect of the present invention is proposed hydrate a of aripiprazole, where specified, the hydrate has an average particle size of 40 microns or less.

In accordance with another embodiment of the first aspect of the present invention is proposed hydrate a of aripiprazole, where specified, the hydrate has an average particle size of 35 μm or less.

In accordance with another embodiment of the first aspect of the present invention is proposed hydrate a of aripiprazole, where specified, the hydrate has an average particle size of 30 μm or less.

In accordance with another embodiment of the first aspect of the present invention is proposed hydrate a of aripiprazole, where specified, the hydrate has an average particle size of 25 microns or less.

In accordance with another embodiment of the first aspect of the present invention is proposed hydrate a of aripiprazole, where specified, the hydrate has an average particle size of 20 μm or less.

In accordance with another embodiment of the first aspect of the present invention is proposed hydrate And Arip is pratola, where specified, the hydrate has an average particle size in the range from 40 to 10 microns.

In accordance with another embodiment of the first aspect of the present invention is proposed hydrate a of aripiprazole, where specified, the hydrate has an average particle size in the range from 36 to 14 microns.

In accordance with the second aspect of the present invention provides a method of producing hydrate And where the method includes the stage of milling conventional hydrate.

In accordance with the first embodiment of the second aspect of the present invention, a method for obtaining hydrate And including stage milling conventional hydrate, where the specified spend grinding machine for grinding.

In accordance with another embodiment of the second aspect of the present invention, a method for obtaining hydrate And including stage milling conventional hydrate, where the specified machine for milling is the setting for fine grinding (aerosol apparatus) spindle mill, jet mill or ball mill.

In accordance with another embodiment of the second aspect of the present invention, a method for obtaining hydrate And including stage milling conventional hydrate, where the specified machine for grinding is to set the subtlest is melcene.

In accordance with another embodiment of the second aspect of the present invention, a method for obtaining hydrate And including stage milling conventional hydrate, where the specified machine for milling is the setting for the finest grinding, using a rotation speed of about 5000-15000./min for the main axis, the rotation of the source material about 10-30./min hole size sieve 1-5 mm

In accordance with the variations of the third aspect of the present invention is proposed hydrate As defined in accordance with one or more variants of the implementation described here, where the specified hydrate receive by the way described here.

In accordance with the fourth aspect of the present invention proposed aripiprazole drug substance of low hygroscopicity.

In accordance with the first embodiment of the fourth aspect of the present invention proposed aripiprazole drug substance of low hygroscopicity, where specified low hygroscopicity represents the moisture content of 0.5% or less after placing the specified medicinal substance for 24 hours in a desiccator, which is kept at a temperature of 60°and a humidity of 100%.

In accordance with the first embodiment of the fourth aspect of this is the future of the invention is provided aripiprazole drug substance of low hygroscopicity, where specified low hygroscopicity represents the moisture content of 0.4% or less after placing the specified medicinal substance for 24 hours in a desiccator, which is kept at a temperature of 60°and a humidity of 100%.

In accordance with another embodiment of the fourth aspect of the present invention is provided aripiprazole drug substance of low hygroscopicity, where specified low hygroscopicity represents the moisture content 0.25% or less after placing the specified medicinal substance for 24 hours in a desiccator, which is kept at a temperature of 60°and a humidity of 100%.

In accordance with another embodiment of the fourth aspect of the present invention is provided aripiprazole drug substance of low hygroscopicity, where specified low hygroscopicity represents the moisture content of 0.15% or less after placing the specified medicinal substance for 24 hours in a desiccator, which is kept at a temperature of 60°and a humidity of 100%.

In accordance with another embodiment of the fourth aspect of the present invention is provided aripiprazole drug substance of low hygroscopicity, where specified low hygroscopicity represents the content is the moisture of 0.10% or less after placing the specified medicinal substance for 24 hours in a desiccator, which is kept at a temperature of 60°and a humidity of 100%.

In accordance with another embodiment of the fourth aspect of the present invention is provided aripiprazole drug substance of low hygroscopicity, where specified low hygroscopicity is a moisture content of 0.05% or less after placing the specified medicinal substance for 24 hours in a desiccator, which is kept at a temperature of 60°and a humidity of 100%.

In accordance with another embodiment of the fourth aspect of the present invention is provided aripiprazole drug substance of low hygroscopicity, where specified low hygroscopicity represents the moisture content of 0.04% or less after placing the specified medicinal substance for 24 hours in a desiccator, which is kept at a temperature of 60°and a humidity of 100%.

In accordance with another embodiment of the fourth aspect of the present invention is provided aripiprazole drug substance of low hygroscopicity, where the specified medicinal substance are crystals of anhydrous aripiprazole, as defined here.

In accordance with another embodiment of the fourth aspect of the present invention proposed aripiprazole the e drug substance of low hygroscopicity, where the specified medicinal substance has a range of powder x-ray diffraction, which is essentially the same as the spectrum of the powder x-ray diffraction, are shown in figure 5.

In accordance with another embodiment of the fourth aspect of the present invention is provided aripiprazole drug with low hygroscopicity, where the specified medicinal substance has characteristic peaks in the powder x-ray diffraction at 2θ=11,0°, 16,6°, 19,3°, 20,3° and 22.1°.

In accordance with another embodiment of the fourth aspect of the present invention is provided aripiprazole drug with low hygroscopicity, where the specified medicinal substance has a characteristic infrared absorption band at 2945, 2812, 1678, 1627, 1448, 1377, 1173, 960 and 779 cm-1in the IR spectrum (KBR).

In accordance with another embodiment of the fourth aspect of the present invention is provided aripiprazole drug with low hygroscopicity, where the specified medicinal substance has1H NMR spectrum, which is essentially the same as1H NMR spectrum (DMSO-d6, TMS)shown in figure 4.

In accordance with another embodiment of the fourth aspect of the present from which retene provided aripiprazole drug with low hygroscopicity, where the specified medicinal substance has1H NMR spectrum (DMSO-d6, TMS)having characteristic peaks at 1.55V-to 1.63 ppm (m, 2H), 1,68-of 1.78 ppm (m, 2H), 2,35 is 2.46 ppm (m, 4H), 2,48-of 2.56 ppm (m, 4H + DMSO), 2,78 ppm (t, J=7, 4 Hz, 2H), 2,97 ppm (shirt, J=4.6 Hz, 4H), to 3.92 ppm (t, J=6.3 Hz, 2H), to 6.43 ppm (d, J=2,4 Hz, 1H), of 6.49 ppm (DD, J=8,4 Hz, J=2.4 Hz, 1H),? 7.04 baby mortality ppm (d, J=8,1 Hz, 1H), 7,11-7,17 ppm (m, 1H), 7,28-to 7.32 ppm (m, 2H) and 10.00 ppm (s, 1H).

In accordance with another embodiment of the fourth aspect of the present invention is provided aripiprazole drug with low hygroscopicity, where the specified medicinal substance has an endothermic peak around 141,5°in thermogravimetric/differential thermal analysis (heating rate 5°C/min).

In accordance with another embodiment of the fourth aspect of the present invention is provided aripiprazole drug with low hygroscopicity, where the specified medicinal substance has an endothermic peak around 140,7°With differential scanning calorimetry (heating rate 5°C/min).

In accordance with another embodiment of the fourth aspect of the present invention is provided aripiprazole drug with low hygroscopicity, where the specified medicinal substance is crystals In anhydrous is aripiprazole and essentially does not turn into water form of aripiprazole when saving properly even within the extended period. For example, the crystals of anhydrous aripiprazole, you can save at a relative humidity (RH) of 60% and at a temperature of 25°even during a period of not less than 1 year.

In accordance with another embodiment of the fourth aspect of the present invention is provided aripiprazole drug with low hygroscopicity, where the specified medicinal substance is crystals of anhydrous aripiprazole and essentially does not turn into water form of aripiprazole when saving properly even within the extended period. For example, the crystals of anhydrous aripiprazole, you can save at a relative humidity (RH) of 60% and at a temperature of 25°even during a period of not less than 4 years.

In accordance with another embodiment of the fourth aspect of the present invention is provided aripiprazole drug with low hygroscopicity, where the specified medicinal substance is crystals of anhydrous aripiprazole and essentially does not turn into water form of aripiprazole when saving properly even during a period of not less than 0.5 years, at a relative humidity (RH) of 75% and at a temperature of 40°C.

In accordance with another embodiment of the fourth aspect of the present izaberete the Oia provides aripiprazole drug with low hygroscopicity, where the specified medicinal substance has an average particle size of 50 μm or less, when ready for formulation such as a tablet or other solid dosage ready preparative forms, including, for example, quickly melting the finished formulation requires particles of small size.

In accordance with another embodiment of the fourth aspect of the present invention is provided aripiprazole drug with low hygroscopicity, where the specified medicinal substance has an average particle size of 40 microns or less, if prepared formulation such as a tablet or other solid dosage ready preparative forms, including, for example, quickly melting the finished formulation requires particles of small size.

In accordance with another embodiment of the fourth aspect of the present invention is provided aripiprazole drug with low hygroscopicity, where the specified medicinal substance has an average particle size of 30 μm or less, if prepared formulation such as a tablet or other solid dosage ready preparative forms, including, for example, quickly melting the finished formulation requires particles of small size.

In soo is according to the fifth aspect of the present invention provides a method of producing crystals of anhydrous aripiprazole.

In accordance with the first embodiment of the fifth aspect of the present invention provides a method of producing crystals of anhydrous aripiprazole, where the method includes heating the hydrate a of aripiprazole.

In accordance with the first embodiment of the fifth aspect of the present invention provides a method of producing crystals of anhydrous aripiprazole, where the method includes heating the hydrate a of aripiprazole at 90-125°for about 3-50 hours.

In accordance with another embodiment of the fifth aspect of the present invention provides a method of producing crystals of anhydrous aripiprazole, where the method includes heating the hydrate a of aripiprazole at 100°C for approximately 18 hours.

In accordance with another embodiment of the fifth aspect of the present invention provides a method of producing crystals of anhydrous aripiprazole, where the method includes heating the hydrate a of aripiprazole at 100°C for approximately 24 hours.

In accordance with another embodiment of the fifth aspect of the present invention provides a method of producing crystals of anhydrous aripiprazole, where the method includes heating the hydrate a of aripiprazole at 120°during the course the e approximately 3 hours.

In accordance with another embodiment of the fifth aspect of the present invention provides a method of producing crystals of anhydrous aripiprazole, where the method includes heating the hydrate a of aripiprazole for about 18 hours at 100°and then further heated for about 3 hours at 120°C.

In accordance with the sixth aspect of the present invention provides crystals of anhydrous aripiprazole, defined in accordance with one or more variants described here implement and received the proposed here method.

In accordance with the seventh aspect of the present invention provides crystals of anhydrous aripiprazole, made with one or more pharmaceutically acceptable carriers.

Other embodiments of the present invention may include any suitable combination of two or more of these embodiments and/or aspects.

Other embodiments of aspects of the invention will be apparent from the following description.

Another aspect of the present invention includes the discovery that when the aripiprazole hydrate (normal hydrate as defined here) are grounded, it turns into the aripiprazole hydrate (hydrate as defined here) with another spectrum is Raskovoy x-ray diffraction due to other peaks intensities. In addition, it was found that hydrate And loses sharp endothermic peak dehydration 123,5°With which characterizes unground normal hydrate in thermogravimetric/differential thermal analysis. Thus, conventional hydrate is converted into hydrate And after grinding conventional hydrate and has mild dehydration endothermic peak between about 60°120°with a weak peak at approximately 71°C.

Another aspect of the invention includes the discovery that when heated to a certain temperature 90-125°within 3-50 hour this new aripiprazole hydrate gradually dehydratases without the phenomenon of aggregation, which is called in conventional aripiprazole hydrate rapid dehydration, and that the crystals of anhydrous aripiprazole obtained by heating a new aripiprazole hydrate to a certain temperature, are crystals of anhydrous aripiprazole with desired properties.

Characterization of hydrate And

The particles used here hydrate And have physicochemical properties that are listed below in(1)-(5):

(1) They have an endothermic curve which is essentially the same as the endothermic curve of thermogravimetric/differential thermal analysis (heating rate 5°C/min), shown in figure 1. Specifically, it h is by the appearance of a small peak at approximately 71° And Unsharp endothermic peak in the range from about 60°to 120°C.

(2) They have1H NMR spectrum, which is essentially the same as1H NMR spectrum (DMSO-d6, TMS)shown in figure 2. Specifically, it has characteristic peaks at 1.55V-to 1.63 ppm (m, 2H), 1,68-of 1.78 ppm (m, 2H), 2,35 is 2.46 ppm (m, 4H), 2,48-of 2.56 ppm (m, 4H + DMSO), 2,78 ppm (t, J=7.4 Hz, 2H), 2,97 ppm (shirt, J=4.6 Hz, 4H), to 3.92 ppm (t, J=6.3 Hz, 2H), to 6.43 ppm (d, J=2.4 Hz, 1H), of 6.49 ppm (DD, J=8,4 Hz, J=2.4 Hz, 1H),? 7.04 baby mortality ppm (d, J=8,1 Hz, 1H), 7,11-7,17 ppm (m, 1H), 7,28-to 7.32 ppm (m, 2H) and 10.00 ppm (s, 1H).

(3) They have a range of powder x-ray diffraction, which is essentially the same as the spectrum of the powder x-ray diffraction, are shown in figure 3. Specifically, it has characteristic peaks at 2θ=12,6°, 15,4°, 17,3°, 18,0°, 18,6°, 22,5° and 24.8°.

(4) They have a clear infrared absorption band at 2951, 2822, 1692, 1577, 1447, 1378, 1187, 963 and 784 cm-1in the IR spectrum (KBR).

(5) They have an average particle size of 50 μm or less.

A method of manufacturing hydrate And

Hydrate And produce by grinding ordinary hydrate. For milling conventional hydrate can be used conventional methods of milling. For example, a typical hydrate can grind in a machine for milling. You can use a widely used machine for grinding, such as setting for Tony is it grinding, spindle mill, jet mill or ball mill. One of them is preferred plant for fine crushing.

With regard to the certain conditions of milling, when you use setup to fine grinding to the main axis, you can use the speed of rotation of about 5000-15000./min, for example, with the rotation of the source material about 10-30./min and the size of the sieve mesh 1-5 mm

The average particle size hydrate a of aripiprazole obtained by grinding should be usually 50 μm or less, preferably 30 μm or less. The average particle size can be set with the following method of measuring the size of particles.

Characterization of crystals of anhydrous aripiprazole

"The crystals of anhydrous aripiprazole" of the present invention used here have physico-chemical properties are given below in(6)-(12).

(6) They have1H NMR spectrum, which is essentially the same as1H NMR spectrum (DMSO-d6, TMS)shown in figure 4. Specifically, it has characteristic peaks at 1.55V-to 1.63 ppm (m, 2H), 1,68-of 1.78 ppm (m, 2H), 2,35 is 2.46 ppm (m, 4H), 2,48-of 2.56 ppm (m, 4H + DMSO), 2,78 ppm (t, J=7.4 Hz, 2H), 2,97 ppm (shirt, J=4.6 Hz, 4H), to 3.92 ppm (t, J=6.3 Hz, 2H), to 6.43 ppm (d, J=2.4 Hz, 1H), of 6.49 ppm (DD, J=8,4 Hz, J=2.4 Hz, 1H),? 7.04 baby mortality ppm (d, J=8,1 Hz, 1H), 7,11-7,17 ppm (m, 1H), 7,28-to 7.32 ppm (m, 2H) and 10.00 ppm (s, 1H).

(7) They have a range of powder diffraction rent the rays, which is essentially the same as the spectrum of the powder x-ray diffraction, are shown in figure 5. Specifically, they have characteristic peaks at 2θ=11,0°, 16,6°, 19,3°, 20,3° and 22.1°.

(8) They have a clear infrared absorption band at 2945, 2812, 1678, 1627, 1448, 1377, 1173, 960 and 779 cm-1in the IR spectrum (KBR).

(9) They are endothermic peak approximately 141,5°in thermogravimetric/differential thermal analysis (heating rate 5°C/min).

(10) They are endothermic peak approximately 140,7°With differential scanning calorimetry (heating rate 5°C/min).

(11) the Crystals of anhydrous aripiprazole of the present invention have low hygroscopicity. For example, crystals of anhydrous aripiprazole of the present invention retain the water content of 0.4% or less after 24 hours of storage inside a desiccator, in which the temperature 60°C and a humidity of 100%. You can use well-known methods of measuring the water content, because they are the methods commonly used for measuring the water content of the crystals. For example, you can use this method as a way of Karl Fischer.

(12) When ready for preparative forms, such as tablets and other solid dosage finish formulation, t is the number for example, rapidly dissolving formulation requires particles of small size, the average particle size is preferably 50 μm or less.

Method of preparation of anhydrous

In the case of finished formulation that requires particles of small size (less than 50 μm), to obtain the necessary grinding. However, when ground into a large number of conventional anhydrous aripiprazole or crystals of anhydrous aripiprazole, having a large particle size, ground substances stick to each other in a machine for milling. In accordance with this appears the drawback consisting in the fact that on an industrial scale is difficult to obtain crystals of anhydrous aripiprazole having a small particle size.

Under these circumstances it was found that the normal hydrate easy to grind and it is possible to obtain crystals of anhydrous aripiprazole having a small particle size, high output and good suitability by heating the thus obtained ground hydrate A.

Crystals of anhydrous aripiprazole of the present invention receives, for example, by heating the above hydrate a of aripiprazole at 90-125°C. the heating Time is usually 3-50 hours, but it may not be accurate, because it changes depending on the temperature of the tours heating. Heating time and temperature of heating is inversely proportional, so that, for example, the heating time will be the longer, the lower the temperature of heating, and the shorter, the higher the temperature of the heating. In particular, if the temperature of the heating hydrate a of aripiprazole is 100°C, the heating time should be usually 18 hours or more, or preferably about 24 hours. On the other hand, if the temperature of the heating hydrate a of aripiprazole 120°C, the heating time may be approximately 3 hours. Crystals of anhydrous aripiprazole of the present invention can be obtained with certainty by heating the hydrate a of aripiprazole for 18 hours at 100°and then heating it for about 3 hours at 120°C. the Crystals of anhydrous aripiprazole of the present invention can also be obtained if the heating time to continue, but it may be uneconomical.

When ready for the preparative form does not require particles of small size, for example, when the manufactured drug is ready for preparative forms in the form of injectable or oral solution, crystals of anhydrous aripiprazole can also be obtained as follows.

It was found that the crystals of anhydrous aripiprazole can be obtained by heating usually is about the aripiprazole hydrate or ordinary crystals of anhydrous aripiprazole to a certain temperature, but this method does not allow to obtain crystals of anhydrous aripiprazole as a crystalline substance that is suitable for commercial use as part of a solid oral dosage ready preparative forms.

In addition, the crystals of anhydrous aripiprazole of the present invention receives, for example, by heating the crystals conventional anhydrous aripiprazole at 90-125°C. the heating Time is usually 3-50 hours, but it may not be accurate, because it changes depending on the heating temperature. Heating time and temperature of heating is inversely proportional, so that, for example, the heating time will be the longer, the lower the temperature of heating, and the shorter, the higher the temperature of the heating.

In particular, if the temperature of the heating crystals of anhydrous aripiprazole is 100°C, the heating time may be approximately 4 hours and, if the temperature of the heating 120°C, the heating time may be approximately 3 hours.

In addition to hydrate a of aripiprazole and crystals of anhydrous aripiprazole mentioned above, the present invention provides the following crystals from C to G of anhydrous aripiprazole.

1. The present invention relates to crystals of anhydrous aripiprazole (hereinafter referred to as a-type crystals With anhydrous Arip is prazole"), having the following physicochemical properties (1) to (5):

(1) an endothermic curve which is essentially identical to the endothermic curve of thermogravimetric/differential thermal analysis (heating rate: 5°C/min), shown in figure 8;

(2)1H NMR spectrum, which is essentially identical to1H NMR spectrum (DMSO-d6, TMS)shown in figure 9;

(3) range of powder x-ray diffraction, which is essentially identical to the spectrum of the powder x-ray diffraction, are shown in figure 10;

(4) the infrared spectrum, which is essentially identical to the IR-spectrum (KBR), shown in figure 11, and

(5)13From the NMR spectrum of the substance in the solid state), which is essentially identical to13With the NMR-spectrum (spectrum of the substance in the solid state), shown in figure 12.

2. The present invention relates to crystals of anhydrous aripiprazole (hereinafter called "the type D crystals of anhydrous aripiprazole"), having the following physico-chemical properties from (6) to (10):

(6) an endothermic curve which is essentially identical to the endothermic curve of thermogravimetric/differential thermal analysis (heating rate: 5°C/min), shown in figure 13;

(7)1H NMR spectrum, which is essentially identical to1H NMR spectrum (DMSO-d6, What MS), shown in figure 14;

(8) range of powder x-ray diffraction, which is essentially identical to the spectrum of the powder x-ray diffraction, are shown in figure 15;

(9) the infrared spectrum, which is essentially identical to the IR-spectrum (KBR), shown in figure 16; and

(10)13From the NMR spectrum of the substance in the solid state), which is essentially identical to13From the NMR spectrum, shown in figure 17.

3. The present invention relates to crystals of anhydrous aripiprazole (hereinafter referred to as "crystals of type E anhydrous aripiprazole"), having the following physico-chemical properties from (11) to (14):

(11) an endothermic curve which is essentially identical to the endothermic curve of thermogravimetric/differential thermal analysis (heating rate: 5°C/min), shown in figure 18;

(12)1H NMR spectrum, which is essentially identical to1H NMR spectrum (DMSO-d6, TMS)shown in figure 19;

(13) range of powder x-ray diffraction, which is essentially identical to the spectrum of the powder x-ray diffraction, are shown in figure 20; and

(14) the infrared spectrum, which is essentially identical to the IR-spectrum (KBR), shown in figure 21.

4. The present invention relates to crystals of anhydrous aripiprazole (hereinafter called "cristalleria F anhydrous aripiprazole"), having the following physico-chemical properties from (15) to (18):

(15) an endothermic curve which is essentially identical to the endothermic curve of thermogravimetric/differential thermal analysis (heating rate: 5°C/min), shown in figure 22;

(16)1H NMR spectrum, which is essentially identical to1H NMR spectrum (DMSO-d6, TMS)shown in figure 23;

(17) the spectrum of the powder x-ray diffraction, which is essentially identical to the spectrum of the powder x-ray diffraction, are shown in figure 24; and

(18) the infrared spectrum, which is essentially identical to the IR-spectrum (KBR), shown in figure 25.

5. The present invention relates to a method for producing crystals of anhydrous aripiprazole defined in the above paragraph 1, wherein the heating crystals of anhydrous aripiprazole at a temperature higher than 140°and lower than 150°C.

6. The present invention relates to a method for producing crystals of anhydrous aripiprazole defined in the above paragraph 2, characterized by recrystallization from toluene.

7. The present invention relates to a method for producing crystals of anhydrous aripiprazole defined in the above paragraph 3, characterized by heating and dissolving crystals of anhydrous aripiprazole in acetonic the silt and cooling solution.

8. The present invention relates to a method for producing crystals of anhydrous aripiprazole defined in the above paragraph 4, characterized by heating a suspension of crystals of anhydrous aripiprazole in acetone.

9. The present invention relates to pharmaceutical compositions containing at least one type of crystals of anhydrous aripiprazole selected from the group consisting of crystals of anhydrous aripiprazole defined in the above paragraph 1, of crystals of anhydrous aripiprazole defined in the above paragraph 2, of crystals of anhydrous aripiprazole defined in the above paragraph 3, of crystals of anhydrous aripiprazole defined in the above paragraph 4, and crystals of anhydrous aripiprazole, defined in the following paragraph 10, together with pharmaceutically acceptable carriers.

10. The present invention relates to crystals of anhydrous aripiprazole (hereinafter called "the type G crystals of anhydrous aripiprazole"), having the following physico-chemical properties from (19) to (22):

(19) an endothermic curve which is essentially identical to the endothermic curve of thermogravimetric/differential thermal analysis (heating rate: 5°C/min), shown in figure 26;

(20)1H NMR spectrum, which is essentially the ID is nicen 1H NMR spectrum (DMSO-d6, TMS)shown in figure 27;

(21) the spectrum of the powder x-ray diffraction, which is essentially identical to the spectrum of the powder x-ray diffraction, are shown in figure 28; and

(22) the infrared spectrum, which is essentially identical to the IR-spectrum (KBR), shown in figure 29.

11. The present invention relates to a method for producing crystals of anhydrous aripiprazole defined in the above paragraph 10 different location anhydrous aripiprazole in the vitreous state in a sealed vessel and keeping it at room temperature for at least 2 weeks.

12. The present invention relates to a process for the preparation of granules, characterized by wet granulation of ordinary crystals of anhydrous aripiprazole or crystals b, C, D, E, F or G of anhydrous aripiprazole, drying the obtained granules at a temperature of from 70 to 100°and screening them, then drying the sifted granules at a temperature of from 70 to 100°C.

13. The present invention relates to a method for producing a pharmaceutical solid oral preparation, characterized by drying a pharmaceutical solid oral preparation comprising crystals conventional anhydrous aripiprazole or crystals b, C, D, E, F or G of anhydrous aripiprazole and one or more of the LCO pharmaceutically acceptable carriers, at a temperature of from 70 to 100°C.

14. The present invention relates to a pharmaceutical solid oral preparation comprising crystals b, C, D, E, F or G of anhydrous aripiprazole, and one or more pharmaceutically acceptable carriers, where specified pharmaceutical solid oral preparation has at least one dissolution rate selected from the group consisting of of dissolution rates of 60% or more at pH 4.5 after 30 minutes, 70% or more at pH 4.5 after 60 minutes, and 55% or more at pH 5.0 after 60 minutes.

15. The present invention relates to a pharmaceutical solid oral preparation has at least one dissolution rate selected from the group consisting of of dissolution rates of 60% or more at pH 4.5 after 30 minutes, 70% or more at pH 4.5 after 60 minutes, and 55% or more at pH 5.0 after 60 minutes.

16. The present invention relates to a pharmaceutical solid oral preparation, obtained by wet granulation of ordinary crystals of anhydrous aripiprazole, drying the obtained granules at a temperature of from 70 to 100°and screening them, then drying the sifted granules at a temperature of from 70 to 100°where the pharmaceutical solid oral preparation has at least one dissolution rate selected from the group consisting of speed races is of its 60% or more at pH 4.5 after 30 minutes, 70% or more at pH 4.5 after 60 minutes, and 55% or more at pH 5.0 after 60 minutes.

17. The present invention relates to a pharmaceutical solid oral preparation obtained by drying a pharmaceutical solid oral preparation comprising crystals conventional anhydrous aripiprazole and one or more pharmaceutically acceptable carriers, at a temperature of from 70 to 100°where the pharmaceutical solid oral preparation has at least one dissolution rate selected from the group consisting of of dissolution rates of 60% or more at pH 4.5 after 30 minutes, 70% or more at pH 4.5 after 60 minutes, and 55% or more at pH 5.0 after 60 minutes.

18. The present invention relates to a process for the preparation of granules, characterized by wet granulation crystals conventional aripiprazole hydrate, drying the obtained granules at a temperature of from 70 to 100°and screening them and then again drying the sifted granules at a temperature of from 70 to 100°C.

19. The present invention relates to a method for producing a pharmaceutical solid oral preparation, characterized by drying a pharmaceutical solid oral preparation comprising crystals of conventional aripiprazole hydrate and one or more pharmaceutically acceptable carriers, at a temperature of from 70 to 100°C.

20. Now izaberete the s refers to a pharmaceutical solid oral preparation, the obtained wet granulation crystals conventional aripiprazole hydrate, drying the obtained granules at a temperature of from 70 to 100°and screening them, then drying the sifted granules at a temperature of from 70 to 100°where the pharmaceutical solid oral preparation has at least one dissolution rate selected from the group consisting of of dissolution rates of 60% or more at pH 4.5 after 30 minutes, 70% or more at pH 4.5 after 60 minutes, and 55% or more at pH 5.0 after 60 minutes.

21. The present invention relates to a pharmaceutical solid oral preparation obtained by drying a pharmaceutical solid oral preparation comprising crystals of conventional aripiprazole hydrate and one or more pharmaceutically acceptable carriers, at a temperature of from 70 to 100°where the pharmaceutical solid oral preparation has at least one dissolution rate selected from the group consisting of of dissolution rates of 60% or more at pH 4.5 after 30 minutes, 70% or more at pH 4.5 after 60 minutes, and 55% or more at pH 5.0 after 60 minutes.

The type crystals from C to F anhydrous aripiprazole of the present invention correspond to the type crystals from III to VI of anhydrous aripiprazole, described in JP-2001-348276.

The type crystals With anhydrous aripiprazole

Crystals of the type of betwedn the th aripiprazole of the present invention have the following physicochemical properties (1) to (5):

(1) an endothermic curve which is essentially identical to the endothermic curve of thermogravimetric/differential thermal analysis (heating rate: 5°C/min), shown in figure 8; more specifically, it has an endothermic peak around 150,2°C;

(2)1H NMR spectrum, which is essentially identical 1H NMR spectrum (DMSO-d6, TMS)shown in figure 9. In particular, it has characteristic peaks at 1.55V-to 1.63 ppm (m, 2H), 1,68-of 1.78 ppm (m, 2H), 2,35 is 2.46 ppm (m, 4H), 2,48-of 2.56 ppm (m, 4H + DMSO), 2,78 ppm (t, J=7, 4 Hz, 2H), 2,97 ppm (shirt, J=4.6 Hz, 4H), to 3.92 ppm (t, J=6, 3 Hz, 2H), to 6.43 ppm (d, J=the 2.4 Hz, 1H), of 6.49 ppm (DD, J=8,4 Hz, J=2.4 Hz, 1H),? 7.04 baby mortality ppm (d, J=8,1 Hz, 1H), 7,11-7,17 ppm (m, 1H), 7,28-to 7.32 ppm (m, 2H) and 10.00 ppm (s, 1H);

(3) range of powder x-ray diffraction, which is essentially identical to the spectrum of the powder x-ray diffraction, are shown in figure 10. In particular, it has characteristic peaks at 2θ=12,6°, 13,7°, 15,4°, 18,1°, 19,0°, 20,6°, 23,5° and 26.4°;

(4) the infrared spectrum, which is essentially identical to the IR-spectrum (KBR), shown in figure 11. In particular, he has a clear infrared absorption band at 2939, 2804, 1680, 1375 and 780 cm-1; and

(5)13From the NMR spectrum of the substance in the solid state), which is essentially identical to13With the NMR-spectrum (spectrum of the substance in the solid state), shown in Fi is ur 12, in particular, it has characteristic peaks at 32,8 ppm, of 60.8 ppm, of 74.9 ppm, 104,9 ppm, 152,2 ppm, 159,9 ppm and 175,2 ppm

The method of obtaining crystals of the type With anhydrous aripiprazole

The type crystals With anhydrous aripiprazole of the present invention receives, for example, by heating anhydrous aripiprazole at a temperature higher than 140°and lower than 150°C.

Anhydrous aripiprazole used as starting material can be ordinary crystals of anhydrous aripiprazole, for example, crystals of type I anhydrous aripiprazole crystals of type II anhydrous aripiprazole, and the like, and these anhydrous crystals can be either purified products or raw materials. In the alternative case as the source material anhydrous aripiprazole you can use the type crystals In anhydrous aripiprazole, type D crystals of anhydrous aripiprazole crystals of type E anhydrous aripiprazole, type F crystals of anhydrous aripiprazole, or the type G crystals of anhydrous aripiprazole obtained in the present invention. These waterless aripiprazole can be used individually or in combination, at least 2 types.

The temperature of the heating is usually higher than 140°and lower than 150°C, preferably 142-148°and the heating time is usually from 15 minutes to 3 hours, etc is doctitle from 30 minutes to 1 hour.

When anhydrous aripiprazole heated at the above temperature, the crystals are formed type With anhydrous aripiprazole.

The thus obtained crystals of the type With anhydrous aripiprazole can be extracted and cleaned well known ways. For example, after heating anhydrous aripiprazole at the above temperature and cooling to room temperature, it is possible to obtain crystals of the type With anhydrous aripiprazole having a purity of 100%.

The type D crystals of anhydrous aripiprazole

The type D crystals of anhydrous aripiprazole of the present invention have the following physicochemical properties from (6) to (10):

(6) an endothermic curve which is essentially identical to the endothermic curve of thermogravimetric/differential thermal analysis (heating rate: 5°C/min), shown in figure 13; more specifically, it has an endothermic peak around 136,8°and 141,6°C;

(7)1H NMR spectrum, which is essentially identical to1H NMR spectrum (DMSO-d6, TMS)shown in figure 14. In particular, it has characteristic peaks at 1.55V-to 1.63 ppm (m, 2H), 1,68-of 1.78 ppm (m, 2H), 2,35 is 2.46 ppm (m, 4H), 2,48-of 2.56 ppm (m, 4H + DMSO), 2,78 ppm (t, J=7.4 Hz, 2H), 2,97 ppm (shirt, J=4.6 Hz, 4H), to 3.92 ppm (t, J=6.3 Hz, 2H), to 6.43 ppm (d, J=2,4Hz, 1H), of 6.49 ppm (DD, J=8,4 Hz, J=2.4 Hz, 1H),? 7.04 baby mortality ppm (d, J=8,1 Hz, 1H), 7,11-7,17 ppm (m, 1H), 7,28-to 7.32 ppm (m, 2H) and 10.00 ppm(s, 1H);

(8) range of powder x-ray diffraction, which is essentially identical to the spectrum of the powder x-ray diffraction, are shown in figure 15. In particular, it has characteristic peaks at 2θ=8,7°, 11,6°, 16,3°, 17,7°, 18,6°, 20,3°and 23.4° and 25.0°;

(9) the infrared spectrum, which is essentially identical to the IR-spectrum (KBR), shown in figure 16. In particular, he has a clear infrared absorption band at 2946, 1681, 1375, 1273, 1175 and 862 cm-1; and

(10)13From the NMR spectrum of the substance in the solid state), which is essentially identical to13With the NMR-spectrum (spectrum of the substance in the solid state), shown in figure 17, in particular, it has characteristic peaks at 32,1 ppm, 62,2 ppm, 66,6 ppm, 104,1 ppm, 152,4 ppm, of 158.4 ppm and 174,1 ppm

The method of obtaining the type D crystals of anhydrous aripiprazole

The type D crystals of anhydrous aripiprazole of the present invention receives, for example, by recrystallization anhydrous aripiprazole from toluene. In particular, anhydrous aripiprazole type in toluene, and then heated and dissolved, and then the resulting solution is cooled. Such procedures the type D crystals of anhydrous aripiprazole of the present invention is separated in the form of crystals in toluene.

Anhydrous aripiprazole, which is used as starting material m which may be of conventional anhydrous aripiprazole, for example, crystals of type I anhydrous aripiprazole crystals of type II anhydrous aripiprazole, and the like, these anhydrous aripiprazole can be either purified products or raw materials. In the alternative case as the source material for anhydrous aripiprazole you can use the type crystals In anhydrous aripiprazole, type crystals With anhydrous aripiprazole crystals of type E anhydrous aripiprazole, type F crystals of anhydrous aripiprazole, or the type G crystals of anhydrous aripiprazole, which are the present invention. These waterless aripiprazole can be used individually or in combination, at least 2 types.

When the solution obtained by heating and dissolving, cool, as the seed crystals to the specified solution add the type D crystals of anhydrous aripiprazole. In addition, the seed crystals can be obtained by gradual cooling of the specified solution, which is obtained by heating and dissolving. In the presence of seed crystals can be separated crystals of type D anhydrous aripiprazole.

Thus separated crystals of type D anhydrous aripiprazole can be extracted and cleaned in accordance with well known methods. Such procedures can be obtained crystals of the D-type anhydrous aripipra the La, having the purity of 100%.

Crystals of type E anhydrous aripiprazole

Crystals of type E anhydrous aripiprazole of the present invention have the following physicochemical properties from (11) to (14):

(11) an endothermic curve which is essentially identical to the endothermic curve of thermogravimetric/differential thermal analysis (heating rate: 5°C/min), shown in figure 18; more specifically, it has an endothermic peak around 146,5°C;

(12)1H NMR spectrum, which is essentially identical to1H NMR spectrum (DMSO-d6, TMS)shown in figure 19. In particular, it has characteristic peaks at 1.55V-to 1.63 ppm (m, 2H), 1,68-of 1.78 ppm (m, 2H), 2,35 is 2.46 ppm (m, 4H), 2,48-of 2.56 ppm (m, 4H + DMSO), 2,78 ppm (t, J=7, 4 Hz, 2H), 2,97 ppm (shirt, J=4.6 Hz, 4H), to 3.92 ppm (t, J=6.3 Hz, 2H), to 6.43 ppm (d, J=2,4 Hz, 1H), of 6.49 ppm (DD, J=8,4 Hz, J=2.4 Hz, 1H),? 7.04 baby mortality ppm (d, J=8,1 Hz, 1H), 7,11-7,17 ppm (m, 1H), 7,28-to 7.32 ppm (m, 2H) and 10.00 ppm (s, 1H);

(13) range of powder x-ray diffraction, which is essentially identical to the spectrum of the powder x-ray diffraction, are shown in figure 20. In particular, it has characteristic peaks at 2θ=8,0°, 13,7°, 14,6°, 17,6°, 22,5° and 24.0°; and

(14) the infrared spectrum, which is essentially identical to the IR-spectrum (KBR), shown in figure 21. In particular, he has a clear infrared absorption band at 2943, 2817, 1686, 1377, 122, 969 and 774 cm-1.

The method of producing crystals of type E anhydrous aripiprazole

Crystals of type E anhydrous aripiprazole of the present invention receives, for example, by recrystallization anhydrous aripiprazole from acetonitrile. In particular, the addition of well-known anhydrous aripiprazole to acetonitrile, heating and dissolving, then the resulting solution can be cooled. In accordance with such procedures crystals of type E anhydrous aripiprazole of the present invention is isolated in acetonitrile.

When to add acetonitrile conventional anhydrous aripiprazole, separating the crystals of type I anhydrous aripiprazole crystals of type II anhydrous aripiprazole and the type D crystals of anhydrous aripiprazole, other than the crystals of type E anhydrous aripiprazole. Tape the crystals which separated from solution in acetonitrile at 70°are crystals of type I crystals of type II and type D crystals, whereas the crystals of type E are deposited in the form of needle crystals. When the solution in acetonitrile after separation of these crystals is heated (for example, heated to over 75° (C), the tape crystals (crystals of type I crystals of type II crystals of type D) to dissolve quickly, on the contrary, the crystals in the form of needles (the crystals-type F) do not dissolve. In addition, when the solution in the tank car is lonitrile again cooled, the crystals in the form of needles (crystals of type E) further highlighted around crystals in the form of needles (crystal type), pre-deposited as the seed crystals. Thus, crystals of type E anhydrous aripiprazole can be precipitated in a solution of acetonitrile.

Anhydrous aripiprazole used as starting materials, may be conventional anhydrous aripiprazole, for example, any one of the crystals of type I anhydrous aripiprazole crystals of type II anhydrous aripiprazole, and the like, and these waterless aripiprazole can be either purified products or raw materials.

In the alternative case as the source material for anhydrous aripiprazole you can use the type crystals In anhydrous aripiprazole, type crystals With anhydrous aripiprazole, type D crystals of anhydrous aripiprazole, type F crystals of anhydrous aripiprazole, or the type G crystals of anhydrous aripiprazole. These waterless aripiprazole can be used individually or in combination, at least 2 types.

When the solution in acetonitrile, obtained by heating (heating and dissolution), cooled to the specified solution as a seed crystal, you can add crystals of type E anhydrous aripiprazole. In addition, the seed crystals can be obtained is ostatnim cooling of the specified solution in acetonitrile, which is obtained by heat.

Thus separated crystals of type E anhydrous aripiprazole can be extracted and cleaned in accordance with well known methods. Such procedures can be obtained crystals of type E anhydrous aripiprazole having a purity of 100%.

The type F crystals of anhydrous aripiprazole

The type F crystals of anhydrous aripiprazole of the present invention have the following physicochemical properties from (15) to (18):

(15) an endothermic curve which is essentially identical to the endothermic curve of thermogravimetric/differential thermal analysis (heating rate: 5°C/min), shown in figure 22; more specifically, it has endothermic peaks around 137,5°and 149,8°C;

(16)1H NMR spectrum, which is essentially identical to1H NMR spectrum (DMSO-d6, TMS)shown in figure 23. In particular, it has characteristic peaks at 1.55V-to 1.63 ppm (m, 2H), 1,68-of 1.78 ppm (m, 2H), 2,35 is 2.46 ppm (m, 4H), 2,48-of 2.56 ppm (m, 4H + DMSO), 2,78 ppm (t, J=7, 4 Hz, 2H), 2,97 ppm (shirt, J=4.6 Hz, 4H), to 3.92 ppm (t, J=6.3 Hz, 2H), to 6.43 ppm (d, J=2,4 Hz, 1H), of 6.49 ppm (DD, J=8,4 Hz, J=2.4 Hz, 1H),? 7.04 baby mortality ppm (d, J=8,1 Hz, 1H), 7,11-7,17 ppm (m, 1H), 7,28-to 7.32 ppm (m, 2H) and 10.00 ppm (s, 1H);

(17) the spectrum of the powder x-ray diffraction, which is essentially identical to the spectrum of the powder x-ray diffraction, are shown in figure 24. In particular, what has characteristic peaks at 2θ =11,3°and 13.3°, 15,4°, 22,8°, 25,2° and 26,9°and

(18) the infrared spectrum, which is essentially identical to the IR-spectrum (KBR), shown in figure 25. In particular, he has a clear infrared absorption band at 2940, 2815, 1679, 1383, 1273, 1177, 1035, 963 and 790 cm-1.

The method of obtaining the type F crystals of anhydrous aripiprazole

The type F crystals of anhydrous aripiprazole of the present invention receives, for example, suspendirovanie anhydrous aripiprazole in acetone and heating the thus obtained suspension in acetone.

Anhydrous aripiprazole used as starting materials, may be conventional anhydrous aripiprazole, for example, any one of the crystals of type I anhydrous aripiprazole crystals of type II anhydrous aripiprazole, and the like, and these waterless aripiprazole can be either purified products or raw materials. In the alternative case as the source material for anhydrous aripiprazole you can use the type crystals In anhydrous aripiprazole, type crystals With anhydrous aripiprazole, type D crystals of anhydrous aripiprazole crystals of type E anhydrous aripiprazole or the type G crystals of anhydrous aripiprazole. These waterless aripiprazole can be used individually or in combination, at least 2 types.

The temperature of heated the project for a suspension in acetone is usually about the boiling point of acetone and heating time is usually from 5 to 10 hours. When the suspension in acetone is heated to approximately the boiling point of acetone, then formed the type F crystals of anhydrous aripiprazole crystals are filtered with heating. The selection of crystals can be performed by well known methods. Such procedures can be obtained the type F crystals of anhydrous aripiprazole, having a purity of 100%.

The type G crystals of anhydrous aripiprazole

The type G crystals of aripiprazole anhydride of the present invention have the following physicochemical properties from (19) to (22):

(19) an endothermic curve which is essentially identical to the endothermic curve of thermogravimetric/differential thermal analysis (heating rate: 5°C/min), shown in figure 26; more specifically, it has an endothermic peak around 141,0°and an exothermic peak around the 122.7°C;

(20)1H NMR spectrum, which is essentially identical to1H NMR spectrum (DMSO-d6, TMS)shown in figure 27. In particular, it has characteristic peaks at 1.55V-to 1.63 ppm (m, 2H), 1,68-of 1.78 ppm (m, 2H), 2,35 is 2.46 ppm (m, 4H), 2,48-of 2.56 ppm (m, 4H + DMSO), 2,78 ppm (t, J=7.4 Hz, 2H), 2,97 ppm (shirt, J=4.6 Hz, 4H), to 3.92 ppm (t, J=6.3 Hz, 2H), to 6.43 ppm (d, J=2.4 Hz, 1H), of 6.49 ppm (DD, J=8,4 Hz, J=2.4 Hz, 1H), of 6.49 ppm (DD, J=8,4 Hz, J=2.4 Hz, 1H),? 7.04 baby mortality ppm (d, J=8,1 Hz, 1H), 7,11-7,17 ppm (m, 1H), 7,28-to 7.32 ppm (m, 2H) and 10.00 ppm (s, 1H);

(21) powder diffraction spectrum roentgen the ski rays, which is essentially identical to the spectrum of the powder x-ray diffraction, are shown in figure 28. In particular, it has characteristic peaks at 2θ=10,1°, 12,8°, 15,2°, 17,0°and 17.5°, 19,1°, 20,1°, 21,2°, 22,4°, 23,3°and 24.5° and 25.8°and

(22) the infrared spectrum, which is essentially identical to the IR-spectrum (KBR), shown in figure 29. In particular, he has a clear infrared absorption band at 2942, 2813, 1670, 1625, 1377, 1195, 962 and 787 cm-1.

The method of obtaining the type G crystals of anhydrous aripiprazole

The type G crystals of anhydrous aripiprazole of the present invention can be obtained, for example, location of anhydrous aripiprazole in the vitreous state in a sealed vessel and keeping it at room temperature for at least two weeks, preferably from two weeks to six months. Next, anhydrous aripiprazole in the vitreous state as starting material can be obtained by heating and grinding anhydrous aripiprazole at approximately 170°C, then cooling it to room temperature.

Anhydrous aripiprazole used as starting material, can be well-known crystals of anhydrous aripiprazole, for example, any one of the crystals of type I anhydrous aripiprazole crystals of type II anhydrous ar is pyrazole and the like, these anhydrous aripiprazole can be either purified products or raw materials. In the alternative case as the source material for anhydrous aripiprazole you can use the type crystals In anhydrous aripiprazole, type crystals With anhydrous aripiprazole, type D crystals of anhydrous aripiprazole crystals of type E anhydrous aripiprazole or the type F crystals of anhydrous aripiprazole, which are the present invention. These waterless aripiprazole can be used individually or in combination, at least 2 types.

Thus obtained crystals of the type G of anhydrous aripiprazole, you can select and clear the well known ways. For example, when the anhydrous aripiprazole in the glassy state is left to stand by the above method, it is possible to get the type G crystals of anhydrous aripiprazole, having a purity of 100%.

The type crystals With anhydrous aripiprazole, type D crystals of anhydrous aripiprazole crystals of type E anhydrous aripiprazole, type F crystals of anhydrous aripiprazole, and the type G crystals of anhydrous aripiprazole of the present invention do not degrade easily in their hydrates, do not reduce essentially the original solubility even when they remain for an extended period of time.

In accordance with us is oasim invention the methods of obtaining crystals of anhydrous aripiprazole, having high purity, which can be applied on an industrial scale with good reproducibility.

In accordance with the present invention proposed a pharmaceutical composition comprising crystals of anhydrous aripiprazole, the solubility of which is not reduced and the stability which it is possible to maintain excellent, even if they are stored for a long time.

Crystals of anhydrous aripiprazole, which are the starting material for obtaining crystals from V to G anhydrous aripiprazole of the present invention, receive, for example, the following method a or b.

"Method and the": Method to obtain crude crystals of aripiprazole

Crystals conventional anhydrous aripiprazole get well-known methods, as described in example 1 of Japanese patent laying No. 191256/1990.

A suspension of 47 g of 7-(4-bromobutoxy)-3,4-dihydroorotase, 35 g of sodium iodide with 600 ml of acetonitrile is refluxed for 30 minutes. To this suspension is added 40 g of 1- (2,3-dichlorophenyl) piperazine and 33 ml of triethylamine and the whole mixture was further refluxed for 3 hours. After removal of the solvent by evaporation the resulting residue is dissolved in chloroform, washed with water and then dried with anhydrous magnesium sulfate. The solvent is removed by evaporation and the floor is built so the residue is recrystallized from ethanol twice, getting to 57.1 g of 7-{4-[4-(2,3-dichlorophenyl)-1-piperazinil]butoxy}-3,4-dihydroorotase.

Colorless flake crystals with TPL: 139,0-139,5°C.

"Method b": a method of obtaining a conventional anhydrous aripiprazole

Method b is described in the Proceedings of the 4th Japanese-Korean Symposium on separation technology (October 6-8, 1996).

In addition, the crystals of anhydrous aripiprazole of the present invention receives, for example, by heating ordinary hydrate conventional aripiprazole at 90-125°C. the heating Time is usually about 3-50 hours, but it may not be accurate, because it changes depending on the heating temperature. Heating time and temperature of heating is inversely proportional, so that, for example, the heating time will be the longer, the lower the temperature of heating, and the shorter, the higher the temperature of the heating. In particular, if the temperature of the heating aripiprazole hydrate is 100°C, the heating time may be approximately 24 hours, while, if the temperature of the heating 120°C, the heating time may be approximately 3 hours.

The aripiprazole hydrate, which is the starting material for obtaining crystals of anhydrous aripiprazole of the present invention, receive, for example, the following method C.

"Method": Method of obtaining obychno the hydrate

The aripiprazole hydrate easily obtained by dissolution of the crystals of anhydrous aripiprazole obtained above method and in aqueous solvent and by heating and then cooling the resulting solution. When using this method, the aripiprazole hydrate precipitates as crystals in aqueous solvent.

As the aqueous solvent is usually used organic solvent containing water. The organic solvent must be a solvent which is miscible with water, such as, for example, alcohol such as methanol, ethanol, propanol or isopropanol, a ketone such as acetone, simple ether, such as tetrahydrofuran, dimethylformamide or mixtures thereof, and especially preferred is ethanol. The amount of water in the aqueous solvent can be 10-25% vol. solvent or preferably close to 20%vol.

A pharmaceutical composition

The medicinal composition of the present invention will contain crystals b, C, D, E, F and G of anhydrous aripiprazole in a pharmaceutically acceptable carrier or combination of carriers.

Carriers which are pharmaceutically acceptable include diluents and excipients commonly used in pharmaceutical preparations, such as fillers, dry diluents, binders, humectants, disintegrators, surface-active veshestva lubricants.

The pharmaceutical composition of the present invention can be manufactured in the form of conventional pharmaceutical preparation, for example, in the form of tablets, fast dissolving tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories or injectable (liquid, suspension etc)

When they are ready preparative form in the form of tablets, you can use a large variety of carriers that are known in this field. Examples include lactose, sucrose, sodium chloride, glucose, xylitol, mannitol, aritra, sorbitol, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid, and other excipients; water, ethanol, propanol, regular syrup, liquid glucose, liquid starch, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone and other binders; dried starch, sodium alginate, agar powder, powder of laminaran, sodium bicarbonate, calcium carbonate, esters of polyoxyethylenesorbitan and fatty acids, sodium lauryl sulfate, stearate of monoglyceride, starch, lactose and other disintegrators; sucrose, stearin, cacao butter, hydrogenated oil, and other inhibitors of disintegration; Quaternary ammonium salts, sodium lauryl sulfate, and other promoters of absorption; glycerin, starch and other means by keeping the Deposit of moisture; starch, lactose, kaolin, bentonite, colloidal silicic acid and other adsorbents and purified talc, stearate, boric acid powder, polyethylene glycol and other lubricants, and the like. Tablets may be produced, if required, in the form of tablets with conventional coatings, such as tablets, coated in sugar, tablets, coated gelatin, tablets intersolubility coated tablets, film-coated, as well as double and multilayer tablets tablets.

When they are ready preparative form of pills, you can use a wide variety of carriers that are known in this field. Examples include glucose, lactose, starch, cacao butter, utverjdenie vegetable oil, kaolin, talc and other excipients; powder Arabian gum, powder tragakant, gelatin, ethanol and other binders; and laminarin, agar-agar and other disintegrators and the like.

When they are ready preparative form in the form of a suppository, you can use a wide variety of carriers that are known in this field. Examples include polyethylene glycol, cacao butter, higher alcohol esters of higher alcohol, gelatin, semisynthetic glycerides, and the like.

Capsules receive in accordance with accepted methods by mixing crystals besod is on aripiprazole with different media, described above, and filling mixtures of hard gelatin capsules, soft capsules, capsules from hydroxypropylmethylcellulose (capsules receiver array) and the like.

In addition, in the pharmaceutical composition can include dyes, preservatives, odorants, corrigentov, sweeteners and the like, as well as other medicines.

In the case of a pharmaceutical solid oral preparation in the form of granules, it can get wet granulation of mixed powder granulomas ingredients, including crystals of anhydrous aripiprazole (ordinary crystals of anhydrous aripiprazole or crystals of anhydrous aripiprazole selected from the group consisting of crystals of type b, C, D, E, F and G of anhydrous aripiprazole) and various media, which are still well known in this field, such as excipients, disintegrators, disintegration inhibitors, moisturizers, absorption accelerators, adsorbents, lubricants, dyes and the like as examples of these agents can be specified previously mentioned agents) with the addition of liquid (usually water or an aqueous solution containing a binding agent). With regard to wet granulation, there are various ways that include, for example, granulation in the fluidized bed, granulation by mixing, granulation is here extrusion, rotary granulation and the like. Among these methods, in the case of granulation in the fluidized bed granulomas ingredients containing various media, mixed with the intake air, then when continuous fluidization granulomas ingredients sprayed liquid to conduct granulation. In the case of granulation by mixing granulomas ingredients containing various media, mixed by stirring, and then with continuous stirring granulomas ingredients granulation is conducted by adding the liquid. After granulation, if necessary, the obtained granules are sieved to obtain from them the granules of the desired size using a suitable sieve or mill having a suitable size sieves. Thus, the granules obtained by the above method, then dried in addition to the usual drying, which is carried out upon receipt of the granules. With regard to methods of drying, you can apply different ways, for example, you can specify how to use the dryer fluidized bed, fan dryers, vacuum dryers, and the like. Methods of drying is usually carried out in a conventional conditions, for example, in the case of use dryers, fluidized bed drying procedure is carried out with the air flow of 0.5 m3/min up to 50 m3/min, temperature is dependent on the incoming air from 70 to 100° C for from 10 minutes to 1 hour. After drying, the granules are subjected to screening, and then dried. In the case of using the dryer fluidized bed dryer or fan or the like, the drying procedure is carried out in the conditions with the air flow of 0.5 m3/min up to 50 m3/min, temperature of the incoming air from 70 to 100°C for from 1 to 6 hours. In the case of vacuum drying the drying procedure is carried out in conditions of reduced pressure of approximately 0-10 Torr at a temperature of shell from 70 to 100°C for 1-6 hours.

The thus obtained pellets can be used directly as a pharmaceutical solid oral preparations or, if necessary, they can take the form of tablets. In addition, dried in the usual way granules turn into the form of pills, which can again be dried.

The thus obtained pharmaceutical solid oral preparation comprising crystals of anhydrous aripiprazole, hardly converted into hydrates, even if they remain for a long period of time, consequently, it is possible to provide a pharmaceutical solid oral preparation, dissolution rate which is almost not reduced (dissolution rate in order to maintain maximum concentration of drug (Cmax): the speed of the solution is s 60% or higher, obtained after 30 minutes at pH 4.5, the dissolution rate of 70% or higher, obtained after 60 minutes at pH 4.5, or the dissolution rate of 55% or higher, obtained after 60 minutes at pH 5.0).

Other pharmaceutical solid oral preparation may be obtained by granulation of crystals conventional aripiprazole hydrate a manner similar to the method mentioned above, and dried in the usual way in a similar situation, then again dried. In the alternative case, the granules are dried in the usual way, turn in the form of tablets, then again dried, then you can offer the pharmaceutical solid oral preparation, the rate of dissolution which is not reduced (dissolution rate in order to maintain maximum concentration of drug (Cmax): the dissolution rate of 60% or higher is obtained after 30 minutes at pH 4.5, the dissolution rate of 70% or higher, obtained after 60 minutes at pH 4.5, or the dissolution rate of 55% or higher, obtained after 60 minutes at pH 5.0). These facts can be interpreted so that ordinary crystals of anhydrous aripiprazole or crystals of aripiprazole hydrate contained in the pharmaceutical solid oral preparation turn into crystals type In" anhydrous aripiprazole double drying.

The number of crystals b, C, D, E, F and G of anhydrous aripiprazole, which must be included in l the drug composition of the present invention, you can choose from a wide range, suitable for the readings. Crystals of anhydrous aripiprazole usually present in amount of about 1-70 wt.% or specifically about 1-30 wt.% in the calculation of the pharmaceutical composition.

Route of administration pharmaceutical compositions of the present invention it is possible to choose so that it was suitable, for example, for the finished formulation of the drug product, age, gender, and other criteria (including the severity of the condition) of the patient. In the case of tablets, pills, liquids, suspensions, emulsions, granules and capsules introduction is, for example, orally. In the case of injections, it is injected either alone or in mixture with conventional excipient such as glucose or amino acids, or, if necessary, it can be entered separately intramuscular, intradermal, subcutaneous or intraperitoneal means. In the case of a suppository introduction is intrarectal.

The dosage of the pharmaceutical compositions of the present invention is selected depending on the application, age, gender and other criteria of the patient, the severity of the condition and so forth, but usually the number of crystals of anhydrous aripiprazole is approximately 0.1 to 10 mg per kg of body weight per day. The drug, which is a uniform dose injection should containing the b crystals of anhydrous aripiprazole in the range of about 1-100 mg, more specifically 1-30 mg generic dosage.

The medicinal composition of the present invention is very stable, essentially does not show reduction in solubility, even when stored for extended periods of time.

The medicinal composition of the present invention is effective in the prevention and treatment of disorders of the Central nervous system such as schizophrenia, it can also be effective in the treatment of intractable (drug-resistant chronic) schizophrenia with a decrease in mental activity and intractable (drug-resistant chronic) schizophrenia without reducing mental activity, anxiety, including anxiety, mild, mania, including acute mania with bipolar disorder and acute mania, bipolar disorder, depression, including depression, bipolar disorder, autism, down syndrome, disturbance type hyperactivity with attention deficit (ADHD), Alzheimer's disease, Parkinson's disease and other neurodegenerative disorders, panic, obsessive compulsive disorders, sleep disorders, disorders of sexual function, alcohol and drug dependence, vomiting, motion sickness, obesity, migraines and reduction of mental activity.

Analyte the static methods

(1)1H NMR spectrum was measured in DMSO-d6using TMS as standard.

(2) Powder x-ray diffraction

Using the meter diffraction Rigaku Denki RAD-2B powder x-ray diffraction pattern was measured at room temperature using a tube filled with Cu Ka (35 kV, 20 mA), as a source of x-rays with a wide-angle goniometer, 1° slit scattering, 0.15 mm svetopronitsaemoe slit, graphite secondary monochromator and a scintillation counter. Data collection was performed in mode 2θ continuous scanning at a scan rate of 5°/min in steps of scanning 0,02° in the range from 3° to 40°.

(3) IR spectrum was measured way with CVG.

(4) Thermogravimetric/differential thermal analysis

Thermogravimetric/differential thermal analysis was performed using device management Seiko SSC 5200 and devices simultaneous differential thermal/thermogravimetric measurement (TG/DTA 220. Samples of 5-10 mg were placed in an open aluminum Cup and heated from 20°to 200°C in an atmosphere of dry nitrogen at a heating rate of 5°C/minute. α-alumina was used as the standard substance.

(5) Differential scanning calorimetry of Thermogravimetry the definition/differential thermal analysis was performed using device management Seiko SSC 5200 and differential scanning calorimeter (DSC 220C. Samples of 5-10 mg were placed in corrugated aluminum Cup and heated from 20°to 200°C in an atmosphere of dry nitrogen at a heating rate of 5°C/minute. α-alumina was used as the standard substance.

(6) Measurement of particle size

0.1 g of the measured particles suspended in 20 ml of a solution of 0.5 g of soybean lecithin in n-hexane and the particle size was measured using a meter distribution of particle sizes (Microtrack HRA, Microtrack Co.).

(7) Method of test for water absorption

One g of sample, accurately weighed in a flask for weighing (diameter 5 cm), covered with Kim wipes, and left alone in the environment with 60°C/100% RH (water, desiccator). After 24 hours, weighed flask was removed, transferred into the environment with room temperature and approximately 30% RH (saturated aqueous solution of uranyl chloride magnesium/desiccator), was left alone for 24 hours and the water content of the sample was measured by the Karl Fischer method.

(8)13With NMR spectroscopy of solid state

13From the NMR spectra of substances in the solid state was measured under the following conditions.

Measurement instrument: the NMR spectrometer SMX-360 Solid State (manufactured Chemagnetic Inc.)

Computer: SPARC Station 2 (manufactured by SUN Microsystem, Inc.)

OS Software: Solalis I.I.I Rev. In (Registered trademark: UNIX), Spinsight Ver. 2.5.

The name of the measured pulse is sa: the way TOSS (TOSS is the name of the instrument program) as part of the way CP/MAS.

The duration of the measured pulse: 90° pulses used in conditions CF.

Tube measurement sample; a test tube made of Zirconia and having an outer diameter of 7, 5 mm and an internal capacity of 0.8 ml.

Frequency: 4250 Hz (Frequency at the second time of contact: 1 msec.

Standby time: 20 sec.

Integrated time: 512 times.

Temperature measurement: the temperature is outside of the test tube about 25°).

External standard: methyl group (δ 17,3) hexamethylbenzene used as an external standard.

The present invention is explained in more detail below using reference examples, examples, preparations of samples and examples ready preparative forms.

Reference example 1

7-(4-Chloroethoxy)-3,4-dihydroxybutyl in the amount of 19.4 g and 16.2 g of the hydrochloride of 1-(2,3-dichlorophenyl)piperidine 1 add to 8,39 g of potassium carbonate, dissolved in 140 ml of water, and the mixture circulates under stirring for 3 hours. After the reaction the mixture is cooled and the precipitated crystals are filtered. These crystals are dissolved in 350 ml of ethyl acetate and approximately 210 ml of a mixture of water/ethyl acetate removed by azeotropic distillation by boiling under reflux. The remaining solution is cooled and the precipitated crystals are filtered. The resulting crystals with the shat for 14 hours at 60° With the receiving of 20.4 g (74,2%) of the crude aripiprazole.

Untreated aripiprazole in the amount of 30 g, obtained above, is recrystallized from 450 ml of ethanol in accordance with the methods described in Japanese patent laying No. 191256/1990, and the resulting crystals are dried for 40 hours at 80°obtaining crystals of anhydrous aripiprazole. The output is of 29.4 g (98,0%).

Melting point (so square) of these crystals of anhydrous aripiprazole was 140°S, which corresponds to the melting point of the crystals of anhydrous aripiprazole, described in Japanese patent laying No. 191256/1990.

When these crystals were left for 24 hours in a desiccator, in which was installed a humidity of 100% and a temperature of 60°they had the hygroscopicity of 3.28% (see table 1 below).

Reference example 2

Intermediate crude aripiprazole in number 6930 g, obtained in reference example 1 was dissolved by heating at 138 liters of aqueous ethanol (water content 20%) according to the method, presented at the 4th Japanese-Korean Symposium on separation technology, gradually (2-3 hours), cooled to room temperature and then cooled to approximately 0°C. the Precipitated crystals are filtered, while receiving approximately 7200 g of aripiprazole hydrate (hydrated state).

Crystals of aripiprazole hydrate raw status is Janie, obtained above is dried for 30 hours at 80°thus 6480 g (93.5 per cent) of ordinary crystals of anhydrous aripiprazole. Melting point (TPL) of these crystals was 139,5°C. by the Method of Karl Fischer confirmed that these crystals are anhydrous, the humidity value of 0.03%.

When these crystals was kept for 24 hours in a desiccator, which was supported by the humidity of 100% and a temperature of 60°they had the hygroscopicity of 1.78% (see table 1 below).

Reference example 3

Intermediate aripiprazole hydrate in the wetted state in the amount of 820 g, obtained in reference example 2, dried for 2 hours at 50°thus the 780 g crystals of aripiprazole hydrate. These crystals have a humidity value 3,82% by Karl Fischer method. As shown in figure 6, thermogravimetric/differential thermal analysis detects endothermic peaks at 75,0, 123,5 and to 140.5°C. Because dehydration begins about 70°With, there was no obvious melting point (i.e. square).

As shown in figure 7, the spectrum of the powder x-ray diffraction of the aripiprazole hydrate, obtained by this method has characteristic peaks at 2θ=12,6°, 15,1°, 17,4°, 18,2°, 18,7°, 24,8° and 27.5°.

Range of powder x-ray diffraction of the aripiprazole hydrate was identical with what ektron powder x-ray diffraction of the aripiprazole hydrate, presented at the 4th Japanese-Korean Symposium on separation technology.

Reference example 4

Receive 15 mg tablets containing crystals of type I of anhydrous aripiprazole obtained in reference example 2.

Crystals of type I of anhydrous aripiprazole (525 g), lactose (1,995 g), corn starch (350 g) and crystalline cellulose (350 g) are loaded into the dryer granulation fluidized bed (Flow Coater FLO-5, manufactured by FREUND INDUSTRIAL CO., LTD.) and these ingredients granulation stirred fluidized bed for about 3 minutes with the temperature at input 70°and the air flow rate 3 m3/min. Further ingredients granulation withstand continuous fluidization in the same conditions and sprayed approximately 1400 g of an aqueous solution to obtain wet granules. The wet granules are dried at the temperature of the air entering the 80°C for approximately 15 minutes. The obtained dried granules contain 4.3% of water (yield 99%). The dried granules are subjected to sorting by means of passing through a sieve of 710 μm.

To the sifted granules add and mix them with about 1 wt.% the magnesium stearate, and then the granules are served on tablet press machine (single Rotary tablet press 12HUK: manufactured by KIKUSUI SEISAKUSHO CO., LTD), as a result, tablets, and each has a mass of 95 mg.

The water content of the tablets was measured according to the method about the roadways titration (Karl Fischer method), described in the method of measuring the water content in the Pharmacopoeia of Japan, or by way of electrical quantitative titration.

The method of measuring the water content of:

The sample (0.1 to 0.5 g) (in the case of tablets take 1 tablet) accurately weighed and the water content is measured by using measuring equipment water content.

Volumetric titration:

Automated equipment for measuring water content

Model: KF-06 (manufactured by MITSUBISHI CHEMICAL CORP.)

The way electric quantitative titration:

Automated equipment for measuring microstorage water

Model: AQ-7F (manufactured by HIRANUMA SANGYO CO., LTD.)

Automated model equipment water evaporation:

LE-20S (manufactured by HIRANUMA SANGYO CO., LTD.)

The temperature of the heating: 165±10°

The flow rate of nitrogen gas: 150 ml/min

Reference example 5

Receive 15 mg tablets containing crystals of the type In anhydrous aripiprazole

Crystals of the type In anhydrous aripiprazole (4500 g), lactose (17100 g), corn starch (3000 g) and crystalline cellulose (3000 g) is loaded into granulating the fluidized bed dryer (NEW-MARUMERIZER Model: NQ-500, manufactured by FUJI PAUDAL CO., LTD.) and these ingredients granulation is mixed fluidized bed for about 3 minutes with the temperature at input 70°With, at a speed of flux is as air from 10 to 15 m 3/min. Further ingredients granulation withstand continuous fluidization in the same conditions and sprayed approximately 12000 g 5% aqueous solution of hydroxypropylcellulose to obtain wet granules. The wet granules are dried at the temperature of the air at the input 85°C for about 28 minutes. Thus obtained dried granules contain 3.8% of water (measured by the method according to reference example 4). (Yield: 96%). The dried granules are subjected to sorting by means of passing through a sieve of 850 μm.

Approximately 1 wt.% the magnesium stearate is added to the sifted granules and mixed with them, and then the granules are served on tablet press machine (single Rotary tablet press 12HUK: manufactured by KIKUSUI SEISAKUSHO CO., LTD), as a result, tablets, and each has a mass of 95 mg).

Example 1

The hydrate crystals of aripiprazole in the number 500,3 g, obtained in reference example 3, ground using a mill for samples (a small plant for fine grinding). The speed of rotation of the main axis set to 12000 rpm and the rotation speed of the feed to about 17./min and use a sieve of 1.0 mm type "Christmas tree". Grinding finish in 3 minutes, which gives 474,6 g (94.9%) powder hydrate a of aripiprazole.

Hydrate a of aripiprazole (powder)obtained in this way, has an average particle size of 20-25 μm. Melting point (so square) is the " is divided, because there is dehydration, starting about 70°C.

The above hydrate a of aripiprazole (powder) has1H NMR spectrum (DMSO-d6, TMS), which is essentially the same as1H NMR spectrum, shown in figure 2. In particular, they have characteristic peaks at 1.55V-to 1.63 ppm (m, 2H), 1,68-of 1.78 ppm (m, 2H), 2,35 is 2.46 ppm (m, 4H), 2,48-of 2.56 ppm (m, 4H + DMSO), 2,78 ppm (t, J=7.4 Hz, 2H), 2,97 ppm (shirt, J=4.6 Hz, 4H), to 3.92 ppm (t, J=6.3 Hz, 2H), to 6.43 ppm (d, J=2.4 Hz, 1H), of 6.49 ppm (DD, J=8,4 Hz, J=2.4 Hz, 1H),? 7.04 baby mortality ppm (d, J=8,1 Hz, 1H), 7,11-7,17 ppm (m, 1H), 7,28-to 7.32 ppm (m, 2H) and 10.00 ppm (s, 1H).

Hydrate a of aripiprazole (powder)obtained above, has a range of powder x-ray diffraction, which is essentially the same as the spectrum of the powder x-ray diffraction, are shown in figure 3. In particular, it has characteristic peaks at 2θ=12,6°, 15,4°, 17,3°, 18,0°, 18,6°, 22,5° and 24.8°. This diffraction pattern is different from the powder x-ray spectrum of unground aripiprazole hydrate, are shown in figure 7.

Hydrate a of aripiprazole (powder)obtained above, has an infrared absorption band at 2951, 2822, 1692, 1577, 1447, 1378, 1187, 963 and 784 cm-1in the IR spectrum (KBR).

As shown in figure 1, hydrate And aripiprazole (powder)obtained above, a weak peak at 71,3° thermogravimetric/differential heat treatment of the x-ray analysis and a broad endothermic peak (observed mass loss corresponding to a single molecule of water) between 60-120°that is clearly different from the endothermic curve of unground aripiprazole hydrate (see figure 6).

Example 2

Hydrate a of aripiprazole (powder) in an amount of 450 g, obtained in example 1, dried for 24 hours at 100°using hot air dryers, while receiving 427 g (yield 98.7 per cent) of crystals of anhydrous aripiprazole.

These crystals of anhydrous aripiprazole have a melting point (so square) 139,7°C.

Crystals of anhydrous aripiprazole obtained above are1H NMR spectrum (DMSO-d6, TMS), which is essentially the same as1H NMR spectrum, shown in figure 4. In particular, they have characteristic peaks at 1.55V-to 1.63 ppm (m, 2H), 1,68-of 1.78 ppm (m, 2H), 2,35 is 2.46 ppm (m, 4H), 2,48-of 2.56 ppm (m, 4H + DMSO), 2,78 ppm (t, J=7.4 Hz, 2H), 2,97 ppm (shirt, J=4.6 Hz, 4H), to 3.92 ppm (t, J=6.3 Hz, 2H), to 6.43 ppm (d, J=2.4 Hz, 1H), of 6.49 ppm (DD, J=8,4 Hz, J=2.4 Hz, 1H),? 7.04 baby mortality ppm (d, J=8,1 Hz, 1H), 7,11-7,17 ppm (m, 1H), 7,28-to 7.32 ppm (m, 2H) and 10.00 ppm (s, 1H).

Crystals of anhydrous aripiprazole obtained above have a range of powder x-ray diffraction, which is essentially the same as the spectrum of the powder x-ray diffraction, are shown in figure 5. In particular, it has characteristic peaks at 2θ=11,0°, 16,6°, 19,3°, 20,3° and 22.1°.

Crystals of anhydrous aripiprazole, recip is installed above have a significant infrared absorption bands at 2945, 2812, 1678, 1627, 1448, 1377, 1173, 960 and 779 cm-1in the IR spectrum (KBR).

Crystals of anhydrous aripiprazole obtained above are endothermic peak approximately 141,5°when thermogravimetric/differential thermal analysis.

Crystals of anhydrous aripiprazole obtained above are endothermic peak approximately 140,7°With differential scanning calorimetry.

Even when the crystals of anhydrous aripiprazole obtained above, was kept for 24 hours in a desiccator, which was set humidity 100%, temperature 60°they did not show the absorption excess of 0.4% (see table 1 below).

Example 3

Hydrate a of aripiprazole (powder)obtained in example 1 in the amount of 44,29 kg heat for drying for 18 hours in a dryer with hot air at 100°and then heated for 3 hours at 120°obtaining of 42.46 kg (yield of 99.3%) of crystals of anhydrous aripiprazole.

Physico-chemical properties of the formed crystals of anhydrous aripiprazole were the same as the physico-chemical properties of crystals of anhydrous aripiprazole obtained in example 2.

Crystals of anhydrous aripiprazole obtained in this way have hygroscopicity higher than 0.4%, even when they are in the support within 24 hours in a desiccator, in which maintain humidity 100%, temperature 60°With (see table 1 below).

Example 4

Hydrate a of aripiprazole (powder)obtained in example 1 in the amount of 40,67 kg heat for drying for 18 hours in a dryer with hot air at 100°and then heated for 3 hours at 120°thus 38,95 kg (output 99,6%) of crystals of anhydrous aripiprazole.

Physico-chemical properties of the formed crystals of anhydrous aripiprazole were the same as the physico-chemical properties of crystals of anhydrous aripiprazole obtained in example 2.

Crystals of anhydrous aripiprazole obtained in this way have hygroscopicity higher than 0.4%, even when incubated for 24 hours in a desiccator in which maintain humidity 100%, temperature 60°With (see table 1 below).

The products of examples 5-10 are suitable for the production of injectable or oral ready preparative forms as solutions, since they are obtained by heating ordinary anhydrous crystals or hydrate instead hydrate A.

Example 5

Hygroscopic crystals of anhydrous aripiprazole obtained in reference example 1, heated for 50 hours at 100°using the same methods as in example 2. Physico-chemical properties of the formed crystals In anhydrous aripipra the Ola were the same as physico-chemical properties of crystals of anhydrous aripiprazole obtained in example 2.

Crystals of anhydrous aripiprazole obtained in this way have hygroscopicity higher than 0.4%, even when incubated for 24 hours in a desiccator in which maintain humidity 100%, temperature 60°With (see table 1 below).

Example 6

Hygroscopic crystals of anhydrous aripiprazole obtained in reference example 1, heated for 3 hours at 120°using the same methods as in example 2. Physico-chemical properties of the formed crystals of anhydrous aripiprazole were the same as the physico-chemical properties of crystals of anhydrous aripiprazole obtained in example 2.

Crystals of anhydrous aripiprazole obtained in this way have hygroscopicity higher than 0.4%, even when incubated for 24 hours in a desiccator in which maintain humidity 100%, temperature 60°With (see table 1 below).

Example 7

Hygroscopic crystals of anhydrous aripiprazole obtained in reference example 2, heated for 50 hours at 100°using the same methods as in example 2. Physico-chemical properties of the formed crystals of anhydrous aripiprazole were the same as the physico-chemical properties of crystals In anhydrous Ari is eprazole, obtained in example 2.

Crystals of anhydrous aripiprazole obtained in this way have hygroscopicity higher than 0.4%, even when incubated for 24 hours in a desiccator in which maintain humidity 100%, temperature 60°With (see table 1 below).

Example 8

Hygroscopic crystals of anhydrous aripiprazole obtained in reference example 2, heated for 3 hours at 120°using the same methods as in example 2.

Physico-chemical properties of the formed crystals of anhydrous aripiprazole were the same as the physico-chemical properties of crystals of anhydrous aripiprazole obtained in example 2.

Crystals of anhydrous aripiprazole obtained in this way have hygroscopicity higher than 0.4%, even when incubated for 24 hours in a desiccator in which maintain humidity 100%, temperature 60°With (see table 1 below).

Example 9

Crystals of aripiprazole hydrate obtained in reference example 3 heated for 50 hours at 100°using the same methods as in example 2. Physico-chemical properties of the formed crystals of anhydrous aripiprazole were the same as the physico-chemical properties of crystals of anhydrous aripiprazole obtained in example 2.

Crystals of anhydrous aripiprazole, polucen the e way, have no hygroscopicity higher than 0.4%, even when incubated for 24 hours in a desiccator in which maintain humidity 100%, temperature 60°With (see table 1 below).

Example 10

Crystals of aripiprazole hydrate obtained in reference example 3, is heated for 3 hours at 120°using the same methods as in example 2. Physico-chemical properties of the formed crystals of anhydrous aripiprazole were the same as the physico-chemical properties of crystals of anhydrous aripiprazole obtained in example 2.

Crystals of anhydrous aripiprazole obtained in this way have the hygroscopicity of no more than 0.4%, even when incubated for 24 hours in a desiccator in which maintain humidity 100%, temperature 60°With (see table 1 below).

Example 11 (Obtaining crystals of the type With anhydrous aripiprazole)

Crystals of type I of anhydrous aripiprazole obtained in reference example 2, in the amount of 100 milligrams heated at approximately 145° (±3°). In this case, there occurs such a phenomenon that the crystals once melt and crystallize again. After receiving 100 mg (yield: 100%) of crystals of the type With anhydrous aripiprazole. The melting point of the crystals is a 150°C. the crystals have the form of colorless prisms.

Crystals of type C betw the underwater aripiprazole, obtained above are endothermic curve which is essentially identical to the endothermic curve of thermogravimetric/differential thermal analysis (heating rate: 5°C/minute)shown in figure 8. In particular, it has an endothermic curve near 150,2°C.

The type crystals With anhydrous aripiprazole obtained in this way have1H NMR spectrum (DMSO-d6, TMS), which is essentially identical to1H NMR spectrum (DMSO-d6, TMS)shown in figure 9. In particular, it has characteristic peaks at 1.55V-to 1.63 ppm (m, 2H), 1,68-of 1.78 ppm (m, 2H), 2,35 is 2.46 ppm (m, 4H), 2,48-of 2.56 ppm (m, 4H + DMSO), 2,78 ppm (t, J=7.4 Hz, 2H), 2,97 ppm (shirt, J=4.6 Hz, 4H), to 3.92 ppm (t, J=6.3 Hz, 2H), to 6.43 ppm (d, J=2.4 Hz, 1H), of 6.49 ppm (DD, J=8,4 Hz, J=2.4 Hz, 1H),? 7.04 baby mortality ppm (d, J=8,1 Hz, 1H), 7,11-7,17 ppm (m, 1H), 7,28-to 7.32 ppm (m, 2H) and 10.00 ppm (s, 1H).

The type crystals With anhydrous aripiprazole obtained above have a range of powder x-ray diffraction, which is essentially identical to the spectrum of the powder x-ray diffraction, are shown in figure 10. In particular, it has characteristic peaks at 2θ=12,6°, 13,7°, 15,4°, 18,1°, 19,0°, 20,6°, 23,5° and 26.4°.

The type crystals With anhydrous aripiprazole obtained above are of the infrared spectrum, which is essentially identical to the IR-spectrum (KBR), shown in figure 11. In particular, he has x racteristics infrared absorption band at 2939, 2804, 1680, 1375 and 780 cm-1.

The type crystals With anhydrous aripiprazole obtained above are13From the NMR spectrum of the substance in the solid state), which is essentially identical to13With the NMR-spectrum (spectrum of the substance in the solid state), shown in figure 12. In particular, it has characteristic peaks at 32,8 ppm, of 60.8 ppm, of 74.9 ppm, 104,9 ppm, 152,2 ppm, 159,9 ppm and 175,2 ppm

In accordance with the above data on endothermic curve of thermogravimetric/differential thermal analysis (heating rate: 5°C/minute) and powder x-ray diffraction pattern of x-rays confirmed the formation of crystals of the type With anhydrous aripiprazole.

When the type crystals With anhydrous aripiprazole obtained above, was kept for 24 hours in a desiccator, which was humidity of 100% and a temperature of 60°With, the crystals did not show hygroscopicity higher than 0.4% (see table 1 below).

Example 12 (getting the type D crystals of anhydrous aripiprazole)

Crystals of type I of anhydrous aripiprazole obtained in reference example 2, add 200 ml of toluene and dissolved by heating at 74°C. After confirming that they are completely dissolved, a solution in toluene is cooled to 7°and the precipitated crystals are collected by filtration. Crystals as such is subjected to drying at the hcpa is heh, while receiving 17.9 g (yield: 89.5 per cent) of the type D crystals of anhydrous aripiprazole.

The type D crystals of anhydrous aripiprazole obtained above are endothermic curve is essentially identical to the endothermic curve of thermogravimetric/differential thermal analysis (heating rate: 5°C/minute)shown in figure 13. In particular, he has endothermic peaks around 136,8°and about 141,6°C.

The type D crystals of anhydrous aripiprazole obtained above are1H NMR spectrum (DMSO-d6, TMS), which is essentially identical to1H NMR spectrum (DMSO-d6, TMS)shown in figure 14. In particular, they have characteristic peaks at 1.55V-to 1.63 ppm (m, 2H), 1,68-of 1.78 ppm (m, 2H), 2,35 is 2.46 ppm (m, 4H), 2,48-of 2.56 ppm (m, 4H + DMSO), 2,78 ppm (t, J=7.4 Hz, 2H), 2,97 ppm (shirt, J=4.6 Hz, 4H), to 3.92 ppm (t, J=6.3 Hz, 2H), to 6.43 ppm (d, J=2.4 Hz, 1H), of 6.49 ppm (DD, J=8,4 Hz, J=2.4 Hz, 1H),? 7.04 baby mortality ppm (d, J=8,1 Hz, 1H), 7,11-7,17 ppm (m, 1H), 7,28-to 7.32 ppm (m, 2H) and 10.00 ppm (s, 1H).

The type D crystals of anhydrous aripiprazole obtained above have a range of powder x-ray diffraction, which is essentially identical to the spectrum of the powder x-ray diffraction, are shown in figure 15. In particular, it has characteristic peaks at 2θ=8,7°, 11,6°, 16,3°, 17,7°, 18,6°, 20,3°and 23.4° and 25.0°.

The type D crystals of anhydrous aripiprazole, receiving the data above, have the infrared spectrum, which is essentially identical to the IR-spectrum (KBR), shown in figure 16. In particular, it has a characteristic infrared absorption band at 2946, 1681, 1375, 1273, 1175 and 862 cm-1.

The type D crystals of anhydrous aripiprazole obtained above are13From the NMR spectrum of the substance in the solid state), which is essentially identical to13With the NMR-spectrum (spectrum of the substance in the solid state), shown in figure 17. In particular, it has characteristic peaks at 32,1 ppm, 62,2 ppm, 66,6 ppm, 104,1 ppm, 152,4 ppm, 158,5 ppm and 174,1 ppm

In accordance with the above data on endothermic curve of thermogravimetric/differential thermal analysis (heating rate: 5°C/minute) and powder x-ray diffraction pattern of x-rays confirmed the formation of crystals of the D-type anhydrous aripiprazole.

When the type D crystals of anhydrous aripiprazole obtained above, was kept for 24 hours in a desiccator, which was humidity of 100% and a temperature of 60°With, the crystals did not show hygroscopicity higher than 0.4% (see table 1 below).

Example 13 (getting the type D crystals of anhydrous aripiprazole)

Crystals of type I of anhydrous aripiprazole obtained in reference example 2, in the amount of 1200 g dissolved in 18 liters of toluene by heating. This solution in Tolu the Le is cooled to 40° And as the seed crystals added 36 g of type D crystals of anhydrous aripiprazole obtained in example 12, then the solution is cooled to 10°and left to stand as it is. The precipitated crystals are collected by filtration, dried at 60°C for 18 hours, while receiving 1,073 g (yield: 86.8%of) the type D crystals of anhydrous aripiprazole (purity: 100%). The crystals have the form of colorless plates.

The type D crystals of anhydrous aripiprazole have the endothermic curve is essentially identical to the endothermic curve of thermogravimetric/differential thermal analysis (heating rate: 5°C/minute)shown in figure 13. In particular, it has endothermic peaks around 136,8°and about 141,6°C.

The type D crystals of anhydrous aripiprazole obtained above are1H NMR spectrum (DMSO-d6, TMS), which is essentially identical to1H NMR spectrum (DMSO-d6, TMS)shown in figure 14. In particular, it has characteristic peaks at 1.55V-to 1.63 ppm (m, 2H), 1,68-of 1.78 ppm (m, 2H), 2,35 is 2.46 ppm (m, 4H), 2,48-of 2.56 ppm (m, 4H + DMSO), 2,78 ppm (t, J=7.4 Hz, 2H), 2,97 ppm (shirt, J=4.6 Hz, 4H), to 3.92 ppm (t, J=6.3 Hz, 2H), to 6.43 ppm (d, J=2.4 Hz, 1H), of 6.49 ppm (DD, J=8,4 Hz, J=2.4 Hz, 1H),? 7.04 baby mortality ppm (d, J=8,1 Hz, 1H), 7,11-7,17 ppm (m, 1H), 7,28-to 7.32 ppm (m, 2H) and 10.00 ppm (s, 1H).

The type D crystals of anhydrous aripiprazole obtained above have a range of the powder Direcci the x-rays, which is essentially identical to the spectrum of the powder x-ray diffraction, are shown in figure 15. In particular, it has characteristic peaks at 2θ=8,7°, 11,6°, 16,3°, 17,7°, 18,6°, 20,3°and 23.4° and 25.0°.

The type D crystals of anhydrous aripiprazole obtained above are of the infrared spectrum, which is essentially identical to the IR-spectrum (KBR), shown in figure 16. In particular, it has a characteristic infrared absorption band at 2946, 1681, 1375, 1273, 1175 and 862 cm-1.

The type D crystals of anhydrous aripiprazole obtained above are13From the NMR spectrum of the substance in the solid state), which is essentially identical to13With the NMR-spectrum (spectrum of the substance in the solid state), shown in figure 17. In particular, it has characteristic peaks at 32,1 ppm, 62,2 ppm, 66,6 ppm, 104,1 ppm, 152,4 ppm, 158,5 ppm and 174,1 ppm

In accordance with the above data on endothermic curve of thermogravimetric/differential thermal analysis (heating rate: 5°C/minute) and the spectrum of the powder x-ray diffraction confirmed the formation of crystals of the D-type anhydrous aripiprazole.

When the type D crystals of anhydrous aripiprazole obtained above, was kept for 24 hours in a desiccator, which was humidity of 100% and a temperature of 60°With, the crystals are not expressed the Yali hygroscopicity higher than 0.4% (see table 1 below).

Example 14 (Obtaining crystals of type E anhydrous aripiprazole)

Crystals of type I of anhydrous aripiprazole obtained in reference example 2, in the amount of 40 grams dissolved in 1000 ml of acetonitrile with heating at 80°C. This solution in acetonitrile is cooled to approximately 70°keeping it for about 10 minutes and maintained at this temperature for approximately 30 minutes for the deposition of the seed crystals. Then the temperature of the specified solution is slowly increased up to 75°and grow crystals by maintaining this temperature for 1 hour. Then the solution is cooled to 10°and keep it for about 4 hours and the precipitated crystals are collected by filtration. The thus obtained crystals are subjected to drying in air during the night, while getting 37,28 g (yield: 93,2%) of crystals of type E anhydrous aripiprazole (purity: 100%). The melting point of these crystals 145°C, the crystals have the form of colorless needles.

Crystals of type E anhydrous aripiprazole have the endothermic curve is essentially identical to the endothermic curve of thermogravimetric/differential thermal analysis (heating rate: 5°C/minute)shown in figure 18. In particular, it has an endothermic peak around 146,5°C.

Kr is the growth of type E anhydrous aripiprazole, obtained above, havelH NMR spectrum (DMSO-d6, TMS), which is essentially identical to1H NMR spectrum (DMSO-d6, TMS)shown in figure 19. In particular, they have characteristic peaks at 1.55V-to 1.63 ppm (m, 2H), 1,68-of 1.78 ppm (m, 2H), 2,35 is 2.46 ppm (m, 4H), 2,48-of 2.56 ppm (m, 4H + DMSO), 2,78 ppm (t, J=7.4 Hz, 2H), 2,97 ppm (shirt, J=4.6 Hz, 4H), to 3.92 ppm (t, J=6.3 Hz, 2H), to 6.43 ppm (d, J=2.4 Hz, 1H), of 6.49 ppm (DD, J=8,4 Hz, J=2.4 Hz, 1H),? 7.04 baby mortality ppm (d, J=8,1 Hz, 1H), 7,11-7,17 ppm (m, 1H), 7,28-to 7.32 ppm (m, 2H) and 10.00 ppm (s, 1H).

Crystals of type E anhydrous aripiprazole obtained above have a range of powder x-ray diffraction, which is essentially identical to the spectrum of the powder x-ray diffraction, are shown in figure 20. In particular, it has characteristic peaks at 2θ=8,0°, 13,7°, 14,6°, 17,6°, 22,5° and 24.0°.

Crystals of type E anhydrous aripiprazole obtained above are of the infrared spectrum, which is essentially identical to the IR-spectrum (KBR), shown in figure 21. In particular, it has a characteristic infrared absorption band at 2943, 2817, 1686, 1377, 1202, 969 and 774 cm-1.

In accordance with the above data on endothermic curve of thermogravimetric/differential thermal analysis (heating rate: 5°C/minute) and powder x-ray diffraction pattern of x-rays confirmed the formation cristalleria E anhydrous aripiprazole.

When crystals of type E anhydrous aripiprazole obtained above, was kept for 24 hours in a desiccator, which was humidity of 100% and a temperature of 60°C, the crystals do not exhibit hygroscopicity higher than 0.4% (see table 1 below).

Example 15 (Obtaining the type F crystals of anhydrous aripiprazole)

Crystals of type I of anhydrous aripiprazole obtained in reference example 2, in the amount of 140 grams suspended in 980 ml of acetone and continue to boil under reflux for 7.5 hours with stirring. Then the suspension was filtered in hot conditions and the separated crystals are subjected to drying in air for 16 hours at room temperature, while receiving 86,19 g (yield: 61,6%) of the type F crystals of anhydrous aripiprazole (purity: 100%). The crystals have the form of colorless prisms.

The type F crystals of anhydrous aripiprazole have the endothermic curve is essentially identical to the endothermic curve of thermogravimetric/differential thermal analysis (heating rate: 5°C/minute)shown in figure 22. In particular, it is exothermic peaks around 137,5°and about 149,8°C.

The type F crystals of anhydrous aripiprazole obtained above are1H NMR spectrum (DMSO-d6TMS), which is essentially identical to1H NMR spectrum (DMSO-d6, TMS)shown in Figo is e 23. In particular, it has characteristic peaks at 1.55V-to 1.63 ppm (m, 2H), 1,68-of 1.78 ppm (m, 2H), 2,35 is 2.46 ppm (m, 4H), 2,48-of 2.56 ppm (m, 4H + DMSO), 2,78 ppm (t, J=7.4 Hz, 2H), 2,97 ppm (shirt, J=4.6 Hz, 4H), to 3.92 ppm (t, J=6.3 Hz, 2H), to 6.43 ppm (d, J=2.4 Hz, 1H), of 6.49 ppm (DD, J=8,4 Hz, J=2.4 Hz, 1H),? 7.04 baby mortality ppm (d, J=8,1 Hz, 1H), 7,11-7,17 ppm (m, 1H), 7,28-to 7.32 ppm (m, 2H) and 10.00 ppm (s, 1H).

The type F crystals of anhydrous aripiprazole obtained above have a range of powder x-ray diffraction, which is essentially identical to the spectrum of the powder x-ray diffraction, are shown in figure 24. In particular, it has characteristic peaks at 2θ=11,3°and 13.3°, 15,4°, 22,8°, 25,2° and 26,9°.

The type F crystals of anhydrous aripiprazole obtained above are of the infrared spectrum, which is essentially identical to the IR-spectrum (KBR), shown in figure 25. In particular, it has a characteristic infrared absorption band at 2940, 2815, 1679, 1383, 1273, 1177, 1035, 963 and 790 cm-1.

In accordance with the data on the endothermic curve of thermogravimetric/differential thermal analysis (heating rate: 5°C/minute) and powder x-ray diffraction pattern of x-rays confirmed the formation of the type F crystals of anhydrous aripiprazole.

When the type F crystals of anhydrous aripiprazole obtained above, was kept for 24 hours in a desiccator, which was the humidity is ü 100% and a temperature of 60° With, the crystals did not show hygroscopicity higher than 0.4% (see table 1 below).

Table 1
SampleThe initial moisture content (%)The moisture content after 24 hours (%)
Reference example 10,043,28
Reference example 20,041,78
Example 20,040,04
Example 30,020,02
Example 40,020,02
Example 50,040,04
Example 60,040,04
Example 70,040,03
Example 80,040,03
Example 90,030,01
Example 100,050,05
Example 110,030,03
Example 120,040,03
Example 130,040,03
Example 140,060,09
Example 150,040,04

Example 16

(a) Crystals of the type which I anhydrous aripiprazole (10 g), obtained in reference example 2, is loaded into a round tray made of stainless steel (diameter: 80 mm) and heated to approximately 170°to melt. When this molten material is cooled, it solidifies with the formation of transparent substances pale brown solid is separated from the round tray made of stainless steel, while receiving of 9.8 g (yield: 98%) of anhydrous aripiprazole in the vitreous state. Received the product in a glassy state is characterized by the absence of a significant peak observed in the powder spectrum of x-rays (see figure 31).

In accordance with a thermogravimetric/differential thermal analysis (heating rate: 5°C/minute), as shown in figure 30, was observed exothermic peak-type crystals In anhydrous aripiprazole about 86,5°C. whereas endothermic peak-type crystals In anhydrous aripiprazole due to melting was observed around 140,1°C.

b) When anhydrous aripiprazole in the vitreous state, obtained in example 16-a)were loaded into a sealed vessel and kept at room temperature for approximately 6 months, then got the type G crystals of anhydrous aripiprazole, having a white color instead of the original pale brown (25 g, yield: 100%). Melting point: 138 to° C.

The type G crystals of anhydrous aripiprazole have the endothermic curve is essentially identical to the endothermic curve of thermogravimetric/differential thermal analysis (heating rate: 5°C/minute)shown in figure 26, more specifically, it has an endothermic peak around 141,0°and an exothermic peak around the 122.7°C.

The type G crystals of anhydrous aripiprazole obtained as described above, have1H NMR spectrum, which is essentially identical to1H NMR spectrum (DMSO-d6, TMS)shown in figure 27. In particular, it has characteristic peaks at 1.55V-to 1.63 ppm (m, 2H), 1,68-of 1.78 ppm (m, 2H), 2,35 is 2.46 ppm (m, 4H), 2,48-of 2.56 ppm (m, 4H + DMSO), 2,78 ppm (t, J=7.4 Hz, 2H), 2,97 ppm (shirt, J=4.6 Hz, 4H), to 3.92 ppm (t, J=6.3 Hz, 2H), to 6.43 ppm (d, J=2.4 Hz, 1H), of 6.49 ppm (DD, J=8,4 Hz, J=2.4 Hz, 1H),? 7.04 baby mortality ppm (d, J=8,1 Hz, 1H), 7,11-7,17 ppm (m, 1H), 7,28-to 7.32 ppm (m, 2H) and 10.00 ppm (s, 1H).

The type G crystals of anhydrous aripiprazole obtained as described above have a range of powder x-ray diffraction, which is essentially identical to the spectrum of the powder x-ray diffraction, are shown in figure 28. In particular, it has characteristic peaks at 2θ=10,1°, 12,8°, 15,2°, 17,0°and 17.5°, 19,1°, 20,1°, 21,2°, 22,4°, 23,3°and 24.5° and 25.8°.

The type G crystals of anhydrous aripiprazole obtained above are of the infrared spectrum,which is essentially identical to the IR-spectrum (KBR), shown in figure 29. In particular, it has a characteristic infrared absorption band at 2942, 2813, 1670, 1625, 1377, 1195, 962 and 787 cm-1.

Example 17

a) Obtaining granules 30 mg tablets, containing crystals of the type In anhydrous aripiprazole, for additional drying

Crystals of the type In anhydrous aripiprazole (1500 g), lactose (5700 g), corn starch (1000 g) and crystalline cellulose (1000 g) are loaded into granulating the fluidized bed dryer (Flow Coater FLO Model-5M; made FROINT SANGYO KABUSHIKI KAISHA), and these ingredients granulation is mixed fluidized bed for about 3 minutes with the temperature at input 60°and a flow rate of 3-4 m3/min. Further ingredients granulation is subjected to continuous fluidization in the same conditions and they sprayed approximately 4000 g 5% aqueous solution of hydroxypropylcellulose to obtain wet granules. The wet granules are dried at the temperature of the air at the input 85°C for approximately 20 minutes. The obtained dried granules contain 3.8% of water (measured by the method according to reference example 4).

b) the Dried granules (4 kg)obtained in example 17-a), sorted by size using a mill (FIORE F-0:manufactured by TOKUJU CORPORATION).

The sifted granules (3 kg) load in granulating the fluidized bed dryer (Flow Coater FLO Model-5M made FREUNDINDUSTRIAL CO., LTD.) and these granulomas ingredients are dried at the temperature of the air at the input 85°and air velocity of 2 m3/min for 2 hours. The obtained dried granules are 3.6% of water (measured by the method according to reference example 4).

Approximately 1 wt.% the magnesium stearate is added to the sifted granules and mixed, and then the granules are served in tablet press machine (single Rotary tablet press, model VIGRO: manufactured by KIKUSUI SEISAKUSHO CO., LTD.), while receiving tablets, and each has a mass of 190 mg.

C) the Dried granules (3 kg)obtained in example 17-a), are loaded into a vacuum dryer (vacuum granulating dryer model; VG-50: manufactured by KIKUSUI SEISAKUSHO CO., LTD.) and dried at a temperature of shirts 70°C, under reduced pressure of 5 Torr vacuum degrees for 1 hour. Thus obtained dried granules contain 3.1% of water (measured by the method according to reference example 4). The dried granules are subjected to sifting by means of passing the sieve of 850 μm.

Approximately 1 wt.% the magnesium stearate is added to the sifted granules and mixed with them, and then the granules are served in tablet press machine (single Rotary tablet press, model VIGRO: manufactured by KIKUSUI SEISAKUSHO CO., LTD.), while receiving tablets, and each has a mass of 190 mg.

Example 18

a) Receiving 30 mg tablets, containing crystals of the type In anhydrous aripiprazole

The anhydrous aripiprazole (crystal type) (4500 g), lactose (1710), corn starch (3000 g) and crystalline cellulose (3000 g) is loaded into granulating the fluidized bed dryer (NEW-MARUMERIZER Model: NQ-500, manufactured by FUJI PAWDAL CO., LTD.) and these granulomata the ingredients are mixed fluidized bed for about 3 minutes when the air temperature at the input 70°and the air flow rate of 10-15 m3/min. Later granulomas ingredients continue pseudoagouti under the same conditions and sprayed approximately 12000 g 5% aqueous solution of hydroxypropylcellulose to obtain wet granules. The wet granules are dried at the temperature of the air at the input 85°C for approximately 30 minutes. The obtained dried granules are 3.6% of water (measured by the method according to reference example 4). (Yield: 96%). The dried granules are sorted by size by passing to the mill (FIOLE F-0: manufactured by TOKUJU CORPORATION).

Approximately 1 wt.% the magnesium stearate is added to the sifted granules and mixed with them, and then the granules are served in tablet press machine (a single Rotary tablet press, VIGRO: manufactured by KIKUSUI SEISAKUSHO CO., LTD.), while receiving tablets, and each has a mass of 190 mg.

b) Tablets (5 kg)obtained in example 18-a), load in a fan dryer (AQUA COATER AQT-48T, manufactured by FREUND INDUSTRIAL CO., LTD.) and dried at air temperature at the input 90°C, air velocity of 2 m3/min for 6 hours. P is obtained dried granules contain 3.3% of water (measured by the method in accordance with reference example 4).

c) the Dried tablets (3 kg)obtained in example 18-a), are loaded into a vacuum dryer (vacuum granulating dryer; VG-50: manufactured by KIKUSUI SEISAKUSHO CO., LTD.) and dried at a temperature of shirts 80°C, under reduced pressure of 5 Torr vacuum degrees for 4 hours. The obtained dried tablets contain 2.7% of water (measured by the method in accordance with reference example 4).

Example 19

a) by Procedures similar to the procedures of example 18-a), you get a tablet (containing crystals of type I of anhydrous aripiprazole obtained in reference example 2), and each has a mass of 190 mg.

b) Tablets are dried by procedures similar to the procedures of example 18-b), except that the temperature at the input 100°and dried for 1 hour.

c) the Tablets are dried by procedures similar to the procedures of example 18-b), except that the temperature at the input is 100°and dried for 3 hours.

Example 20

Procedures similar to the procedures of example 18-a), is obtained tablets, each has a weight of 190 mg, containing crystals of the type With anhydrous aripiprazole.

Example 21

Procedures similar to the procedures of example 18-a), is obtained tablets, each has a weight of 190 mg, containing the type D crystals of anhydrous aripiprazole.

Example 22

(a) Crystals of aripiprazole hydrate (156 g)obtained in reference p is the iMER 3, lactose (570 g), corn starch (100 g) and crystalline cellulose (100 g) is loaded into granulating the fluidized bed dryer (NEW-MARUMERIZER, NQ-160: manufactured by FUJI POWDAL CO., LTD.) and these granulomata the ingredients are mixed in the fluidized bed for about 3 minutes with the temperature at input 60°C, air flow rate from 1.0 to 1.5 m3/min and a rotating disk with a rotational speed of 400 rpm./minutes Later granulomas ingredients continue pseudoagouti under the same conditions and sprayed approximately 500 g of 4% aqueous solution of hydroxypropylcellulose to obtain wet granules. The air temperature at the input increases to 85°and the product is dried up until the product temperature reaches 46°C. the Obtained dried granules are sieved by passing the sieve of 850 μm. The dried granules contain 4,37% of water (measured in a manner consistent reference example 4).

d) the Dried granules (200 g)obtained in example 22-a), are loaded into a fluidized bed dryer (multiplex MP-01: manufactured by POWREX CORPORATION) and dried at air temperature at the input 85°C, air velocity of 0.5 m3/min for 2 hours. The dried granules contain 3,50% of water (measured in a manner consistent reference example 4).

C) the Dried granules (100 g)obtained in example 22-a), are loaded into a vacuum is usiku (vacuum granulating dryer LCV-232: made TAVA CO., LTD.) and dried at a temperature of tray 80°C, the vacuum of 760 mm Hg for 2 hours. The dried granules are optionally dried under the same conditions for 6 hours. The dried granules contain 3,17% water (product, which was dried for 2 hours: the measurement was performed in a way appropriate to reference example 4). Additionally, the dried granules contain 2,88% water (product, which was dried for 6 hours: measurement conducted in a manner consistent reference example 4).

d) About 1 wt.% the magnesium stearate is added to the sifted granules, which are obtained in example 22-b), and mix with them, then mixed granules served in tablet press machine (Single type Tablet machine no. 2B:manufactured by KIKUSUI SEISAKUSHO CO., LTD.) and tabletirujut stamp, while receiving tablets, and each has a mass of 191 mg

e) About 1 wt.% the magnesium stearate is added to the sifted granules, which are obtained in example 22-(C), and mix with them, then mixed granules served in tablet press machine (Single type Tablet machine no. 2B: manufactured by KIKUSUI SEISAKUSHO CO., LTD.) and tabletirujut stamp, while receiving tablets, and each has a mass of 191 mg

Example 23

a) using procedures similar to the procedures of example 17 and receive the dried granules containing crystals of type I of anhydrous aripiprazole, such as were obtained in referential example 2.

b) the Floor is built granules graded according to size by sieving and dried procedures similar to the procedures of example 17-(b).

c) thus Obtained granules are dried by procedures similar to the procedures of example 17-(C).

Example 24

a) by Procedures similar to the procedures of example 18-a), receive a tablet containing the aripiprazole hydrate obtained in reference example 3, and each has a mass of 190 mg.

b) Tablets are dried by procedures similar to the procedures of example 18-b), except that the temperature of the inlet air is 100°and dried for 1 hour.

(C) the Tablets are dried by procedures similar to the procedures of example 18-b), except that the temperature of the inlet air is 100°and dried for 3 hours.

The test for dissolution

Each of the tablets of the pharmaceutical solid oral preparations, previously obtained, maintained, respectively, in the open space at 25°C/60% RH for 6 months and at 40°C/75% RH for 1 week, then their dissolution rate was measured in the following ways. The dissolution rate obtained after 60 minutes of dissolution, are shown in tables 2 and 3. The dissolution rate after 60 minutes using tablets, sustained in the open space at 40°C/75% RH for 2 weeks, are shown in tables 4 and 5. The dissolution rate after 60 minutes using tablets, sustained in the open space at 40°C/75% RH for 1 week, shown in table 6.

Equipment for testing solubility: USP Model: NTR-6100 (manufactured by TOYAMA SANGYO CO., LTD) Model: DT-610 (manufactured by JASCO CORPORATION)

a) Method of testing the solubility of 15 mg tablets

One tablet (containing 15 mg of each of anhydrous aripiprazole or aripiprazole hydrate) was tested using 900 ml of buffer solution with acetic acid (pH 5.0) (note: 1) as the test solution and by rotating paddle stirrer at 100 rpm./min according to the method of USP (United States Pharmacopeia) (note: 2).

Tested solutions obtained respectively after 10 minutes, 20 minutes, 30 minutes, 45 minutes and 60 minutes after the start of the test, denoted as T10, T20, T30, T45 and KZT60.

On the other hand, approximately 0.05 g of the standard sample aripiprazole accurately weighed, was dissolved in ethanol (95%)to get exactly 50 ml solution in ethanol. Took exactly twenty (20) ml of this solution in ethanol and to get exactly 1000 ml standard solution was added 0.01 mol/liter of reagent solution of hydrochloric acid (note 3).

The tested solution and standard solution was subjected to filtration, respectively, using a filter having micropores of 10 to 20 microns in diameter, then each of the filtrates was inserted in the spectrophotometer, set the cell flow type (dynacache: 10 mm), for measuring the absorption at a wavelength of 249 nm and absorption at a wavelength of 325 nm and determined the difference between the acquisition marked as At10, At20, At30, At45, At60 and As, respectively.

After the measurements the subjects solutions T10, T20, T30 and T45 was placed back into the vessels for testing, respectively. Next, a similar procedure was performed for the other 5 samples of test solutions.

The dissolution rate (%)related to the specified

the number of aripiprazole = the number of standard sample

aripiprazole (mg) × At × As × 9/5 × 20/S

where At: At10, At20, At30, At45 or At60

As: standard solution

From: the specified number of aripiprazole (mg)

(Note:1) Water added to 1,97 g of acetic acid (100) and 9.15 g of three-hydrate of sodium acetate to obtain 1000 ml of solution (0.1 mol/l).

(Note: 2) Way blade mixer

(Note:3) Water is added to 100 ml of 0.1 mol/l hydrochloric acid (note: 4) to obtain 1000 ml of solution.

(Note:4) Water added to 0.9 ml of hydrochloric acid, to obtain 1000 ml of solution.

b) test Method for solubility of 30 mg tablets

One tablet of each of the pharmaceutical solid oral preparations (containing 30 mg of each of anhydrous aripiprazole or aripiprazole hydrate) was tested using 900 ml of buffer solution with vinegar is Oh acid (pH 4.5) (note: 5) as the test solution and the test was performed by mixing paddle stirrer at about 75./min according to the method of USP (United States Pharmacopeia) (note: 6).

Tested solutions obtained respectively after 10 minutes, 20 minutes, 30 minutes, 45 minutes and 60 minutes after the start of the test, were identified as T10, T20, T30, T45 and KZT60.

On the other hand, weighed approximately 0.05 g of a standard sample of aripiprazole was dissolved in ethanol (95%)to get exactly 50 ml solution in ethanol. Took exactly twenty (20) ml of this solution in ethanol and received exactly 1000 ml of a standard solution by adding 0.01 mol/liter of reagent solution of hydrochloric acid (note 7).

The tested solution and standard solution was subjected to filtration, respectively, using a filter having micropores of 10 to 20 microns in diameter, then each of the filtrates was inserted in the spectrophotometer, set the cell flow type (length cell: 10 mm) and measured the absorbance at a wavelength of 249 nm and absorption at a wavelength of 325 nm and determined the difference between the acquisition marked as At10, At20, At30, At45, At60 and As, respectively.

After the measurements the subjects solutions T10, T20, T30 and T45 was placed back into the vessels for testing, respectively. Next, a similar procedure was performed for the other 5 samples of test solutions.

The dissolution rate (%)related to the specified number of aripiprazole, = the number of standard sample of aripiprazole (mg) x At × As × 9/5 × 20/S

<> where At: At10, At20, At30, At45 or At60

As: standard solution

From: the specified number of aripiprazole (mg)

(Note:5) Water was added to 1,91 g of acetic acid (100) and to 2.99 g of three-hydrate of sodium acetate to obtain 1000 ml of solution (0.05 mol/l).

(Note: 6) Way blade mixer

(Note:7) Water is added to 100 ml of 0.1 mol/l hydrochloric acid (note: 8) to obtain 1000 ml of solution.

(Note:8) Water added to 0.9 ml of hydrochloric acid, to obtain 1000 ml of solution.

Table 2
Used sampleOpen space at 25°C/60% RHOpen space at 40°C/75% RH
InitialAfter 6 monthsInitialAfter 1 week
Tablet (15 mg) of reference example 483.4%of44,3%83.4%of44,1%
Tablet (15 mg) of reference example 590.1%of61,9%90.1%of65,2%
Table 3
Used sampleopen space at 25° C/60% RHOpen space at 40°C/75% RH
InitialAfter 6 monthsInitialAfter 1 week
Tablet (30 mg) of example 18-a)96,7%77,1%96,7%75,9%
Tablet (30 mg) of example 17-(b)96,5%93,6%95,0%92,2%
Tablet (30 mg) of example 17-(C)97,0%96,3%94,7%94,8%
Tablet (30 mg) of reference example 18-(b)97,2%for 95.3%97,2%of 97.8%
Tablet (30 mg) of reference example 18-(C)of 97.8%96,3%of 97.8%to 96.9%

Table 4
Used sampleInitialAfter 2 weeks
Samples using the tablet (30 mg) of example 19-a)89,8%66,9%
Tablet (30 mg) use the and 19-b) -79,8%
Tablet (30 mg) of example 19)-85,9%
Table 5
Used sampleInitialAfter 2 weeks
Tablet (30 mg) of example 18-a)94,8%94,7%
Tablet (30 mg) of example 2093,7%93.1%of
Tablet (30 mg) of example 2194,8%90,9%

Note: Test solubility, are shown in table 5, was carried out similarly to the procedures in the above "(b) the method of testing the solubility of 30 mg tablets, except that used 900 ml buffer solution with acetic acid (pH 4.0) as the test solution and stirring was performed paddle stirrer at 50 rpm./minutes

As is clearly evident from the data given in table 2, compared with 15 mg tablet containing crystals conventional anhydrous aripiprazole (reference example 4), 15 mg tablet, containing crystals of the type In anhydrous aripiprazole (reference example 5)had a rate of dissolution, which supports a maximum concentration of drug (Cmax) at pH ,0 through 60 minutes, even if this tablet was kept in the open space at 25°C/60% RH for 6 months and in the open space at 40°C/75% RH for 1 week.

As is clearly evident from the data given in table 3, even if the 30 mg tablets (examples 17-b and 17-C)), obtained from the double-dried granules of the type crystals In anhydrous aripiprazole, 30 mg tablets (examples 18-b and 18-C)), obtained from the addition of dried pharmaceutical solid oral preparation containing crystals of the type In anhydrous aripiprazole, stood in the open space at 25°C/60% RH for 6 months or 40°/75% RH for 1 week, the dissolution rate of these tablets obtained after 60 minutes after the start of the test at pH 4.5, was not significantly decreased.

As is clearly evident from the data given in table 4, when 30 mg tablets (examples 19-a, 19-b and 19-C))containing crystals conventional anhydrous aripiprazole, then dried and kept in the open space at 40°C/75% RH for 2 weeks, then the dissolution rate of the tablets obtained after 60 minutes after the test at pH 4.5, were the speed of dissolution, which kept the maximum concentration of drug (Cmax).

As is clearly evident from the data given in table 5, when 30 mg tablet (example 18-a)), containing crystals of the type In anhydrous, aripiprazol is a, 30 mg tablet (example 20), containing crystals of the type With anhydrous aripiprazole, 30 mg tablet (example 21), containing the type D crystals of anhydrous aripiprazole, kept at 40°C/75% RH for 2 weeks, then the dissolution rate of the tablets obtained after 60 minutes when tested at pH 4.0 was not significantly decreased.

As is clearly evident from the data given in table 6, when 30 mg tablet (examples 22 d and 22 e))obtained from the pellets of conventional aripiprazole hydrate, double-dried and kept at 40°C/75% RH for 1 week, then the dissolution rate of the tablets obtained after 60 minutes after the test at pH 4.5, were the speed of dissolution, which kept the maximum concentration of drug (Cmax).

Preparation of 1 sample
Crystals of anhydrous aripiprazole5 mg
Starch131 mg
Magnesium stearate4 mg
Lactose60 mg
Only200 mg

Tablets containing the above ingredients in each tablet was obtained by methods of manufacture of the finished formulation, well-known specialist in the manufacture of finished pharmaceutical formulation.

Drug 2 sample Crystals of anhydrous aripiprazole5 mgStarch131 mgMagnesium stearate4 mgLactose60 mgOnly200 mg

In accordance with the generally accepted method received the drug in the form of tablets containing the above ingredients in 1 tablet.

Preparation of 3 sample
The D crystals of anhydrous aripiprazole5 mg
Starch131 mg
Magnesium stearate4 mg
Lactose60 mg
Only200 mg

In accordance with the generally accepted method received the drug in the form of tablets containing the above ingredients in 1 tablet.

Preparation of 4 sample
Crystals E. anhydrous aripiprazole5 mg
Starch131 mg
Magnesium stearate4 mg
Lactose60 mg
Only200 mg

In accordance with the generally accepted method received the drug in the form of tablets containing the above ingredients in 1 tablet.

The drug 5 sample
Crystals F anhydrous aripiprazole5 mg
Starch131 mg
Magnesium stearate4 mg
Lactose60 mg
Only200 mg

In accordance with the generally accepted method received the drug in the form of tablets containing the above ingredients in 1 tablet.

Preparation of 6 sample
Crystals G of anhydrous aripiprazole5 mg
Starch131 mg
Magnesium stearate4 mg
Lactose60 mg
Only200 mg

In accordance with the generally accepted method received the drug in the form of tablets containing the above ingredients in 1 tablet.

An example of the finished formulation

In the following examples used aripiprazole medicinal substance obtained first by grinding or by spraying normal Hydra is the aripiprazole and then heating it with the formation of the anhydrous form (crystals of anhydrous aripiprazole).

Example 1 ready preparative form.

Fast dissolving tablets were received as follows:

Intragranular:

IngredientPercent wt./wt.mg tablet
Xylitol (300) xiliary2652
Avicel®PH 1021224
The calcium silicate43,3586,7
Crosspovidone36
Amorphous silicon dioxide24
Aspartame24
Perfume with the smell of cherry0,150,3
Tartaric acid24
Acesulfame K24
Magnesium stearate0,251,5
The total mass92,75185,5

Ingredients, except magnesium stearate were mixed in industrial V-mixer in geometric proportions for 5 minutes each, until, until you have added all the ingredients. Then add the magnesium stearate and the mixture was stirred for an additional three minutes. Mixed composition extruded the ri pressure of 30-35 kg/cm 2industrial seal, provided with such a hole that the CDs were in the form of tapes. The tape was passed through a sieve of 30 mesh (600 microns) for the formation of stable granules of approximately from 150 to 400 microns.

The ingredients of extracranial:

IngredientPercent wt./wt.mg tablet
Product intragranular92,75185,5
Avicel®PH 20036
Crosspovidone48
Magnesium stearate0,250,5
The total mass100200

Product intragranular was placed in the mixer and to it was added Avicel® PH 200 and crosspovidone and all was stirred for five minutes. Then add the magnesium stearate and the mixture was stirred for an additional three minutes with the formation of the final mixture. Tablets obtained from pressing her, had the destructive force of 2.3 KP (3,5 SCU) and disintegrated for 30 seconds in 5 ml of water. The final mixture showed excellent flowability and was deprived of other problems, such as breaking, clogging and adhesion. It was found that the use of Avicel®PH 102 for intra is ranolazine and Avicel ®PH 200 as an ingredient of extracranial improves the quality of the resulting tablets.

Example 2 ready preparative form.

Fast dissolving tablets containing a combination of two types of calcium silicate, was prepared as follows:

Intragranular:

IngredientPercent wt./wt.mg tablet
Xylitol (300) xiliary2652
Avicel®PH 1021224
Calcium silicate (crystalline, alpha trilineage)33,3566,7
Huberson 600 NF (amorphous calcium silicate)1020
Crosspovidone36
Amorphous silicon dioxide24
Aspartame24
Perfume with the smell of cherry0,150,3
Tartaric acid24
Acesulfame K24
Magnesium stearate0,250,5
The total mass92,75185,5

Ingredients per drop is an stearate, mixed industrial V-mixer in geometric proportions for 5 minutes each, until, until you have added all the ingredients. Then add the magnesium stearate and the mixture was stirred for an additional three minutes. Mixed composition was pressed and sieved to the formation of stable granules in accordance with the procedure of example 1 is ready preparative form.

The ingredients of extracranial:

IngredientPercent wt./wt.mg tablet
Product intragranular92,75185,5
Avicel®PH 20036
Crosspovidone48
Magnesium stearate0,250,5
The total mass100200

Product intragranular were placed in a mixer, were added Avicel®PH 200 and crosspovidone and all was stirred for five minutes. Then add the magnesium stearate and the mixture was stirred for an additional three minutes with the formation of the final mixture. Tablets obtained from pressing her, had the destructive force of 2.0 CP (3,1 SCU) and disintegrated for 10 seconds in 5 ml of water.

Example 3 the finished drug is the main form

Fast dissolving tablets containing aripiprazole, protiwaritmicescoe drug, was prepared as follows:

Intragranular:

IngredientPercent wt./wt.mg tablet
Aripiprazole1530
Xylitol (300) xiliary2550
Avicel®PH 102612
The calcium silicate3774
Crosspovidone36
Amorphous silicon dioxide24
Aspartame24
Perfume with the smell of cherry0,150,3
Tartaric acid24
Acesulfame K24
Magnesium stearate0,250,5
The total mass94,4to 188.8

Ingredients, except magnesium stearate were mixed in industrial V-mixer in geometric proportions for 5 minutes each, until, until you have added all the ingredients. Then added stearate MAGN what I and the mixture was stirred for an additional three minutes. Mixed composition was pressed and sieved to the formation of stable granules in accordance with the procedure of example 1 is ready preparative form.

The ingredients of extracranial:

IngredientPercent wt./wt.mg tablet
Product intragranular94,4to 188.8
Avicel®PH 2001.12,2
Crosspovidone48
Magnesium stearate1,51
The total mass100200

Product intragranular were placed in a mixer, were added Avicel®PH 200 and crosspovidone and all was stirred for five minutes. Then add the magnesium stearate and the mixture was stirred for an additional three minutes with the formation of the final mixture. Tablets obtained from pressing her, had the destructive force of 2.0 CP (3,1 SCU) and disintegrated for 10 seconds in 5 ml of water.

Example 4 ready preparative form.

Fast dissolving tablets containing aripiprazole, was prepared as follows:

Intragranular:

IngredientPercent wt./wt. mg tablet
Aripiprazole0,51
Xylitol (300) xiliary2754
Avicel®PH 1021224
The calcium silicate4284
Crosspovidone36
Amorphous silicon dioxide24
Aspartame24
Perfume with the smell of cherry0,150,3
Tartaric acid24
Acesulfame K24
Magnesium stearate0,250,5
The total mass92,9185,8

Ingredients, except magnesium stearate were mixed in industrial V-mixer in geometric proportions for 5 minutes each, until, until you have added all the ingredients. Added magnesium stearate and the mixture was stirred for an additional three minutes. Mixed composition was pressed and sieved to the formation of stable granules in accordance with the procedure of example 1 is ready preparative form.

IngredientPercent wt./wt.mg tablet
Product intragranular92,9185,8
Avicel®PH 2002,65,2
Crosspovidone48
Magnesium stearate0,51
The total mass100200

Product intragranular were placed in a mixer, were added Avicel®PH 200 and crosspovidone and all was stirred for five minutes. Then add the magnesium stearate and the mixture was stirred for an additional three minutes with the formation of the final mixture. Tablets obtained from pressing her, had the destructive force of 2.3 KP (3,5 SCU) and disintegrated for 10 seconds in 5 ml of water.

1. Hydrate a of aripiprazole where specified hydrate has

range of powder x-ray diffraction with characteristic peaks in the powder x-ray diffraction at 2θ=12,6°, 15,4°, 17,3°, 18,0°, 18,6°, 22,5° and 24.8°;

characteristic infrared absorption band at 2951, 2822, 1692, 1577, 1447, 1378, 1187, 963 and 784 cm-1in the IR spectrum (KBR) ;

weak endothermic peak at 71°and not a sharp endothermic peak in the range of 60-120°is in thermogravimetric/differential thermal analysis (heating rate 5° C/min), and

the average particle size of 50 μm or less.

2. Hydrate a of aripiprazole according to claim 1, where the specified hydrate has a range of average particle sizes from 36 to 14 microns.

3. The method of producing hydrate a of aripiprazole, where the method includes grinding conventional aripiprazole hydrate to an average particle size of 50 μm or less.

4. The method according to claim 3, where the specified grinding is carried out in the plant for fine grinding using the speed of rotation of the main axis 5000-15000 rpm, the rotation speed of the raw material 10-30 rpm and size of the sieve mesh 1-5 mm

5. Hydrate a of aripiprazole obtained by the method according to claim 3, comprising a grinding conventional aripiprazole hydrate to an average particle size of 50 μm or less.

6. Hydrate And according to claim 5, where the specified grinding is carried out in the plant for fine grinding using the speed of rotation of the main axis 5000-15000 rpm, the rotation speed of the raw material 10-30 rpm and size of the sieve mesh 1-5 mm

7. Crystals of anhydrous aripiprazole, which have a range of powder x-ray diffraction with characteristic peaks in the powder x-ray diffraction at 2θ=11,0°, 16,6°, 19,3°, 20,3° and 22.1°;

characteristic infrared absorption band at 2945, 2812, 1678, 1627, 1448, 1377, 1173, 960 and 779 cm-1in the IR spectrum (KBr) ;

endothermic the ski peak at 141,5° In thermogravimetric/ differential thermal analysis (heating rate: 5°/min) ;

the endothermic peak at 140,7° differential scanning calorimetry (heating rate 5°C/min).

8. Crystals of anhydrous aripiprazole according to claim 7, having a low hygroscopicity, characterized by a moisture content of 0.40% or less after placing the medicinal product crystals for 24 h in a desiccator, which maintain a temperature of 60°and With a humidity level of 100%.

9. Crystals of anhydrous aripiprazole of claim 8, having a low hygroscopicity, characterized by a water content of 0.10% or less after placing the medicinal product crystals for 24 h in a desiccator, which maintain a temperature of 60°and With a humidity level of 100%.

10. Crystals of anhydrous aripiprazole according to claim 7, where these crystals have an average particle size of 50 μm or less.

11. Crystals of anhydrous aripiprazole of claim 10, where these crystals have an average particle size of 30 μm or less.

12. Crystals of anhydrous aripiprazole according to claim 7 where these crystals In essentially will not turn into a water form of aripiprazole when saving properly when relative humidity (RH) of 60% and at a temperature of 25°With, even over a long period of not less than 4 years.

13. The method receiving the Oia crystals of anhydrous aripiprazole, where this method involves the heating of the hydrate a of aripiprazole according to any one of claim 1 or 2.

14. The method of obtaining crystals of anhydrous aripiprazole indicated in paragraph 13, where the method includes heating the hydrate a of aripiprazole at 90-125°within 3-50 hours

15. The method of obtaining crystals of anhydrous aripiprazole indicated in paragraph 13, where the method includes heating the hydrate a of aripiprazole at 100°C for 18 hours

16. The method of obtaining crystals of anhydrous aripiprazole indicated in paragraph 13, where the method includes heating the hydrate a of aripiprazole at 100°within 24 hours

17. The method of obtaining crystals of anhydrous aripiprazole indicated in paragraph 13, where the method includes heating the hydrate a of aripiprazole at 120°C for 3 hours

18. The method of obtaining crystals of anhydrous aripiprazole indicated in paragraph 13, where the method includes heating the hydrate a of aripiprazole for 18 h at 100°and then further heated for 3 h at 120°C.

19. Crystals of anhydrous aripiprazole according to any one of claims 7 to 12, obtained by the process comprising heating a hydrate a of aripiprazole according to any one of claim 1 or 2 for 18 h at 100°and then further heated for 3 h at 120°C.

20. Pharmaceutical composition containing crystals of anhydrous aripiprazole according to any one of claims 7 to 12 together with the ne or more pharmaceutically acceptable carriers.

21. The pharmaceutical composition according to claim 20 in the form of a solid oral tablets.

22. The pharmaceutical composition according to claim 20 in the form of oral fast melting tablets.

23. A method of obtaining a pharmaceutical solid oral preparation comprising crystals of anhydrous aripiprazole defined in claim 8, and one or more pharmaceutically acceptable carriers, by wet granulation of a mixture of powder crystals of anhydrous aripiprazole and media, where the method includes heating the hydrate a of aripiprazole defined in claim 1.

24. A method of obtaining a pharmaceutical solid oral preparation comprising crystals of anhydrous aripiprazole defined in claim 8, and one or more pharmaceutically acceptable carriers, by wet granulation of a mixture of powder crystals of anhydrous aripiprazole and media, where the method includes heating the hydrate a of aripiprazole defined in claim 1, 90-125°within 3-50 hours

25. A method of obtaining a pharmaceutical solid oral preparation comprising crystals of anhydrous aripiprazole defined in claim 9, and one or more pharmaceutically acceptable carriers, by wet granulation of a mixture of powder crystals of anhydrous aripiprazole and media, where the method includes n is GREVENA hydrate a of aripiprazole, defined in claim 1.

26. A method of obtaining a pharmaceutical solid oral preparation comprising crystals of anhydrous aripiprazole defined in claim 9, and one or more pharmaceutically acceptable carriers, by wet granulation of a mixture of powder crystals of anhydrous aripiprazole and media, where the method includes heating the hydrate a of aripiprazole defined in claim 1, 90-125°within 3-50 hours

27. Crystals of anhydrous aripiprazole according to claim 7, where these crystals In essentially will not turn into a water form of aripiprazole when stored properly at a relative humidity (RH) of 60% and at a temperature of 25°With, even over a long period of not less than 1 year.

28. Crystals of anhydrous aripiprazole according to claim 7, where these crystals In essentially will not turn into a water form of aripiprazole when stored properly at a relative humidity (RH) of 75% and at a temperature of 40°With, even over a long period of not less than 0.5 years.

29. Pharmaceutical composition containing crystals of anhydrous aripiprazole in item 27 or 28, together with one or more pharmaceutically acceptable carriers.

30. The pharmaceutical composition according to clause 29 in the form of a solid oral tablets.

31. The pharmaceutical composition according to clause 29 in the form of peroral the Oh fast-melting tablets.

32. A method of treating disorders of the Central nervous system, including the introduction of crystals of anhydrous aripiprazole according to claims 7 to 12, 27-28.

33. A method of treating schizophrenia, comprising the introduction crystals of anhydrous aripiprazole according to claims 7 to 12, 27-28,

34. A method of treatment of bipolar disorders, including

introduction crystals of anhydrous aripiprazole according to claims 7 to 12, 27-28.

35. A method of treating intractable (drug-resistant chronic) schizophrenia with a decrease in mental activity or intractable (drug-resistant chronic) schizophrenia without reducing mental activity, including the introduction of crystals of anhydrous aripiprazole according to claims 7 to 12, 27-28.

36. A method of treating autism, down syndrome or disorders of the type of hyperactivity with attention deficit (ADHD), including the introduction of crystals of anhydrous aripiprazole according to claims 7 to 12, 27-28.

37. A method of treating Alzheimer's disease, Parkinson's disease and other neurodegenerative diseases, including the introduction of crystals of anhydrous aripiprazole according to claims 7 to 12, 27-28.

38. A method of treating panic condition, obsessive compulsive disorders (OCD), sleep disorders, disorders of sexual function, alcohol and drug dependence, vomiting, motion sickness, obesity, migraines or reduce mental activity, VK is uchumi introduction crystals of anhydrous aripiprazole according to claims 7 to 12, 27-28.

39. Method for the treatment of anxiety, depression or mania, including the introduction of crystals of anhydrous aripiprazole according to claims 7 to 12, 27-28.

40. Method for the treatment or prevention of schizophrenia or the symptoms associated with schizophrenia, including the introduction of crystals of anhydrous aripiprazole according to claims 7 to 12, 27-28.

41. Drug for treatment of schizophrenia or the symptoms associated with schizophrenia, which includes crystals of anhydrous aripiprazole according to claims 7 to 12, 27-28 in amounts effective for the treatment of schizophrenia or its symptoms, in a mixture with a pharmaceutically acceptable carrier.

42. Drug in paragraph 41, which is contained in the trade package, with instructions that the drug can be used for the treatment of schizophrenia or its symptoms.

43. A method of producing granules of crystals of anhydrous aripiprazole according to claim 8, characterized in that it comprises wet granulation crystals of anhydrous aripiprazole defined in claim 8, drying the obtained granules at 70 to 100°, sorting them by size and then again drying the sifted granules at 70 to 100°C.

44. A method of producing granules of crystals of anhydrous aripiprazole according to claim 9, characterized in that it comprises wet granulation crystals of anhydrous aripiprazole defined in claim 9, drying the obtained granules at 70 to 100°, sorting them by size click again drying the sifted granules at 70 to 100° C.

45. A method of obtaining a pharmaceutical solid oral preparation, characterized in that it comprises drying a pharmaceutical solid oral preparation comprising crystals of anhydrous aripiprazole defined in claim 8, and one or more pharmaceutically acceptable carriers at 70 to 100°C.

46. A method of obtaining a pharmaceutical solid oral preparation, characterized in that it comprises drying a pharmaceutical solid oral preparation comprising crystals of anhydrous aripiprazole specified in claim 9 and one or more pharmaceutically acceptable carriers at 70 to 100°C.

47. The pharmaceutical solid oral preparation comprising crystals of anhydrous aripiprazole defined in claim 8, and one or more pharmaceutically acceptable carriers, where specified pharmaceutical solid oral preparation has at least one dissolution rate selected from the group consisting of 60% or more at pH 4.5 after 30 minutes, 70% or more at pH 4.5 after 60 minutes, and 55% or more at pH 5.0 after 60 minutes

48. The pharmaceutical solid oral preparation comprising crystals of anhydrous aripiprazole defined in claim 9, and one or more pharmaceutically acceptable carriers, where specified pharmaceutical solid oral preparation has, by at least one dissolution rate selected from the group consisting of 60% or more at pH 4.5 after 30 minutes, 70% or more at pH 4.5 after 60 minutes, and 55% or more at pH 5.0 after 60 minutes

49. A method of producing granules containing crystals of anhydrous aripiprazole according to any one of claims 7 to 12, 27 and 28, characterized in that it comprises wet granulation regular crystals of anhydrous aripiprazole, drying the obtained granules at 70 to 100°, sorting them by size and then again drying the sifted granules at 70 to 100°.

50. A method of obtaining a pharmaceutical solid oral preparation containing crystals of anhydrous aripiprazole according to any one of claims 7 to 12, 27 and 28, characterized in that it comprises drying a pharmaceutical solid oral preparation comprising the usual crystals of anhydrous aripiprazole, and one or more pharmaceutically acceptable carriers at 70 to 100°C.

51. The pharmaceutical solid oral preparation containing crystals of anhydrous aripiprazole according to any one of claims 7 to 12, 27 and 28, characterized in that it has at least one dissolution rate selected from the group consisting of 60% or more at pH 4.5 after 30 minutes, 70% or more at pH 4.5 after 60 minutes, and 55% or more at pH 5.0 after 60 minutes

52. The pharmaceutical solid oral preparation containing crystals of anhydrous aripiprazole according to any one of claims 7 to 1, 27 and 28, characterized in that it is obtained by the method according to § 49, where the specified pharmaceutical solid oral preparation has at least one dissolution rate selected from the group consisting of 60% or more at pH 4.5 after 30 minutes, 70% or more at pH 4.5 after 60 minutes, and 55% or more at pH 5.0 after 60 minutes

53. The pharmaceutical solid oral preparation containing crystals of anhydrous aripiprazole according to any one of claims 7 to 12, 27 and 28, characterized in that it is obtained by the method according to item 50, where the specified pharmaceutical solid oral preparation has at least one dissolution rate selected from the group consisting of 60% or more at pH 4.5 after 30 minutes, 70% or more at pH 4.5 after 60 minutes, and 55% or more at pH 5.0 after 60 minutes

54. A method of producing granules containing crystals of anhydrous aripiprazole according to any one of claims 7 to 12, 27 and 28, characterized in that it comprises wet granulation regular crystals of aripiprazole hydrate, drying the obtained granules at 70 to 100°, sorting them by size and then again drying the sifted granules at 70 to 100°C.

55. A method of obtaining a pharmaceutical solid oral preparation containing crystals of anhydrous aripiprazole according to any one of claims 7 to 12, 27 and 28, characterized in that it comprises drying a pharmaceutical solid oral preparation, including the normal to Italy of aripiprazole hydrate and one or more pharmaceutically acceptable carriers, when 70-100°C.

56. The pharmaceutical solid oral preparation containing crystals of anhydrous aripiprazole according to any one of claims 7 to 12, 27 and 28, characterized in that it is obtained by the method according to item 54, where specified pharmaceutical solid oral preparation has at least one dissolution rate selected from the group consisting of 60% or more at pH 4.5 after 30 minutes, 70% or more at pH 4.5 after 60 minutes, and 55% or more at pH 5.0 after 60 minutes

57. The pharmaceutical solid oral preparation containing crystals of anhydrous aripiprazole according to any one of claims 7 to 12, 27 and 28, characterized in that it is obtained by the method according to § 55, where the specified pharmaceutical solid oral preparation has at least one dissolution rate selected from the group consisting of 60% or more at pH 4.5 after 30 minutes, 70% or more at pH 4.5 after 60 minutes, and 55% or more at pH 5.0 after 60 minutes

Priority items:

25.09.2001 according to claims 1, 3-8, 13-26;

27.03.2002 according to claim 2, 9-12, 27-42;

25.09.2002 on p-57.



 

Same patents:

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of cyanoaryl (or cyanoheteroaryl)-carbonylpiperazinyl-pyrimidines of the general formula and their physiologically acceptable salts that elicit the broad spectrum of biological activity exceeding activity of structurally related known compounds. In the general formula (I) R1 represents radical OR3 wherein R3 represents saturated hydrocarbon radical with linear or branched chain and comprising from 1 to 4 carbon atoms; R2 represents phenyl radical substituted with cyano-radical (-C≡N) or radical representing 5- or 6-membered heteroaromatic ring wherein heteroatom is taken among oxygen (O), nitrogen (N) or sulfur (S) atom and substituted with cyano-radical (-C≡N). Also, invention relates to methods for preparing compounds of the general formula (I) that involve incorporation of group of the formula:

into piperazinyl-pyrimidine compound or by the condensation reaction of corresponding pyrimidine with piperazine comprising group of the formula:

. Also, invention relates to pharmaceutical composition and applying these compounds. Compounds can be used for preparing medicinal agents useful in human therapy and/or for therapeutic applying in veterinary science as agents eliciting ant-convulsive and soporific effect or for the general anesthesia.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

13 cl, 7 sch, 8 tbl, 41 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes diazepane derivative of the general formula (I)

or its pharmaceutically acceptable salt wherein ring B means phenyl; ring A means pyridyl substituted with halogen atom optionally, or phenyl substituted optionally with lower alkyl, lower alkoxy-group or halogen atom; X1 represents -C(=O)-NR2- or -NR2-C(=O)- wherein R2 means hydrogen atom; X2 represents -C(=O)-NR3- or NR3-C(=O)- wherein R3 means hydrogen atom; R represents hydrogen atom or halogen atom; R1 means lower alkyl. Also, invention relates to a pharmaceutical composition and inhibitor of blood coagulation activated factor X that can be used for prophylaxis and treatment of patients suffering with thrombosis or embolism.

EFFECT: valuable medicinal properties of compound.

5 cl, 5 tbl, 6 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of indol-3-yl of the formula (I):

wherein each A and B represents independently of one another oxygen atom (O), NH, CONH, NHCO or a direct bond; X means (C1-C2)-alkylene or a direct bond; R1 means hydrogen atom (H); R2 means hydrogen atom (H); R3 means NHR6, -NR6-C(=NR6)-NHR6, -C(=NR6)-NHR6, -NR6-C(=NR9)-NHR6, -C(=NR9)-NHR6 or Het1; each R4 and R5 represents independently of one another hydrogen atom (H); R7 means -(CH2)o-Ar, Het, OR6; R6 means hydrogen atom (H); R7 means (C1-C10)-alkyl, (C3-C10)-cycloalkyl; R8 means Hal, NO2 (nitro-group), CN (cyano-group), Z, -(CH2)o-Ar, COOR1, OR1, CF3, OCF3, NHR1; R9 means CN or NO2; Z means (C1-C6)-alkyl; Ar means aryl that can represent unsubstituted, monosubstituted, or polysubstituted R8; Hal means F, Cl, Br, J; Het means saturated, partially or completely saturated monocyclic or bicyclic heterocyclic radical comprising from 5 to 10 ring members wherein 1 or 2 nitrogen atom (N) and/or 1 or two sulfur atom (S) present, and heterocyclic radical can be monosubstituted with phenyl; Het1 means saturated, partially or completely unsaturated monocyclic or bicyclic heterocyclic radical comprising from 5 to 10 ring members and from 1 to 4 nitrogen atoms (N) that can be unsubstituted or monosubstituted NHX, or oxo-group; n = 0, 1 or 2; m = 0, 1, 2, 3, 4, 5 or 6; o means 0, 1 or 2; and their physiologically acceptable salts and solvates. Compounds of the formula (I) elicit intergin-inhibitory effect that allows their using as components of pharmaceutical composition. Also, invention describes intermediate compounds.

EFFECT: valuable medicinal properties of compounds.

11 cl, 4 sch, 1 tbl, 34 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of tetrahydroisoquinoline of the formula [I] wherein R1 represents hydrogen atom or lower alkyl; R2 represents alkyl having optionally a substitute taken among alkoxycarbonyl and carboxy-group, cycloalkyl, cycloalkylalkyl, aryl having optionally a substitute taken among lower alkyl, arylalkyl having optionally a substitute taken among lower alkyl, lower alkoxy-group, halogen atom and acyl, alkenyl, alkynyl, or monocyclic heterocyclylalkyl wherein indicated heterocycle comprises 5- or 6-membered ring comprising nitrogen atom and having optionally a substitute taken among lower alkyl; R3 represents hydrogen atom or lower alkoxy-group; A represents a direct bond or >N-R5 wherein R5 represents lower alkyl; B represents lower alkylene; Y represents aryl or monocyclic or condensed heterocyclyl comprising at least one heteroatom taken among oxygen atom and nitrogen atom and having optionally a substitute taken among lower alkyl, carboxy-group, aryl, alkenyl, cycloalkyl and thienyl, or to its pharmaceutically acceptable salt. Also, invention relates to pharmaceutical composition eliciting hypoglycaemic and hypolipidemic effect based on these derivatives. Invention provides preparing new compounds and pharmaceutical agents based on thereof, namely, hypoglycaemic agent, hypolipidemic agent, an agent enhancing resistance to insulin, therapeutic agent used for treatment of diabetes mellitus, therapeutic agent against diabetic complication, agent enhancing the tolerance to glucose, agent against atherosclerosis, agent against obesity, an anti-inflammatory agent, agent for prophylaxis and treatment of PPAR-mediated diseases and agent used for prophylaxis and treatment of X-syndrome.

EFFECT: valuable medicinal properties of compounds and composition.

13 cl, 7 tbl, 75 ex

FIELD: organic chemistry, insecticides, chemical technology.

SUBSTANCE: invention describes derivative of 1-aryl-3-cyano-5-heteroarylalkylaminopyrazole of the general formula (1): wherein A means: (A-1) , (A-2) , (A-3) and (A-4) and wherein X represents C-halogen; R1 represents (C1-C4)-alkyl group or halogen-(C1-C4)-alkyl group; A represents any group among (A-1) - (A-4) wherein R4 represents hydrogen atom or (C1-C4)-alkyl group; n = 0, 1 or 2 under condition that R1 represents halogen-(C1-C4)-alkyl group with exception for perhalogenalkyl group when A represents (A-1) and n = 0, and that n doesn't equal 0 when A represents (A-4). Also, invention describes derivative of pyrazole of the formula (2): wherein A means: (A-1) and Y means: (Y-1) , (Y-2) and (Y-3) wherein X, R2, R3 and R4 have values given above; R5 represents hydrogen atom; A represents (A-1); Y means any group among (Y-1) - (Y-3); Z represents halogen atom that are intermediate compounds used for synthesis of the compound (1). Invention describes methods for preparing compounds of the formula (1) and (2) and insecticide comprising compound of the formula (1) as an active component. Insecticide shows high systemic activity, high safety and reduced harmful effect on environment in vicinity areas of its applying.

EFFECT: improved methods for preparing, valuable insecticide properties of compound.

11 cl, 9 tbl, 19 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new compound of the formula (I) or its pharmaceutically acceptable salt or solvate wherein X represents CH or nitrogen atom (N); Z represents CH; R1 represents hydrogen atom; R2 and R3 can be similar or different and represent (C1-C6)-alkoxy-group that is optionally substituted with halogen atom, hydroxyl, (C1-C4)-alkoxycarbonyl, amino-group wherein one or two hydrogen atom are optionally replaced for (C1-C4)-alkyl that is optionally substituted with hydroxyl or (C1-C4)-alkoxy-group, the group R12R13N-C(=O)-O- wherein R12 and R13 can be similar or different and represent hydrogen atom or (C1-C4)-alkyl substituted optionally with (C1-C4)-alkoxy-group or the group R14-(S)m- wherein R14 represents phenyl or saturated or unsaturated 5-7-membered heterocyclic group substituted optionally with (C1-C4)-alkyl; m = 0 or 1; R4 represents hydrogen atom; R5, R6, R7 and R8 can be similar or different and represent hydrogen atom, halogen atom, (C1-C4)-alkyl, (C1-C4)-alkoxy-group or nitro-group under condition that R5, R6, R7 and R don't represent hydrogen atom simultaneously; R9 represents hydrogen atom, (C1-C6)-alkyl or (C1-C4)-alkylcarbonyl wherein alkyl fragment of indicated (C1-C6)-alkyl or (C1-C4)-alkylcarbonyl is optionally substituted with (C1-C4)-alkoxy-group; R10 represents hydrogen atom or (C1-C6)-alkyl; R11 represents (C1-C6)-alkyl, (C2-C6)-alkenyl or (C2-C6)-alkynyl (wherein each (C1-C6)-alkyl, (C2-C6)-alkenyl and (C2-C6)-alkynyl is substituted optionally with halogen atom or (C1-C6)-alkoxy-group), or R15-(CH2)n- wherein n is a whole number from 0 to 3; R15 represents naphthyl or 6-membered saturated or unsaturated carbocyclic or saturated or unsaturated 5-7-membered heterocyclic group that are substituted optionally with halogen atom, (C1-C6)-alkyl or (C1-C6)-alkoxy-group. Also, invention relates to variants of compounds of the formula (I). Compounds elicit antitumor activity and don't effect on cytomorphosis. Also, invention relates to pharmaceutical composition based on above described compounds, to a method for treatment of such diseases as malignant tumor, diabetic retinopathy, chronic rheumatism, psoriasis, atherosclerosis, Kaposi's sarcoma, and to a method for inhibition of vascular vessels angiogenesis.

EFFECT: valuable medicinal properties of compounds and composition.

22 cl, 4 tbl, 186 ex

FIELD: organic chemistry, heterocyclic compounds, medicine, pharmacy.

SUBSTANCE: invention relates to new heterocyclic compounds corresponding to general formulas: (I) , (II) , (Ia) and (Ib) wherein substitutes have values given in the description. Such compounds are reversible inhibitors of cathepsins S, K, F, L and B. Also, invention relates to a method for preparing these compounds, pharmaceutical composition eliciting inhibitory activity with respect to cysteine proteases and to a method for modulation of autoimmune diseases, treatment of Alzheimer's disease and osteoporosis.

EFFECT: improved method for preparing, valuable medicinal properties of compounds.

42 cl, 106 ex

FIELD: organic chemistry, medicine, hormones, pharmacy.

SUBSTANCE: invention relates to new biologically active compounds that act as agonists of peptide hormone vasopressin. Invention describes the compound of the general formula (1) or its pharmaceutically acceptable salt wherein V represents a covalent bond or NH; X is taken among CH2, oxygen atom (O) and N-alkyl; Z represents sulfur atom (S) or -CH=CH-; R1 and R2 are taken independently among hydrogen (H), fluorine (F), chlorine (Cl), bromine (Br) atom and alkyl; R3 is taken among hydroxyl group (OH), O-alkyl and NR4R5 wherein each R4 and R5 represents independently hydrogen atom (H) or alkyl, or both represent -(CH2)q-; p = 0, 1, 2, 3 or 4; q = 4 or 5. Also, invention describes a pharmaceutical composition eliciting agonistic activity with respect to V2-receptors, a method for treatment of enuresis, nicturia and diabetes insipidus, method for control of enuresis and a method for treatment of enuresis and a method for treatment of diseases associated with damage in blood coagulability. Invention provides preparing new compounds eliciting useful biological properties.

EFFECT: valuable medicinal properties of compounds.

17 cl, 31 ex

FIELD: organic chemistry, pharmaceutical compositions.

SUBSTANCE: invention relates to substituted 3-oxo-1,2,3,4-tetrahydroxinoxalines of general formula 1 , wherein R1 represents substituted sulfanyl or substituted sulfonyl group, containing as substituent optionally substituted C1-C4-alkyl, optionally substituted C3-C8-cycloalkyl, aryl-(C1-C4)alkyl optionally substituted in aril or alkyl group, heterocyclyl-(C1-C4)alkyl optionally substituted in heterocycle or alkyl group; R2 and R3 independently represent hydrogen, halogen, CN, NO2, optionally substituted hydroxyl, optionally substituted amino group, optionally substituted carboxylic group, optionally substituted carbamoyl group, optionally substituted arylcarbonyl group or optionally substituted heterocyclylcarbonyl group; R4 and R5 independently represent hydrogen or inert substituent. Claimed compounds are high effective kaspase-3 inhibitors and are useful in production of pharmaceutical compositions for treatment of diseases associated with excess apoptosis activation, as well as for experimental investigations of apoptosis in vivo and in vitro. Also disclosed are pharmaceutical composition in form of tablets, capsules or injections in pharmaceutically acceptable package, as well as method for production thereof and therapy method.

EFFECT: pharmaceutical composition for apoptosis treatment and investigation.

6 cl, 3 dwg, 8 ex, 1 tbl

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to new compound: N-[2-hydroxy-3(1-piperidinyl)-propoxy]-pyridine-1-oxyde-3-carboxyimidoyl chloride, stereoisomers thereof acid additional salts useful in treatment of pathological insulin resistance.

EFFECT: new compound useful in medicine.

5 cl, 10 tbl, 10 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes derivatives of benzodiazepines of the general formula (I):

wherein X means ordinary bond or ethynediyl group wherein if X mean ordinary bond then R1 means halogen atom or phenyl substituted with halogen atom optionally or (C1-C7)-alkyl group; in case when X means ethynediyl group then R1 mean phenyl substituted with halogen atom optionally; R2 means halogen atom, hydroxy-group, lower alkyl, lower alkoxy-group, hydroxymethyl, hydroxyethyl, lower alkoxy-(ethoxy)n wherein n = 1-4, cyanomethoxy-group, morpholine-4-yl, thiomorpholine-4-yl, 1-oxothiomorpholine-4-yl, 1,1-dioxothiomorpholine-4-yl, 4-oxopiperidine-1-yl, 4-(lower)-alkoxypiperidine-1-yl, 4-hydroxypiperidine-1-yl, 4-hydroxyethoxypiperidine-1-yl, 4-(lower)-alkylpiperazine-1-yl, lower alkoxycarbonyl, 2-di-(lower)-alkylaminoethylsulfanyl, N,N-bis-(lower)-alkylamino-(lower)-alkyl, (lower)-alkoxycarbonyl-(lower)-alkyl, (lower)-alkylcarboxy-(lower)-alkyl, lower alkoxycarbonylmethylsulfanyl, carboxymethylsulfanyl, 1,4-dioxa-8-azaspiro[4,5]dec-8-yl, carboxy-(lower)-alkoxy-group, cyano-(lower)-alkyl, 2-oxo[1,3]dioxolane-4-yl-(lower)-alkoxy-group, 2,2-dimethyltetrahydro[1,3]dioxolo[4,5-c]pyrrole-5-yl, (3R)-hydroxypyrrolidine-1-yl, 3,4-dihydroxypyrrolidine-1-yl, 2-oxooxazolidine-3-yl, carbamoylmethyl, carboxy-(lower)-alkyl, carbamoylmethoxy-, hydroxycarbamoyl-(lower)-alkoxy-, lower alkoxycarbamoyl-(lower)-alkoxy-, (lower)-alkylcarbamoylmethoxy-group; R3 means phenyl, thiophenyl, pyridinyl that are substituted with halogen atom, cyano-group, carbamoyl, imidazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl or isoxazolyl wherein groups of 1,2,3-triazolyl, 1,2,4-triazolyl or isoxazolyl are substituted optionally with (C1-C7)-alkyl or (C1-C7)-alkylsulfanyl, and to their pharmaceutically acceptable salts. Also, invention describes a medicinal agent that is antagonist of mGlu receptors of the group II based on compound of the formula (I). The medicinal agent can be used in treatment and prophylaxis of acute and/or chronic neurological disturbances including psychosis, schizophrenia, Alzheimer's disease, disturbances in cognitive ability and memory damage.

EFFECT: valuable medicinal properties of compounds.

7 cl, 1 tbl, 98 ex

FIELD: organic chemistry, medicine, psychiatry, pharmacy.

SUBSTANCE: invention relates to medicinal agents used for prophylaxis and treatment of schizophrenia by inhibition or suppression of neurodegenerative disease caused by hypofunction of glutamic acid receptors. As an active component agents comprise derivative of 5-substituted 3-oxadiazolyl-1,6-naphthiridine-2(1H)-one of the formula (I):

wherein Het represents oxadiazolyl group; R1 represents hydrogen atom, lower alkyl group, lower cycloalkyl group, trifluoromethyl group, lower alkenyl group, lower alkynyl group, lower alkoxyl group, lower alkoxy-(lower)-alkyl group, lower hydroxyalkyl group, substituted or unsubstituted aryl group, substituted or unsubstituted heteroaryl group; R2 represents hydrogen atom, lower alkyl group, lower cycloalkyl group, lower cycloalkylmethyl group, lower alkenyl group, lower cycloalkenyl group, lower alkynyl group, substituted or unsubstituted aryl group and substituted or unsubstituted heteroaryl group wherein indicated groups represent phenyl or naphthyl and indicated heteroaryl groups represents furyl, thienyl or pyridyl, or their physiologically acceptable acid-additive salts.

EFFECT: valuable medicinal properties of agents.

10 cl, 1 tbl

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention describes derivatives of benzodiazepine of the general formula (I)

and their pharmaceutically acceptable acid-additive salts wherein X means a ordinary bond or ethynediyl group; when X means ordinary bond then R1 means halogen atom, (lower)-alkyl, (lower)-alkylcarbonyl, (lower)-cycloalkyl, benzoyl, phenyl substituted optionally with halogen atom, hydroxyl, (lower)-alkyl, (lower)-alkoxy-group, halogen-(lower)-alkoxy-group or cyano-group; styryl, phenylethyl, naphthyl, diphenyl, benzofuranyl, or 5- or 6-membered heterocyclic ring representing thiophenyl, furanyl, pyridinyl, dihydropyridinyl, tetrahydropyridinyl which are optionally substituted; when X means ethynediyl group then R1 means hydrogen atom, (lower)-alkyl substituted optionally with oxo-group; (lower)-cycloalkyl substituted with hydroxyl; (lower)-cycloalkenyl substituted optionally with oxo-group; (lower)-alkenyl, optionally substituted phenyl; 5- or 6-membered heterocyclic ring representing thiophenyl, thiazolyl, pyridinyl, dihydropyridinyl, tetrahydropyridinyl or dihydropyranyl and substituted optionally; R3 means phenyl, pyridyl, thiophenyl or thiazolyl which are substituted optionally. These compounds can be used for treatment or prophylaxis of acute and/or chronic neurological diseases, such as psychosis, schizophrenia, Alzheimer's disease, disorder of cognitive ability and memory disorder. Also, invention describes a medicinal agent based on these compounds and a method for preparing compounds of the formula (I).

EFFECT: improved method for preparing, valuable medicinal properties of compounds.

10 cl, 1 tbl, 173 ex

FIELD: medicine, pharmaceutical technology, pharmacy.

SUBSTANCE: invention relates to granulated composition containing 11-[4-[2-(2-hydroxyethyl)ethyl]-1-piperazinyl]dibenzo[b,f][1,4]thiazepine (quetiapine) or its pharmaceutically acceptable salt, preferably quetiapine fumarate, as an active substance and a water-soluble binding agent. Invention relates to a method for preparing this composition and to a method for treatment of patients with nervous system diseases such as psychotic states including schizophrenia. Invention alleviates dosing of drugs by patients in required dose and solves problem concerning maintenance of regimen and schedule of treatment.

EFFECT: improved and valuable properties of composition.

16 cl, 2 ex

FIELD: medicine.

SUBSTANCE: method involves administering typical neuroleptics according to titration scheme and tricyclic antidepressants. Neuroleptics are applied according to titration scheme in the morning and tricyclic antidepressants are introduced as intravenous drop-by-drop infusion in the evening in combination with per os application of atypic neuroleptic risperidon. After having given 12-14 intravenous infusions, strategic supporting risperidon psychopharmacotherapy in combination with tricyclic antidepressants during 4-6 months.

EFFECT: enhanced effectiveness in overcoming pharmacological resistance; accelerated schizo-affective syndrome relief.

FIELD: organic chemistry, biochemistry, biology.

SUBSTANCE: invention relates to a pharmaceutical composition eliciting the inhibitory effect on activity of serine protease (caspase-3) in the form of tablet, capsule or injections placed into acceptable package, to a method for its preparing and a method for treatment of diseases associated with enhanced activation of apoptosis. The composition comprises compound 2,3-dihydro-1H-benzo[g]pteridine-4-one of the general formula (1) (1)

or its salt with pharmacologically acceptable acid as an active component taken in pharmaceutically effective amount wherein X means oxygen (O) or sulfur (S) atom; R1 and R2 represent independently of one another hydrogen atom, inert substitute taken among the group including low- or non-reactive and optionally substituted radical, such as (C1-C7)-alkyl, (C2-C7)-alkenyl, (C2-C7)-alkynyl, (C1-C7)-alkoxy-group, (C7-C12)-aralkyl, (C7-C12)-heterocyclylalkyl, (C7-C12)-alkaryl, (C3-C10)-cycloalkyl, (C3-C10)-cycloalkenyl, phenyl, aryl, heterocyclyl; optionally substituted hydroxy-(C1-C5)-alkyl group; R3, R4, R5 and R6 represent independently of one another hydrogen, halogen atom, -CF3, -CN, inert substitute taking among the group including low- or non-reactive and optionally substituted radical, optionally substituted hydroxyl group, optionally substituted hydroxy-(C1-C5)-alkyl group, optionally substituted amino-group, optionally substituted amino-(C1-C7)-alkyl group, optionally substituted carboxy-(C1-C7)-alkyl group, optionally substituted (C1-C6)-alkylcarboxy-(C1-C6)-alkyl group, optionally substituted carbamoyl group, optionally substituted (C1-C6)-alkylcarbamoyl group, optionally substituted sulfamoyl group. Also, invention relates to applying compounds of the formula (1) for preparing pharmaceutical composition and experimental study (in vitro and in vivo) processes associated with apoptosis.

EFFECT: improved preparing method, valuable medicinal and biochemical properties of composition.

7 cl, 1 dwg, 2 tbl, 5 ex

The invention relates to new highly efficient ligands (agonists, antagonists, modulators, etc.) nicotinic receptors - new substituted 1,2-dihydro[2,7]naphthirydines General formula 1 in the form of single stereoisomers, racemic or additive mixtures, or their pharmaceutically acceptable salts, N-oxides or hydrates

in which: R1and R2independently from each other represent a hydrogen atom, an inert Deputy, optionally substituted C1-C5alkyl, or R1and R2together represent polymethene chain, including 2-5 optionally substituted methylene group; R3and R4independently from each other represent a hydrogen atom, an inert Deputy, optionally substituted C1-C5alkyl, optionally substituted C1-6allyloxycarbonyl group, optionally substituted karbamoilnuyu group; R5located at the carbon atoms of the pyridine fragment represents: a hydrogen atom, an inert Deputy, optionally substituted hydraxis1-5alkyl, optionally substituted by an amino group, optionally substituted hydroxyl is the function group; or R5if it is at the nitrogen atom of the pyridine fragment, form a pyridinium salt with a pharmacologically acceptable anion and is inert Deputy

The invention relates to the field of medicine and relates to a pharmaceutical composition having anticonvulsant and psychotropic action

The invention relates to pharmaceutical

The invention relates to pharmaceutical industry and AA derivatives of N-(aryloxyalkyl)-heteroarylboronic and-heteroarylboronic General formula (I) used to obtain drugs with antipsychotic or analgesic activity, and a method of treating psychoses by using these derivatives

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a biologically active microparticles composition comprising microparticles that involve: (a) polymer taken among group consisting of poly-(α-hydroxyacid), polyhydroxybutyric acid, polycaprolactam, poly-ortho-ester, polyanhydride and polycyanoacrylate, and (b) the first part of detergent that is bound with polymer, and also complex adsorbed on microparticles complex that comprises: (a) biologically active macromolecule, and (b) the second part of detergent wherein the first part of detergent and the second part of detergent comprise the same detergent or different detergents and wherein biologically active macromolecule is taken above group consisting of polypeptide, polynucleotide, polynucleoside, antigen, pharmaceutical agent, hormone, enzyme, transcription or translation mediating agent, metabolite, an immunomodulating agent and adjuvant. Also, invention relates to methods for preparing the composition and its applying. Invention provides improvement of adsorption of biologically active agents on microparticles surface in delivery systems, especially, for medicinal agents that are characterized with high sensitivity and complexity in their preparing based on the composition proposed.

EFFECT: improved method preparing, improved and enhanced properties of composition.

44 cl, 1 tbl, 1 dwg, 7 ex

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