Mechano-activated amorphous and amorphous-crystalline calcium salts of gluconic acid, compositions, methods of production, pharmaceutical preparations and method of treatment based on said preparations

FIELD: chemistry.

SUBSTANCE: crystalline calcium salt of gluconic acid or its compound with excipients is processed in grinding activator devices, or to a value of supplied specific energy of not more than 10.4 kJ/g and achieving amorphous-crystalline state, or to a value of specific energy of not less than 10.5 kJ/g and achieving amorphous state. The obtained substances are analysed using X-ray diffraction, infrared, NMR, EPR spectroscopy, mass- and chromatography-mass spectrometry and differential thermal analysis.

EFFECT: mechano-activated amorphous and amorphous-crystalline compounds and compositions are used as active compounds for making pharmaceutical preparations.

13 cl, 10 dwg, 12 ex

 

The invention relates to a method for producing a crystalline calcium salt of gluconic acid with pharmaceutical trading name calcium gluconate, mechanically activated amorphous and amorphous-crystalline forms of the calcium salt of gluconic acid, mixtures based on them, pharmaceuticals.

They can be used in the medical industry for the production of biologically active substances, preventive and curative medicines and pharmaceutical preparations for the treatment of severe bone, dental and other diseases associated with impaired calcium metabolism in the body, and also as additives in medical and hygiene products.

The invention can be used in various sectors of the food industry and in agriculture, in particular animal husbandry and veterinary medicine.

Methods of obtaining therapeutically effective and sustainable composites with amorphous forms of calcium gluconate are not described in literature.

A solid crystalline substance with the chemical name calcium salt of gluconic acid with pharmaceutical trading name calcium gluconate, known as pharmacological tool group containing macro - and micronutrients.

Calcium gluconate refers to the pharmacological group of substances, which, Nar is do with vitamins and other biologically active substances, are mandatory elements in the normal flow of vital processes of the human body. Calcium plays a multifaceted role in the life of the body: transmission of nerve impulses, maintenance of skeletal muscle and smooth muscles in the functioning of the myocardium, blood clotting and other physiological processes in the formation and preservation of the integrity of bone tissue. Various pathological processes, including tetany, dysfunction of skeletal and smooth muscles, cardiovascular system, blood clotting, osteoporosis, many serious dental diseases are manifestations of a lack of calcium in the body. In this regard, calcium gluconate is used in various fields of medicine.

However, the known calcium gluconate and medicinal compositions containing the active substance is calcium gluconate, like all other currently known calcium supplements, lack of therapeutic efficacy for effective conservative treatment of diseases caused by disorders of calcium metabolism in the body, in particular osteoporosis and other heavy bone and dental diseases. In particular, osteoporosis, including due to their low efficiency available in the Arsenal IU Iceni calcium supplements, recognized in the present global and directly related to the lifetime health problem. The task of developing therapeutically more effective forms of calcium supplements and how they receive is relevant and has a global social and economic value.

Known amorphous calcium (amorphous phosphate, forfattere, carbontrust, carbonatisation calcium), obtained by chemical means, and the method of processing teeth using amorphous compounds by drawing on the tooth cloth or inside it [1]. The disadvantage of this method is that the deposition of amorphous calcium compounds on dental tissue does not solve the problem of normalization of calcium metabolism of the organism as a whole, is directed only to the treatment of defects of teeth, but not elimination of the reasons causing them.

There is a method of treatment of hypocalcaemia, osteoporosis, fractures [2] using amortyzowania method of mechanical activation of calcium. However, the claimed scope of the invention do not cover the whole spectrum of diseases, in particular dental, therefore, the method does not solve all the problems associated with the metabolism of calcium in the body.

Known x-ray amorphous nanosized powder obtained by the method of mechanical activation officinal containing standard excep the coefficients, drug - tablets calcium gluconate [3]. However, the claimed x-ray amorphous state is actually a state of a substance of unknown structure, the characteristics of which are necessary physico-chemical and other characteristics, allowing it to be identified.

The objective of this invention to provide a mechanically activated amorphous and amorphous-crystalline compounds and compositions of the calcium salt of gluconic acid, creating the basis of a therapeutically effective pharmaceutical products to ensure the proper flow of vital processes of the human body and treatment of a wide range of diseases caused by disorders of calcium metabolism in the body, including severe periodontal disease, expanding Arsenal of pharmaceutical preparations and creation on their basis of biologically active additives to food, medical and hygiene products.

The technical result is achieved in the invention by obtaining a mechanically activated amorphous calcium salt of gluconic acid in the processing of crystalline calcium salt of gluconic acid in energonaprjazhenie grinding activator devices during the time required for the supply of specific energy of at least 10.5 kJ/,

The advantage of this mechanically activated amorphous salt of gluconic acid is that she received for the first time, the first set allows her to identify the physico-chemical characteristics and she, unlike [3], does not contain excipients that in the case of the use of salt for the treatment of patients with a weakened immune system or the like, or in the complex treatment of the most complex diseases (e.g. chronic renal failure and hemodialysis) is vital from the point of view of the absence or reduction of side effects.

In addition, the technical result is achieved in the invention by obtaining the composition of the mechanically activated amorphous calcium salt of gluconic acid with pharmaceutically acceptable excipients in the following ratio of ingredients, wt.%:

mechanically activated amorphous calcium salt
gluconic acid94÷97
talc2÷1
starch2÷1
calcium stearate2÷1

The advantage of this composition relative to the tion known in [3] is the excipients in the composition are not mechanochemically activated, do not change their physico-chemical properties and are typical of neutral additives to existing substance (mechanically activated amorphous calcium salt of gluconic acid)that in the case of the use of the composition in treatment of particularly complex diseases (e.g. chronic renal failure and hemodialysis) is vital from the point of view of the absence or reduction of side effects.

In addition, the technical result is achieved in the invention by mixing the calcium salt of gluconic acid with pharmaceutically acceptable excipients in the following ratio of ingredients, wt.%:

crystalline calcium salt
gluconic acid94÷97
talc2÷1
starch2÷1
calcium stearate2÷1

and its subsequent processing in energonaprjazhenie grinding activator devices during the time required for the supply of specific EN is rgii at least 10.5 kJ/g

The advantage of this composition is relatively well-known in [3] is that for the first time defined allowing her to identify the physico-chemical characteristics and that its content of calcium stearate is increased to 2%. When grinding the powder composition becomes nanodispersed and considerably increases its specific surface and its protective coating requires a greater amount of the substance. The high content of calcium stearate has improved the stability of the nanoparticles in the liquid environment of the esophagus and stomach due to more reliable formation from it of the surface layer of the nanoparticles ("encapsulation"), which provides that, in cases where it is medically necessary, more effective delivery of nanoparticles in the gut. In addition, the increase in the content of strata calcium increases the resistance of the composition to moisture and increases the shelf life, which is an important technical condition of production of medicines. Mechanically activated preformed shape officinal drug calcium gluconate, which we used for mechanical activation in our published article [3], as the composition of the calcium salt of gluconic acid contains talc <2%, starch <3% and calcium stearate <1% (FSP-0173654505, CJSC Irbit is HFZ).

On receipt of the mechanically activated amorphous calcium salt of gluconic acid and mechanically activated amorphous composition of the calcium salt of gluconic acid is judged by

- homogeneous diffuse halo in the spectrum of the powder x-ray diffraction;

the center of gravity of the absorption bands 3000-3600 cm-1in the region of large wave numbers by a value not more than 200 cm-1the presence of absorption bands with frequencies 3308±20, 2933±10, 1602±10, 1420±10 with shoulder 1260±40, 1085±10, 1044±10, 877±10, 682±10, 577±10 cm1and additional absorption band with a frequency 947±10 cm-1the IR spectrum (KBr);

- reduced the endothermic peaks in the temperature range of 125-165°C and the increase of the peak in the temperature range of 30-100°C. in differential thermal analysis (DTA);

the presence of intense single line electron paramagnetic resonance (EPR) with the Lande factor from 2,000 to 2.006 and width from 8 to 9 e;

- the emergence of unresolved broad line of fine structure in the areas of 60-90 ppm and 170-190 ppm in13With the spectra of nuclear magnetic resonance (NMR);

- shift of the resonance lines of their aqueous solutions in the field of 62.8-179,2 ppm by an amount not exceeding 0.1 ppm13With NMR-spectra;

- shift of the resonance lines of their aqueous solutions in the field of 1,2-4,95 ppm by an amount not to exceed 0.02 ppm1H NMR spectra;

- increase intensity if the s 160 m/z mechanically activated samples not less than 2.5 times and lines 780-1000 m/z of their extracts solutions in ethanol not less than three times in the mass spectroscopic analysis.

The technical result is achieved in the present invention by obtaining mechanically activated amorphous-crystalline calcium salt of gluconic acid in the processing of the calcium salt of gluconic acid in energonaprjazhenie grinding activator devices during the time required for the supply of the energy density is not more than 10.4 kJ/year

The advantage of this mechanically activated amorphous-crystalline calcium salt of gluconic acid is that she received for the first time, the first set allows her to identify the physico-chemical characteristics and she, unlike [3], does not contain excipients that in the case of the use of salt for the treatment of patients with a weakened immune system or the like, or in the complex treatment of the most complex diseases (e.g. chronic renal failure and hemodialysis) is vital from the point of view of the absence or reduction of side effects.

In addition, the technical result is achieved in the invention by obtaining the composition of the mechanically activated amorphous-crystalline calcium salt of gluconic acid with pharmaceutically acceptable excipients in the following ratio of ingredients, wt.%:

amorphous-crystal is practical calcium salt
gluconic acid94÷97
talc2÷1
starch2÷1
calcium stearate2÷1

The advantage of this composition is relatively well-known in [3] is that the excipients in the composition are not mechanochemically activated, do not change their physico-chemical properties and are typical of neutral additives to existing substance (mechanically activated amorphous calcium salt of gluconic acid)that in the case of the use of the composition in treatment of particularly complex diseases (e.g. chronic renal failure and hemodialysis) is vital from the point of view of the absence or reduction of side effects.

In addition, the technical result is achieved in the invention by mixing the calcium salt of gluconic acid with pharmaceutically acceptable excipients in the following ratio of ingredients, wt.%:

crystalline calcium salt
gluconic is sloty 94÷97
talc2÷1
starch2÷1
calcium stearate2÷1

and subsequent processing in energonaprjazhenie grinding activator devices during the time required for the supply of the energy density is not more than 10.4 kJ/year

The advantage of this composition is relatively well-known in [3] is that for the first time defined allowing her to identify the physico-chemical characteristics and that its content of calcium stearate is increased to 2%. When grinding the powder composition becomes nanodispersed and considerably increases its specific surface and its protective coating requires a greater amount of the substance. The high content of calcium stearate has improved the stability of the nanoparticles in the liquid environment of the esophagus and stomach due to more reliable formation from it of the surface layer of the nanoparticles ("encapsulation"), which provides that, in cases where it is medically necessary, more effective delivery of nanoparticles in the gut. In addition, the increase in the content of strata calcium increases the resistance of the composition to moisture and increases cf the key store, that is an important technical condition of production of medicines. Mechanically activated preformed shape officinal drug calcium gluconate, which we used for mechanical activation in our published article [3] as the composition of the calcium salt of gluconic acid, contains talc <2%, starch <3% and calcium stearate <1% (FSP-0173654505, CJSC Irbit HFZ).

On receipt of the mechanically activated amorphous-crystalline calcium salt of gluconic acid and mechanically activated amorphous-crystalline compositions of the calcium salt of gluconic acid is judged by

- the simultaneous presence of diffuse halos and structural crystalline reflexes in the spectrum of the powder x-ray diffraction;

- the offset of the center of gravity of the area of absorption 3000-3600 cm-1in the region of large wave numbers by a value not more than 200 cm-1the presence of absorption bands with frequencies 3480±10, 3241±30, 2933±10, 2912±10, 1597±10, 1392±20, 1306±10, 1296±10, 1085±10, 1044±10, 973±10, 908±10, 881±10, 699±10, 565±10 cm-1and additional absorption band with a frequency 947±10 cm-1in the infrared spectrum;

- the emergence of slabozaselennyh broad lines of the fine structure in the areas of 60-90 ppm and 170-190 ppm in13With NMR-spectra;

- shift of the resonance lines of their aqueous solutions in the field of 62.8-179,2 ppm by an amount not exceeding the Yu 0,09 ppm in 13With NMR-spectra;

- shift of the resonance lines of their aqueous solutions in the field of 1,2-4,95 ppm by an amount not in excess of 0.015 ppm in1H NMR spectra;

- increase of the intensities of the lines 160 m/z mechanically activated samples is not more than 2.5 times and lines 780-1000 m/z of their extracts solutions in ethanol not more than three times in the mass spectroscopic analysis;

the presence of intense single EPR line with the Lande factor from 2,000 to 2.006 and width from 8 to 9 E.

On the basis of amorphous and amorphous-crystalline compounds and compositions receive pharmaceutical preparations for the treatment of dental or bone diseases caused by calcium deficiency in the body, in the form of powder, tablets, capsules and the like, which are used orally in doses of 0.2-0.4 g or 0.6-6 g, 1-6 times a day, a course of not less than 1 month.

The advantages of this method of treatment is that as pharmaceutical drugs are used first, the substance is first defined, allowing to identify these substances, physical and chemical characteristics which make them unique, which has no analogues efficiency.

Figure 1-10 presents the results of studies using different methods the original, mechanically activated amorphous and amorphous-crystalline compositions of calcium gluconate.

Figure 1: the changing structure of the s powder x-ray diffraction (si α-radiation) of the following samples:

- the original crystalline calcium salt of gluconic acid, curve 1;

- mechanically activated amorphous-crystalline calcium salt of gluconic acid, curve 2;

- mechanically activated amorphous calcium salt of gluconic acid, curve 3.

Powder x-ray diffraction pattern was recorded on an x-ray diffractometer DRON-SM in monochromatization Cuα-radiation.

The diffraction pattern of calcium gluconate, processed in the shredder-activator when summed specific energy to 10.8 kJ/g (curve 3), does not contain structural crystalline reflexes and is a diffuse halo, characteristic of amorphous material. In powder diffraction pattern of amorphous-crystalline calcium salt of gluconic acid, obtained by processing in the shredder-activator when summed energy density of 3.6 kJ/g (curve 2)are simultaneously diffuse amorphous halo and structural crystalline reflexes that correspond to the content of the amorphous and crystalline phase ≈90 ≈10 wt.% respectively. In contrast to the above-mentioned diffraction pattern of the known crystalline compounds, the calcium salt of gluconic acid (curve 1), contains the characteristic of the crystalline state of the set of structural reflexes.

Figure 2: IR spectra of the following samples:

- the original crystalline calcium salt of gluconic acid, curve 1;

- mechanically activated amorphous-crystalline calcium salt of gluconic acid, curve 2;

- mechanically activated amorphous calcium salt of gluconic acid, curve 3.

Infrared (IR) transmission spectra were shot on IR Fourier spectrometer FSM-1202. The samples were mixed with KBr (IR purity) and was compactional in tablets. All spectra were registered, spending 64 scan (repeated measurements of each outcome) at a resolution of 1 cm-1.

In the FTIR spectrum of mechanically activated amorphous-crystalline compositions of the calcium salt of gluconic acid (curve 2) of the absorption bands are less resolved structure lines in contrast to the well-resolved spectrum of the calcium salt of gluconic acid in the crystalline state (curve 1). The center of gravity of the area of absorption 3000-3600 cm-1shifted into the region of large wave numbers by a value not more than 200 cm-1. Observed absorption bands with frequencies 3480±10, 3241±30, 2933±10, 2912±10, 1597±10, 1392±20, 1306±10, 1296±10, 1085±10, 1044±10, 973±10, 908±10, 881±10, 699±10, 565±10 cm-1and there is an additional absorption band with a frequency 947±10 cm-1.

In the FTIR spectrum of mechanically activated amorphous form (curve 3) are slaborebristaya structure lines, the shift of the center of gravity of the region of the STI absorption 3000-3600 cm -1in the region of large wave numbers by a value not more than 200 cm-1the absorption bands with frequencies 3308±20, 2933±10, 1602±10, 1420±10 with shoulder 1260±40, 1085±10, 1044±10, 877±10, 682±10, 577±10 cm-1and there is an additional absorption band with a frequency 947±10 cm-1.

The above data indicate a change in the vibrational spectra of mechanically activated samples with partial preservation of the chemical bond between the calcium cation with the anion of gluconic acid, a decrease in the number of hydrogen bonds (the center of gravity of the broad absorption bands of Oh-groups 3000-3600

cm-1in the region of large wave numbers) and the formation of complex compounds and compositions of salts of gluconic acid with a cyclic saccharides.

Figure 3:13From the NMR spectra of the samples in the solid state:

- the original crystalline calcium salt of gluconic acid, curve 1;

- mechanically activated amorphous-crystalline calcium salt of gluconic acid, curve 2;

- mechanically activated amorphous calcium salt of gluconic acid, curve 3.

NMR spectra were taken on a pulsed NMR spectrometer with Fourier transform AVANCE-400 Bruker at a temperature of 295 K.

In13From the NMR spectra of the amorphous form (curve 3) and amorphous-crystalline salt (curve 2) in the region of 60-90 ppm and 170-190 ppm are observed broad lines unresolved fine structure of the tours. In13From the NMR spectra of the crystalline calcium salt of gluconic acid in the same areas observed well-resolved fine structure of the resonance NMR absorption spectra (curve 1).

From the above data it is evident that the mechanical treatment of the crystalline compounds of the calcium salt of gluconic acid in energonaprjazhenie grinding devices-activators there is a change in the local molecular structure of calcium gluconate, which is characterized by the increase in the number of nonequivalent local atomic States of carbon atoms characteristic of disordered crystalline or amorphous state of matter.

Figure 4 and 5 shows the NMR spectra of the nuclei13C and1N, respectively, for the following samples:

- an aqueous solution of the original crystalline calcium salt of gluconic acid, curve 1;

- an aqueous solution of the mechanically activated amorphous-crystalline calcium salt of gluconic acid, curve 2;

- an aqueous solution of the mechanically activated amorphous calcium salt of gluconic acid, curve 3.

NMR spectra were taken on a pulsed NMR spectrometer with Fourier transform AVANCE-400 Bruker at a temperature of 295 K.

13From the NMR spectra of aqueous solutions of amorphous form (figure 4, curves 3) and amorphous-crystalline composition (figure 4, curves 2) which are identical with the spectra of aqueous solutions of crystalline calcium salt of gluconic acid structure resonance absorption lines in the area of 62.8-179,2 ppm (figure 4, curves 1). Spectra of amorphous forms and amorphous-crystalline compositions differ only in that they have a chemical shift by an amount not exceeding 0.1 ppm relative to lines13From the NMR spectra of aqueous solutions of crystalline calcium gluconate.

In1H NMR spectra of aqueous solutions of amorphous form (figure 5, curves 3) and amorphous-crystalline composition (figure 5, curve 2) is similar to the spectra of aqueous solutions of crystalline calcium salt of gluconic acid structure resonance lines1H NMR spectra (figure 5, curves 1) in 1,2-4,95 ppm. Spectra of amorphous forms and amorphous-crystalline compositions differ only in that they have a chemical shift by an amount not to exceed 0.02 ppm, relative to lines1H NMR spectra of aqueous solutions of crystalline calcium gluconate.

From the above data it is evident that during mechanical processing in energonaprjazhenie grinding devices, which are activators of crystalline calcium gluconate is changing its local molecular structure, leading to the shift of the NMR lines of absorption. It should be noted that the magnitude and direction of the bias is different for different lines. This behavior can be caused by several factors, in particular the destruction of molecules, the emergence of paramagnetism in resulttemplate stable free radicals, as well as conformational changes of the original molecule after mechanical activation.

Figure 6 presents the EPR spectra of mechanically activated amorphous calcium salt of gluconic acid (curve 1) and coal benchmark (curve 2).

Figure 7 shows the curve of the intensity of the EPR signal from the time of machining the calcium salt of gluconic acid.

EPR spectra were taken on the EPR spectrometer VARIAN E-12 at the frequency to ~9.5 GHz at a temperature of 295 K. the Normalization of the intensity and determination of the g-factor of the EPR lines produced by coal standard (g=2,0030).

In the EPR spectrum mechanoactivation amorphous calcium gluconate (6, curve 1) has an intense EPR line with g≈2,005. In the original sample of crystalline calcium salt of gluconic acid EPR signal is absent. The intensity of the EPR signal increases with increasing content of amorphous phase (time of mechanical treatment calcium gluconate) in amorphous-crystalline compositions and reaches a maximum value at achieving the amorphous state. The intensity of the EPR signal is stored in a period of time not less than 6 months. That is, the mechanical processing of the calcium salt of gluconic acid leads to the formation of stable paramagnetic centers in amorphous phase and in the intermediate amorphous-crystalline composition.

From preveden the x data obviously, that changes the local atomic structure during mechanical processing in energonaprjazhenie grinding devices-activators crystalline compounds of the calcium salt of gluconic acid lead to the formation of chemically active stable paramagnetic centers, which may lead to a change in the reactivity and biological activity of the resulting substance.

On Fig shows mass spectra of electron ionization (EI) of the following samples:

- the original crystalline calcium salt of gluconic acid, curve 1;

- mechanically activated amorphous calcium salt of gluconic acid, curve 2.

Mass spectrometric measurements by the method of mass spectrometry electron ionization (EI) was performed on the instrument MAT-212.

Mass spectra EI mechanically activated samples in amorphous and amorphous-crystalline state is fundamentally no different from the mass spectra of the original crystalline calcium salt of gluconic acid. Also in the machining of calcium gluconate was not observed the formation of new volatile compounds. The main difference was detected only in the fact that in the mass spectra electron ionization mechanically activated amorphous forms and amorphous-crystalline composition is more intense peak with 160 m/z (Fig, Criva).

Figure 9 shows mass spectra laser desorption from the matrix (MALDI-TOF) extracts solutions in ethanol following samples:

- the original crystalline calcium salt of gluconic acid, curve 1;

- mechanically activated amorphous-crystalline calcium salt of gluconic acid, curve 2;

- mechanically activated amorphous calcium salt of gluconic acid, curve 3.

Mass spectrometric measurements by the method of mass spectrometry laser desorption from the matrix (MALDI-TOF) was performed on the device DYNAMO. Were investigated extracts in water, ethanol, chloroform and hexane mechanically activated samples.

As can be seen from Fig.9, in the mass spectrum of the extract of the original crystalline calcium gluconate (curve 1) are high-molecular peaks of relatively low intensity at m/z 750-950. In the mass spectrum of the extract of the mechanically activated amorphous-crystalline compositions of amorphous and crystalline calcium gluconate (curve 2) the relative intensity of these peaks increased significantly. An even higher intensity of the high-molecular peaks at m/z 750-950 observed in the mass spectrum of the extract of the mechanically activated amorphous calcium gluconate (curve 3).

In MALDI-TOF mass spectra of extracts of solutions of the samples in water and chloroform significant differences were observed.

In General, given the data of mass spectrometry EI and MALDI-TOF data show, when machining calcium gluconate amorphous or amorphous-crystalline polymers and their extracts consist of the calcium salt of gluconic acid with m/z=430 and high-molecular compounds of the calcium salt of gluconic acid with m/z from 470 to 950.

Figure 10 shows the curves of differential thermal analysis (DTA) of the following samples:

- the original crystalline calcium salt of gluconic acid, curve 1;

- mechanically activated amorphous-crystalline calcium salt of gluconic acid, curve 2;

- mechanically activated amorphous calcium salt of gluconic acid, curve 3.

DTA curves were shot on the device Shimazu DSC-60 in argon atmosphere with a heating rate of 10°C/min To DTA curve of the amorphous form substantially offset the endothermic peaks in the temperature range of 125-165°C and there is an additional endothermic peak in the temperature range of 30-100°C (figure 10, curve 3). On the DTA curve of amorphous-crystalline form of the observed increase in the endothermic peak in the temperature range of 30-100°C. and reducing the endothermic peak in the temperature region 125-165°C.

Examples of the method

Example 1. A method of obtaining a mechanically activated amorphous calcium salt of gluconic acid is implemented as follows.

Crystalline calcium salt of gluconic acid in weight is ω with respect to the grinding balls 1:11 loaded in sealed vessels and in the conditions of the inert atmosphere was treated in energyprogram grinding device activator with energonapryazhennosti 6 W/g (6 j/s·g) at a temperature not exceeding 60 degrees Celsius for 30 minutes. The magnitude of the summed energy density of 10.8 kJ/year

Considering the fact that the amorphization of crystalline calcium gluconate in the activator requires a minimum of 10.5 kJ/g summed energy density, the processing time was sufficient to obtain an amorphous state. It should be noted that the processing time depends on energonapryazhennosti activator. If energonapryazhennosti activator 3 W/g to obtain a mechanically activated amorphous calcium salt of gluconic acid from salt crystals requires 1 hour of processing, and if energonapryazhennosti 6 W/g processing time should be 30 minutes.

Grinding also conducted in an open atmosphere, the residual atmosphere in the isolated volume, with the addition of the gas environment in an outdoor or a stand-alone volume of the grinding device, under vacuum conditions up to 10-4PA.

Example 2. A method of obtaining a mechanically activated amorphous-crystalline calcium salt of gluconic acid.

Crystalline calcium salt of gluconic acid in a weight ratio to the grinding balls 1:11 loaded in sealed vessels and in the conditions of the inert atmosphere was treated in energyprogram grinding device activator with energonapryazhennosti 6 W/g at a temperature of not offset the setup portion 60 degrees Celsius, within 10 minutes. The magnitude of the summed energy density was 3.6 kJ/g, which is insufficient for complete amorphization of the original crystalline state of matter, since the magnitude of the summed energy density is not more than 10.4 kJ/g, respectively mechanically activated substance applied two-phase amorphous-crystalline state. In mechanically activated the product contained ≈90 wt.% amorphous phase and ≈10 wt.% crystal.

Grinding also conducted in an open atmosphere, the residual atmosphere in the isolated volume, with the addition of the gas environment in an outdoor or a stand-alone volume of the grinding device, under vacuum conditions up to 10-4PA.

Example 3. A method of obtaining a mechanically activated amorphous composition of the calcium salt of gluconic acid with pharmaceutically acceptable excipients.

Crystalline calcium salt of gluconic acid in a weight ratio with pharmaceutically acceptable excipients (talc, starch, calcium stearate) 94:2:2:2 was loaded in sealed vessels at the weight ratio of the mixture to a grinding balls 1:11 and under conditions of inert atmosphere was treated in energyprogram grinding device activator with energonapryazhennosti 6 W/g at a temperature not exceeding 60°C for 30 minutes. The magnitude of the summed Ude is Inoi energy of 10.8 kJ/g, that more than 10.5 kJ/g and sufficient for the formation of the amorphous state.

Grinding also conducted in an open atmosphere, the residual atmosphere in the isolated volume, with the addition of the gas environment in an outdoor or a stand-alone volume of the grinding device, under vacuum conditions up to 10-4PA.

Example 4. A method of obtaining a mechanically activated amorphous-crystalline compositions of the calcium salt of gluconic acid with pharmaceutically acceptable excipients.

Crystalline calcium salt of gluconic acid in a weight ratio with pharmaceutically acceptable excipients (talc, starch, calcium stearate) 94:2:2:2 was loaded into a sealed vessel in a weight ratio of the mixture to a grinding balls 1:11 and under conditions of inert atmosphere was treated in energyprogram grinding device activator with energonapryazhennosti 6 W/g at a temperature not exceeding 60 degrees Celsius for 10 minutes. The magnitude of the supplied energy was 3.6 kJ/g, which is insufficient for complete amorphization of the original crystalline state of matter, since the magnitude of the summed energy density was not more than 10.4 kJ/g, respectively mechanically activated substance applied two-phase amorphous-crystalline state. In mechanically activated the product contained ≈90 mA is.% amorphous phase and ≈10 wt.% - crystal.

Grinding also conducted in an open atmosphere, the residual atmosphere in the isolated volume, with the addition of the gas environment in an outdoor or a stand-alone volume of the grinding device, under vacuum conditions up to 10-4PA.

Example 5. A method of obtaining a composition of amorphous calcium salt of gluconic acid with pharmaceutically acceptable excipients implemented as follows.

Crystalline calcium salt of gluconic acid in a weight ratio to the grinding balls 1:11 loaded in sealed vessels and in the conditions of the inert atmosphere was treated in energyprogram grinding device activator with energonapryazhennosti 6 W/g (6 j/s·g) at a temperature not exceeding 60 degrees Celsius for 30 minutes. The magnitude of the summed energy density of 10.8 kJ/g, which is enough for amorphization of crystalline calcium gluconate, since the magnitude of the summed energy density exceeds that of 10.5 kJ/, Then the mechanically activated amorphous calcium salt of gluconic acid in a weight ratio of 94:2:2:2 was mixed with talc, starch and calcium stearate.

Example 6. The method of obtaining the composition of the amorphous-crystalline calcium salt of gluconic acid with pharmaceutically acceptable excipients.

Crystalline calcium salt Glu is about acid in weight ratio to the grinding balls 1:11 loaded in sealed vessels and in the conditions of the inert atmosphere was treated in energyprogram grinding device activator with energonapryazhennosti 6 W/g at a temperature not exceeding 60 degrees Celsius for 10 minutes. The magnitude of the summed energy density was 3.6 kJ/g, which is insufficient for complete amorphization of the original crystalline state of matter, since the magnitude of the summed energy density is not more than 10.4 kJ/g, respectively mechanically activated substance applied two-phase amorphous-crystalline state. In mechanically activated the product contained ≈90 wt.% amorphous phase and ≈10 wt.% crystalline. Then the mechanically activated amorphous-crystalline calcium salt of gluconic acid in a weight ratio of 94:2:2:2 was mixed with talc, starch and calcium stearate.

The benefits of implementation methods 1-6 are that they simplify the methods of obtaining the mechanically activated amorphous and amorphous-crystalline calcium salts of gluconic acid and their compositions, determining the required grinding time is not time-consuming empirically, and knowing only necessary to obtain a summed value of the specific energy characteristics of an activator device and specific energyproject mode grinding, the relevant physico-chemical properties of crushed substances.

Example 7. Pharmaceutical drug.

Obtained in any of examples 1-6, the substance is a powder packaged in packages so each package contained 0.5 g of substance. Packages of 10 pieces are placed in a sealed package.

Example 8. Pharmaceutical drug.

Obtained in any of examples 1-6 substance in powder form, if necessary, in a therapeutically effective amount is mixed with pharmaceutically acceptable excipients and tabletroute in apparatus for the production of tablets such that each tablet contained 0.5 g of the active substance. Tablets are placed in a sealed package.

Example 9. Pharmaceutical drug.

Obtained in any of examples 1-6 substance in powder form in the apparatus for filling capsules fall asleep in gelatin or cellulose capsules so that each capsule contained 0.5 g of substance. Capsules are placed in a sealed package.

Advantage of pharmaceutical preparations of examples 7-9 are relatively well-known in [3] and [6] the powder obtained by the method of mechanical activation of a tablet form officinal drug calcium gluconate containing <2% talc, <3% starch and <1% calcium stearate (FSP-0173654505, CJSC Irbit HFZ), is that they made from the first compounds and compositions with certain first physico-chemical characteristics that they are due to these physico-chemicalcharacteristics have a unique, no analogues in the world of therapeutic efficacy. Adjustable content and properties of additives to avoid unwanted side effects taking into account the individual characteristics of the organism and health of patients and to adjust them if necessary passage through the esophagus and gastrointestinal tract.

Example 10.

The obtained preparations of examples 1-6 was used orally in doses of 1.5 to 3 grams a day course in 15-30 days for at least 2 months in the group of patients from 127 people with dental diseases. All patients had positive dynamics: reduced bleeding gums, reducing the sensitivity of the necks of the teeth, the disappearance of unpleasant smell from a mouth, reducing tooth mobility, the reduction of periodontal pockets, restoration of physiological color of the mucous membrane of the gums. X-ray revealed the structure of the bones of the upper and lower jaws and the restoration of bone beams, restoring the structure of the bone in the apical periodontitis. The duration of treatment of patients with periodontal disease and teeth decreased from 2.5 to 3 months to 1.5-2 months. Known in the world of medicine medicines of calcium do not have at all or have incomparably less therapeutic efficacy in the treatment of such t is PA diseases. In the publications [3] and [6] there was also no published data indicating that the powder obtained by the method of mechanical activation of a tablet form officinal drug calcium gluconate content <2% talc, <3% starch and <1% calcium stearate (FSP-0173654505, CJSC Irbit HFZ), has such a unique no analogues in the world of therapeutic efficacy in the treatment of dental diseases. First obtained physico-chemical characteristics first obtained substances provides their unique, which has no analogues among other calcium-containing substances, preventive and therapeutic efficacy.

Example 11.

Patient A. 75 years. Diagnosis: according to the densitometry osteoporosis of the proximal femur 2 degrees. For treatment was applied to the obtained mechanically activated amorphous composition according to example 3. The drug is used orally in doses of 3 grams a day course in 15-30 days within 1 year. During the year of treatment bone mineral density (BMD) in the proximal femur increased by 4.2%, in the left - 10.5%. Osteoporosis femur 1 degree. Received a unique positive dynamics. Known in the world of medicine medicines of calcium do not have at all or have considerably smaller therapeutic is effective in treating this type of disease. The drug Calcium D3Nycomed are only able to slow the reduction of BMD in the femoral neck (slow destruction of bone tissue) [4]. Drug Bonviva during the year of application can increase BMD of the femoral neck by 1.3 to 3.5% [5]. In the publications [3] and [6] there was also no published data indicating that the powder obtained by the method of mechanical activation of a tablet form officinal drug calcium gluconate content <2% talc, <3% starch and <1% calcium stearate (FSP-0173654505, CJSC Irbit HFZ), has such a unique, unequaled in the world of therapeutic efficacy in the treatment of osteoporosis in adults and the elderly over 70 years of age. First obtained physico-chemical characteristics first obtained substances provides their unique, which has no analogues among other calcium-containing substances, preventive and therapeutic efficacy.

Example 12.

Patient B. 58 years. Diagnosis: chronic renal failure (CRF), uremic osteodystrophy pain syndrome. A patient of the Department of hemodialysis, may 1999 in complex treatment of ESRD received medication calcium as calcium carbonate. With informed consent from August 2007 in complex therapy was applied mechanically activated amorphous composition of example 1. The drug is used orally in doses of 3 grams a day course in 15-30 days for 5 months. Significant improvement of health of the patient. Pain disappeared. The content of Ca++in the blood increased from 0.77 to 1.03 mmol/l at the rate of 1.17 mmol/L. Known in the world of medicine medicines calcium not only have little or possess incomparably less therapeutic efficacy in the treatment of this type of diseases, but for the most part do not apply in such therapy because they have side effects. In the publications [3] and [6] there was also no published data indicating that the powder obtained by the method of mechanical activation of a tablet form officinal drug calcium gluconate content <2% talc, <3% starch and <1% calcium stearate (FSP-0173654505, CJSC Irbit HFZ), is applicable and has such a unique, unequaled in the world of therapeutic efficacy in the treatment of chronic renal failure. First obtained physico-chemical characteristics first, the substance provides his unique, which has no analogues among other calcium-containing substances, preventive and therapeutic efficacy.

Preferred modes of implementation of the present invention are, thus, fully described. However, the above examples are only Illus the radio of the invention and may not be considered as limiting the invention in essence or scope.

Sources of information

1. Ming C. Tang. Amorphous calcium, the retrieval method, the processing method and remineralization of the teeth, the compressed solution saturated with carbon dioxide containing amorphous calcium compound, non-aqueous dispersion of the carbonate salt and the acid or acid salt, a method of processing bone tissue nonaqueous dispersion. // US patent No. 9422264. Publ. 27.05.1996.

2. Konygin G.N., Shooters NS and other treatment of hypocalcaemia, osteoporosis, fractures. // Patent RF №2268053. Publ. 20.01.2006 (prototype).

3. Genchanges and other "mechanically activated drug calcium gluconate: x-ray, microscopic and photoelectron studies" // Chemistry for sustainable development, 2005, s-252.

4. Nowtopia and other Osteoporosis: opportunities for prevention calcium and vitamin D // Farmateka, 2007, No. 5 (140), p.56-61.

5. Nowtopia and other New bisphosphonate Bonviva for treatment of postmenopausal osteoporosis /Osteoporosis and osteopathy, 2006, No. 2, pp.42-45.

6. Genchanges. "Our bones will be stronger", the newspaper "Science of the Urals", №1 (888), 2005.

1. Mechanically activated amorphous calcium salt of gluconic acid with uniform diffuse halo in its powder x-ray diffraction pattern characterized by the offset of the center of gravity of the absorption bands 3000-3600
cm-1in the region of high olnowich numbers by a value not more than 200 cm -1, the presence of absorption bands with frequencies 3308±20, 2933±10, 1602±10, 1420±10 with shoulder 1260±40, 1085±10, 1044±10, 877±10, 682±10, 577±10 cm-1and additional absorption band with a frequency 947±10 cm-1in the infrared spectrum, reducing the endothermic peaks in the temperature range of 125-165°C and the increase of the peak in the temperature range of 30-100°C. in differential thermal analysis, the presence of intense single line with the Lande factor from 2,000 to 2.006 and width from 8 to 9 e in the spectrum of electron paramagnetic resonance, the emergence of unresolved broad line of fine structure in the areas of 60-90 and 170-190 million-1in13From the NMR spectra, the shift of the resonance lines of their aqueous solutions in the field of 62.8-179,2 million-1at a value not greater than 0.1 million-1in13From the NMR spectra, the shift of the resonance lines of their aqueous solutions in the field of 1,2-4,95 million-1on the value of not more than 0.02 million-1in1H NMR spectra, increasing the intensities of the peaks 160 m/z mass spectra of not less than 2.5 times and peaks 780-1000 m/z extracts their solutions in ethanol not less than three times in the mass spectroscopic analysis.

2. A method of obtaining a mechanically activated amorphous calcium salt of gluconic acid according to claim 1, characterized in that the crystalline calcium salt of gluconic acid is treated in the grinding activator devices within the time required is for the supply of specific energy of at least 10.5 kJ/g

3. Mechanically activated amorphous-crystalline calcium salt of gluconic acid with the simultaneous presence of diffuse halos and structural crystalline reflexes in its powder x-ray diffraction pattern characterized by the shift of the center of gravity of the absorption bands 3000-3600 cm-1in the region of large wave numbers by a value not more than 200 cm-1, the presence of absorption bands with frequencies 3480±10, 3241±30, 2933±10, 2912±10, 1597±10, 1392±20, 1306±10, 1296±10, 1085±10, 1044±10, 973±10, 908±10, 881±10, 699±10, 565±10 cm-1and additional absorption band with a frequency 947±10 cm-1in the infrared spectrum, the appearance of slabozaselennyh broad lines of the fine structure in the areas of 60-90 and 170-190 million-1in13From the NMR spectra, characterized by the shift of the resonance lines of their aqueous solutions in the field of 62.8-179,2 million-1at a value not greater than 0,09 million-1in13From the NMR spectra, characterized by the shift of the resonance lines of their aqueous solutions in the field of 1,2-4,95 million-1a value of less than 0.015 million-1in1H NMR spectra, characterized by the increase of the intensities of the peaks 160 m/z of their mass spectra not more than 2.5 times and peaks 780-1000 m/z extracts their solutions in ethanol not more than three times in the mass spectroscopic analysis, characterized by the presence of intense single line with the Lande factor from 2,000 to 2.006 and width from 8 to 9 e spectra electron paramagnetic resonance.

4. A method of obtaining a mechanically activated amorphous-crystalline calcium salt of gluconic acid according to claim 3, characterized in that the crystalline calcium salt of gluconic acid is treated in the grinding activator devices energonapryazhennosti during the time required for the supply of the energy density is not more than 10.4 kJ/year

5. The composition of the amorphous calcium salt of gluconic acid with pharmaceutically acceptable excipients for the treatment of dental or bone diseases associated with impaired metabolism of calcium in the body, characterized in that the salt according to claim 1 and excipients are mixed in the following ratio of ingredients, wt.%:

mechanically activated amorphous calcium
salt of gluconic acid94÷97
talc2÷1
starch2÷1
calcium stearate2÷1

6. The composition of the amorphous-crystalline calcium salt of gluconic acid with pharmaceutically acceptable excipients for the treatment of dental or bone related disease is a disturbance of calcium metabolism in the body, characterized in that the salt according to claim 3 and excipients are mixed in the following ratio of ingredients, wt.%:

mechanically activated amorphous-crystalline
calcium salt of gluconic acid94÷97
talc2÷1
starch2÷1
calcium stearate2÷1

7. Mechanically activated amorphous composition of the calcium salt of gluconic acid with the following ratio of ingredients, wt.%:

calcium salt of gluconic acid94÷97
talc2÷1
starch2÷1
calcium stearate2÷1

for the treatment of dental or bone diseases associated with impaired metabolism of calcium in the body, with uniform diffuse halo in its powder x-ray diffraction pattern characterized by the offset center of gravity stripe POG is osenia 3000-3600 cm -1in the region of large wave numbers by a value not more than 200 cm-1, the presence of absorption bands with frequencies 3308±20, 2933±10, 1602±10, 1420±10 with shoulder 1260±40, 1085±10, 1044±10, 877±10, 682±10, 577±10 cm-1and additional absorption band with a frequency 947±10 cm-1in the infrared spectrum, reducing the endothermic peaks in the temperature range of 125-165°C and the increase of the peak in the temperature range of 30-100°C. in differential thermal analysis, the presence of intense single line with the Lande factor from 2,000 to 2.006 and width from 8 to 9 e in the spectrum of electron paramagnetic resonance, the emergence of unresolved broad line of fine structure in the areas of 60-90 and 170-190 million-1in13From the NMR spectra, the shift of the resonance lines of their aqueous solutions in the field of 62.8-179,2 million-1at a value not greater than 0.1 million-1in13From the NMR spectra, the shift of the resonance lines of their aqueous solutions in the field of 1,2-4,95 million-1on the value of not more than 0.02 million-1in1H NMR spectra, increasing the intensities of the peaks 160 m/z mass spectra of not less than 2.5 times and peaks 780-1000 m/z extracts their solutions in ethanol not less than three times in the mass spectroscopic analysis.

8. A method of obtaining a mechanically activated amorphous composition of the calcium salt of gluconic acid according to claim 7, characterized in that the composition in the following ratio of ingredients, wt.%:
crystalline calcium saltgluconic acid94÷97talc2÷1starch2÷1calcium stearate2÷1
is processed in the grinding activator devices during the time required for the supply of specific energy of at least 10.5 kJ/g

9. Mechanically activated amorphous-crystalline composition of the calcium salt of gluconic acid with the following ratio of ingredients, wt.%:

calcium salt of gluconic acid94÷97
talc2÷1
starch2÷1
calcium stearate2÷1

for the treatment of dental or bone diseases associated with impaired metabolism of calcium in the body, with the simultaneous presence of diffuse halos and structural crystalline reflexes in its powder x-ray diffraction pattern characterized by the offset is m of the center of gravity of the absorption bands 3000-3600 cm -1in the region of large wave numbers by a value not more than 200 cm-1, the presence of absorption bands with frequencies 3480±10, 3241±30, 2933±10, 2912±10, 1597±10, 1392±20, 1306±10, 1296±10, 1085±10, 1044±10, 973±10, 908±10, 881±10, 699±10, 565±10 cm-1and additional absorption band with a frequency 947±10 cm-1in the infrared spectrum, the appearance of slabozaselennyh broad lines of the fine structure in the areas of 60-90 and 170-190 million-1in13From the NMR spectra, the shift of the resonance lines of their aqueous solutions in the field of 62.8-179,2 million-1at a value not greater than 0,09 million-1in13From the NMR spectra, the shift of the resonance lines of their aqueous solutions in the field of 1,2-4,95 million-1a value of less than 0.015 million-1in1H NMR spectra, increasing the intensities of the peaks 160 m/z of their mass spectra not more than 2.5 times and peaks 780-1000 m/z extracts their solutions in ethanol not more than three times in the mass spectroscopic analysis, the presence of intense single line with the Lande factor from 2,000 to 2.006 and width from 8 to 9 e in the spectrum of electron paramagnetic resonance.

10. A method of obtaining a mechanically activated amorphous-crystalline compositions of the calcium salt of gluconic acid according to claim 9, characterized in that the composition in the following ratio of ingredients, wt.%:

crystalline calcium salt of gluconic is sloty 94÷97
talc2÷1
starch2÷1
calcium stearate2÷1,

is processed in the grinding activator devices during the time required for the supply of the energy density is not more than 10.4 kJ/year

11. Pharmaceutical preparation for the treatment of dental or bone diseases associated with impaired metabolism of calcium in the body, in the form of powder, tablets or capsules with powder containing a therapeutically effective amount of the salt according to any one of claim 1 or 3, and optionally in a mixture with pharmaceutically acceptable excipients.

12. Pharmaceutical preparation for the treatment of dental or bone diseases associated with impaired metabolism of calcium in the body, in the form of powder, tablets or capsules with powder containing a therapeutically effective amount of a composition according to any one of pp.5, 6, 7, and 9.

13. A method for the treatment of dental or bone diseases associated with impaired metabolism of calcium in the body, oral, characterized in that the use of the pharmaceutical preparation according to any one of claim 11 or 12, doses of 0.2-0.4 g or 0.6-6 g, 1-6 times a day, a course of not less than 1 month.



 

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FIELD: chemistry.

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19 cl, 1 dwg, 6 ex, 4 tbl

FIELD: chemical industry; methods of production of the purified crystalline terephthalic acid.

SUBSTANCE: the invention is pertaining to the improved method of production and separation of the crystalline terephthalic acid containing less than 150 mass ppm of the p-toluene acid in terms of the mass of the terephthalic acid. The method provides for the following stages: (1) loading of (i) para- xylene, (ii) the water reactionary acetic-acidic medium containing the resolved in it components of the oxidation catalyst, and (iii) the gas containing oxygen fed under pressure in the first zone of oxidation, in which the liquid-phase exothermal oxidization of the para-xylene takes place, in which the temperature and the pressure inside the first being under pressure reactor of the oxidization are maintained at from 150°С up to 180°С and from 3.5 up to 13 absolute bars; (2) removal from the reactor upper part of the steam containing the evaporated reactionary acetic-acidic medium and the gas depleted by the oxygen including carbon dioxide, the inertial components and less than 9 volumetric percents of oxygen in terms of the non-condensable components of the steam; (3) removal from the lower part of the first reactor of the oxidized product including (i) the solid and dissolved terephthalic acid and (ii) the products of the non-complete oxidation and (ii) the water reactionary acetic-acidic medium containing the dissolved oxidation catalyst; (4) loading of (i) the oxidized product from the stage (3) and (ii) the gas containing oxygen, into the second being under pressure zone of the oxidation in which the liquid-phase exothermal oxidization of the products of the non-complete oxidization takes place; at that the temperature and the pressure in the second being under pressure reactor of the oxidization are maintained from 185°С up to 230°С and from 4.5 up to 18.3 absolute bar; (5) removal from the upper part of the second steam reactor containing the evaporated water reactionary acetic-acidic medium and gas depleted by the oxygen, including carbon dioxide, the inertial components and less, than 5 volumetric percents of oxygen in terms of the non-condensable components of the steam; (6) removal from the lower part of the second reactor of the second oxidized product including (i) the solid and dissolved terephthalic acid and the products of the non-complete oxidation and (ii) the water reactionary acetic-acidic medium containing the dissolved oxidation catalyst; (7) separation of the terephthalic acid from (ii) the water reactionary acetic-acidic medium of the stage (6) for production the terephthalic acid containing less than 900 mass ppm of 4- carboxybenzaldehyde and the p-toluene acid; (8) dissolution of the terephthalic acid gained at the stage (7) in the water for formation of the solution containing from 10 up to 35 mass % of the dissolved terephthalic acid containing less than 900 mass ppm of the 4- carboxybenzaldehyde and the p-toluene acid in respect to the mass of the present terephthalic acid at the temperature from 260°С up to 320°С and the pressure sufficient for maintaining the solution in the liquid phase and introduction of the solution in contact with hydrogen at presence of the catalytic agent of hydrogenation with production of the solution of the hydrogenated product; (9) loading of the solution of the stage (8) into the crystallization zone including the set of the connected in series crystallizers, in which the solution is subjected to the evaporating cooling with the controlled velocity using the significant drop of the temperature and the pressure for initiation of the crystallization process of the terephthalic acid, at the pressure of the solution in the end of the zone of the crystallization is atmospheric or below; (10) conduct condensation of the dissolvent evaporated from the crystallizers and guide the condensed dissolvent back into the zone of the crystallization by feeding the part of the condensed dissolvent in the line of removal of the product of the crystallizer, from which the dissolvent is removed in the form of the vapor; and (11) conduct separation of the solid crystalline terephthalic acid containing less than 150 mass ppm of the p-toluene acid in terms of the mass of the terephthalic acid by separation of the solid material from the liquid under the atmospheric pressure. The method allows to obtain the target product in the improved crystalline form.

EFFECT: the invention ensures production of the target product in the improved crystalline form.

8 cl, 3 tbl, 2 dwg, 3 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to the improved method for isolating crystalline terephthalic acid comprising less 150 mas. p. p. per million (ppm) of p-toluic acid with respect to weight of terephthalic acid. Method involves the following steps: (1) preparing a solution containing from 10 to 35 wt.-% of dissolved terephthalic acid wherein from 150 to 1100 ppm of p-toluic acid is dissolved with respect to mass of terephthalic acid at temperature from 260°C to 320°C and under pressure providing maintaining the solution in liquid phase; (2) charge of solution from step (1) to crystallization zone comprising multitude amount of associated crystallizers wherein the solution is subjected for cooling at evaporation at the controlled rate by the moderate pressure and temperature reducing resulting to crystallization of terephthalic acid and wherein the solution pressure at the end of crystallization zone is equal to atmosphere pressure or lower; (3) condensation of solvent evaporated from crystallizers and recovering the condensed solution to the crystallization zone to place of descending flow from crystallizer wherein solvent is removed by evaporation, and (4) isolation of solid crystalline terephthalic acid comprising less 150 ppm of p-toluic acid with respect to the terephthalic acid mass by separation of the phase liquid-solid substance under atmosphere pressure. The advantage of method is preparing the end product in improved crystalline form and carrying out the process under atmosphere pressure or pressure near to atmosphere pressure.

EFFECT: improved method of crystallization.

3 cl, 1 dwg, 1 tbl, 2 ex

FIELD: crystal growing.

SUBSTANCE: invention relates to adipic acid crystals and treatment thereof to achieve minimum crystal caking. Crystals are prepared by crystallization of adipic acid from aqueous medium or between treating it with aqueous solution. Crystals are then subjected to ripening stage, that is crystals are held at temperature between 10 and 80°C until content of exchangeable water in crystals falls below 100 ppm, while using an appropriate means to maintain ambient absolute humidity at a level of 20 g/m3. Renewal of ambient medium is accomplished by flushing crystal mass with dry air flow having required absolute humidity. Means to maintain or to lower absolute humidity contains moisture-absorption device placed in a chamber. Content of exchangeable water in crystals is measured for 300 g of adipic acid crystals, which are enclosed in tightly sealed container preliminarily flushed with dry air and containing 2 g of moisture absorbing substance. In chamber, temperature between 5 and 25°C is maintained for 24 h. Content of water will be the same as amount of water absorbed by absorbing substance per 1 g crystals. Total content of water exceeds content of exchangeable water by at least 20 ppm.

EFFECT: minimized caking of crystals and improved flowability.

13 cl, 5 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing malonate or manganese (II) succinate, which can be used in different areas of chemical practice, in analytical control and scientific research, through direct reaction of a metal and its dioxide with carboxylic acid in the presence of an organic solvent and stimulating iodine additive in a vertical type bead mill with a high-speed mixer and glass beads as grinding medium, where manganese, its dioxide and carboxylic acid in the initial load are taken in molar ratio 1+x):1:(2+x) so as to obtain (2+x)m moles of salt, where x in the given molar ratio of reagents equals 0.4±0.1 for amber acid and 1.0±0.1 for malonic acid, and m is the number of moles of manganese dioxide in the load; iodine is taken in amount of 0.05 mol/kg of the reaction mixture after loading organic solvent and acid, but before loading manganese dioxide and metal. Total mass of acid, metal and its dioxide lies between 15 and 25% of the mass of the initial load, and ratio of mass of beads to mass of the load is 1:1. The process is started at room temperature and carried out under forced cooling conditions at temperature ranging from room temperature to 40°C while controlling by taking samples until exhaustion of all loaded reagents into the target salt, after which the process is stopped. The suspension of the final reaction mixture is separated from the beads and filtered. The product residue is washed with a liquid phase solvent and taken for purification from trace metal and its dioxide through recrystallisation, and the filtrate and washing solvent are returned to the repeated process.

EFFECT: process takes place at acceptable rates and ends with virtually complete consumption of all loaded reagents.

2 cl, 19 ex

FIELD: chemistry.

SUBSTANCE: invention relates to an improved method of producing manganese (II) fumarate from manganese metal and its oxide (III) through direct reaction of the metal and its oxide Mn2O3 with an acid in the presence of a liquid phase and a stimulating iodine additive in a vertical type bead mill with glass beads as grinding agent. The metal and its oxide are loaded in molar ratio (2±0.1):1 in total amount of 7.87 to 10.93% of the mass of the load. Acid is added with 15 to 25% excess of the calculated value, equal to the number of moles of metal and twice the number of moles of metal oxide in the load. The base of the liquid phase is isoamyl alcohol, in which the iodine stimulating additive is dissolved in amount of 0.02 to 0.05 mol/kg. Glass beads are loaded first, in mass ratio to the reaction mixture of 1.35:1, and then later the liquid phase solvent, acid and stimulating additive, and after brief stirring, metal oxide and metal, stirring all the while. Taking this moment as the beginning of the process, forced cooling is introduced right away. Operating temperature is stabilised in the range 33 to 45°C and in this mode, the process is carried out until virtually quantitative conversion of metal and its oxide to the target salt, after which stirring and forced cooling are stopped. The reaction mixture is separated from the glass beads, cooled to temperature 5 to 6°C and kept at that temperature for 1 to 2 hours. The solid phase of the target salt is filtered off and washed with isoamyl on a filter cooled to approximately the same temperature, after which it is taken for purification by recrystallisation. The filtrate and the cleaning solvent, containing excess acid, the bulk of the stimulating additive and a certain amount of dissolved target salt, are returned for loading in the repeated process. The process is carried out in light temperature conditions. The target substance can be easily separated.

EFFECT: design of a low-waste method, which allows for obtaining target product from available manganese oxide with an easy to implement process.

9 ex

FIELD: medicine.

SUBSTANCE: invention refers to a new product in the form of solution for treatment of benign, virus, premalignant and malignant nonmetastasing skin affections, dysontogenetic lesions of visible mucous membranes, skin mycoses, wrinkle correction and senile pigment spots. The product represents a compound of general formula H2SeO3·x·[R-CXY-(CH2)m-COOH], where x=2-6 prepared from reaction of selenium dioxide and haloid carboxylic acids of general formula R-CXY-(CH2)m-COOH, where R = phenyl, alkyl of general formula CnH2n+1; n=1-5, X=H or Y, Y=F, CI, Br or J, m = 0-10. Besides, the invention concerns a product in the form of solution for treatment benign, virus, premalignant and malignant nonmetastasing skin affections, dysontogenetic lesions of visible mucous membranes, skin mycoses, wrinkle correction and senile pigment spots, containing 0.1-50 wt % of said product, 1-99 wt % of haloid carboxylic acids and the rest - water. Also the invention concerns method of treatment of various skin diseases, including topic applications of the product.

EFFECT: improved clinical effectiveness of the product and method of treatment.

6 cl, 3 dwg, 1 tbl, 68 ex

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