Crystal-modification of the hydrochloride of 2 - dimethylaminoethanol ether p-butylaminoethyl acid as a local anesthetic means and how you can get

 

The invention relates to a new crystalline-modification of the hydrochloride of 2 - dimethylaminoethanol ether p-butylaminoethyl acid as a local anesthetic remedies, the way it is received, namely, that the solution of the hydrochloride of 2 - dimethylaminoethanol ether p-butylaminoethyl acid in water, in an organic solvent or their mixture is heated to boiling, it is dispersed in the refrigerant and subjected to freeze-drying. New crystal-modification of the hydrochloride of 2-dimethylaminoethanol ether p-butylaminoethyl acid is a crystalline white powder, easily soluble in water and ethanol (95-96%), moderately soluble in chloroform, so pl. of 149.50,4oS. 2 S. p. f-crystals, 5 tab., 3 Il.

The invention relates to organic chemistry and relates to a new crystalline modification of the hydrochloride of 2-dimethylaminoethanol ether p-butylaminoethyl acid called usis modification, and how it is received, and can be used in pharmaceutical industry and medicine as a local anesthetic cf is minethrower ether p-butylaminoethyl acid: 6 anhydrous crystalline modifications, one x-ray amorphous and 3 crystallohydrate form, characterized by the method of x-ray phase analysis (XRD) in a certain set of diffraction peaks (d,) and their intensity (IRel), as well as specific values of melting temperature (135-150oC). These modifications get one from another, varying conditions: isothermal exposures, heating and cooling, and crystallization from water or saturated anhydrous modifications of water vapor (D. Giron, M. Draghi, Goldbronn S., Pfeffer, S., Piechon P. J. Thermal Anal. 1997, v.49, p.913-927).

Known modifications are white powder, odorless, slightly bitter taste, which cause a temporary anesthesia of the tongue. They are easily soluble in water, soluble in alcohol, sparingly soluble in chloroform and practically insoluble in ether (international Pharmacopoeia. 3eed., Who, Geneva, 1990, I. 3, S. 356).

Known modification, showing a strong local anesthetic effect, have high toxicity (2 times more toxic than cocaine and 10 times - novocaine) and significant side effects: oftalmologii - damage of the corneal epithelium, the occurrence of erosion and a significant expansion of the conjunctiva (Mashkovsky M. D. Drug among the policy hydrochloride 2-dimethylaminoethanol ether p-butylaminoethyl acid (leaquin), characterized by xfa particular set of diffraction peaks (d,) and their intensity (IRel, %), melting point (of 148.60,3)oS. the Method of obtaining this modification is that the solution of the hydrochloride of 2-dimethylaminoethanol ether p-butylaminoethyl acid (dikaina) in water or an organic solvent, or a mixture thereof is cooled in the refrigerant with a minimum speed of 8oC/min until complete crystallization solution with subsequent freeze-drying at a pressure in the chamber 10-2mm RT.article (Torr) up to a residual moisture content of 3% (RF patent 2028289, C 07 C 219/34 from 09.02.95,, bull. 4).

This modification is a white, very light, powder, easily soluble in water and ethanol (95%), soluble in chloroform. It has a local anesthetic action (PL.1).

Of patent and technical literature is not known crystal-modification of the hydrochloride of 2-dimethylaminoethanol ether p-butylaminoethyl acid and its preparation.

We discovered a new crystalline-modification of the hydrochloride of 2-dimethylaminoethanol ether p- -modification of the hydrochloride of 2-dimethylaminoethanol ether p-butylaminoethyl acid is a crystalline white powder, easily soluble in water and ethanol (95-96%), moderately soluble in chloroform.

To identify the obtained material was carried out complex of physicochemical methods of analysis. Initially, methods of nuclear magnetic resonance (NMR13-1N) and gas chromatographically was established the identity of the chemical formulas of the original hydrochloride 2-dimethylaminoethanol ether p-butylaminoethyl acid and a new crystal-modification of the hydrochloride of 2-dimethylaminoethanol ether p-butylaminoethyl acid.

Determination of the chemical shifts obtained substance was held in its saturated solution in deuterated dimethylsulfoxide (DMSO-D6) on the NMR spectrometer of high resolution VXR-400 "VARIAN (USA). The data obtained are given in table.2. Comparison of the results presented in table.2, with the data given in the literature (RF patent 2028289, C 07 C 219/34 from 09.02.95,, bull. 4), shows that the obtained substance is the hydrochloride of 2-dimethylaminoethanol EF the-dimethylaminoethanol ether p-butylaminoethyl acid and a new crystal-modification of the hydrochloride of 2-dimethylaminoethanol ether p-butylaminoethyl acid was carried out on the installation: "Hewlet Packard (HP) 5890 series II; with mass-selective detector HP Mass Selective Detector 5972, on a column of HP-5SM (Crosslinked 5% PH ME siloxane), length 30 m, diameter 0.25 mm, using helium as the carrier gas, the flow velocity of 1 cm3/min. the Subjects of the substance was injected in the form of a 0.1 wt.% solution in 95% ethanol. Standard test conditions were: injector temperature of 200oC; the detector temperature is 280oC; initial column temperature after sample introduction - 80o(3 min) followed by heating with a speed of 15oC/min to 250oC (2 min).

The resulting chromatogram and mass spectrum of the source hydrochloride 2-dimethylaminoethanol ether p-butylaminoethyl acid (dikaina) and synthesized by us-the modification shown in Fig.1 and 2, respectively. In Fig.1 and shows the chromatogram of the original sample dikaina (tetracaine), which contains one peak of the main component with a characteristic retention time 15,306 min On the chromatogram-modification dikaina (Fig.2A) also observed one intense peak hold time is I identical within experimental error. In Fig.3 presents: mass spectrogram of tetracaine hydrochloride, included in the international data Bank NBS 75K, and chemical formula corresponding to this spectrum. Comparison of the experimental results (Fig.1 and 2) with the values of international data Bank (Fig.3) indicate that the resulting substance is a hydrochloride 2-dimethyl-aminoethylamide ether p-butylaminoethyl acid.

Thus, the obtained NMR spectroscopy and chromatographically experimental results clearly indicate that the resulting substance is the hydrochloride of 2-dimethylaminoethanol ether p-butylaminoethyl acid.

To confirm that the obtained substance is a new crystalline-modification of the hydrochloride of 2-dimethyl-aminoethylamide ether p-butylaminoethyl acid were carried out x-ray analysis and differential scanning calorimetry.

According to x-ray phase analysis conducted on the unit "Dron-3M C K- radiation at the speed of rotation of the goniometer 2 deg/min, the resulting substance is a new crystalline) and their intensity (IRel, %) (table.3).

The results of differential scanning calorimetry (DSC), obtained with the device "Perkm Elmer DSC - 7 in a stream of nitrogen with a heating rate of 2 deg/min, using as a sample holders aluminum micro-containers, showed that the process of melting the obtained crystal-modification of the hydrochloride of 2-dimethylaminoethanol ether p-butylaminoethyl acid is characterized by an endothermic effect at a temperature (at 149.50,4)oC.

Thus, the experimental results of XRD and DSC unequivocally testify that the substance is a new crystalline-modification of the hydrochloride of 2-dimethylaminoethanol ether p-butylaminoethyl acid, which is characterized by a different set of diffraction peaks and their intensity, as well as individual, different from the other modifications melting temperature TPL=(at 149.50,4)oC.

The method of obtaining crystalline-modification of the hydrochloride of 2-dimethylaminoethanol ether p-butylaminoethyl acid the conclusion is(dikaina) in water, in an organic solvent or their mixture is heated to boiling, it is dispersed in the refrigerant and subjected to freeze-drying.

As a solvent source hydrochloride 2-dimethylaminoethanol ether p-butylaminoethyl acid, you can use water or any organic solvent, or a mixture in which dikain soluble. Most appropriate to apply the solvent water or ethanol, or mixtures thereof, in which the hydrochloride of 2-dimethylaminoethyl ether p-butylaminoethyl acid is highly soluble. The increasing concentration of the original solution allows to increase the productivity of the process of obtaining a new crystal-modification of the hydrochloride of 2-dimethylaminoethanol ether p-butylaminoethyl acid.

Lowering the temperature of the initial solution temperature below its boiling results in crystalline-modification of the hydrochloride of 2-dimethylaminoethanol ether p-butylaminoethyl acid.

The dispersion solution dikaina at boiling point can be performed by any known method using various types of spray devices: pneumatic and mechanical f is one solution before freezing results in well-known-modification of the hydrochloride of 2-dimethylaminoethanol ether p-butylaminoethyl acid.

Freezing dispersed solution, as a rule, carried out in the liquid refrigerant, which is usually (for reasons of cost and availability) use of liquid nitrogen (TKip=-196oC), but may use other refrigerants, for example, cooled to -70 -94...oWith hexane.

Dispersed and frozen solutions of the original hydrochloride 2-dimethylaminoethanol ether p-butylaminoethyl acid in the form of granules is subjected to freeze-drying under standard conditions at low temperature and pressure.

The invention is illustrated by the following examples.

Example 1. 750 ml of 4 wt.% solution of the hydrochloride of 2-dimethylaminoethanol ether p-butylaminoethyl acid in water heated to boiling and dispersed it through mnogonitochnoy die plate with a hole diameter of 90 mm at a pressure of 1.2 ATM and a frequency of vibration of the nozzle of 5.8 kHz cooled to - 80oWith hexane. Pellets of the frozen solution with a diameter of ~180 μm is separated from the chilled hexane cold filtered on a Buechner funnel, put them on pallets stainless Stalis and the residual pressure in the chamber 610-2Torr for 24 hours, the Yield of product amounted to 29,16 g (97,2 wt. %). According to the XRD obtained substance is characterized by a set of diffraction peaks and their intensities, coinciding with the corresponding values for crystalline-modification of the hydrochloride of 2-dimethylaminoethanol ether p-butylaminoethyl acid, are presented in table.3. The results of the DSC show that the melting point of the obtained substances - TPL= (at 149.50,4)oWith the same melting point crystalline-modification of the hydrochloride of 2-dimethylaminoethanol ether p-butylaminoethyl acid. These results indicate that the resulting substance is a new crystalline-modification of the hydrochloride of 2-dimethylaminoethanol ether p-butylaminoethyl acid.

Example 2. 300 g 52 wt.% solution of the hydrochloride of 2-dimethylaminoethanol ether p-butylaminoethyl acid in water heated to boiling and dispersed it through a mechanical injector at a pressure of 5.8 psi liquid nitrogen (TKip= -196oC). Pellets of the frozen solution with a diameter of ~10...50 μm is placed on the u at the capacitor -50 -60...oWith; the product -196...+30oWith residual pressure in the chamber 610-2Torr within 22 hours the Yield of product amounted to 142,58 g (91,4 wt.%). According to the XRD obtained substance is characterized by a set of diffraction peaks and their intensities, coinciding with the corresponding values crystalline-modification of the hydrochloride of 2-dimethylaminoethanol ether p-butylaminoethyl acid, are presented in table.3. The results of the DSC show that the melting point of the obtained substances - TPL=(at 149.50,4)oWith the same melting point crystalline-modification of the hydrochloride of 2-dimethylaminoethanol ether p-butylaminoethyl acid. These results indicate that the resulting substance is a new crystalline-modification of the hydrochloride of 2-dimethylaminoethanol ether p-butylaminoethyl acid.

Example 3. 250 ml of 4 wt.% solution of the hydrochloride of 2-dimethylaminoethanol ether p-butylaminoethyl acid in water heated to +95oWith and dispersed it through mnogonitochnoy die plate with a hole diameter of 90 μm at a gauge pressure with a diameter of ~180 μm is separated from the chilled hexane cold filtered on a Buechner funnel, put them on pallets of stainless steel and is subjected to the freeze-drying process similar to that described in example 1. The product yield was 9,42 g (a 94.2 wt.%). According to the XRD obtained substance is characterized by a set of diffraction peaks and their intensities are presented in table.4. Comparison results table.4 and the data given in the literature (RF patent 2028289, C 07 C 219/34 from 09.02.95,, bull. 4), shows that the obtained substance is-modification of the hydrochloride of 2-dimethylaminoethanol ether p-butylaminoethyl acid. These data are confirmed by the results of the DSC. The melting point of the obtained substances (of 148.60,3)oWith the same as well-known-modification of the hydrochloride of 2-dimethylaminoethanol ether p-butylaminoethyl acid.

Example 4. 250 ml of 4 wt.% solution of the hydrochloride of 2-dimethylaminoethanol ether p-butylaminoethyl acid in water heated to boiling and cool it with liquid nitrogen until complete crystallization at a rate of 8 deg/min Obtained frozen mass is placed on pallets of stainless steel and is subjected to the freeze-drying process similar to that described in example 1. The output is Simanov and their intensities, similar to those shown in table.4. The results of DSC showed that the melting point of the obtained substances TPL=(of 148.60,3)oC. These data indicate that the resulting substance is-modification of the hydrochloride of 2-dimethylaminoethanol ether p-butylaminoethyl acid.

Example 5. 250 ml of 3 wt.% solution of the hydrochloride of 2-dimethylaminoethanol ether p-butylaminoethyl acid in methanol is heated to boiling and dispersed mechanical nozzle at a pressure of 0.5 ATM in liquid nitrogen. The obtained granules with a diameter of ~5...100 microns are placed on pallets of stainless steel and subjected to freeze-drying at temperatures in the condenser -196oWith; the product -196. ..+50oWith residual pressure in the chamber 810-2Torr for 26 hours the Yield of product amounted to 7.32 g (is 97.6 wt.%). According to the XRD obtained is a crystalline substance-modification of the hydrochloride of 2-dimethylaminoethanol ether p-butylaminoethyl acid. The melting point of the obtained substances - TPL=(at 149.50,4)oWith the same melting temperature of the crystal is the notes.

Example 6. 500 ml of 2 wt.% solution of the hydrochloride of 2-dimethylaminoethanol ether p-butylaminoethyl acid in acetone is heated to boiling, dispersed, frozen and subjected to freeze-drying according to example 5. The yield of product amounted to 9.25 g (of 92.5 wt.%). According to the results of XRD and DSC resulting substance is a crystalline-modification of the hydrochloride of 2-dimethylaminoethanol ether p-butylaminoethyl acid.

Example 7. 500 ml of 8 wt.% solution of the hydrochloride of 2-dimethylaminoethanol ether p-butylaminoethyl acid in water-ethanol mixture (50% vol.) heated to boiling, dispersed, frozen and subjected to freeze-drying according to example 5. The product yield was 38,36 g (95.9 wt.%). According to the results of XRD and DSC resulting substance is a crystalline-modification of the hydrochloride of 2-dimethylaminoethanol ether p-butylaminoethyl acid.

Define the time of onset and duration of anesthetic action solutions-modification of the hydrochloride of 2-dimethylaminoethanol ether p-butylaminoethyl acid in physiological solution (0.9 wt.% NaCl in H2O) was carried out on generalizirovanny rabbits-capacity box with a hole, the locking head. The sensitivity threshold of the cornea of the eye to tactile effects were determined using nylon thread, the tip of which was fused in the flame of the burner in the form of a ball with a diameter of ~0.5 mm, 0.1 ml of the solution was dropped into the conjunctival SAC of the eyes of the rabbit and immediately determined the beginning of full anesthesia no batting eyelids when you touch the tip of the filament to the cornea of the rabbit (the time of onset of anesthesia). Then repeating the detection of anesthesia after a certain period of time before the release of the animal from anesthesia. The output of anesthesia was established by batting eyelids when you touch the tip of the filament to the cornea of the eye, fixing the time of anesthesia, which took over the duration of anesthesia. In parallel, carried out the experiments at least 5 rabbits. The data obtained are given in table.5.

From the data table. 5 shows that in comparison with the known modifications hydrochloride 2-dimethylaminoethanol ether p-butylaminoethyl acid-modification of the has increased local anesthetic activity.

Visual observations using a magnifying glass with 10xthe increase showed that the use of solutions

Thus, we have discovered a new crystalline-modification of the hydrochloride of 2-dimethylaminoethanol ether p-butylaminoethyl acid with enhanced local anesthetic activity compared with known modifications and a method of its receipt.

Claims

1. Crystal-modification of the hydrochloride of 2-dimethylaminoethanol ether p-butylaminoethyl acid as a local anesthetic tools.

2. The method of obtaining crystalline-modification of the hydrochloride of 2-dimethylaminoethanol ether p-butylaminoethyl acid is that the solution of the hydrochloride of 2-dimethylaminoethanol ether p-butylaminoethyl acid in water, in an organic solvent or their mixture is heated to boiling, it is dispersed in the refrigerant and subjected to freeze-drying.

 

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