RU2028289C1 - Crystalline modification of hydrochloride of 2 dimethylaminoethyl ether of n-butylaminobenzoic acid and method for its production - Google Patents

Abstract

FIELD: medicine. SUBSTANCE: product: novel crystalline modification of hydrochloride of 2-dimethylaminorthyl ether of n-butylaminobenzoic acid of β-form is characterized by one endothermic melting effect at 148.6148,6 ± 0,3^°C0.3 C and definite values of interplanar spacing and relative reflex intensities. Reagent 1 is solution of tetracaine hydromixture: cooling with coolant at rate of not below 8 C/min up to full crystallization of solution with subsequent drying up to residual moisture content not above 3%. EFFECT: higher efficiency. 4 cl, 3 dwg

Description

 The invention relates to organic chemistry, in particular, to a new crystalline modification of hydrochloride of 2-dimethylaminoethyl ester of n-butylaminobenzoic acid (dicaine) and a new method for its preparation, and can be used in the pharmaceutical industry and medicine.

 Known crystalline modification of dicain (tetracaine), characterized by a set of certain values of interplanar distances d and relative intensities of reflexes 1, the characteristic values of d and I of which are presented in table. eleven].

 Another crystalline modification of dicain (amethocaine) is known, characterized by a set of values of interplanar distances d and relative reflections I, presented in table. 2 [2].

The melting point of these modifications is in the range from 147 to ¹⁵⁰ ° C (≈148 ° ^C). The melting process is a sequence of two endothermic effects (Fig. 1) [3].

There are two other crystalline modifications tetracaine a melting point of one of them 134 ^{° C,} the other - 139 ^{° C.} [4]. The crystal structures of the modifications are not described.

 Known modifications are a white crystalline powder of slightly bitter taste, which causes temporary anesthesia of the tongue, soluble in water and alcohol, sparingly soluble in chloroform, and practically insoluble in ether [4].

Known process for the preparation of pharmaceutical dikaina comprising bottling process N-β -dimetilaminoetilovogo p- aminobenzoic acid, followed by crystallization of the resulting product mixed with hydrosulfite and coal from alcohol at 2-3 ^{° C} and drying [5].

Obtained in a known manner, pharmacopeia dicain is the described crystalline modification, characterized by a set of values of d and I, are presented in table. 1 and 2 [2]. The melting point lies in the range 147-150 ^about With two consecutive endothermic effects (Fig. 2), which completely coincides with the data [3] (Fig. 1).

 Known crystalline modifications of dicain, exhibiting a local anesthetic effect, are highly toxic (the drug belongs to group A) [4-6].

 A disadvantage of the known modifications of dicain is also the significant side effect they cause: in ophthalmic surgery - edema of the eyelid, damage to the corneal epithelium, the appearance of erosion, a significant expansion of the conjunctiva [6].

 The aim of the invention is to obtain a new crystalline modification of dicaine with an increased local anesthetic effect and reduced side effects.

3 26,140
100 12,755
27 8,538
6 6,380
2 6,117
6 5,644
12 5,491
56 5,096
17 4,874
10 4,486
15 4,244
7 4,418
1 4,137
5 4,001
3 3,949
5 3,828
3 3,585
7 3,515
3 3,427
4 2,824
2 2,798
1 2,762
2 2,744
2 2,678
1 2,631
1 2,570
1 2,534
1 2,514
1 2,454
1 2,419
1 2,346
1 2,308
1 2,256
1 2,232
1 2,166
1 2,008
2 1,953
1 1,691
3 3,341
I_отн d,

3 3,310
3 3,170
4 3,156
4 3,149
1 3,064
2 2,979
1 2,944
1 2,903
1 1,584 и обладающая местно-анестезирующей активностью.The goal is achieved due to the fact that a new crystalline modification of the hydrochloride of 2-dimethylaminoethyl ester of n-butylaminobenzoic acid (dicain) was obtained, conventionally called the β-form, characterized by one endothermic melting effect at 148.6 ± 0.3 ^о С and the following values of interplanar spacings d and relative intensities of reflexes I:
I _rel d

3 26,140
100 12,755
27 8.538
6 6.380
2 6.117
6 5,644
12 5,491
56 5,096
17 4,874
10 4,486
15 4,244
7,4,418
1 4,137
5 4,001
3 3,949
5 3,828
3 3,585
7 3,515
3 3,427
4 2,824
2 2,798
1 2,762
2 2,744
2 2,678
1 2,631
1 2,570
1 2,534
1 2,514
1 2,454
1 2,419
1 2,346
1 2,308
1 2,256
1 2,232
1 2,166
1 2,008
2 1,953
1 1,691
3 3,341
I _rel d

3 3,310
3 3,170
4 3,156
4 3,149
1 3,064
2 2,979
1 2,944
1 2,903
1 1,584 and with local anesthetic activity.

A method of obtaining a new crystalline modification of dicain according to the invention is that a solution of pharmacopeia dicain in water or an organic solvent or a mixture thereof is cooled with a refrigerant at a rate of at least 8 ^° C / min until the solution crystallizes. In this case, ethanol can be used as an organic solvent, and liquid nitrogen as a coolant, drying can be carried out by vacuum at a pressure of no higher than 10 ^-2 mm Hg. to a residual moisture content of not more than 3%.

 A new crystalline modification of dicain (β-form) is a tiny crystalline powder of white color, soluble in water and alcohol, practically insoluble in ether. Unlike the known crystalline modifications, it is soluble in chloroform. An aqueous solution (1%) has a pH value in the range of 4.5-6.0.

In contrast to the known crystal modifications obtained β-form is characterized by a melting endothermic effect at a temperature of 148.6 ± 0.3 ^{° C} (FIG. 3).

As already mentioned, the melting process of the known crystalline modifications of dicaine, having a melting point of about 148 ^about C (147-150 ^about C), is a sequence of two endothermic effects (Fig. 1, 2).

Melting process dikaina β-form in contrast to the known modifications characterized by a melting endothermic effect at 148.6 ± 0.3 ^{° C} (FIG. 3).

 Thermal analysis was carried out on a TA-3000 thermal analyzer from Mettler (Switzerland) in a nitrogen atmosphere. Presented in FIG. 3 thermoanalytical data indicate that the obtained substance is a new crystalline modification of dicain (β-form).

 For the subsequent identification of the obtained substance, a complex of chemical, physicochemical and pharmacopoeial methods of analysis was used.

, Те - стандарт, камера FR-552.To confirm that the product obtained is a new crystalline modification of dicain, an X-ray phase analysis was performed in a Guinier chamber with the registration of diffraction maxima on the X-ray film under λCu - K radiation

Those are the standard, FR-552 camera.

 The experimentally obtained diffraction reflections were induced using the INDEX program of the STADT powder program package on a PDP computer.

 The values of interplanar distances d and relative intensities of reflexes I of the obtained substance and the initial pharmacopoeial dicain are given in table. 3.

 Comparison of the data presented in table. 1, 2 and 3, shows that the substance is a new crystalline modification of dicaine.

 Qualitative and quantitative analysis confirms that the obtained substance is hydrochloride of 2-dimethylaminoethyl ester of n-butylaminobenzoic acid (dicain) with a purity of 99.8%, which coincides with the purity of pharmacopoeial dicain.

These data are confirmed by high resolution ¹³ C NMR spectroscopy and gas chromatography.

The high-resolution ¹³ C NMR spectral parameters were measured on a VXR-400 NMR spectrometer with a VARIAN superconducting magnet (USA) with an observation frequency for carbon nuclei of 131.00 MHz. Measurement of ¹³ C - 1 _H NMR chemical shifts of the samples of the starting dicain and the obtained substance was carried out for their saturated solutions in DMSO-D ₆ deuterodimethyl sulfoxide with an accuracy of 0.01 ppm. The values of ¹³ C NMR chemical shifts were measured relative to the solvent signal and were converted to the TMS scale (TMS - Si (CH ₃ ) ₄ σ _TMS = = _DMSO σ - 39.56 ppm. The values of chemical shifts are presented in Table 5. Analysis ¹³ C NMR spectra of the compared samples of the starting pharmacopeia dicain and a new modification of dicain showed that no impurities were observed in the spectra at the signal-to-noise ratio = 100.

 The data presented allow us to conclude that the new substance according to the invention has a chemical formula identical to dicaine.

The retention time was measured on a high-performance capillary column with a non-polar liquid phase DB-1 (analogue SE-30) on a VARIAN-3700 gas chromatograph (USA). Column length 30 m, carrier gas (helium) velocity 40 cm / min. Measurements were performed at temperatures of 220, 230, 240 ^C. The results are shown in Table. 4 show the identity of retention times of the starting pharmacopeia dicain and the resulting crystalline modification. The data presented allow us to conclude that the crystalline modification of dicain according to the invention has the chemical formula of dicain.

To compare the spectral characteristics of the known crystalline modification of pharmacopoeial dicain and the obtained new form, their IR and Raman spectra were measured. IR spectroscopic analysis was carried out on an Karl Zeiss-Jena M-80 IR spectrophotometer in the frequency range 400-4000 cm ^-1 in KBr.

The characteristic IR frequencies are given in table. 6. As follows from the table. 6, the main difference between the IR spectrum of the new crystalline modification (β-form) and pharmacopoeial dicain is the absence of band splitting at 1284, 1172 and 1124 cm ^-1 .

Raman spectra were measured on a Raman spectrometer DFS-52M NPO Lomo in the frequency range 10-2000 cm ^-1 . Raman characteristic frequencies are given in table. 7.

The Raman spectra of the new modification are significantly different from the Raman spectra of pharmacopeia dicain. From the table. 7 it can be seen that the pharmacopoeial starting dicain has a highly structured spectrum in the region of 150-10 cm ^-1 , consisting of 8 bands with maxima at 122, 100, 87, 77, 62, 51, 37, and 23 cm ^-1 . The obtained new crystalline modification of dicain (β-form) in this region is characterized only by weakly pronounced bands at 84, 58 and 39 cm ^-1 .

 Thus, the above data indicate that the obtained substance is a new crystalline modification of dicain.

 Study of the biological activity of a new crystalline modification of the hydrochloride of 2-dimethylaminoethyl ester of n-butylaminobenzoic acid (β-form) of dicaine.

 To study the local anesthetic activity of the obtained new modification (β-form) of dicain and compare it with the activity of the known crystalline modification of dicain (pharmacopeia dicain), we used the standard method of touching the cornea of an animal’s eye (Rainier method) [7].

 A standard 1% solution of the starting (pharmacopoeial) dicain, widely used in eye microsurgery, and a 0.3% solution of a new crystalline modification of dicain (β-form) were compared.

 The choice of the concentration of the solution of the new crystalline modification (β-form) is due to the fact that, as shown by preliminary experiments, a local anesthetic effect comparable to the pharmacopeia manifests itself when using a solution with a concentration of 0.3%.

 All test solutions were prepared by dissolving the powder in physiological saline under the same conditions.

 0.06 ml of pharmacopeia dicain and β-form (new modification) dicain were instilled into the rabbit's eye in equal amounts.

 1.5 hours after exiting the anesthesia, the rabbits were killed, the eyes were extirpated and given for electron microscopy and for normal histological studies.

 The experimental values of the time of onset and the duration of the anesthetic effect of the compared solutions are presented in table. 8 (95% reliability).

 When a 1% solution of the known crystalline modification of dicain (pharmacopoeial dicain) is instilled into the rabbit’s eye, the surface of the eye becomes wavy and dull.

 Histological and electron microscopic studies show stromal damage and ulceration of the cornea.

 When exposed to a rabbit eye with a solution of the β-form of dicain, no changes in the surface of the eye were observed, the visually examined eye did not differ from the intact one.

 Thus, the data presented indicate that the new crystalline modification of dicain (β-form) exhibits increased local anesthetic activity and reduced side effects. These properties will significantly reduce the dosage of the drug while increasing its therapeutic effectiveness.

According to the invention, a new crystalline modification of n-butylamino-benzoic acid 2-dimethylaminoethyl ester hydrochloride (β-form of dicaine) is obtained by cooling the pharmacopeia dicaine solution with a refrigerant at a rate of at least 8 ^° C / min until the solution crystallizes.

In any substance capable of reducing the temperature of coolant at a rate not lower than 8 ° ^C / min can be used as the refrigerant. The most optimal substance serving as a refrigerant is liquid nitrogen, the use of which allows to increase the yield of the target product due to the rapid establishment and further maintenance of the required cooling rate.

Selecting a cooling rate of feed solution Pharmacopeial dikaina refrigerant due to the fact that the goal (the preparation of a new crystal modification) is achieved at a cooling rate no lower than 8 ^{° C} per minute. Carrying out the crystallization process at a cooling rate of less than 8 ° ^C / min did not allow to obtain a new crystalline modification dikaina (β -form).

 The upper limit of the cooling rate is not limited. At any maximum achievable cooling rate of the dicaine solution, a new crystalline modification (β-form) is formed.

 A new substance according to the invention can be obtained by cooling a solution of pharmacopoeial dicain in water or in any organic solvent in which dicain is soluble. At the same time, the best solvents in which dicain is soluble are water and ethanol. When cooling an aqueous or alcoholic solution of pharmacopoeial dicain, the highest yield of the target product is achieved. A new substance according to the invention can also be obtained from a solution of pharmacopeia dicain in a homogeneous mixture of water and an organic solvent. In this case, the β-form is obtained regardless of the ratio of these solvents in solution.

 A new substance according to the invention is obtained by the proposed method, regardless of the concentration of pharmacopoeial dicain in the initial solution.

The choice of the drying mode at a pressure of no higher than 10 ^-2 mm Hg due to the fact that the finished dried product must have a moisture content of not higher than 3% [4,5].

Drying at a pressure above 10 ^-2 mm Hg leads to a crude spreading unstable mass.

 To illustrate the invention, specific examples of obtaining a new crystalline modification (β-form) of dicaine are provided.

 In FIG. 1-3 are the curves of differential scanning calorimetry: dicain (tetracaine) - standard in a nitrogen atmosphere (Fig. 1); pharmacopoeial dicain, in a nitrogen atmosphere (Fig. 2), a new crystalline modification of dicain in a nitrogen atmosphere (Fig. 3).

PRI me R 1. 500 ml of a 10% aqueous solution of pharmacopoeial dicain is cooled with liquid nitrogen at a rate of 8 ^about C / min until the solute crystallizes. The resulting frozen mass is transferred to pallets and loaded into a sublimator. Drying is carried out at a pressure of 10 ^-2 mm RT.article to a residual moisture content of 3%.

The resulting material was characterized by the values of interplanar distances d and relative reflexes 1, coinciding with the corresponding values of the new crystal modification dikaina (Table. 3) has a melting point of 148.6 ± 0.3 ^{° C} with a single endothermic effect (Fig. 3). In all respects, the obtained substance according to the invention corresponds to a new crystalline modification of dicain (β-form).

 The yield of 95.7%.

 PRI me R 2. The process is carried out analogously to example 1, changing the concentration of dicaine to 50%.

Obtained according to the invention, a crystalline modification of dicain with so pl. 148.6 ± 0.3 ^about With one endothermic effect (β-form), similar to example 1.

 Yield 96.2%.

PRI me R 3. The process is carried out analogously to example 1 with a cooling rate of 300 ^about C / min

The crystalline modification (β-form) of dicain obtained according to the invention, so pl. 148.6 ± 0.3 ^about With one endothermic effect, similar to example 1.

 Yield 97.5%.

PRI me R 4. The process is carried out analogously to example 1, changing the drying parameters of the target product. Drying was carried out in a sublimator at a pressure of 10 ^-5 mm Hg.

 The crystalline modification (β-form) of dicaine obtained in accordance with the invention is similar to Example 1.

 Yield 96.8%.

 PRI me R 5. The process is carried out analogously to example 1, using methanol as a solvent. The concentration of dicain in the solution is 3% - the maximum achievable concentration in methanol.

 The crystalline modification (β-form) of dicaine obtained in accordance with the invention is similar to Example 1.

 Yield 91.5%.

 PRI me R 6. The process is carried out analogously to example 1, using isopropanol as a solvent. The concentration of dicain in the solution is 3% - the maximum attainable concentration in isopropanol.

 The crystalline modification (β-form) of dicaine obtained in accordance with the invention is similar to Example 1.

 Yield 94.2%.

 PRI me R 7. The process is carried out analogously to example 1, using acetone as a solvent. The concentration of dicain in the solution is 3% - the maximum attainable concentration in acetone.

 The crystalline modification (β-form) of dicaine obtained in accordance with the invention is similar to Example 1.

 Yield 95%.

 PRI me R 8. The process is carried out analogously to example 1, using dimethylformamide as a solvent. The concentration of dicain in the solution is 3% - the maximum attainable concentration in dimethylformamide.

 The crystalline modification (β-form) of dicaine obtained in accordance with the invention is similar to Example 1.

 The yield of 93.7%.

PRI me R 9. 500 ml of a 10% solution of dicaine in ethanol is cooled with liquid nitrogen at a rate of 8 ^about C / min until the solution crystallizes. The resulting frozen mass is transferred to pallets and loaded into a sublimator. Drying is carried out at a pressure of 10 ^-2 mm RT.article

The obtained substance in all respects corresponds to the substance of example 1 - β-form of dicaine with so pl. 148.6 ± 0.3 ^о С with one endothermic effect.

 Yield 95.6%.

 PRI me R 10. The process is carried out analogously to example 5, changing the concentration of dicaine to 50%. Received crystalline modification (β-form) of dicaine, similar to example 1.

 Yield 97.0%.

PRI me R 11. The process is carried out analogously to example 5 with a cooling rate of 300 ^about C / min The crystalline modification (β-form) of dicaine obtained in accordance with the invention is similar to Example 1.

 Yield 98.2%.

 PRI me R 12. The process is carried out analogously to example 5, changing the drying parameters of the target product.

Drying is carried out in a sublimator at a pressure of 10 ^-5 mm Hg.

 Received crystalline modification (β-form) of dicaine, similar to example 1.

 Yield 96.3%.

PRI me R 13. 500 ml of a 10% solution of dicaine in a mixture of water-ethanol (1: 1) is cooled with liquid nitrogen at a rate of 8 ^about C / min until the solution crystallizes. The resulting frozen mass is loaded into a sublimator and drying is carried out at a pressure of 10 ^-2 mm Hg.

 The obtained substance according to the invention is a crystalline modification (β-form) of dicaine, similar to example 1.

 Yield 96.0%.

 PRI me R 14. The process is carried out analogously to example 9, changing the ratio of water to ethanol in solution (1: 9).

 The obtained substance according to the invention is a crystalline modification (β-form) of dicaine, similar to example 1.

 Yield 96.5%.

 The test results presented in the text of the test obtained crystalline modification (β-form) of hydrochloride of 2-dimethylaminoethyl ester of n-butylaminobenzoic acid (dicain) prove the possibility of using this substance as a local anesthetic. Moreover, the obtained substance, in contrast to the known crystalline modification, pharmacopoeial dicain, has an increased local anesthetic activity with reduced side effects, which can be widely used in various fields of medicine.

Claims (5)

 CRYSTALLINE MODIFICATION OF 2-DIMETHYLAMINOETHYL ETHER HYDROCHLORIDE OF P-BUTYLAMINOBENZOIC ACID AND METHOD FOR PRODUCING IT. 1. The crystal modification of 2-dimethylaminoethyl p-butilaminobenzoynoy acid, characterized by a melting endothermic effect at (148,6 ± 0,3) ^o C and the following interplanar distances d and relative intensity _{of the} reflexes I _Sc:
I _{about t n} -

3 - 26,140
100 - 12,755
27 - 8.538
6 - 6,380
2 - 6.117
6 - 5,644
12 - 5,491
56 - 5,096
17 - 4.874
10 - 4,486
15 - 4,244
7 - 4.418
1 - 4.137
5 - 4,001
3 - 3,949
5 - 3,828
3 - 3,585
7 - 3,515
3 - 3,427
3 - 3,341
3 - 3,310
3 - 3,170
4 - 3,156
4 - 3,149
1 - 3.064
2 - 2,979
1 - 2,944
1 - 2,903
4 - 2,824
2 - 2,798
1 - 2,762
2 - 2,744
2 - 2,678
1 - 2,631
1 - 2,570
1 - 2,534
1 - 2,514
1 - 2,454
1 - 2,419
1 - 2,346
1 - 2,308
1 - 2,256
1 - 2,232
1 - 2,166
1 - 2,008
2 - 1,953
1 - 1,691
1 - 1,584
with menthol anesthetic activity. 2. A process for preparing crystal modification of 2-dimethylaminoethyl p-butilaminobenzoynoy acid, characterized by a melting endothermic effect at (148,6 ± 0,3) ^o C and the following interplanar distances d and relative intensity _{of the} reflexes I _Sc:
I _{about t n} -

3 - 26,140
100 - 12,755
27 - 8.538
6 - 6,380
I _{about t n} -

2 - 6.117
6 - 5,644
4 - 2,824
2 - 2,798
1 - 2,762
2 - 2,744
2 - 2,678
1 - 2,631
I _{o t n} -

12 - 5,491
56 - 5,096
17 - 4.874
10 - 4,486
15 - 4,244
7 - 4.418
1 - 4.137
5 - 4,001
3 - 3,949
5 - 3,828
3 - 3,585
7 - 3,515
3 - 3,427
3 - 3,341
3 - 3,310
3 - 3,170
4 - 3,156
4 - 3,149
1 - 3.064
2 - 2,979
1 - 2,944
1 - 2,903
I _{o t n} -

1 - 2,570
1 - 2,534
1 - 2,514
1 - 2,454
1 - 2,419
1 - 2,346
1 - 2,308
1 - 2,256
1 - 2,232
1 - 2,166
1 - 2,008
2 - 1,953
1 - 1,691
1 - 1,584
characterized in that the solution of dicain in water, or in an organic solvent, or in a mixture thereof, is cooled with a refrigerant at a rate of at least 8 degrees. / min until the solution crystallizes completely.  3. The method according to claim 2, characterized in that liquid nitrogen is used as the refrigerant.  4. The method according to PP.2 and 3, characterized in that the resulting product is dried to a residual moisture content of not more than 3%.

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