RU2340347C2 - Method of obtaining of sterilised microcrystallic salt of cis-dichloroamminizopropylaminplatinum (ii) - Google Patents

Abstract

FIELD: medicine; pharmacology.

SUBSTANCE: microcrystallic salt of cis-dichloramminizopropylaminplatinum (II) of not less than 99.5% (mole per cent) cleanliness according to the basic component expose to heat treatment at temperature of 120°C within 4 hours.

EFFECT: method is simple and accessible to realisation in laboratory scale and allows obtaining the pure medicinal form of the compound, ready for application in injections.

2 ex, 3 tbl

Description

The invention relates to a method for producing a pure dosage form of a sterilized microcrystalline salt of cis-dichloroammisinopropylamineplatinum (II), ready for use in chemotherapy of malignant diseases.

Several methods have been described for the preparation of sterilized microcrystalline cis-dichlorodiammineplatinum (II) [1, 2]. Method [1] is based on the dissolution of the salt of cis-dichlorodiammineplatinum (II) in dimethylformamide, followed by the addition of hydrochloric acid and the isolation of microcrystalline cis- [Pt (NH ₃ ) ₂ Cl ₂ ]. The resulting product is subjected to high vacuum drying for 24 hours at temperatures up to 42 ° C.

Closest to the claimed is a method of obtaining a sterilized microcrystalline cis-dichlorodiammineplatinum (II) [2].

4 g of the microcrystalline salt of cis-dichlorodiammineplatinum (II) obtained by the method of [3, 4] were subjected to heat treatment in a drying cabinet at a temperature of 160 ° for 6 hours. This method [2] allows to obtain a sterilized microcrystalline cis-dichlorodiammineplatinum (II), used in medicine as an antitumor drug of the first generation, using a higher temperature and longer heating time.

The aim of the invention is to obtain a sterilized microcrystalline salt of cis-dichloroammisinopropylamineplatinum (II) in the form of a third generation dosage form in the treatment of malignant diseases.

The goal is achieved by using a high-purity substance in the main component, lowering the sterilization temperature to 120 ° C and time up to 4 hours. Thus, the time and temperature of sterilization are reduced.

The essence of the claimed invention is as follows: the microcrystalline salt of cis-dichloroamminisopropylamineplatinum (II) is subjected to heat treatment at a temperature of 120 ° C for 4 hours.

The basis of the proposed method for the production of sterilized microcrystalline cis-dichloroammisinopropylamineplatinum (II) is based on the following new results. Under normal conditions and when heated to 200 ° C, the stability of the antitumor substance was studied. The conditions for the preparation and purification of salts of cis-dichloroammisinopropylamineplatinum (II) of various degrees of purity were studied [3-5]. The temperature range of stability of this substance up to 120 ° C is established. The conditions for its storage are found depending on the purity.

The proposed method for the preparation of a sterilized microcrystalline cis-dichloroammisinopropylamineplatinum (II) preparation, ready for use, is simple and available for laboratory use. It is applicable only for a high-purity substance, not less than 99.5 mol.% Salt of cis-dichloroammisinopropylamine platinum (II). Methods for producing microcrystalline cis-dichloroammisinopropylamineplatinum (II) [3-5] satisfy these requirements. Samples of preparations obtained by other methods [6, 7] are not thermally stable due to the content of impurities of other complex platinum (II) compounds in them. The results of the study are shown in examples 1 and 2 and in tables 1-3.

Example 1. 7 g of microcrystalline cis-dichloroammisinopropylamineplatinum (II) obtained by the methods [3-5], was subjected to heat treatment in an oven at a temperature of 120 ° C for 4 hours. The obtained sample 1 after heat treatment is a yellow microcrystalline substance, the weight of the substance remains unchanged. A comparative analysis of the initial cis-dichloroammisinopropylamineplatinum (II) and sample 1 by various physicochemical methods (elemental analysis, XRD, PC spectroscopy, and UV spectrophotometry) shows that the substance did not change during heat treatment. The data are shown in tables 1-3.

Example 2. 7 g of microcrystalline cis-dichloroammisinopropylamineplatinum (II) obtained by the methods of [6-8], was subjected to heat treatment at a temperature of 120 ° C for 4 hours. The resulting sample 2 is a green microcrystalline substance, the weight of the substance has not changed. Comparative studies by the above physicochemical methods indicate that in sample 2 there is an admixture of a substance related to cis-dichlorodiisopropylamineplatinum (II) and other unidentified impurities. That is, at a higher temperature, the sterilization process is accompanied by a change in the phase and component compositions of cis-dichloroammisinopropylamineplatinum (II) obtained by the methods of [6-8]. Comparative data shown in tables 1-3, confirm this fact.

X-ray diffraction data for the initial cis-dichloroammisinopropylamine platinum (II), cis-dichlorodiisopropylamine platinum (II) and the obtained samples
Table 1 Cis- [Pt (iC ₃ H ₇ NH _{2) 2} Cl ₂ Cis- [Pt (iC ₃ H ₇ NH ₂ ) NH ₃ Cl ₂ ] [3-5] Cis- [Pt (iC ₃ H ₇ NH ₂ ) NH ₃ Cl ₂ ] [7, 8] Sample 1 Sample 2 d, Å J / J ₀ , 100% d, Å J / J ₀ , 100% d, Å J / J ₀ , 100% d, Å J / J _0, 100% d, Å J / J ₀ , 100% 8.33 one hundred 8.67 one hundred 8.85 one hundred 8.67 one hundred 8.62 one hundred 5.35 thirty 6.86 28 8.22 thirty 6.86 28 8.34 88 5.0 13 6.42 fifteen 6.94 eleven 6.42 fifteen 7.03 26 4.52 10 6.07 eighteen 6.43 5 6.07 eighteen 6.85 twenty 4.34 3 5.01 four 6.05 8 5.01 four 6.40 19 4.17 12 4.44 6 5.03 5 4.44 6 6.32 twenty 4.12 twenty 4.38 19 4.22 16 4.38 19 6.05 26 3.87 13 4.30 fifteen 4.10 6 4.30 fifteen 5.01 7 3.69 5 4.09 fifteen 3.67 eleven 4.09 fifteen 4.51 5 3.29 7 3.92 9 3.52 four 3.92 9 4.37 31 3.0 2 3.78 10 2.85 21 3.79 10 4.18 10 2.87 2 3.66 28 2.77 9 3.66 28 4.09 16 2.78 6 3.52 fifteen 2.68 5 3.52 fifteen 3.92 fifteen

Assignment of absorption frequencies cm ^-1 in the IR spectra for the initial cis-dichloroamminisopropylamineplatinum (II), cis-dichlorodiisopropylamineplatinum (II) and the resulting samples

Table 2. Cis- [Pt (iC ₃ H ₇ NH ₂ ) ₂ Cl ₂ ] Cis- [Pt (iC ₃ H ₇ NH ₂₎ NH ₃ Cl _2], [3-5] Cis- [Pt (iC ₃ H ₇ NH ₂₎ NH ₃ Cl _2], [7, 8] Sample 1 Sample 2 Attribution 3248 3284 3290 3285 3290 3211 3260 3270 3260 3270 ν (NH) 3212 3220 3212 3248 2975 2972 2970 2972 2973 2929 2927 2930 2927 2928 ν (CH) 2875 2875 2890 2875 2875 1640 1660 1639 1639 δ _as (NH ₃ ) 1592 1570 1580 1570 1570 δ _as (NH ₂ ) 1572 1550 1560 1550 1549 1304 1310 1304 1310 δ (NH ₃ ) 1462 1460 1470 1460 1465 δ _as (CH ₃ ) 1388 1390 1390 1390 1389 δ _s (CH ₃ ) 1160 1161 1160 1161 1161 ν (C-C) 830 830 830 830 ρ (NH ₃ ) 817 815 817 817 802 805 802 802 762 738 740 738 756 ρ (NH ₂ ) 440 442 435 442 441 γ (Pt-N)

The molar absorption coefficient ε (mol ^-1 l cm ^-1 ) of the starting cis-dichloroamminisopropylamineplatinum (II), cis-dichlorodiisopropylamineplatinum (II) and the resulting samples

Table 3. ν · 10 ^-3 cm ^-1 Cis- [Pt (iC ₃ H ₇ NH _{2) 2} Cl _2] Cis- [Pt (iC ₃ H ₇ NH ₂ ) NH ₃ Cl ₂ ] [3-5] Sample 1 Sample 2 ε ε ε ε 41 142.1 86.2 86.2 88.3 40 112.4 74.6 74.6 76.0 39 120.5 87.5 87.5 88.8 38 150.2 114.6 114.6 106,2 37 180.3 139.3 139.3 141.1 36 191.4 152.0 152.0 153.7 35 183.2 151.8 151.8 153.2 34 160,0 147.3 147.3 147.8 33 153.4 148.1 148.1 147.3 32 135.5 124.9 124.9 125.4 31 97.3 80,4 80,4 80.6 thirty 67.2 52.1 52.1 52.8

Thus, the use of the proposed method allows to obtain a pure dosage form of a sterilized microcrystalline cis-dichloroammisinopropylamineplatinum (II), ready for use for injection, using a simple procedure of heating to 120 ° C for 4 hours.

Information sources

1. US patent No. 4302446, 1981.

2. Kazbanov V.I., Starkov A.K., Kozhukhovskaya G.A., Neklyudova V.V. Method for the production of sterilized microcrystalline cis-dichlorodiammineplatinum (II). RF patent No. 2292210, dated 01.29.2007.

3. Kazbanov V.I., Kozhukhovskaya G.A., Starkov A.K. The method of obtaining cis-dichloroamminisopropylamineplatinum (II). RF patent No. 2086559 from 08/10/1997.

4. Kazbanov V.I., Starkov A.K., Kozhukhovskaya G.A. The method of purification of cis-dichloroamminisopropylamineplatinum (II). RF patent №2186068 from 07.27.2002.

5. S. D. Kirik, A. K. Starkov, G. A. Kozhuhovskaya. Cis-Amminedichloroisopropylamineplatinum (II) by X-ray powder diffraction analysis // Acta Cristallographica C62, No. 6, P.249-251, 2006.

6. UK patent No. 2060615, CL C01G 55/00, 1981.

7. Zheligovskaya NN, Fatkin A.YU. Investigation of the physicochemical properties of asymmetric cis-diamindichlorocomplexes of platinum (II). Coord. Chemistry, T.12, Issue 8, S.1127-1131, 1986.

8. Zheligovskaya NN, Dyakova GB, Fatkin A.YU., Bokareva S.S. Synthesis and physicochemical studies of cis-diamindichlorocomplexes of platinum (II) with various amines. Coord. Chemistry, T.17., Issue 10, S.1412-1415, 1991.

Claims (1)

A method of obtaining a sterilized microcrystalline salt of cis-dichloroammisinopropylamineplatinum (II) is that the microcrystalline salt of cis-dichloroammisinopropylamineplatinum (II) is subjected to heat treatment at a temperature of 120 ° C for at least 99.5 mol% of the main component for 4 hours.