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

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

 

The invention relates to method of obtaining pure dosage forms sterilized microcrystalline salt of CIS-dichlorobenzophenone (II), ready to use in chemotherapy of malignant diseases.

There are several ways to get sterilized microcrystalline CIS-dichlorodiammineplatinum (II) [1, 2]. Method [1] based on the dissolution of the salt of CIS-dichlorodiammineplatinum (II) in dimethylformamide followed by the addition of hydrochloric acid and the allocation of microcrystalline CIS-[Pt(NH3)2Cl2]. The resulting product is subjected to high-vacuum drying for 24 hours at a temperature of up to 42°C.

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

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

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

This goal is achieved using high-purity substance to the main component by lowering the temperature sterilization up to 120°and With time up to 4 hours. Thus, reducing the time and temperature of sterilization.

The essence of the invention consists in the following: microcrystalline salt of CIS-dichlorobenzophenone (II) is subjected to heat treatment at a temperature of 120°C for 4 hours.

The basis of the proposed method to obtain sterilized microcrystalline CIS-dichlorobenzophenone (II) based on these new results. Under normal conditions, and when heated to 200°studied the stability of the antitumor substance. Studied the conditions for obtaining and purifying salt of CIS-dichlorobenzophenone (II) different degrees of purity [3-5]. Set temperature range of stability of the substance to 120°C. the conditions of its storage depending on purity.

The proposed method for the preparation of sterilized microcrystalline CIS-dichlorobenzophenone (II), ready-to-use, simple and affordable to implement in laboratory scale. It is applicable only for high-purity substances, not less of 99.5 mol.% salt of CIS-dichlorobenzophenone (II). Methods of obtaining microcrystallite the coy CIS-dichlorobenzophenone (II) [3-5] satisfy these requirements. Samples obtained by other methods [6, 7], thermally little resistant because of the content of impurities other complex compounds of platinum (II). The results of the study described in examples 1 and 2 and in tables 1-3.

Example 1. 7 g of microcrystalline CIS-dichlorobenzophenone (II)obtained according to the methods [3-5], was subjected to heat treatment in a drying Cabinet at a temperature of 120°C for 4 hours. The obtained sample 1 after the heat treatment is a microcrystalline yellow substance, the weight of the substance remains unchanged. A comparative analysis of the original CIS-dichlorobenzophenone (II) and sample 1 different physico-chemical methods (elemental analysis, XRD, PC-spectroscopy and UV spectrophotometry) shows that the substance by heat treatment has not changed. The data are presented in tables 1-3.

Example 2. 7 g of microcrystalline CIS-dichlorobenzophenone (II)obtained according to the methods [6-8], was subjected to heat treatment at a temperature of 120°C for 4 hours. The obtained sample 2 is a microcrystalline substance green color, the weight of the substance has not changed. A comparative study of the above physico-chemical methods indicates that sample 2 has an impurity substances is a, related to CIS-dichlorodiammineplatinum (II), and other unidentified impurities. That is at a higher temperature sterilization process is accompanied by a change in the phase and component of the compositions of CIS-dichlorobenzophenone (II)obtained according to the methods [6-8]. Comparative data are presented in tables 1-3, confirm this fact.

100
X-ray data for the initial CIS-dichlorobenzophenone (II), CIS-dichlorodiammineplatinum (II) and obtained samples

Table 1
CIS-[Pt(iC3H7NH2)2Cl2CIS-[Pt(iC3H7NH2)NH3Cl2] [3-5]CIS-[Pt(iC3H7NH2)NH3Cl2] [7, 8]Sample 1Sample 2
d ÅJ/J0, 100%d ÅJ/J0, 100%d ÅJ/J0, 100%d ÅJ/J0, 100%d ÅJ/J0, 100%
8.331008.671008.851008.67100At 8.62
5.35306.86288.22306.86288.3488
5.0136.42156.94116.42157.0326
4.52106.07186.4356.07186.8520
4.3435.0146.0585.0146.4019
4.17124.4465.0354.4466.3220
4.12204.38194.22164.38196.0526
3.87134.30154.1064.30155.017
3.6954.09153.67114.09154.515
3.2973.9293.5243.9294.3731
3.023.78102.85213.79104.1810
2.8723.66282.7793.66284.0916
2.7863.52152.6853.52153.9215

The assignment of the absorption frequencies cm-1in the IR spectra for the original CIS-dichlorobenzophenone (II), CIS-dichlorodiammineplatinum (II) and obtained samples

Table 2.
CIS-[Pt(iC3H7NH2)2Cl2]CIS-[Pt(iC3H7NH2)NH3Cl2] [3-5]CIS-[Pt(iC3H7NH2)NH3Cl2] [7, 8]Sample 1Sample 2Assignment
32483284329032853290
32113260327032603270ν(NH)
3212322032123248
29752972297029722973
29292927293029272928ν(CH)
28752875289028752875
1640166016391639δas(NH3)
15921570158015701570δas(NH2)
15721550156015501549
1304131013041310δ(NH3)
14621460147014601465δas(CH3)
13881390139013901389δs(CH3)
116011611160 11611161ν(C-C)
830830830830ρ(NH3)
817815817817
802805802802
762738740738756ρ(NH2)
440442435442441γ(Pt-N)

The molar absorption coefficient ε mol-1l cm-1) the original CIS-dichlorobenzophenone (II), CIS-dichlorodiammineplatinum (II) and obtained samples

Table 3.
ν·10-3cm-1CIS-[Pt(iC3H7NH2)2Cl2]CIS-[Pt(iC3H7NH2)NH3Cl2] [3-5]Sample 1Sample 2
εεεε
41142,186,286,288,3
40 to 112.474,674,676,0
39of 120.587,587,5and 88.8
38150,2114,6114,6106,2
37180,3139,3139,3141,1
36191,4to 152.0to 152.0153,7
35183,2to 151.8to 151.8153,2
34160,0147,3147,3147,8
33153,4148,1148,1147,3
32135,5124,9124,9125,4
3197,380,480,480,6
3067,252,152,152,8

Thus, using the proposed method allows to obtain a pure pharmaceutical form sterilized microcrystalline CIS-dichlorobenzophenone (II), ready to use for injection, using a simple procedure that has been heated to 120°C for 4 hours.

Sources of information

1. U.S. patent No. 4302446, 1981.

2. Kabanov VI,Starkov, A., Kozhukhovskaya GA, Neklyudov VV Method of getting sterilized microcrystalline CIS-dichlorodiammineplatinum (II). RF patent №2292210, from 29.01.2007.

3. Kabanov VI, Kozhukhovskaya GA, Starkov A.K. Way to obtain CIS-dichlorobenzophenone (II). RF patent №2086559 from 10.08.1997.

4. Kabanov VI, Starkov, A., Kozhukhovskaya G.A. Method of purification of CIS-dichlorobenzophenone (II). RF patent №2186068 from 27.07.2002.

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. Patent of great Britain No. 2060615, CL 01G 55/00, 1981.

7. Jelihovsky N.N., Fatkin A. Study of physico-chemical properties of the asymmetric CIS-diaminedichloroplatinum platinum (II). Coord. chemistry, Vol.12, Issue 8, S-1131, 1986.

8. Jelihovsky N.N., Dyakova G.B., Patkin, A., Bokarev S. Synthesis and physicochemical studies of CIS-diaminedichloroplatinum platinum (II) with various amines. Coord. chemistry, V.17., VIP, S-1415, 1991.

The method of obtaining sterilized microcrystalline salt of CIS-dichlorobenzophenone (II) is that microcrystalline salt of CIS-dichlorobenzophenone (II) not less than 99,5 mol.% purity to the main component is subjected to heat treatment at a temperature of 120°C for 4 hours



 

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