CN101993439B

CN101993439B - Lamivudine crystal form and preparation method thereof

Info

Publication number: CN101993439B
Application number: CN 201010254731
Authority: CN
Inventors: 陈国华; 康惠燕
Original assignee: Fujian Cosunter Pharmaceutical Co Ltd
Current assignee: Fujian Cosunter Pharmaceutical Co Ltd
Priority date: 2009-03-24
Filing date: 2009-03-24
Publication date: 2013-04-24
Anticipated expiration: 2029-03-24
Also published as: CN101993439A

Abstract

The invention relates to lamivudine crystal form and a preparation method thereof. Under the Cu-Ka radiation, the characteristic peaks of the lamivudine crystal form IV of the invention appear on the crystal X-ray powder diffraction pattern at the following reflection angle 2 theta: 9.7+/-0.2, 10.02+/-0.2, 11.24+/-0.2, 11.52+/-0.2, 12.80+/-0.2 and 13.10+/-0.2.

Description

Lamivudine crystal form and preparation method thereof

1, technical field

The invention belongs to medical technical field, be specifically related to lamivudine new crystal and preparation method thereof.

2, background technology

Lamivudine is known compound, and English name Lamivudine claims again 3-TC.The chemical nature of lamivudine is nucleoside analog, and nucleoside analog is structurally simulated the structure of Nucleotide, but does not have the function of Nucleotide.Therefore in the DNA building-up process, nucleoside analog can mix into, but can not synthesize the nucleic acid chains that normal function is arranged, thereby makes the termination that copies of virus.Its mechanism of action is for suppressing viral DNA polymerase and reverse transcriptase activity, and to the synthetic of viral DNA chain with prolong competitive restraining effect.

In recent years, lamivudine was extensively accepted by doctors and patients as a kind of new nucleoside analog, was best, the most representative nucleoside analog of curative effect in the present clinical application.

At present, the existing document that lamivudine is carried out study on the synthesis.Applied for that in China denomination of invention is such as Chinese patent nineteen ninety Canada Bio-chemical pharmacy Corp: the patent of " replacement 1 of antiviral property being arranged, the preparation method of 3-oxygen thia alkane ", this patent were authorized in 1996, and notification number is 1033640C.Canadian Bio-chemical pharmacy Corp had applied in China that denomination of invention was in 1991: the patent of " 1; preparation method of 3-Oxathiolane Nucleoside Analogues "; the method for splitting of the claimed cis lamivudine of this patent, this patent was authorized in 1997, and notification number is 1036196C.Canadian Bio-chemical pharmacy Corp had applied in China that denomination of invention was: the patent of " method of diastereoselective synthesis nucleosides " in 1992, this patent was authorized in 1998, notification number is 1038591C, Canadian Bio-chemical pharmacy Corp had applied in China that denomination of invention was in 1994: the patent of " synthesizing with three-dimensional selection of the nucleoside analog of bicyclic intermediate ", publication number is 1110479A.Nineteen ninety-five, Glan element company applied for that in China denomination of invention is: the patent of " the non-mapping of nucleoside analog is selected synthetic ", publication number is 1149871.

But above-mentioned document does not illustrate the crystal habit of lamivudine.

The raw produce; raw products of existing lamivudine, poor stability, the preparation difficulty of moulding is made in difficult quality control.

The present invention finds unexpectedly, lamivudine is prepared into certain new crystallized form can makes it stable, for this reason, the invention provides the new crystal of two kinds of lamivudines.

3, summary of the invention

The inventor has carried out the experimental study of a large amount of systems to the crystal formation of lamivudine, obtained the new crystal formation of two kinds of lamivudines, i.e. III type crystal formation and IV type crystal formation.

The present invention also provides the preparation method of two kinds of crystal formations of lamivudine.

Lamivudine III crystal formation of the present invention uses the Cu-Ka radiation, and the X-ray powder diffraction that represents with 2 θ angles has characteristic peak 9.5 ± 0.2,10.3 ± 0.2,11.14 ± 0.2,13.08 ± 0.2.

Its infrared analysis data are as follows:

IR(KBr)cm ^-1：3417，3359，3232，2925，1644，1613，1493，1403，1356，1289，1197，1108，1053，786

Its fusing point is as follows:

DSC (10 ℃ of heat-up rates/min): a little endothermic melting peak occurs at 121.9 ℃, a sharp-pointed endothermic melting peak occurs again at 176.3 ℃.

Concrete X-ray powder diffraction data are as follows:

Powder X-ray-diffraction: Cu-Ka radiation, the 2 θ angles of this product, spacing (d value) and I/I ₀As follows:

Table 1

2θ	d	I/I ₀	2θ	d	I/I ₀	2θ	d	I/I ₀
									9.500	9.3020	21	19.200	4.6189	76	24.860	3.5786	27
10.300	8.5812	33	19.600	4.5255	41	25.220	3.5283	52
									11.140	7.9360	66	19.900	4.4579	43	25.660	3.4628	48
13.080	6.7630	35	20.180	4.3967	21	26.480	3.3632	35
									15.540	5.6975	43	20.840	4.2589	39	27.200	3.2758	34
16.380	5.4071	21	21.700	4.0920	59	28.100	3.1729	23
									17.440	5.0808	31	22.500	3.9483	26	29.320	3.0436	40
17.860	4.9623	41	22.860	3.8870	21	30.620	2.9173	28
									18.600	4.7665	28	23.360	3.8049	100	30.880	2.8933	27
18.940	4.6817	53	24.220	3.6717	27	33.240	2.6931	26

Process for purification: the 0.5g lamivudine adds 4.5ml methyl alcohol, 10ml acetone, heating for dissolving, cooling crystallization, suction filtration, the dry 0.35g white powder crystal that gets.

Lamivudine IV crystal formation of the present invention uses the Cu-Ka radiation, and the X-ray powder diffraction that represents with 2 θ angles has characteristic peak 9.7 ± 0.2,10.02 ± 0.2,11.24 ± 0.2,11.52 ± 0.2,12.80 ± 0.2,13.10 ± 0.2.

Its infrared analysis data are as follows:

IR(KBr)cm ^-1：3340、3235、3075、2927、1647、1613、1493、1404、1357、1289、1198、1108、1053、786

Its fusing point is as follows:

DSC (10 ℃ of heat-up rates/min): a little endothermic melting peak occurs at 119.5 ℃, a sharp-pointed endothermic melting peak occurs again at 176.5 ℃.

Concrete X-ray powder diffraction data are as follows:

Powder X-ray-diffraction: Cu-Ka radiation, the 2 θ angles of this product, spacing (a value) and I/I ₀As follows:

Table 2

2θ	d	I/I ₀	2θ	d	I/I ₀	2θ	d	I/I ₀
									9.700	9.1106	18	18.600	4.7665	55	24.500	3.6304	27
10.020	8.8204	20	19.520	4.5439	100	24.800	3.5871	32
									11.240	7.8656	38	20.380	4.3540	74	25.280	3.5201	42
11.520	7.6750	28	21.140	4.1992	48	25.940	3.4320	36
									12.800	6.9103	19	21.560	4.1183	31	26.320	3.3833	22
13.100	6.7527	23	22.000	4.0369	26	27.220	3.2734	29
									15.060	5.8780	38	22.260	3.9904	29	27.540	3.2361	24
15.680	5.6469	35	22.760	3.9038	24	29.240	3.0517	25
									17.580	5.0407	30	23.240	3.8243	38	31.180	2.8661	24
18.020	4.9186	27	23.580	3.7699	69	31.780	2.8134	21

Process for purification: the 0.6g lamivudine adds 2ml water, 6ml acetone, heating for dissolving, cooling crystallization, suction filtration, the dry 0.4g white powder crystal that gets.

The inventor is studied the chemical stability of two kinds of crystal formations of lamivudine, the investigation condition is high temperature (60 ℃), high humidity (92.5%), strong illumination (4500Lx), investigating index is content and relative substance for investigating index, and contrasts with the listing lamivudine.After placing under various conditions 10 days, two kinds of crystal formation chemical stabilities of lamivudine of the present invention significantly are better than the lamivudine that goes on the market;

Table 3 study on the stability

Table 4 study on the stability

Two kinds of crystal formations of the discovery that the inventor is surprised lamivudine of the present invention have good stability, and drug quality is significant for improving.In addition, lamivudine crystal form of the present invention also has the advantages such as degree of crystallinity is high, size-grade distribution is concentrated, good product mobility, any surface finish.

4, description of drawings

Fig. 1 is the infrared spectrogram of lamivudine III crystal formation;

Fig. 2 is the DSC differential thermal analysis curve of lamivudine III crystal formation;

Fig. 3 is the X-ray powder diffraction spectrogram of lamivudine III crystal formation;

Fig. 4 is the infrared spectrogram of lamivudine IV crystal formation;

The DSC differential thermal analysis curve of Fig. 5 lamivudine IV crystal formation;

Fig. 6 is the X-ray powder diffraction spectrogram of lamivudine IV crystal formation.

5, embodiment

Further describe by the following examples the present invention in detail.But not as limitation of the present invention.

The preparation of embodiment 1 lamivudine III crystal formation

The preparation method: the 0.5g lamivudine adds 4.5ml methyl alcohol, 10ml acetone, heating for dissolving, cooling crystallization, suction filtration, the dry 0.35g white powder crystal that gets.

The preparation of embodiment 2 lamivudine III crystal formations

Get the 1g lamivudine, add 8mL methyl alcohol and 20mL acetone, stir, 60 ℃ of heating 1h filter, and filtrate is left standstill, and is cooled to room temperature, again at 0 ℃ of crystallization 12h, and suction filtration, 50 ℃ of dry 2h get 0.73g white powder crystal.

The preparation of embodiment 3 lamivudine IV crystal formations

The preparation method: the 0.6g lamivudine adds 2ml water, 6ml acetone, heating for dissolving, cooling crystallization, suction filtration, the dry 0.4g white powder crystal that gets.

The preparation of embodiment 4 lamivudine IV crystal formations

Get the 1.2g lamivudine, add 4mL water and 12mL acetone, stir, 55 ℃ of heating 1h filter, and filtrate is left standstill, and is cooled to room temperature, again at 0 ℃ of crystallization 10h, and suction filtration, 50 ℃ of dry 2h get 0.9g white powder crystal.

Claims

1. lamivudine crystal form is characterized in that, is lamivudine IV crystal formation,

Its infrared analysis data are as follows:

IR KBrcm ^-1：3340、3235、3075、2927、1647、1613、1493、1404、1357、1289、1198、1108、1053、786

Its fusing point is as follows:

DSC, 10 ℃/min of heat-up rate: a little endothermic melting peak occurs at 119.5 ℃, occur again sharply at 176.5 ℃

Endothermic melting peak,

Concrete X-ray powder diffraction data are as follows:

Powder X-ray-diffraction: Cu-Ka radiation, 2 θ angles, spacing a value and the I/I of this product ₀As follows:

2θ d I/I ₀ 2θ d I/I ₀ 2θ d I/I ₀ 9.700 9.1106 18 18.600 4.7665 55 24.500 3.6304 27 10.020 8.8204 20 19.520 4.5439 100 24.800 3.5871 32 11.240 7.8656 38 20.380 4.3540 74 25.280 3.5201 42 11.520 7.6750 28 21.140 4.1992 48 25.940 3.4320 36 12.800 6.9103 19 21.560 4.1183 31 26.320 3.3833 22 13.100 6.7527 23 22.000 4.0369 26 27.220 3.2734 29 15.060 5.8780 38 22.260 3.9904 29 27.540 3.2361 24 15.680 5.6469 35 22.760 3.9038 24 29.240 3.0517 25 17.580 5.0407 30 23.240 3.8243 38 31.180 2.8661 24 18.020 4.9186 27 23.580 3.7699 69 31.780 2.8134 21。

2. the preparation method of lamivudine crystal form as claimed in claim 1 is characterized in that, preparation process is as follows: lamivudine adds entry and acetone, heating for dissolving, cooling crystallization, suction filtration, the dry white powder crystal that gets.

3. preparation method as claimed in claim 2 is characterized in that, step is as follows: the 0.6g lamivudine adds 2ml water, 6ml acetone, heating for dissolving, cooling crystallization, suction filtration, the dry 0.4g white powder crystal that gets.

4. the pharmaceutical composition that contains the lamivudine crystal form of claim 1.