CN102311443B

CN102311443B - Novel crystal form of irinotecan hydrochloride and preparation method thereof

Info

Publication number: CN102311443B
Application number: CN201110247797.1A
Authority: CN
Inventors: 秦东光; 张五军; 孙婧; 康立涛; 李倩; 黄凤群
Original assignee: SHANGHAI BIOCOMPOUNDS CHEMLAB CO Ltd
Current assignee: SHANGHAI BIOCOMPOUNDS CHEMLAB CO Ltd
Priority date: 2011-08-24
Filing date: 2011-08-24
Publication date: 2014-07-16
Anticipated expiration: 2031-08-24
Also published as: CN102311443A

Abstract

The invention relates to a novel crystal form of irinotecan hydrochloride. An X-ray powder diffraction of the crystal form shows characteristic peaks at a 2 theta of 11.14 DEG, 11.30 DEG, 14.14 DEG, 16.70 DEG, 16.90 DEG, 17.18 DEG, 20.40 DEG, 21.30 DEG, 22.20 DEG, 22.70 DEG, 22.94 DEG and 28.54 DEG. The invention also discloses a preparation method of the crystallized powder; the method is simply operated and at low costs, and can effectively guarantee complete salt forming and water feeding of a product. The product obtained from the method has high purity (HPLC>=99.5%) and good storage stability.

Description

New crystal of U 101440E and preparation method thereof

Technical field

The present invention relates to a kind of new crystal of U 101440E and preparation method thereof.

Background technology

U 101440E is developed by Japan the earliest, within 1987, start clinical trial, extensive clinical experiment shows, it is the active drug for the treatment of transitivity colorectal carcinoma, within 1994, head goes on the market in Japan, nineteen ninety-five is obtained listing in France, and existing this medicine has obtained the common approval of U.S. FDA and European Union, more than 100 country's listings in the whole world.Its chemical structural formula is as follows:

U 101440E is mainly cancer therapy drug, can be used for treating colorectal carcinoma, gastrointestinal cancer, the cancer of the brain, osteocarcinoma, epithelial cancer, rodent cancer, gland cancer, esophagus cancer, small intestine love, liver cancer, bladder cancer, ovarian cancer, cervical cancer, mammary cancer, cutaneous gland cancer, prostate cancer, renal cell carcinoma, minicell and nonsmall-cell lung cancer and other malignant tumour etc.

At present, existing many documents are studied the crystal formation of U 101440E, and for example US7435818B2 has described 4 kinds of crystal formations, and data sheet is as follows:

Table 1

US Patent No. 2010179180A1 provides two kinds of H crystal formations, and data sheet is as follows:

Table 2

US Patent No. 206234904 has been described a kind of C type polymorphic, and data sheet is as follows:

Table 3

The crystal formation data that Chinese patent CN101318964A describes are as follows:

Table 4

Document [Chem.Pharm.Bul11991,1446] also discloses a kind of Type B crystal formation, and data are as follows:

Table 5

These crystal formations of above document description are all finally gone up water (planar water) or directly from organic phase, crystallized out by absorption, all could not ensure abundant salify and the upper crystal water of product.

Planar water be mechanically adsorbed in product or between product particle with neutral water molecule (H ₂o) water that form exists, it does not participate in forming lattice, and content is unfixing yet.In the time that temperature reaches certain temperature, planar water is just all overflowed.In the time that moisture is overflowed, the destruction that does not cause product lattice.Crystal water be solute from solution when crystallization, in crystal in conjunction with the water molecules of certain number.Crystal water is in crystalline material, with the water molecules that chemical bonding force combines with lewis' acid, quantity is certain.

Summary of the invention

The object of the invention is to overcome above the deficiencies in the prior art, new crystal of a kind of U 101440E and preparation method thereof is provided.

For achieving the above object, the present invention adopts following technical scheme:

A kind of U 101440E crystallization, it is characterized in that, the powder x-ray diffraction of this crystallization is 11.14 °, 11.30 °, 14.14 °, 16.70 °, 16.90 °, 17.18 °, 20.40 °, 21.30 °, 22.20 °, 22.70 °, 22.94 ° and 28.54 ° at 2 θ and has characteristic peak.

The corresponding intensity in above-mentioned crystalline powder X ray diffracting characteristic peak is as shown in table 6:

Table 6

2θ(°)	Relative Intensity(％)
		11.14	100
11.3	97
		22.2	80
21.3	62
		22.7	47
22.94	43
		16.9	41
14.14	39
		28.54	38
17.18	31
		20.4	31
16.7	30

Further, the DSC figure of above-mentioned crystalline powder is between 52-100 DEG C, between 189-252 DEG C and have endotherm(ic)peak (as shown in Figure 2) between 252-280 DEG C.

Further, in above-mentioned crystalline powder, water content is 7.0-9.0wt% (being measured by Ka Shi moisture determination instrument).

Further, purity >=99.5% of above-mentioned crystalline powder.

Above-mentioned crystalline powder is measured (as shown in Figure 3) by DSC/TG: DSC figure is presented between 52-100 DEG C a large endotherm(ic)peak, corresponding to the process that loses crystal water; Between 189-252 DEG C, there is a little endotherm(ic)peak to turn brilliant process corresponding to melting; Between 252-280 DEG C, there is a large endotherm(ic)peak, the process of decomposing corresponding to product.It is 7.48% that TG is presented at 81 DEG C of former weightlessness, complete agravity after 252 DEG C.This and Ka Shi moisture determination instrument are measured moisture content and are met at 7.0-9.0%.Therefore, think that this product should be DQ-2805.

The present invention also further discloses the preparation method of above-mentioned U 101440E crystallization, comprises the steps:

1) CPT-11 is added to the water to dissolving, is heated to 45-55 DEG C, filtered while hot;

2) by the mother liquid obtained room temperature that is cooled to after filtration, add dichloromethane extraction; Extraction gained water is concentrated into its volume and step 1) in the CPT-11 weight ratio that adds be 4.8-5.2ml/g, stirring and crystallizing, filters, the U 101440E crystallization described in obtaining.

Preferably, described CPT-11 is unbodied CPT-11.

Preferably, step 2) in, consumption and the step 1 of described methylene dichloride) in the CPT-11 weight ratio that adds be (3～4): 1ml/g.

Preferably, step 2) in, temperature when described water is concentrated is 43-47 DEG C.

Preferably, step 2) in, the time of described stirring and crystallizing is 23-25h.

Above-mentioned preparation method provided by the present invention is simple to operate, and cost is low, can effectively ensure the abundant salify of product and upper crystal water.The product purity high (HPLC >=99.5%) obtaining by this method, stability in storage is good.

brief description of the drawings

Fig. 1 is the HPLC figure of the prepared U 101440E of the present invention;

Fig. 2 is the X-ray powder diagram of the prepared U 101440E of the present invention;

Fig. 3 is the DSC/TG figure of the prepared U 101440E of the present invention.

embodiment

Reaction scheme of the present invention is as follows:

Embodiment 1:

15g CPT-11 (amorphous) adds in 150ml water, be heated to 50 DEG C molten clear, filtered while hot.Mother liquor is cooled to room temperature, adds 50ml dichloromethane extraction once, discard organic phase, water is concentrated into 5 times of water gagings (be concentrated solution be 5ml/1g with the envelope-bulk to weight ratio of the CPT-11 adding) in 45 DEG C, and stirring and crystallizing is spent the night.Filter, gained solid, in 35-45 DEG C of vacuum-drying 3h, obtains beige solid 12g.

Analyzing and testing: it is 99.70% that gained solid phase prod detects its purity through HPLC.It is 7.8% that Ka Shi moisture determination instrument is measured moisture content.Measure (as shown in Figure 3) by DSC/TG: DSC figure is presented between 52-100 DEG C a large endotherm(ic)peak, corresponding to the process that loses crystal water; Between 189-252 DEG C, there is a little endotherm(ic)peak to turn brilliant process corresponding to melting; Between 252-280 DEG C, there is a large endotherm(ic)peak, the process of decomposing corresponding to product.It is 7.48% that TG is presented at 81 DEG C of former weightlessness, complete agravity after 252 DEG C.

The powder x-ray diffraction (as shown in Figure 2) of this crystallization, (2 θ) 11.14 °, 11.30 °, 14.14 °, 16.70 °, 16.90 °, 17.18 °, 20.40 °, 21.30 °, 22.20 °, 22.70 °, 22.94 ° and 28.54 ° have characteristic peak.

Embodiment 2:

25g CPT-11 (amorphous) adds in 250ml water, be heated to 50 DEG C molten clear, filtered while hot.Mother liquor is cooled to room temperature, add 85ml dichloromethane extraction once, discard organic phase, it (is that concentrated solution is 5 with the envelope-bulk to weight ratio of the CPT-11 adding: 1ml/g) that water is concentrated into 5 times of water gagings in 45 DEG C, stirring and crystallizing is spent the night, filter, 35-45 DEG C of vacuum-drying of gained solid, obtains beige solid 20g.

Analyzing and testing: it is 99.71% that gained solid phase prod detects its purity through HPLC.It is 8.0% that Ka Shi moisture determination instrument is measured moisture content.

Embodiment 3:

50g CPT-11 (amorphous) adds in 500ml water, be heated to 50 DEG C molten clear, filtered while hot.Mother liquor is cooled to room temperature, add 200ml dichloromethane extraction once, discard organic phase, it (is that concentrated solution is 5 with the envelope-bulk to weight ratio of the CPT-11 adding: 1ml/g) that water is concentrated into 5 times of water gagings in 45 DEG C, stirring and crystallizing is spent the night, filter, 35-45 DEG C of vacuum-drying of gained solid, obtains beige solid 40g.

Analyzing and testing: it is 99.69% that gained solid phase prod detects its purity through HPLC.It is 7.9% that Ka Shi moisture determination instrument is measured moisture content.

Claims

1. a preparation method for U 101440E crystallization, comprises the steps:

2) by the mother liquid obtained room temperature that is cooled to after filtration, add dichloromethane extraction; It is 4.8-5.2ml/g that extraction gained water is concentrated into the CPT-11 weight ratio adding in its volume and step 1), and stirring and crystallizing, filters, and obtains described U 101440E crystallization, as shown in Figure of description 2;

In step 1), described CPT-11 is unbodied CPT-11;

Step 2) in, the CPT-11 weight ratio adding in the consumption of described methylene dichloride and step 1) is 3～4ml:1g;

Step 2) in, temperature when described water is concentrated is 43-47 DEG C;

Step 2) in, the time of described stirring and crystallizing is 23-25h;

Making U 101440E crystalline powder X-ray diffraction is 11.14 °, 11.30 °, 14.14 °, 16.70 °, 16.90 °, 17.18 °, 20.40 °, 21.30 °, 22.20 °, 22.70 °, 22.94 ° and 28.54 ° at 2 θ and has characteristic peak.

2. the preparation method of U 101440E crystallization as claimed in claim 1, is characterized in that, the DSC figure of described crystalline powder is between 52-100 DEG C, between 189-252 DEG C and have endotherm(ic)peak between 252-280 DEG C.

3. the preparation method of U 101440E crystallization as claimed in claim 1, is characterized in that, in described crystalline powder, water content is 7.0-9.0wt%.

4. the preparation method of U 101440E crystallization as claimed in claim 1, is characterized in that, purity >=99.5% of described crystalline powder.