CN103664781B - Crystal form I and form II of drataverine hydrochloride and preparation method thereof - Google Patents

Abstract

The invention discloses a crystal form I of drotaverine hydrochloride. The X-ray powder diffraction spectrum of the crystal form I represented by the diffraction angle of 2θ±0.2° is at 5.422°, 6.699°, 8.108°, 10.067°, 10.698°, There are characteristic peaks at 12.093°, 13.232°, 14.513°, 16.133°, 22.183°, 24.225° and 24.766°. The present invention also discloses another crystal form II of drataverine hydrochloride. The X-ray powder diffraction spectrum of the crystal form II represented by 2θ±0.2° diffraction angle is at 3.955°, 4.22°, 6.364°, 7.784°, 8.307° , 9.646°, 11.628°, 13.012°, 13.233°, 16.171°, 17.379°, 20.76° and 23.262° showed characteristic peaks. The invention also discloses the preparation methods of the above two crystal forms. The crystal form I and the crystal form II disclosed by the present invention have strong stability, and the preparation method has simple steps and strong practicability.

Description

Crystal form I and form II of drataverine hydrochloride and preparation method thereof

technical field

The invention relates to the technical field of preparation of drotaverine hydrochloride, in particular to crystal forms I and II of drotaverine hydrochloride and a preparation method.

Background technique

Papaverine (Papaverine) is an alkaloid isolated from opium. It has non-selective smooth muscle relaxation, weak central analgesic effect and local anesthetic effect. It is used to treat smooth muscle spasm in various situations, mainly including gastrointestinal spasm , biliary colic, ureteral colic, bronchospasm, angina and other disorders.

Drotaverine is a derivative of papaverine. Its antispasmodic effect is stronger than that of papaverine and lasts longer, and it is non-addictive. It also has the effects of dilating coronary arteries and relaxing smooth muscles. Drotaverine hydrochloride has obvious antispasmodic, analgesic and symptom relieving effects on abdominal pain caused by peptic ulcer, biliary colic, acute pancreatitis, stomach cramps, irritable bowel syndrome, appendicitis, and urinary calculi. It only acts on smooth muscle without affecting the autonomic nervous system, without atropine-like adverse reactions, and can be applied to patients with glaucoma and prostatic hypertrophy.

Drotaverine hydrochloride was developed by Chinoin Chemical Pharmaceutical Company in Hungary. Its structure is shown in the following formula:

In the 1960s, drotaverine hydrochloride was used clinically in foreign countries, and it was promoted in my country in the 1990s. At present, the drug is widely used in Hungary, Russia, China and other countries approved for marketing.

The crystal forms of drataverine hydrochloride reported in the literature are mainly obtained from ethanol. In Example 10 of the patent document US4126615A, drotaverine hydrochloride is crystallized into a salt in absolute ethanol. In the literature (ActaPharmaceuticaHungarica69/1999/24-29), drotaverine hydrochloride was crystallized in 96% ethanol and benzene respectively to obtain a single crystal containing 1/2 ethanol molecule and 1/2 benzene molecule. We found that the product obtained by crystallization in ethanol, the crystalline ethanol in the molecule is easy to exchange with the water molecule in the air, which is not conducive to stable storage.

Contents of the invention

The object of the present invention is to provide two new crystal forms of drataverine hydrochloride: crystal form I and crystal form II. Compared with the compounds produced in the prior art, this crystal form is directly obtained by using water as a recrystallization solvent, so it is stable sex is better. At the same time, the present invention also provides a preparation method for the above two new crystal forms. The method has simple process, uses water as a recrystallization solvent, and has low cost and strong practicability.

In order to solve the above-mentioned first technical problem, the technical solution adopted in the present invention is:

A crystal form I of drotaverine hydrochloride, the X-ray powder diffraction spectrum of the crystal form I represented by 2θ±0.2° diffraction angle is at 5.422°, 6.699°, 8.108°, 10.067°, 10.698°, 12.093°, 13.232° °, 14.513°, 16.133°, 22.183°, 24.225° and 24.766° showed characteristic peaks.

Preferably, the X-ray powder diffraction spectrum of the crystal form I represented by 2θ±0.2° diffraction angle is at 5.422°, 6.699°, 8.108°, 10.067°, 10.698°, 12.093°, 13.232°, 14.513°, 16.133° °, 18.319°, 18.918°, 19.260°, 22.183°, 24.225°, 24.766°, 25.808°, 26.207° and 29.030° showed characteristic peaks.

As a preference, the characteristic peaks and diffraction intensities (I/I ₀ ) in the X-ray powder diffraction spectrum of the crystal form I expressed at 2θ±0.2° diffraction angle are as follows:

As a preference, the X-ray powder diffraction spectrum of the crystal form I is shown in FIG. 1 .

Preferably, the crystallization water removal temperature of the crystal form I is 119.55°C, and the melting point is 205.2°C. The DSC spectrum of the crystal form I is shown in FIG. 2 .

A drotaverine hydrochloride crystalline form II, the X-ray powder diffraction spectrum of the crystalline form II represented by 2θ±0.2° diffraction angle is at 3.955°, 4.220°, 6.364°, 7.784°, 8.307°, 9.646°, 11.628 °, 13.012°, 13.233°, 16.171°, 17.379°, 20.760° and 23.262° showed characteristic peaks.

Preferably, the X-ray powder diffraction spectrum of the crystal form II represented by 2θ±0.2° diffraction angle is at 3.955°, 4.220°, 6.364°, 7.784°, 8.307°, 9.646°, 9.949°, 11.628°, 12.488° °, 13.012°, 13.233°, 15.714°, 16.171°, 17.379°, 20.760°, 23.262°, 23.623°, 23.903° showed characteristic peaks.

As a preference, the characteristic peaks and diffraction intensities (I/I ₀ ) in the X-ray powder diffraction spectrum of the crystal form II expressed at 2θ±0.2° diffraction angle are as follows:

As a preference, the X-ray powder diffraction spectrum of the crystal form II is shown in FIG. 3 .

As a preference, the dehydration temperature of crystal form II is 101.22°C, and the melting point is 205.73°C. The DSC spectrum of the crystal form II is shown in FIG. 4 .

Tests have shown that two different crystal forms are obtained under different preparation conditions using water as a solvent. The specific methods for preparing the above-mentioned crystal form I and crystal form II are respectively:

A preparation method for preparing the above-mentioned drotaverine hydrochloride crystal form I, comprising: mixing drotaverine hydrochloride with water to form a slurry, the volume to mass ratio of water to drotaverine hydrochloride is 6-8 mL/g, heating When the temperature reaches 65-70°C, the whole system turns into a light yellow slurry; keep warm for 5-40 minutes, lower the temperature to below 35°C, and dry the precipitated crystals under reduced pressure at 45-65°C to obtain Form I.

A method for preparing drotaverine hydrochloride crystal form II, comprising: adding drotaverine hydrochloride to water to form a slurry, the volume-to-mass ratio of water to drotaverine hydrochloride is about 6-8 mL/g, and the temperature is raised to 75-80°C, the system is completely dissolved; the temperature is lowered to below 35°C, and the precipitated crystals are dried below 40°C to obtain the crystal form II.

The drotaverine hydrochloride crystalline form I and crystalline form II prepared by the present invention, like common drotaverine hydrochloride, can be used for the treatment of smooth muscle spasm in various situations, mainly including gastrointestinal spasm, biliary colic, ureteral colic pain, bronchospasm, angina, and other disorders. Moreover, the drotaverine hydrochloride crystalline form I and crystalline form II prepared by the present invention have better purity and stability.

The drataverine hydrochloride crystalline form I and crystalline form II of the present invention are directly prepared by using water as a recrystallization solvent, have good stability, and are beneficial for later use and storage, and the preparation methods of the above two crystalline forms are simple, Suitable for industrial production.

Description of drawings

Fig. 1 is the X-ray powder diffraction spectrum of the drotaverine hydrochloride crystal form I prepared in Example 1.

Figure 2 is the DSC chart of the drotaverine hydrochloride crystal form I prepared in Example 1.

Fig. 3 is the X-ray powder diffraction spectrum of the drotaverine hydrochloride crystal form II prepared in Example 2.

Figure 4 is the DSC chart of the drotaverine hydrochloride crystal form II prepared in Example 2.

5 is an X-ray powder diffraction spectrum of the drotaverine hydrochloride crystal form prepared in Comparative Example 1.

Detailed ways

X-ray diffraction pattern detection method:

(1) Testing instrument: German Bruker D8AdvanceX diffractometer

(2) Measurement conditions: target: copper

Pipe pressure/pipe flow: 40kV/40mA

Scanning angle: 3°～40°

Scan step: 0.02°

Scanning speed: 0.2 seconds/step

DCS (Differential Scanning Calorimetry) Analysis:

(1) Testing instrument: Swiss Mettler-Toledo DSC1 differential scanning calorimeter

(2) Heating program: 30～190℃, 10℃/mIn; 190～220℃, 2℃/mIn.

Example 1:

Preparation of drataverine hydrochloride crystal form I

Put 150mL of purified water, 22.5g of drotaverine hydrochloride, and 4.5mL of concentrated hydrochloric acid into a 250mL three-necked flask, and raise the temperature to 70°C. Most of the system will dissolve, and the undissolved part will turn pale yellow. After stirring for 30 minutes, remove the hot water bath, cool down to 30°C naturally, and filter with suction. The wet product was baked under reduced pressure in an oven at 50°C for 24 hours to obtain Form I with a yield of 86.4% and a water content of 4.0%. The HPLC purity is above 99.5%.

The H-NMR data of product are as follows:

1H-NMR (500MHz, DMSO-d6, TMS) δ13.89 (s, 1H), δ7.59 (s, 1H), δ7.22 (d, J=1.5, 1H), δ7.10 (s, 1H ), δ6.92 (dd, J=8.3, 1.7, 1H), δ6.87 (d, J=8.3, 1H), δ4.53 (s, 2H), δ4.14～4.18 (q, J=6.9 , 2H), δ4.06～4.10 (q, J=6.9, 2H), δ3.98～4.02 (q, J=6.9, 2H), δ3.93～3.97 (q, J=6.8, 2H), δ3 .82 (t, J=7.9, 2H), δ2.97 (t, J=7.9, 2H), δ1.26～1.35 (m, 12H).

The crystal form I prepared in this embodiment is subjected to powder X-ray diffraction measurement and DSC (differential scanning calorimetry) analysis. The results of X-ray diffraction pattern detection and DCS (differential scanning calorimetry) analysis are shown in Figure 1 and Figure 2:

The main characteristic peaks in Figure 1 (X powder ray diffraction spectrum) are shown in Table 1 below.

Table 1

In Figure 2 (DSC spectrum), the crystallization water removal temperature of the sample is 119.55°C, and the melting point is 205.2°C (decomposition).

Example 2:

Preparation of drataverine hydrochloride crystal form II

Preparation of crystal form II of drotaverine hydrochloride: 150 mL of purified water, 22.5 g of drotaverine hydrochloride, and 4.5 mL of concentrated hydrochloric acid were put into a 250 mL three-necked flask, and the temperature was raised to 80°C. After the system was dissolved, cool it in a tap water bath, lower the temperature to 31°C, filter with suction, and dry the wet product in a 40°C oven under reduced pressure for 24 hours to obtain Form II, with a yield of 88.1% and a moisture content of 5.6%. HPLC purity is more than 99.5%, and nuclear magnetic detection data is with embodiment 1.

The sample prepared according to this embodiment is subjected to X-ray powder diffraction detection (the detection instrument and scanning conditions are the same as in Example 1), the detection results are shown in Figure 3, and the main characteristic peak parameters in Figure 3 are shown in Table 2 below:

Table 2

The sample was subjected to DSC analysis (detection instrument and heating program were the same as in Example 1), and the test results were shown in Figure 4. From Figure 4, it can be seen that the crystal water removal temperature of the sample was 101.22°C, and the melting point was 205.73°C (decomposition).

Comparative example 1:

According to the method in Example 10 of the document US4126615A, ethanol was used as the recrystallization solvent, and the obtained crystal detection data were as follows: moisture: 0.2%, residual ethanol: 4.9%, and yield: 88.2%. HPLC purity was 99.0%. The NMR data of product are with embodiment 1. The powder X-ray diffraction measurement was carried out according to the same test method as in Example 1. The measurement results are shown in Figure 5. The main characteristic peaks are shown in Table 3:

table 3

As shown in Table 3 and Figure 5, the powder X-ray diffraction characteristic peaks prepared from the existing literature are different from those of drotaverine hydrochloride crystalline form I and crystalline form II prepared in the present invention. And the stability experiment shows that the crystal form I and the crystal form II obtained by the present invention are more stable than the comparison crystal form, and the water content is basically unchanged. After standing for 48 hours, the residual ethanol in the comparison crystal form decreased from 4.9% to about 1%, and the water content increased to 3.8%.

Claims (10)

1. a drotaverine hydrochloride crystal formation I, it is characterized in that, the X-ray powder diffraction spectrogram that this crystal formation I represents with 2 θ ± 0.2 ° diffraction angle locates indicating characteristic peak 5.422 °, 6.699 °, 8.108 °, 10.067 °, 10.698 °, 12.093 °, 13.232 °, 14.513 °, 16.133 °, 22.183 °, 24.225 ° and 24.766 °.

2. drotaverine hydrochloride crystal formation I according to claim 1, it is characterized in that, the X-ray powder diffraction spectrogram that described crystal formation I represents with 2 θ ± 0.2 ° diffraction angle locates indicating characteristic peak 5.422 °, 6.699 °, 8.108 °, 10.067 °, 10.698 °, 12.093 °, 13.232 °, 14.513 °, 16.133 °, 18.319 °, 18.918 °, 19.260 °, 22.183 °, 24.225 °, 24.766 °, 25.808 °, 26.207 ° and 29.03 °.

3. drotaverine hydrochloride crystal formation I according to claim 1, is characterized in that, in the X-ray powder diffraction spectrogram of described crystal formation I as shown in Figure 1.

4. drotaverine hydrochloride crystal formation I according to claim 1, is characterized in that, it is 119.55 DEG C that described crystal formation I crystal water sloughs temperature, and fusing point is 205.2 DEG C.

5. prepare the preparation method of the drotaverine hydrochloride crystal formation I described in the arbitrary claim of Claims 1 to 4 for one kind, it is characterized in that, comprise: drotaverine hydrochloride and water are mixed to form slurry, water is 6 ~ 8mL/g with the volume mass ratio of drotaverine hydrochloride, be warming up to 65 ~ 70 DEG C, system all changes faint yellow slurries into; Insulation 5 ~ 40min, be cooled to less than 35 DEG C, the crystal of precipitation is dried at 45 ~ 65 DEG C, obtains crystal formation I.

6. a drotaverine hydrochloride crystal form II, it is characterized in that, the X-ray powder diffraction spectrogram that this crystal form II represents with 2 θ ± 0.2 ° diffraction angle locates indicating characteristic peak 3.955 °, 4.220 °, 6.364 °, 7.784 °, 8.307 °, 9.646 °, 11.628 °, 13.012 °, 13.233 °, 16.171 °, 17.379 °, 20.760 ° and 23.262 °.

7. drotaverine hydrochloride crystal form II according to claim 6, it is characterized in that, the X-ray powder diffraction spectrogram that described crystal form II represents with 2 θ ± 0.2 ° diffraction angle locates indicating characteristic peak at 3.955 °, 4.22 °, 6.364 °, 7.784 °, 8.307 °, 9.646 °, 9.949 °, 11.628 °, 12.488 °, 13.012 °, 13.233 °, 15.714 °, 16.171 °, 17.379 °, 20.760 °, 23.262 °, 23.623 °, 23.903 °.

8. drotaverine hydrochloride crystal form II according to claim 6, is characterized in that, the X-ray powder diffraction spectrogram of described crystal form II as shown in Figure 3.

9. drotaverine hydrochloride crystal form II according to claim 6, is characterized in that, it is 101.22 DEG C that described crystal form II crystal water sloughs temperature, and fusing point is 205.73 DEG C.

10. prepare the method for the drotaverine hydrochloride crystal form II described in the arbitrary claim of claim 6 ~ 9 for one kind, it is characterized in that, comprise: be added to the water drotaverine hydrochloride formation slurry, water is 6 ~ 8mL/g with the volume mass ratio of drotaverine hydrochloride, be warming up to 75 ~ 80 DEG C, system is whole clearly molten; Be cooled to less than 35 DEG C, the crystal of precipitation is dried below 40 DEG C, obtains crystal form II.