CN103664781A - Drotaverine hydrochloride crystal form I and crystal form II and preparation method - Google Patents
Drotaverine hydrochloride crystal form I and crystal form II and preparation method Download PDFInfo
- Publication number
- CN103664781A CN103664781A CN201310681825.XA CN201310681825A CN103664781A CN 103664781 A CN103664781 A CN 103664781A CN 201310681825 A CN201310681825 A CN 201310681825A CN 103664781 A CN103664781 A CN 103664781A
- Authority
- CN
- China
- Prior art keywords
- crystal form
- drotaverine hydrochloride
- degrees
- crystal
- crystal formation
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 239000013078 crystal Substances 0.000 title claims abstract description 97
- OMFNSKIUKYOYRG-MOSHPQCFSA-N drotaverine Chemical compound C1=C(OCC)C(OCC)=CC=C1\C=C/1C2=CC(OCC)=C(OCC)C=C2CCN\1 OMFNSKIUKYOYRG-MOSHPQCFSA-N 0.000 title claims abstract description 51
- 238000002360 preparation method Methods 0.000 title claims abstract description 11
- 238000000634 powder X-ray diffraction Methods 0.000 claims abstract description 23
- 238000000034 method Methods 0.000 claims abstract description 9
- 230000015572 biosynthetic process Effects 0.000 claims description 42
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 22
- 239000002002 slurry Substances 0.000 claims description 6
- 238000010792 warming Methods 0.000 claims description 6
- 238000009413 insulation Methods 0.000 claims description 2
- 238000005755 formation reaction Methods 0.000 description 31
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 13
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- 229960004756 ethanol Drugs 0.000 description 6
- XQYZDYMELSJDRZ-UHFFFAOYSA-N papaverine Chemical compound C1=C(OC)C(OC)=CC=C1CC1=NC=CC2=CC(OC)=C(OC)C=C12 XQYZDYMELSJDRZ-UHFFFAOYSA-N 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 208000007101 Muscle Cramp Diseases 0.000 description 4
- 208000005392 Spasm Diseases 0.000 description 4
- 238000002425 crystallisation Methods 0.000 description 4
- 230000008025 crystallization Effects 0.000 description 4
- 238000001953 recrystallisation Methods 0.000 description 4
- 206010004663 Biliary colic Diseases 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- 229930008281 A03AD01 - Papaverine Natural products 0.000 description 2
- 206010002383 Angina Pectoris Diseases 0.000 description 2
- 208000009079 Bronchial Spasm Diseases 0.000 description 2
- 208000014181 Bronchial disease Diseases 0.000 description 2
- 206010006482 Bronchospasm Diseases 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- 206010038419 Renal colic Diseases 0.000 description 2
- 125000003158 alcohol group Chemical group 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 208000035475 disorder Diseases 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 210000001035 gastrointestinal tract Anatomy 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 210000003205 muscle Anatomy 0.000 description 2
- 229960001789 papaverine Drugs 0.000 description 2
- 239000008213 purified water Substances 0.000 description 2
- 210000002460 smooth muscle Anatomy 0.000 description 2
- 238000000967 suction filtration Methods 0.000 description 2
- 206010000087 Abdominal pain upper Diseases 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 102100021202 Desmocollin-1 Human genes 0.000 description 1
- 206010052804 Drug tolerance Diseases 0.000 description 1
- 208000010412 Glaucoma Diseases 0.000 description 1
- 101000968043 Homo sapiens Desmocollin-1 Proteins 0.000 description 1
- 101000880960 Homo sapiens Desmocollin-3 Proteins 0.000 description 1
- 239000008896 Opium Substances 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- 206010033645 Pancreatitis Diseases 0.000 description 1
- 206010033647 Pancreatitis acute Diseases 0.000 description 1
- 240000001090 Papaver somniferum Species 0.000 description 1
- 206010051482 Prostatomegaly Diseases 0.000 description 1
- 208000025865 Ulcer Diseases 0.000 description 1
- 201000003229 acute pancreatitis Diseases 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- 150000003797 alkaloid derivatives Chemical class 0.000 description 1
- 230000003444 anaesthetic effect Effects 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 210000003403 autonomic nervous system Anatomy 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 210000004351 coronary vessel Anatomy 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 229960000935 dehydrated alcohol Drugs 0.000 description 1
- 229960002065 drotaverine Drugs 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000026781 habituation Effects 0.000 description 1
- 208000002551 irritable bowel syndrome Diseases 0.000 description 1
- 230000005311 nuclear magnetism Effects 0.000 description 1
- 229960001027 opium Drugs 0.000 description 1
- 235000006502 papoula Nutrition 0.000 description 1
- DDBREPKUVSBGFI-UHFFFAOYSA-N phenobarbital Chemical compound C=1C=CC=CC=1C1(CC)C(=O)NC(=O)NC1=O DDBREPKUVSBGFI-UHFFFAOYSA-N 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 230000004648 relaxation of smooth muscle Effects 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 230000036269 ulceration Effects 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
- C07D217/18—Aralkyl radicals
- C07D217/20—Aralkyl radicals with oxygen atoms directly attached to the aromatic ring of said aralkyl radical, e.g. papaverine
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a drotaverine hydrochloride crystal form I, according to the crystal form I, the characteristic peaks are shown at the angles of 5.422 degrees, 6.699 degrees, 8.108 degrees, 10.067 degrees, 10.698 degrees, 12.093 degrees, 13.232 degrees, 14.513 degrees, 16.133 degrees, 22.183 degrees, 24.225 degrees and 24.766 degrees of the X-ray powder diffraction spectrogram expressed by the diffraction angle of (2 theta-0.2)-(2 theta+0.2) degrees. The invention further discloses a drotaverine hydrochloride crystal form II; according to the crystal form II, the characteristic peaks are shown at the angles of 3.955 degrees, 4.22 degrees, 6.364 degrees, 7.784 degrees, 8.307 degrees, 9.646 degrees, 11.628 degrees, 13.012 degrees, 13.233 degrees, 16.171 degrees, 17.379 degrees, 20.76 degrees and 23.262 degrees of the X-ray powder diffraction spectrogram expressed by the diffraction angle of (2 theta-0.2)-(2 theta+0.2) degrees. The invention further discloses a preparation of the crystal form I and the crystal form II. The crystal form I and the crystal form II disclosed by the invention are high in stability, and the preparation method is simple in process, and the practicability is high.
Description
Technical field
The present invention relates to drotaverine hydrochloride preparing technical field, be specifically related to drotaverine hydrochloride crystal formation I and crystal form II and preparation method.
Background technology
Papaverine (Papaverine) is a kind of alkaloid separated from opium, there is non-selective smooth muscle relaxation, faint maincenter analgesic effect drawn game anaesthetic effect, be used for the treatment of smooth muscle spasm in various situations, mainly comprise cramps of gastrointestinal tract, biliary colic, ureteral colic, bronchospasm, stenocardia and other disorder.
Drotaverine is the derivative of Papaverine, and spasmolysis is strong and the time length is long compared with opium poppy bases, and without habituation, also has the effects such as coronary artery dilator, loose unstriated muscle.The stomachache that drotaverine hydrochloride causes peptide ulceration, biliary colic, acute pancreatitis, stomach spasm, irritable bowel syndrome, ecphyaditis, lithangiuria etc. has obvious relieving spasm to stop pain and remission effect.It only acts on unstriated muscle and does not affect autonomic nervous system, without atropine-like untoward reaction, can be applicable to the patient of glaucoma and prostatomegaly.
Drotaverine hydrochloride is that Hungary Chinoin chemical pharmacy company develops.Its structure is shown below:
Start drotaverine hydrochloride to be applied to clinical the external sixties, enters China the nineties and promote.The country of Gai Yao Hungary, Russia, China and other approval listings is used widely at present.
That in document, reports at present mainly obtains about drotaverine hydrochloride crystal formation from ethanol.In patent documentation US4126615A embodiment 10, drotaverine hydrochloride is crystallization salify in dehydrated alcohol.In document (Acta Pharmaceutica Hungarica69/1999/24-29), drotaverine hydrochloride is crystallization in 96% ethanol and benzene respectively, obtains the monocrystalline that contains 1/2 ethanol molecule and 1/2 benzene molecular.We find the product that crystallization obtains in ethanol, and the crystallization ethanol in molecule easily exchanges with airborne water molecules, are unfavorable for stable preservation.
Summary of the invention
The object of the present invention is to provide two kinds of drotaverine hydrochloride new crystal: crystal formation I and crystal form II, with the Compound Phase ratio that production in prior art obtains, this crystal formation is directly to adopt water to do recrystallization solvent to obtain, so stability is better.The present invention simultaneously also provides the preparation method of above-mentioned two new crystal, and the method technique is simple, utilizes water to do recrystallization solvent, and cost is low, practical.
For solving above-mentioned first technical problem, the technical solution used in the present invention is:
A drotaverine hydrochloride crystal formation I, the X-ray powder diffraction spectrogram that this crystal formation I represents with 2 θ ± 0.2 ° diffraction angle is located indicating characteristic peak 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 °.
As preferably, the X-ray powder diffraction spectrogram that described crystal formation I represents with 2 θ ± 0.2 ° diffraction angle is located indicating characteristic peak 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 °.
As preferably, the characteristic peak in the X-ray powder diffraction spectrogram that described crystal formation I represents with 2 θ ± 0.2 ° diffraction angle and diffracted intensity (I/I
0) as follows:
As preferably, the X-ray powder diffraction spectrogram of described crystal formation I as shown in Figure 1.
As preferably, it is 119.55 ℃ that described crystal formation I crystal water is sloughed temperature, and fusing point is 205.2 ℃.The DSC spectrogram of described crystal formation I as shown in Figure 2.
A drotaverine hydrochloride crystal form II, the X-ray powder diffraction spectrogram that this crystal form II represents with 2 θ ± 0.2 ° diffraction angle is located indicating characteristic peak 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 °.
As preferably, the X-ray powder diffraction spectrogram that described crystal form II represents with 2 θ ± 0.2 ° diffraction angle is located indicating characteristic peak 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 °.
As preferably, the characteristic peak in the X-ray powder diffraction spectrogram that described crystal form II represents with 2 θ ± 0.2 ° diffraction angle and diffracted intensity (I/I
0) as follows:
As preferably, the X-ray powder diffraction spectrogram of described crystal form II as shown in Figure 3.
As preferably, it is 101.22 ℃ that described crystal form II crystal water is sloughed temperature, and fusing point is 205.73 ℃.The DSC spectrogram of described crystal form II as shown in Figure 4.
Test shows, take water as solvent, under different preparation conditions, obtains two kinds of different crystal formations.The concrete grammar of preparing above-mentioned crystal formation I and crystal form II is respectively:
A preparation method who prepares above-mentioned drotaverine hydrochloride crystal formation I, comprising: drotaverine hydrochloride and water are mixed to form to slurry, and water is 6～8mL/g with the volume mass ratio of drotaverine hydrochloride, is warming up to 65～70 ℃, and system all changes faint yellow slurries into; Insulation 5～40min, is cooled to below 35 ℃, and the crystal of separating out is decompression drying at 45～65 ℃, obtains crystal formation I.
A method of preparing drotaverine hydrochloride crystal form II, comprising: by the drotaverine hydrochloride formation slurry that is added to the water, water is about 6～8mL/g with the volume mass ratio of drotaverine hydrochloride, is warming up to 75～80 ℃, and system is all molten clear; Be cooled to below 35 ℃, the crystal of separating out, 40 ℃ of following oven dry, obtains crystal form II.
Of the present inventionly prepare can be used as the same with common drotaverine hydrochloride with crystal form II of drotaverine hydrochloride crystal formation I and be used for the treatment of smooth muscle spasm in various situations, mainly comprise cramps of gastrointestinal tract, biliary colic, ureteral colic, bronchospasm, stenocardia and other disorder.And drotaverine hydrochloride crystal formation I prepared by the present invention and crystal form II purity and stability are better.
Drotaverine hydrochloride crystal formation I of the present invention and crystal form II directly adopt water to do recrystallization solvent and make, and stability is better, and for the using and store all favourablely of later stage, and the preparation method of above-mentioned two kinds of crystal formations is simple, is suitable for suitability for industrialized production.
Accompanying drawing explanation
Fig. 1 is the X-ray powder diffraction spectrogram of the drotaverine hydrochloride crystal formation I for preparing of embodiment 1.
Fig. 2 is the DSC figure of the drotaverine hydrochloride crystal formation I for preparing of embodiment 1.
Fig. 3 is the X-ray powder diffraction spectrogram of the drotaverine hydrochloride crystal form II for preparing of embodiment 2.
Fig. 4 is the DSC figure of the drotaverine hydrochloride crystal form II for preparing of embodiment 2.
Fig. 5 is the X-ray powder diffraction spectrogram of the drotaverine hydrochloride crystal formation for preparing of comparative example 1.
Embodiment
X-ray diffractogram detection method:
(1) detecting instrument: German Bruker D8Advance X diffractometer
(2) measuring condition: target: copper
Press/pipe of pipe stream: 40kV/40mA
Scanning angle: 3 °～40 °
Scanning step: 0.02 °
Sweep velocity: 0.2 second/step
The hot method of DCS(differential scanning) analyze:
(1) detecting instrument: Switzerland plum Teller-Tuo benefit DSC1 differential scanning calorimeter
(2) heating schedule: 30～190 ℃, 10 ℃/mIn; 190～220 ℃, 2 ℃/mIn.
Embodiment 1:
Prepare drotaverine hydrochloride crystal formation I
Purified water 150mL, drotaverine hydrochloride 22.5g, concentrated hydrochloric acid 4.5mL are put in 250mL there-necked flask, be warming up to 70 ℃, most of molten clear in system, do not dissolve part and be faint yellow.Stir after 30min, remove hot water bath, be naturally cooled to 30 ℃, suction filtration.Wet product reduces pressure and dries 24h in 50 ℃ of baking ovens, obtains crystal formation I, yield: 86.4%, and moisture content: 4.0%.HPLC purity is more than 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 formation I that this embodiment is prepared carries out powder x-ray diffraction and measures and the hot method of DSC(differential scanning) analyze.X-ray diffractogram detects and the hot method of DCS(differential scanning) analysis measurement result is shown in Fig. 1 and Fig. 2:
Principal character peak in Fig. 1 (X powder ray diffraction spectrogram) is as shown in table 1 below.
Table 1
In Fig. 2 (DSC spectrogram), the crystal water of sample is sloughed temperature: 119.55 ℃, and fusing point: 205.2 ℃ (decomposition).
Embodiment 2:
Prepare drotaverine hydrochloride crystal form II
Crystal drotaverine hydrochloride crystal form II preparation: purified water 150mL, drotaverine hydrochloride 22.5g, concentrated hydrochloric acid 4.5mL are dropped in 250mL there-necked flask, be warming up to 80 ℃.Until system molten clear after, cooling with water-bath from the beginning, be cooled to 31 ℃, suction filtration, the wet product baking 24h that reduce pressure in 40 ℃ of baking ovens, obtains crystal form II, yield: 88.1%, moisture content: 5.6%.HPLC purity is more than 99.5%, and nuclear-magnetism detects data with embodiment 1.
Sample prepared by this embodiment carries out X-ray powder diffraction detection (detecting instrument and the condition of scanning are with embodiment 1), and detected result is shown in Fig. 3, and the principal character peak parameter in Fig. 3 sees the following form 2:
Table 2
This sample carries out dsc analysis (detecting instrument and heating schedule are with embodiment 1), and as shown in Figure 4, as shown in Figure 4, the crystal water of sample is sloughed temperature to detected result: 101.22 ℃, and fusing point: 205.73 ℃ (decomposition).
Comparative example 1:
According to the method for document US4126615A embodiment 10, take ethanol as recrystallization solvent, it is as follows that the crystal obtaining detects data: moisture content: 0.2%, alcohol residue: 4.9%, yield: 88.2%.HPLC purity is 99.0%.The nuclear magnetic data of product is with embodiment 1.According to carrying out powder x-ray diffraction mensuration with embodiment 1 same test method.Measurement result is shown in Fig. 5.Principal character peak is as shown in table 3:
Table 3
Shown in table 3 and Fig. 5, drotaverine hydrochloride crystal formation I and crystal form II that the powder x-ray diffraction characteristic peak being prepared by existing document prepares from the present invention are all different.And by stability experiment, show that the present invention obtains crystal formation I and crystal form II comparison is more stable than crystal formation, wherein moisture content is substantially constant.After placing 48, the alcohol residue in contrast crystal formation is reduced to 1% left and right from 4.9%, and moisture content correspondence is 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 is located indicating characteristic peak 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 °.
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 is located indicating characteristic peak 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 29.03 °.
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 ℃ that described crystal formation I crystal water is sloughed temperature, and fusing point is 205.2 ℃.
5. a preparation method who prepares the drotaverine hydrochloride crystal formation I described in the arbitrary claim of claim 1～4, it is characterized in that, comprise: drotaverine hydrochloride and water are mixed to form to slurry, water is 6～8mL/g with the volume mass ratio of drotaverine hydrochloride, be warming up to 65～70 ℃, system all changes faint yellow slurries into; Insulation 5～40min, is cooled to below 35 ℃, and the crystal of separating out is dried at 45～65 ℃, 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 is located indicating characteristic peak 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 °.
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 is located 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 ℃ that described crystal form II crystal water is sloughed temperature, and fusing point is 205.73 ℃.
10. a method of preparing the drotaverine hydrochloride crystal form II described in the arbitrary claim of claim 6～9, it is characterized in that, comprise: by the drotaverine hydrochloride formation slurry that is added to the water, water is 6～8mL/g with the volume mass ratio of drotaverine hydrochloride, be warming up to 75～80 ℃, system is all molten clear; Be cooled to below 35 ℃, the crystal of separating out, 40 ℃ of following oven dry, obtains crystal form II.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310681825.XA CN103664781B (en) | 2013-12-13 | 2013-12-13 | Drotaverine hydrochloride crystal formation I and crystal form II and preparation method |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310681825.XA CN103664781B (en) | 2013-12-13 | 2013-12-13 | Drotaverine hydrochloride crystal formation I and crystal form II and preparation method |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103664781A true CN103664781A (en) | 2014-03-26 |
| CN103664781B CN103664781B (en) | 2015-12-09 |
Family
ID=50303661
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201310681825.XA Active CN103664781B (en) | 2013-12-13 | 2013-12-13 | Drotaverine hydrochloride crystal formation I and crystal form II and preparation method |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103664781B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106706789A (en) * | 2016-12-26 | 2017-05-24 | 江苏联环药业股份有限公司 | Method for detecting related substances in drotaverine hydrochloride injection by high performance liquid chromatography |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1011554A (en) * | 1961-08-30 | 1965-12-01 | Chinoin Gyogyszer Es Vegyeszet | Substituted isoquinolines and pharmaceutical compositions thereof |
| US4126615A (en) * | 1975-12-12 | 1978-11-21 | Chinoin Gyogyszer Es Vegyeszeti Termekek Gyara Rt | Process for the manufacture of pure isoquinoline derivatives |
| WO1999004822A2 (en) * | 1997-07-25 | 1999-02-04 | Chinoin Gyógyszer és Vegyészeti Termékek Gyára Rt. | New salts with beneficial organoleptic properties |
-
2013
- 2013-12-13 CN CN201310681825.XA patent/CN103664781B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1011554A (en) * | 1961-08-30 | 1965-12-01 | Chinoin Gyogyszer Es Vegyeszet | Substituted isoquinolines and pharmaceutical compositions thereof |
| US4126615A (en) * | 1975-12-12 | 1978-11-21 | Chinoin Gyogyszer Es Vegyeszeti Termekek Gyara Rt | Process for the manufacture of pure isoquinoline derivatives |
| WO1999004822A2 (en) * | 1997-07-25 | 1999-02-04 | Chinoin Gyógyszer és Vegyészeti Termékek Gyára Rt. | New salts with beneficial organoleptic properties |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106706789A (en) * | 2016-12-26 | 2017-05-24 | 江苏联环药业股份有限公司 | Method for detecting related substances in drotaverine hydrochloride injection by high performance liquid chromatography |
| CN106706789B (en) * | 2016-12-26 | 2019-02-01 | 江苏联环药业股份有限公司 | With the method in relation to substance in high effective liquid chromatography for measuring drotaverine hydrochloride injection |
Also Published As
| Publication number | Publication date |
|---|---|
| CN103664781B (en) | 2015-12-09 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| KR101284202B1 (en) | Agomelatine hydrohalide complex and preparation method thereof | |
| JP6609065B2 (en) | Novel acid addition salts of 1- (5- (2,4-difluorophenyl) -1-((3-fluorophenyl) sulfonyl) -4-methoxy-1H-pyrrol-3-yl) -N-methylmethanamine | |
| TWI624447B (en) | Process for producing pyrrole derivative and crystalline form thereof | |
| US10836783B2 (en) | Inclusion compound of 3′ ,5′-cyclic diadenylic acid and manufacturing method thereof | |
| CN113912509B (en) | Preparation method of amide compound | |
| CN103787975A (en) | Huperzine A D-dibenzoyltartartrate and preparation method and application thereof | |
| CN103664781B (en) | Drotaverine hydrochloride crystal formation I and crystal form II and preparation method | |
| CN108947946B (en) | Brain injury resistant deuterated compound and medical application thereof | |
| CN111732539A (en) | Chloroquine phosphate enantiomer crystal form and preparation method thereof | |
| CN102924474A (en) | Preparation method of crystal form I of clopidogrel hydrogen sulfate | |
| CN105777573B (en) | The preparation method of N coumaric acyl dopamines | |
| CA3089268C (en) | Crystalline forms of mesaconine and preparation methods therefor | |
| CN110981832A (en) | Preparation method of roxatidine acetate hydrochloride | |
| CN103694171B (en) | Drotaverine hydrochloride crystal form II I and form IV and preparation method thereof | |
| CA2792430C (en) | Agomelatine hydrobromide hydrate and preparation thereof | |
| CN107011322B (en) | Preparation and purification method of dehydrophenylahistine compound | |
| CN103073570A (en) | Moxifloxacin and salt intermediate thereof and preparation methods thereof | |
| CN105237547B (en) | A kind of preparation method of hydroxyl benzoxazole | |
| WO2015012271A1 (en) | Method for producing heterocyclic compound | |
| WO2024022426A1 (en) | Method for preparing 4-(trimethylammonio)pentanoate | |
| CN112457243B (en) | Synthesis method of 7-bromo-5-methoxyquinoline | |
| KR20200024302A (en) | Salts, Polymorphs, and Pharmaceutical Compositions and Uses of Phenylpyrimidone Compounds | |
| JP2007530681A (en) | 5,11-dihydro-11-ethyl-5-methyl-8- {2-{(1-oxide-4-quinolinyl) oxy} ethyl} -6H-dipyrido [3,2-b: 2 ', 3'- e] Crystalline form of [1,4] diazepin-6-one | |
| EP3377478B1 (en) | Co-crystals of bilastine | |
| WO2019129801A1 (en) | Process for the purification of methyl-2,2-dithienylglycolate |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20200629 Address after: No.333, Jiangnan Road, Hengdian, Dongyang City, Jinhua City, Zhejiang Province Co-patentee after: APELOA PHARMACEUTICAL Co.,Ltd. Patentee after: ZHEJIANG APELOA KANGYU PHARMACEUTICAL Co.,Ltd. Address before: 322118, No. 333 South Zhenjiang Road, Dongyang, Zhejiang, Jinhua, Hengdian Patentee before: ZHEJIANG APELOA KANGYU PHARMACEUTICAL Co.,Ltd. |
|
| TR01 | Transfer of patent right | ||
| PE01 | Entry into force of the registration of the contract for pledge of patent right | ||
| PE01 | Entry into force of the registration of the contract for pledge of patent right |
Denomination of invention: Drotavirin hydrochloride crystal form I and crystal form II and preparation method thereof Effective date of registration: 20210922 Granted publication date: 20151209 Pledgee: Dongyang sub branch of Bank of China Ltd. Pledgor: ZHEJIANG APELOA KANGYU PHARMACEUTICAL Co.,Ltd. Registration number: Y2021330001745 |
|
| PC01 | Cancellation of the registration of the contract for pledge of patent right | ||
| PC01 | Cancellation of the registration of the contract for pledge of patent right |
Date of cancellation: 20230925 Granted publication date: 20151209 Pledgee: Dongyang sub branch of Bank of China Ltd. Pledgor: ZHEJIANG APELOA KANGYU PHARMACEUTICAL Co.,Ltd. Registration number: Y2021330001745 |
|
| PE01 | Entry into force of the registration of the contract for pledge of patent right | ||
| PE01 | Entry into force of the registration of the contract for pledge of patent right |
Denomination of invention: Crystal forms I and II of tratavirin hydrochloride and their preparation method Effective date of registration: 20231007 Granted publication date: 20151209 Pledgee: Dongyang sub branch of Bank of China Ltd. Pledgor: ZHEJIANG APELOA KANGYU PHARMACEUTICAL Co.,Ltd. Registration number: Y2023980059587 |