CN114685370A - Butorphanol tartrate crystal form I and preparation method and application thereof - Google Patents
Butorphanol tartrate crystal form I and preparation method and application thereof Download PDFInfo
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- CN114685370A CN114685370A CN202111597130.4A CN202111597130A CN114685370A CN 114685370 A CN114685370 A CN 114685370A CN 202111597130 A CN202111597130 A CN 202111597130A CN 114685370 A CN114685370 A CN 114685370A
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- 239000013078 crystal Substances 0.000 title claims abstract description 47
- GMTYREVWZXJPLF-AFHUBHILSA-N butorphanol D-tartrate Chemical compound OC(=O)[C@@H](O)[C@H](O)C(O)=O.N1([C@@H]2CC3=CC=C(C=C3[C@@]3([C@]2(CCCC3)O)CC1)O)CC1CCC1 GMTYREVWZXJPLF-AFHUBHILSA-N 0.000 title claims abstract description 26
- 229960001590 butorphanol tartrate Drugs 0.000 title claims abstract description 19
- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 24
- IFKLAQQSCNILHL-QHAWAJNXSA-N butorphanol Chemical compound N1([C@@H]2CC3=CC=C(C=C3[C@@]3([C@]2(CCCC3)O)CC1)O)CC1CCC1 IFKLAQQSCNILHL-QHAWAJNXSA-N 0.000 claims abstract description 24
- 239000002904 solvent Substances 0.000 claims abstract description 24
- 229960001113 butorphanol Drugs 0.000 claims abstract description 22
- 238000000634 powder X-ray diffraction Methods 0.000 claims abstract description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 19
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims abstract description 12
- 235000002906 tartaric acid Nutrition 0.000 claims abstract description 12
- 239000011975 tartaric acid Substances 0.000 claims abstract description 12
- 239000003513 alkali Substances 0.000 claims abstract description 11
- 238000002425 crystallisation Methods 0.000 claims abstract description 9
- 230000008025 crystallization Effects 0.000 claims abstract description 9
- 238000000034 method Methods 0.000 claims abstract description 8
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- 238000010438 heat treatment Methods 0.000 claims description 8
- 238000001816 cooling Methods 0.000 claims description 7
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- 208000002193 Pain Diseases 0.000 claims description 6
- 230000036592 analgesia Effects 0.000 claims description 6
- 239000007864 aqueous solution Substances 0.000 claims description 5
- 239000003814 drug Substances 0.000 claims description 5
- 230000036407 pain Effects 0.000 claims description 4
- 238000001757 thermogravimetry curve Methods 0.000 claims description 3
- 238000011282 treatment Methods 0.000 claims description 3
- 230000001476 alcoholic effect Effects 0.000 claims description 2
- 238000002844 melting Methods 0.000 claims description 2
- 230000008018 melting Effects 0.000 claims description 2
- 239000012046 mixed solvent Substances 0.000 claims description 2
- 239000003960 organic solvent Substances 0.000 claims description 2
- 229940124583 pain medication Drugs 0.000 claims 1
- 230000003321 amplification Effects 0.000 abstract description 4
- 239000007788 liquid Substances 0.000 abstract description 4
- 238000003199 nucleic acid amplification method Methods 0.000 abstract description 4
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 238000003825 pressing Methods 0.000 abstract description 2
- 239000005456 alcohol based solvent Substances 0.000 abstract 1
- 238000003908 quality control method Methods 0.000 abstract 1
- 238000003860 storage Methods 0.000 abstract 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 14
- 238000004128 high performance liquid chromatography Methods 0.000 description 10
- 238000003756 stirring Methods 0.000 description 10
- 239000007787 solid Substances 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- 229960001367 tartaric acid Drugs 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 6
- 238000000113 differential scanning calorimetry Methods 0.000 description 6
- 229960001270 d- tartaric acid Drugs 0.000 description 5
- 239000012535 impurity Substances 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 239000008213 purified water Substances 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 238000001228 spectrum Methods 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 238000002411 thermogravimetry Methods 0.000 description 4
- 229940079593 drug Drugs 0.000 description 3
- 238000005303 weighing Methods 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 239000012458 free base Substances 0.000 description 2
- 239000003193 general anesthetic agent Substances 0.000 description 2
- 238000005286 illumination Methods 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 239000007922 nasal spray Substances 0.000 description 2
- 229940097496 nasal spray Drugs 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000010926 purge Methods 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- LEJBBGNFPAFPKQ-UHFFFAOYSA-N 2-(2-prop-2-enoyloxyethoxy)ethyl prop-2-enoate Chemical compound C=CC(=O)OCCOCCOC(=O)C=C LEJBBGNFPAFPKQ-UHFFFAOYSA-N 0.000 description 1
- 101100223811 Caenorhabditis elegans dsc-1 gene Proteins 0.000 description 1
- 208000000094 Chronic Pain Diseases 0.000 description 1
- 102000003840 Opioid Receptors Human genes 0.000 description 1
- 108090000137 Opioid Receptors Proteins 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 208000005298 acute pain Diseases 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 239000012296 anti-solvent Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 230000035606 childbirth Effects 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- INAXVFBXDYWQFN-XHSDSOJGSA-N morphinan Chemical compound C1C2=CC=CC=C2[C@]23CCCC[C@H]3[C@@H]1NCC2 INAXVFBXDYWQFN-XHSDSOJGSA-N 0.000 description 1
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- ZQBVUULQVWCGDQ-UHFFFAOYSA-N propan-1-ol;propan-2-ol Chemical compound CCCO.CC(C)O ZQBVUULQVWCGDQ-UHFFFAOYSA-N 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 150000003892 tartrate salts Chemical class 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
- C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
- C07D221/22—Bridged ring systems
- C07D221/28—Morphinans
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/42—Separation; Purification; Stabilisation; Use of additives
- C07C51/43—Separation; Purification; Stabilisation; Use of additives by change of the physical state, e.g. crystallisation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C59/235—Saturated compounds containing more than one carboxyl group
- C07C59/245—Saturated compounds containing more than one carboxyl group containing hydroxy or O-metal groups
- C07C59/255—Tartaric acid
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Abstract
The invention discloses a new crystal form I of butorphanol tartrate, wherein an X-ray powder diffraction spectrogram expressed by a 2 theta +/-0.2-degree diffraction angle has characteristic peaks at 10.42 degrees, 12.66 degrees, 14.72 degrees, 16.08 degrees, 20.18 degrees, 21.70 degrees, 23.42 degrees, 24.46 degrees, 25.28 degrees, 27.30 degrees and the like. The invention also discloses a preparation method of the crystal form, the crystal form I disclosed by the invention adopts a water-containing crystallization solvent system, excessive alcohol solvents are adopted to dissolve butorphanol free alkali, water is adopted to dissolve tartaric acid, feed liquid is not easy to separate out in the filter pressing operation process of entering a clean area, industrial amplification operation is utilized, and meanwhile, the obtained crystal form has the advantages of high crystallinity, good stability of the crystal form and convenience for production and storage, and in addition, ethanol which uses water and three solvents is used as a crystallization solvent, so that the crystal form has the advantages of easiness in finished product quality control and lower risk.
Description
Technical Field
The invention belongs to the field of drug crystal forms, and particularly relates to a butorphanol tartrate bulk drug crystal form I and a preparation method and application thereof.
Background
Butorphanol was originally developed by the company Bristol-Myers Squibb Co, a central analgesic, a mixed opioid receptor agonist-antagonist, whose tartrate salt was used clinically, mainly as a preoperative or pre-anesthetic drug, an adjuvant anesthetic drug, for childbirth analgesia and for severe pain requiring opioid analgesia or other therapies ineffective therapies.
Butorphanol is chemically named as levo (-) -17-cyclobutylmethyl-3, 14-dihydroxy morphinan, and has a typical morphinan structural mother nucleus. Butorphanol is a white crystalline solid with molecular formula C12H29NO2Molecular weight 327.47, CAS number 42408-82-2. The first approved by FDA to market in 1978, the trade name is Stadol, and the two dosage forms of injection and nasal spray are injection (1mg/1ml and 2mg/1ml) and nasal spray (25mg/2.5 ml). The chemical structural formula of the butorphanol tartrate is shown as the following formula:
the original research company Bristol-Myers Co. has disclosed the therapeutic application of butorphanol tartrate for relieving acute and chronic pain in the first preparation method patents US3775414, US3819635, US3980641, US4017497, US4058531 and US4139534, and has disclosed the synthetic routes of butorphanol free base in each generation, but the preparation of butorphanol tartrate and its crystal form is not reported in the above-mentioned publications.
At present, only a Master's academic paper published by Li Ice, Zhaofli and the like of Zhejiang industry university reports the synthesis method of tartrate, and the paper discloses a crystal form of butorphanol tartrate, which is obtained by heating butorphanol and tartaric acid in a solvent to form salt, cooling and crystallizing, and screening the solvent, wherein the solvent is methanol, ethanol, isopropanol/water, acetone/water and the like. And the solvent amount is less, under the condition, the butorphanol free alkali is in a supersaturated state, the feed liquid is easy to cool and separate out in the process of entering a clean area through filter pressing in the production amplification stage, the condition of blocking a pipeline occurs, and the increase of the volume of a crystallization solvent can possibly cause the reduction of crystallization yield or the change of the crystal form or the purity of a product.
In addition to the master thesis, no other new crystal forms of butorphanol tartrate have been reported so far, and no other more economical and industrialized production processes are disclosed, so that the butorphanol tartrate polymorph and the preparation method thereof are worthy of deep research.
Disclosure of Invention
The invention aims to provide a crystal form I of butorphanol tartrate, wherein an X-ray powder diffraction pattern of the crystal form I has diffraction peaks at the following 2 theta angles: 10.30 +/-0.2 degrees, 12.56 +/-0.2 degrees, 14.72 +/-0.2 degrees, 16.08 +/-0.2 degrees, 20.18 +/-0.2 degrees, 21.70 +/-0.2 degrees, 23.42 +/-0.2 degrees, 24.46 +/-0.2 degrees, 25.28 +/-0.2 degrees, 25.88 +/-0.2 degrees and 27.30 +/-0.2 degrees.
Further, the X-ray powder diffraction pattern thereof has diffraction peaks at the following 2 θ angles: 10.30 +/-0.2 degrees, 12.56 +/-0.2 degrees, 12.88 +/-0.2 degrees, 14.72 +/-0.2 degrees, 16.08 +/-0.2 degrees, 19.74 +/-0.2 degrees, 20.18 +/-0.2 degrees, 20.64 +/-0.2 degrees, 21.70 +/-0.2 degrees, 23.42 +/-0.2 degrees, 24.46 +/-0.2 degrees, 25.28 +/-0.2 degrees, 25.88 +/-0.2 degrees, 27.30 +/-0.2 degrees and 28.18 +/-0.2 degrees.
Further, the crystal form has an X-ray powder diffraction pattern as shown in figure 1.
Further, the DSC melting endothermic peak of the crystal form I is 223-230 ℃, preferably 226 ℃, and more preferably has a DSC pattern as shown in figure 2.
Further, the crystalline form I has a TGA profile as shown in figure 3.
The invention also provides a preparation method of the butorphanol tartrate crystal form I, which comprises the following steps:
the first step is as follows: dissolving butorphanol in a suitable solvent selected from organic solvents, preferably alcoholic solvents, more preferably methanol, ethanol or isopropanol, most preferably ethanol, by heating;
the second step is that: dissolving tartaric acid by using water or a mixed solvent of water and other solvents, preferably water;
the third step: adding tartaric acid aqueous solution into butorphanol free alkali dissolved by a solvent;
the fourth step: cooling to below 30 deg.c to separate out crystal.
Further, the volume mass ratio of the proper solvent to the butorphanol in the first step is 5-15: 1mL/g, preferably 10: 1 mL/g.
Further, the heating temperature in the first step is 60-80 ℃.
Further, the volume mass ratio of water to tartaric acid is 3-5: 1mL/g, preferably 3: 1 mL/g.
Further, the crystallization temperature in the fourth step is selected from 30 ℃ or lower, preferably from-20 ℃ to 30 ℃, and more preferably from-20 ℃ to 25 ℃.
The invention also provides application of the butorphanol tartrate crystal form I in preparing a medicine for treating pain, in particular application in labor analgesia and severe pain medicines requiring opioid analgesia or other ineffective treatments.
The invention has the beneficial effects that the crystal form I of the butorphanol tartrate is provided, has good stability, high solubility, poor hygroscopicity, high HPLC (high performance liquid chromatography) purity and less total impurities, and is more suitable for medicinal use. According to the preparation method of the crystal form I, water is used as an anti-solvent to dissolve tartaric acid, an excessive alcohol solvent is used to dissolve butorphanol free alkali, the butorphanol free alkali is in an unsaturated state, materials are not separated out in the operation process that a feed liquid enters a clean area after being filtered in the amplification process, pipelines are not blocked, and the preparation method is suitable for industrial amplification.
Drawings
Figure 1 is an X-ray powder diffraction pattern of form I prepared in example 1.
Figure 2 is a DSC profile of form I prepared in example 1.
Figure 3 is a TGA profile of form I prepared in example 1.
Figure 4 is an HPLC profile of form I prepared in example 1.
FIG. 5 is an X-ray powder diffraction superposition spectrum of the crystal forms prepared in examples 2 and 3.
FIG. 6 is an X-ray powder diffraction superposition spectrum of the crystal forms prepared in examples 4, 5 and 6.
FIG. 7 is an X-ray powder diffraction overlay spectrum of the crystal forms prepared in example 7, example 8 and example 9.
FIG. 8 is an X-ray powder diffraction overlay contrast plot of a sample after 30 days of 0 day, high temperature, high humidity, and light conditions.
Detailed Description
The present invention is described in further detail with reference to the following examples, but the present invention is not limited thereto, and any equivalent replacement in the field made in accordance with the present disclosure is included in the scope of the present invention.
The abbreviations used in this application are explained as follows:
XRD: powder X-ray diffraction
The determination of X-ray powder diffraction (XRD) described in this application is collected by powder diffractometer Liaoning Danhaoyuan DX-2700B, and the specific parameters are as follows:
DSC: differential scanning calorimeter
The Differential Scanning Calorimetry (DSC) described herein employs METTLER TOLEDO model DSC-1 for collection, with a temperature rise rate of 10 deg.C/min, a temperature range of 25-250 deg.C, and a nitrogen purge rate of 60mL/min during testing.
TGA: thermogravimetric analyzer
Thermogravimetric analysis (TGA) described herein is measured using a METTLER TOLEDO model TGA-2 with a temperature rise rate of 10 ℃/min, a temperature range of 30-250 ℃, and a nitrogen purge rate of 20mL/min during the test.
KF: ka's moisture tester
The moisture described herein was measured using a Metrohm model 870KF Titrino plus karman moisture meter.
HPLC: high performance liquid chromatography
The HPLC spectrogram is determined by Agilent1260DAD liquid chromatograph, chromatographic column with octadecylsilane chemically bonded silica as filler, and ultraviolet detector with wavelength of 220 nm.
Example 1:
0.79Kg (1.0L) of ethanol and butorphanol free base (100g, 0.306mol) are added into the reaction kettle A, stirred and heated until the solution is clear after reflux. Adding 0.21Kg of purified water into a reaction kettle B, adding 68.8g (1.5eq.) of D-tartaric acid, adding the D-tartaric acid solution in the reaction kettle B into the clear solution of butorphanol, slowly cooling to below 30 ℃, continuously stirring for 4-6h, filtering, and drying a filter cake under reduced pressure to constant weight to obtain 121g of crystalline solid, wherein the yield is as follows: 83%, HPLC purity 99.98%, total impurities 0.02%.
The powder diffraction pattern of the crystal sample is shown in figure 1, the data are shown in the following table 1, the DSC has a characteristic absorption peak at 223.38 ℃, the TGA shows that the crystal sample starts to decompose and lose weight when being heated to 223.38 ℃, and the moisture of the crystal form is measured by a KF method, so that the water content of the crystal form is 0.16 percent.
Table 1:
example 2, example 3:
adding butorphanol free alkali (0.5g) into a reaction bottle, adding a proper amount of solvent according to the following table 2, and heating to reflux, stirring and dissolving. Quantitatively weighing 0.25g of D-tartaric acid, adding 0.75ml of purified water, stirring for dissolving, slowly adding the tartaric acid aqueous solution into the butorphanol free alkali solution, slowly cooling to 0 ℃ after dropwise adding, stirring for crystallization for 4-6h, separating out solids, centrifuging, and drying the obtained solids at 40 ℃ to constant weight, wherein the yield is as follows: 84%, HPLC purity 99.98%, total impurities 0.02%, and XRD of the obtained sample, as shown in FIG. 5.
Table 2:
| solvent(s) | Amount of solvent used | Crystal form | |
| Example 2 | Methanol | 2.5mL | Crystal form I |
| Example 3 | Isopropanol (I-propanol) | 5.0mL | Crystal form I |
Examples 4, 5, 6:
adding butorphanol free alkali (0.5g) into a reaction bottle, adding a proper amount of ethanol according to the following table 3, heating, refluxing and stirring until the solution is clear. Quantitatively weighing 0.25g of D-tartaric acid, adding 0.75ml of purified water, stirring for dissolving, slowly adding the tartaric acid aqueous solution into the ethanol solution of butorphanol free alkali, slowly cooling to 0 ℃ after dropwise addition, stirring for crystallization for 4-6h, separating out a large amount of solids, centrifuging, and drying the obtained solids to constant weight at 40 ℃, wherein the yield is as follows: 84%, HPLC purity 99.97%, total impurities 0.03%, and XRD measurement of the obtained sample, as shown in figure 6.
Table 3:
| amount of solvent used | Crystal form | |
| Example 4 | 2.5ml | Crystal form I |
| Example 5 | 5.0ml | Crystal form I |
| Example 6 | 7.5ml | Crystal form I |
Example 7, example 8, example 9:
adding butorphanol free alkali (0.5g) into a reaction bottle, adding 5.0ml of ethanol as a solvent, heating, refluxing and stirring until the solution is clear. Quantitatively weighing 0.25g of D-tartaric acid, adding 0.75ml of purified water, stirring for dissolving, slowly adding the tartaric acid aqueous solution into the methanol solution, slowly cooling to the temperature shown in Table 4 after dropwise adding, stirring for crystallizing for 4-6h, separating out solids, centrifuging, and drying the obtained solids at 40 ℃ to constant weight, wherein the yield is as follows: 85%, HPLC purity 99.96%, total impurities 0.04%, and XRD measurement of the obtained sample, as shown in FIG. 7.
Table 4:
| crystallization temperature (. degree.C.) | Crystal form | |
| Example 7 | 30 | Crystal form I |
| Example 8 | 0 | Crystal form I |
| Example 9 | -20 | Crystal form I |
Example 10:
taking butorphanol tartrate to be placed in a naked sample under the conditions of high temperature (60 ℃), high humidity (92 percent relative humidity) and illumination (4500LX) for 0 day and 30 days respectively, carrying out stability investigation on the crystal form, finding that the crystal form and the crystal form purity of a test sample are not changed, and showing an XRD test superposition spectrum under the conditions of high temperature, high humidity and illumination for 0 day and 30 days in figure 8.
Claims (10)
1. A butorphanol tartrate crystal form I, characterized in that: the X-ray powder diffraction pattern has diffraction peaks at the following 2 theta angles: 10.30 +/-0.2 degrees, 12.56 +/-0.2 degrees, 14.72 +/-0.2 degrees, 16.08 +/-0.2 degrees, 20.18 +/-0.2 degrees, 21.70 +/-0.2 degrees, 23.42 +/-0.2 degrees, 24.46 +/-0.2 degrees, 25.28 +/-0.2 degrees, 25.88 +/-0.2 degrees and 27.30 +/-0.2 degrees.
2. Crystalline form I of butorphanol tartrate according to claim 1, characterized in that: the X-ray powder diffraction pattern has diffraction peaks at the following 2 theta angles: 10.30 +/-0.2 degrees, 12.56 +/-0.2 degrees, 12.88 +/-0.2 degrees, 14.72 +/-0.2 degrees, 16.08 +/-0.2 degrees, 19.74 +/-0.2 degrees, 20.18 +/-0.2 degrees, 20.64 +/-0.2 degrees, 21.70 +/-0.2 degrees, 23.42 +/-0.2 degrees, 24.46 +/-0.2 degrees, 25.28 +/-0.2 degrees, 25.88 +/-0.2 degrees, 27.30 +/-0.2 degrees and 28.18 +/-0.2 degrees.
3. Crystalline form I of butorphanol tartrate according to claim 1, characterized in that: the crystal form has an X-ray powder diffraction pattern shown in figure 1.
4. The butorphanol tartrate form I according to claim 1, wherein the DSC melting endotherm of the form I is 223-230 ℃, preferably 226 ℃, more preferably has the DSC profile as shown in figure 2.
5. The crystalline form I of butorphanol tartrate of claim 1, having a TGA profile as shown in figure 3.
6. The process for the preparation of butorphanol tartrate form I according to any one of claims 1 to 5, comprising the steps of:
the first step is as follows: dissolving butorphanol in a suitable solvent selected from an organic solvent, preferably an alcoholic solvent, more preferably methanol, ethanol or isopropanol, most preferably ethanol, by heating;
the second step is that: dissolving tartaric acid using water or a mixed solvent of water and other solvents, preferably water;
the third step: adding tartaric acid aqueous solution into butorphanol free alkali dissolved by a solvent;
the fourth step: cooling to below 30 deg.c to separate out crystal.
7. The method for preparing butorphanol tartrate form I according to claim 6, wherein the heating temperature in the first step is 60-80 ℃, and the volume-to-mass ratio of the suitable solvent to butorphanol in the first step is 5-15: 1mL/g, preferably 10: 1 mL/g.
8. The preparation method of butorphanol tartrate form I according to claim 6, wherein the volume to mass ratio of water to tartaric acid is 3-5: 1mL/g, preferably 3: 1 mL/g.
9. The process for the preparation of butorphanol tartrate form I according to claim 6, wherein the crystallization temperature in the fourth step is selected from the group consisting of below 30 ℃, preferably from-20 ℃ to 30 ℃, more preferably from-20 ℃ to 25 ℃.
10. Use of butorphanol tartrate form I according to any one of claims 1 to 6 in the preparation of a medicament for the treatment of pain, preferably in labor analgesia and in severe pain medications requiring opioid analgesia or other treatment inefficiencies.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN116818928A (en) * | 2023-04-28 | 2023-09-29 | 杭州沐源生物医药科技有限公司 | Separation detection method for impurities in butorphanol tartrate injection |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007064845A1 (en) * | 2005-11-29 | 2007-06-07 | Pr Pharmaceuticals, Inc. | Sustained release butorphanol drug delivery compositions for analgesia |
| CN102036946A (en) * | 2008-05-21 | 2011-04-27 | 埃斯蒂文博士实验室股份有限公司 | Co-crystals of duloxetine and Cox-inhibitors for the treatment of pain |
| US20190112273A1 (en) * | 2016-03-29 | 2019-04-18 | Hikal Limited | An improved process for the preparation of butorphanol tartrate |
| CN112142668A (en) * | 2019-06-28 | 2020-12-29 | 苏州盛迪亚生物医药有限公司 | Preparation method of butorphanol tartrate and intermediate thereof |
-
2021
- 2021-12-24 CN CN202111597130.4A patent/CN114685370A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007064845A1 (en) * | 2005-11-29 | 2007-06-07 | Pr Pharmaceuticals, Inc. | Sustained release butorphanol drug delivery compositions for analgesia |
| CN102036946A (en) * | 2008-05-21 | 2011-04-27 | 埃斯蒂文博士实验室股份有限公司 | Co-crystals of duloxetine and Cox-inhibitors for the treatment of pain |
| US20190112273A1 (en) * | 2016-03-29 | 2019-04-18 | Hikal Limited | An improved process for the preparation of butorphanol tartrate |
| CN112142668A (en) * | 2019-06-28 | 2020-12-29 | 苏州盛迪亚生物医药有限公司 | Preparation method of butorphanol tartrate and intermediate thereof |
Non-Patent Citations (2)
| Title |
|---|
| 李冰: "酒石酸布托啡诺的合成工艺研究" * |
| 聂建军: "《药物化学》", 1 December 2015, 吉林大学出版社 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN116818928A (en) * | 2023-04-28 | 2023-09-29 | 杭州沐源生物医药科技有限公司 | Separation detection method for impurities in butorphanol tartrate injection |
| CN116818928B (en) * | 2023-04-28 | 2024-04-19 | 杭州沐源生物医药科技有限公司 | Separation detection method for impurities in butorphanol tartrate injection |
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