WO2022199707A1 - Sel pharmaceutiquement acceptable de pimavansérine, procédé de préparation associé, composition pharmaceutique la contenant et utilisation associée - Google Patents
Sel pharmaceutiquement acceptable de pimavansérine, procédé de préparation associé, composition pharmaceutique la contenant et utilisation associée Download PDFInfo
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- WO2022199707A1 WO2022199707A1 PCT/CN2022/083287 CN2022083287W WO2022199707A1 WO 2022199707 A1 WO2022199707 A1 WO 2022199707A1 CN 2022083287 W CN2022083287 W CN 2022083287W WO 2022199707 A1 WO2022199707 A1 WO 2022199707A1
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- WIPO (PCT)
- Prior art keywords
- pimaserin
- solvent
- acid
- hydroxy
- preparation
- Prior art date
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- 150000003839 salts Chemical class 0.000 title claims abstract description 74
- 238000002360 preparation method Methods 0.000 title claims abstract description 73
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 13
- RKEWSXXUOLRFBX-UHFFFAOYSA-N pimavanserin Chemical compound C1=CC(OCC(C)C)=CC=C1CNC(=O)N(C1CCN(C)CC1)CC1=CC=C(F)C=C1 RKEWSXXUOLRFBX-UHFFFAOYSA-N 0.000 title abstract description 8
- 229960003300 pimavanserin Drugs 0.000 title abstract description 5
- 150000007524 organic acids Chemical class 0.000 claims abstract description 14
- 239000002904 solvent Substances 0.000 claims description 178
- 239000013078 crystal Substances 0.000 claims description 115
- 238000003756 stirring Methods 0.000 claims description 81
- SJJCQDRGABAVBB-UHFFFAOYSA-N 1-hydroxy-2-naphthoic acid Chemical compound C1=CC=CC2=C(O)C(C(=O)O)=CC=C21 SJJCQDRGABAVBB-UHFFFAOYSA-N 0.000 claims description 80
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 69
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- 238000000634 powder X-ray diffraction Methods 0.000 claims description 50
- -1 1-hydroxy-2-naphthoate monohydrate Chemical compound 0.000 claims description 48
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 48
- 238000000034 method Methods 0.000 claims description 46
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 45
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 40
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 36
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- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 33
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- 230000008025 crystallization Effects 0.000 claims description 25
- 238000006243 chemical reaction Methods 0.000 claims description 24
- WLJNZVDCPSBLRP-UHFFFAOYSA-N pamoic acid Chemical compound C1=CC=C2C(CC=3C4=CC=CC=C4C=C(C=3O)C(=O)O)=C(O)C(C(O)=O)=CC2=C1 WLJNZVDCPSBLRP-UHFFFAOYSA-N 0.000 claims description 22
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 20
- UKMSUNONTOPOIO-UHFFFAOYSA-N docosanoic acid Chemical compound CCCCCCCCCCCCCCCCCCCCCC(O)=O UKMSUNONTOPOIO-UHFFFAOYSA-N 0.000 claims description 20
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- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 18
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- 231100000868 delusion Toxicity 0.000 claims description 6
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- GHVNFZFCNZKVNT-UHFFFAOYSA-N decanoic acid Chemical compound CCCCCCCCCC(O)=O GHVNFZFCNZKVNT-UHFFFAOYSA-N 0.000 claims description 4
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- VXZBFBRLRNDJCS-UHFFFAOYSA-N heptacosanoic acid Chemical compound CCCCCCCCCCCCCCCCCCCCCCCCCCC(O)=O VXZBFBRLRNDJCS-UHFFFAOYSA-N 0.000 claims description 4
- KEMQGTRYUADPNZ-UHFFFAOYSA-N heptadecanoic acid Chemical compound CCCCCCCCCCCCCCCCC(O)=O KEMQGTRYUADPNZ-UHFFFAOYSA-N 0.000 claims description 4
- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 claims description 4
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- ISYWECDDZWTKFF-UHFFFAOYSA-N nonadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCCC(O)=O ISYWECDDZWTKFF-UHFFFAOYSA-N 0.000 claims description 4
- BDJRBEYXGGNYIS-UHFFFAOYSA-N nonanedioic acid Chemical compound OC(=O)CCCCCCCC(O)=O BDJRBEYXGGNYIS-UHFFFAOYSA-N 0.000 claims description 4
- FBUKVWPVBMHYJY-UHFFFAOYSA-N nonanoic acid Chemical compound CCCCCCCCC(O)=O FBUKVWPVBMHYJY-UHFFFAOYSA-N 0.000 claims description 4
- UTOPWMOLSKOLTQ-UHFFFAOYSA-N octacosanoic acid Chemical compound CCCCCCCCCCCCCCCCCCCCCCCCCCCC(O)=O UTOPWMOLSKOLTQ-UHFFFAOYSA-N 0.000 claims description 4
- CXMXRPHRNRROMY-UHFFFAOYSA-N sebacic acid Chemical compound OC(=O)CCCCCCCCC(O)=O CXMXRPHRNRROMY-UHFFFAOYSA-N 0.000 claims description 4
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- YAQXGBBDJYBXKL-UHFFFAOYSA-N iron(2+);1,10-phenanthroline;dicyanide Chemical compound [Fe+2].N#[C-].N#[C-].C1=CN=C2C3=NC=CC=C3C=CC2=C1.C1=CN=C2C3=NC=CC=C3C=CC2=C1 YAQXGBBDJYBXKL-UHFFFAOYSA-N 0.000 claims description 3
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- QVZZOQYGVUGLSI-UHFFFAOYSA-N n,n-dimethylformamide;formamide Chemical compound NC=O.CN(C)C=O QVZZOQYGVUGLSI-UHFFFAOYSA-N 0.000 description 1
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- RQFLGKYCYMMRMC-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O.CCCCCCCCCCCCCCCCCC(O)=O RQFLGKYCYMMRMC-UHFFFAOYSA-N 0.000 description 1
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- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
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Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/56—Nitrogen atoms
- C07D211/58—Nitrogen atoms attached in position 4
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4468—Non condensed piperidines, e.g. piperocaine having a nitrogen directly attached in position 4, e.g. clebopride, fentanyl
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
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- 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
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/41—Preparation of salts of carboxylic acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/41—Preparation of salts of carboxylic acids
- C07C51/412—Preparation of salts of carboxylic acids by conversion of the acids, their salts, esters or anhydrides with the same carboxylic acid part
-
- 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
- C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C65/01—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups
- C07C65/105—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups polycyclic
- C07C65/11—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups polycyclic with carboxyl groups on a condensed ring system containing two rings
-
- 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
Definitions
- the invention belongs to the technical field of medicine, and in particular relates to a medicinal salt of pimaserin and a preparation method and application thereof.
- Pimavanserin is an atypical antipsychotic that is an inverse agonist and antagonist of the serotonin 5-HT2A receptor.
- Pemaserin is available in the United States as form of sales. Contains pemaserin hemitartrate, indicated for the treatment of hallucinations and delusions associated with Parkinson's disease psychosis (also known as PDP), and is widely used clinically.
- Pimaserin N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N'-(4-(2-methylpropoxy)-phenyl Methyl)urea
- the molecular formula is C 25 H 34 FN 3 O 2
- the molecular weight is 427.55
- the CAS number is 706779-91-1
- the chemical structural formula is shown in the following formula.
- pimaserin tablets and capsules the raw material of which is pimaserin hemi-tartrate crystal form C, which are oral preparations that require daily administration and can only reach effective plasma levels within a limited time range . Due to the need for frequent dosing, the patient's medication compliance is poor.
- Patent document CN 101031548 A discloses various salt forms of pimaserin (including phosphate, sulfate, nitrate, diphosphate, bicarbonate, carbonate, clavulanate, isothiosulfate, borate, halide, acetate, succinate, lactate, lactobionate, laurate, mandelate, malate, citrate, fumarate, maleate, oleate , oxalate, ascorbate, nicotinate, benzoate, mesylate, salicylate, stearate, tannin, tosylate, valerate, ethanesulfonate , benzenesulfonate, p-toluenesulfonate, 2-ethanedisulfonate and naphthoate) and compositions comprising these salts; and further discloses citrate, fumarate, maleate, Crystal form, preparation method and solubility in water of malate, phosphate, succinate,
- Patent document CN 1816524A discloses pimaserin L-tartrate.
- Patent document CN 101035759 A discloses pimaserin hemitartrate crystal form A to crystal form F, and discloses that crystal form C is highly water-soluble, with a solubility of about 50 to 100 mg/mL, and crystal forms A, B, D, E and F has a high water solubility higher than 200 mg/mL, and Form C has higher thermodynamic and chemical stability than Form A or Form B.
- Patent document CN 106916098 A discloses pimaserin monotartrate hemihydrate.
- Patent document CZ 2015702 A discloses pimaserin dibenzoyl L-tartrate, hydrochloride, p-toluenesulfonate, benzenesulfonate, 4-hydroxybenzoate, benzoate, Hydrobromide, mesylate and their crystalline or amorphous forms.
- Patent document WO 2018007842 A1 discloses pimaserin besylate, cyclamate, p-toluenesulfonate, benzoate and mandelate.
- pimaserin salts and their crystalline forms that can prolong the efficacy of the drug and are suitable for long-acting preparations, so as to ensure that the drug can play a long-term role in the patient's body. Reduce the frequency of medication and improve the clinical efficacy of patients.
- sustained-release dosage form of pemaserin and a pimaserin salt and its crystalline form suitable for the application of the sustained-release dosage form are very useful for maintaining treatment and improving patient compliance.
- the present invention provides a medicinal salt of pimaserin, which is a salt formed by pimaserin free base and an organic acid having more than six carbons, wherein the structure of pimaserin free base is as formula I shown:
- the organic acids with more than six carbons in the present invention are C6 - C30 organic acids, including but not limited to: caproic acid, heptanoic acid, octanoic acid, nonanoic acid, azelaic acid, capric acid, sebacic acid, tenacic acid Monodecanoic acid, lauric acid (dodecanoic acid), tridecanoic acid, myristic acid (tetradecanoic acid), pentadecanoic acid, palmitic acid (hexadecanoic acid), heptadecanoic acid, stearic acid (octadecanoic acid), nonadecanoic acid, eicosanoic acid (arachidic acid), oleic acid, behenic acid, behenic acid, behenic acid, behenic acid, eicosanoic acid Pentadecanoic acid, behenic acid, heptacosanoic acid, octaco
- the medicinal salt of pimaserin is pimaserin hemipamoate or pimaserin 1-hydroxy-2-naphthoate.
- the pharmaceutical salt of pimaserin is in the form of crystal, polymorph or amorphous.
- the pharmaceutically acceptable salt of pimaserin includes its solvate formed with a solvent.
- the "solvate” includes a hydrate of a pharmaceutically acceptable salt of pimaserin or a solvate formed by a pharmaceutically acceptable salt of pimaserin and an organic solvent.
- the organic solvent can be one, two or more of methanol, ethanol, dimethyl sulfoxide and N,N-dimethylformamide, preferably methanol and/or N,N-dimethylformamide formamide.
- the pimaserin hemipamoic acid salt is a salt formed by compounding pimaserin and pamoic acid in a molar ratio of 1:0.5.
- the pimaserin hemi-pamoate salt may be a pimaserin hemi-pamoate crystal form A, a pimaserin hemi-pamoate crystal form B or an amorphous form.
- the X-ray powder diffraction pattern of the crystalline form A of pimaserin hemipramogenate has 2 ⁇ values of 3.3° ⁇ 0.2°, 6.7° ⁇ 0.2°, and 7.5° ⁇ 0.2°. Diffraction peaks.
- the X-ray powder diffractogram of the crystalline form A of pemaserin hemipamoate has 2 ⁇ values of 3.3° ⁇ 0.2°, 6.7° ⁇ 0.2°, 7.5° ⁇ 0.2°, 12.2° ⁇ 0.2° , 13.7° ⁇ 0.2°, and 17.0° ⁇ 0.2° have diffraction peaks.
- the X-ray powder diffraction pattern of the crystalline form A of pemaserin hemipamoate has 2 ⁇ values of 3.3° ⁇ 0.2°, 6.7° ⁇ 0.2°, 7.5° ⁇ 0.2°, 12.2° ⁇ 0.2 There are diffraction peaks at °, 13.7° ⁇ 0.2°, 17.0° ⁇ 0.2°, 19.5° ⁇ 0.2°, 20.4° ⁇ 0.2°, and 21.1° ⁇ 0.2°.
- the X-ray powder diffraction pattern of the pimaserine hemipamoate crystal form A is basically as shown in FIG. 6 .
- the differential scanning calorimetry analysis diagram of the crystalline form A of pimaserin hemipamoate is substantially as shown in FIG. 4 , and FIG. 4 shows that its melting point is about 180° C., and the peak value is about 186° C. °C.
- thermogravimetric analysis diagram of the crystalline form A of the pimaserin hemipamoate salt is substantially as shown in FIG. 5 , and FIG. 5 shows that the weight loss at 100° C. is about 0.2%.
- the X-ray powder diffraction pattern of the crystalline form B of pimaserin hemipamoate has 2 ⁇ values of 6.1° ⁇ 0.2°, 8.6° ⁇ 0.2°, and 19.9° ⁇ 0.2°. Diffraction peaks.
- the X-ray powder diffractogram of the crystalline form B of pemaserin hemipamoate has 2 ⁇ values of 6.1° ⁇ 0.2°, 8.6° ⁇ 0.2°, 19.9° ⁇ 0.2°, 9.6° ⁇ 0.2° , 13.0° ⁇ 0.2°, 17.9° ⁇ 0.2°, 19.9° ⁇ 0.2° have diffraction peaks.
- the X-ray powder diffraction pattern of the crystalline form B of pemaserin hemipamoate has 2 ⁇ values of 6.1° ⁇ 0.2°, 8.6° ⁇ 0.2°, 9.6° ⁇ 0.2°, 13.0° ⁇ 0.2 °, 13.3° ⁇ 0.2°, 15.6° ⁇ 0.2°, 17.0° ⁇ 0.2°, 17.3° ⁇ 0.2°, 17.9° ⁇ 0.2°, 18.9° ⁇ 0.2°, 19.1° ⁇ 0.2°, 19.9° ⁇ 0.2°, There are absorption peaks at 20.2° ⁇ 0.2° and 20.7° ⁇ 0.2°.
- the X-ray powder diffraction pattern of the pemaserin hemipamoate crystal form B is basically as shown in FIG. 8 .
- the 1-hydroxy-2-naphthoic acid salt of pimaserin is a salt formed by compounding pimaserin and 1-hydroxy-2-naphthoic acid in a molar ratio of 1:1, which can be It is the crystalline form A of pimaserin 1-hydroxy-2-naphthoate or the crystalline form B of pimaserin 1-hydroxy-2-naphthoate monohydrate.
- the X-ray powder diffraction pattern of the 1-hydroxy-2-naphthoate crystalline form A of pimaserin has 2 ⁇ values of 4.3° ⁇ 0.2°, 13.2° ⁇ 0.2°, 18.6° There are diffraction peaks at ⁇ 0.2°.
- the X-ray powder diffraction pattern of the 1-hydroxy-2-naphthoate crystalline form A of pimaserin has 2 ⁇ values of 4.3° ⁇ 0.2°, 8.8° ⁇ 0.2°, 13.2° ⁇ 0.2°, There are characteristic peaks at 17.7° ⁇ 0.2°, 18.6° ⁇ 0.2°, and 20.2° ⁇ 0.2°.
- the X-ray powder diffraction pattern of the 1-hydroxy-2-naphthoate crystalline form A of pimaserin has 2 ⁇ values of 4.3° ⁇ 0.2°, 7.7° ⁇ 0.2°, 8.8° ⁇ 0.2° , 13.2° ⁇ 0.2°, 17.0° ⁇ 0.2°, 17.7° ⁇ 0.2°, 18.6° ⁇ 0.2°, 19.0° ⁇ 0.2°, 20.2° ⁇ 0.2° have absorption peaks.
- the X-ray powder diffraction pattern of the 1-hydroxy-2-naphthoate crystalline form A of pimaserin has 2 ⁇ values of 4.3° ⁇ 0.2°, 7.7° ⁇ 0.2°, 8.8° ⁇ 0.2° , 11.4° ⁇ 0.2°, 13.2° ⁇ 0.2°, 15.1° ⁇ 0.2°, 17.0° ⁇ 0.2°, 17.7° ⁇ 0.2°, 18.6° ⁇ 0.2°, 19.0° ⁇ 0.2°, 20.2° ⁇ 0.2°, 20.6 There are absorption peaks at ° ⁇ 0.2°, 21.3° ⁇ 0.2°, 21.6° ⁇ 0.2°, 22.7° ⁇ 0.2°, and 25.8° ⁇ 0.2°.
- the X-ray powder diffraction pattern of the 1-hydroxy-2-naphthoate crystalline form A of pemaserin is basically as shown in FIG. 11 .
- the differential scanning calorimetry analysis diagram of the 1-hydroxy-2-naphthoate crystalline form A of pimaserin is substantially as shown in FIG. 9 , and FIG. 9 shows that its melting point is about 166° C. , the peak value is about 169°C.
- thermogravimetric analysis diagram of the 1-hydroxy-2-naphthoate crystalline form A of Pimaserin is substantially as shown in FIG. 10 , and FIG. 10 shows that its weight loss at 100° C. is about 0.05% .
- the X-ray powder diffraction pattern of the 1-hydroxy-2-naphthoate monohydrate crystal form B of pimaserin has 2 ⁇ values of 3.8° ⁇ 0.2°, 7.8° ⁇ 0.2° , There are diffraction peaks at 14.2° ⁇ 0.2°.
- the X-ray powder diffraction pattern of the 1-hydroxy-2-naphthoate monohydrate crystal form B of pimaserin has 2 ⁇ values of 3.8° ⁇ 0.2°, 7.8° ⁇ 0.2°, 14.2° ⁇ There are diffraction peaks at 0.2°, 15.7° ⁇ 0.2°, 17.7° ⁇ 0.2°, and 20.2° ⁇ 0.2°.
- the X-ray powder diffraction pattern of the 1-hydroxy-2-naphthoate monohydrate crystal form B of pimaserin has 2 ⁇ values of 3.8° ⁇ 0.2°, 7.8° ⁇ 0.2°, 11.7° There are diffraction peaks at ⁇ 0.2°, 14.2° ⁇ 0.2°, 15.7° ⁇ 0.2°, 17.7° ⁇ 0.2°, 21.3° ⁇ 0.2°, and 22.4° ⁇ 0.2°.
- the X-ray powder diffraction pattern of the 1-hydroxy-2-naphthoate monohydrate crystal form B of pimaserin has 2 ⁇ values of 3.8° ⁇ 0.2°, 7.8° ⁇ 0.2°, 11.7° ⁇ 0.2°, 14.2° ⁇ 0.2°, 15.7° ⁇ 0.2°, 17.7° ⁇ 0.2°, 21.3° ⁇ 0.2°, 22.4° ⁇ 0.2°, 23.0° ⁇ 0.2°, 25.3° ⁇ 0.2°, 26.8° ⁇ 0.2 There is an absorption peak at °.
- the X-ray powder diffraction pattern of the 1-hydroxy-2-naphthoate monohydrate crystal form B of Pimaserin is basically as shown in FIG. 14 .
- the differential scanning calorimetry analysis diagram of the 1-hydroxy-2-naphthoate monohydrate crystal form B of Pimaserin is basically as shown in FIG. 12 , and FIG. 12 shows that it is in There is an endothermic peak between 100°C and 150°C, which is caused by the removal of crystal water, the melting point is about 168°C, and the peak is about 169°C.
- thermogravimetric analysis diagram of the 1-hydroxy-2-naphthoate monohydrate crystal form B of Pimaserin is basically as shown in FIG. 13 , and FIG. 13 shows that it is before 110° C. There is a period of about 2.6% weight loss, which is about one molecule of crystal water, which is the crystalline form of Pimaserin 1-hydroxy-2-naphthoate monohydrate.
- the NMR data of the 1-hydroxy-2-naphthoate monohydrate crystal form B of pimaserin shows that pimaserin and 1-hydroxy-2-naphthoic acid have a molar ratio of 1 :1 into salt.
- the present invention also provides the above-mentioned preparation method of the pharmaceutical salt of pimaserin, which comprises the following steps: reacting the free base of pimaserin with the organic acid with more than six carbons.
- the reaction may be referred to as a "salt formation reaction” or a “neutralization reaction”.
- the preparation method of the pharmaceutical salt of pimaserin is carried out in a solvent selected from the group consisting of water, methanol, ethyl acetate, tetrahydrofuran, isopropanol, dichloromethane, N, One, two or more of N-dimethylformamide, acetone, methyl tert-butyl ether and isopropyl ether solvents.
- the mass-volume ratio of pimaserin to the organic solvent is (1:10) g/mL ⁇ (1:50) g/mL Or 20 ⁇ 600mg/mL, preferably (1:10)g/mL ⁇ (1:30)g/mL or 40 ⁇ 550mg/mL; for example 50mg/mL, 214mg/mL, 42.8mg/mL, 416.7mg/mL , 400 mg/mL, 501 mg/mL, 90.8 mg/mL, 166.7 mg/mL or 142.7 mg/mL.
- the molar ratio of pimaserin to the organic acid is preferably (1:0.5) ⁇ (1:3), more preferably (1:0.5) ) ⁇ (1:1), for example (2 ⁇ 0.33):1, preferably (2 ⁇ 0.5):1; for example 1.9:1, 1.8:1, 1.55:1, 1.33:1, 1.40:1, 0.88: 1 or 0.83:1.
- the reaction temperature may be 0-80°C, preferably 25°C-65°C, for example 20°C-35°C.
- the reaction time in the preparation method of the pharmaceutically acceptable salt of pimaserin, can be monitored by a conventional detection method in the art (such as TLC, HPLC or NMR), generally with pimaserin
- a conventional detection method in the art such as TLC, HPLC or NMR
- the end of the reaction is when the free base disappears, and the reaction time is 0.5 hours to 10 days, preferably 1 hour to 7 days.
- the preparation method of the pharmaceutical salt of pimaserin comprises the following steps:
- Method 1 Mix the solution formed by pimasholine and a good solvent with an organic acid, and then add a poor solvent to crystallize; or,
- Method 2 Add the solution formed by pimazoline, good solvent and organic acid into poor solvent, and crystallize; or,
- Method 3 removing the solvent from the solution formed by the pimachromoline, the solvent and the organic acid for crystallization; the solvent is a good solvent or a mixed solvent of a good solvent and a poor solvent.
- the preparation method of the Pimaserin Hemipamoate Crystal Form A is selected from one of the following methods:
- Method (a3) adding pimaserine and pamoic acid to a good solvent for stirring reaction, filtering, adding the filtrate to a poor solvent, optionally, adding a crystalline form of pimaserine hemipamoate to the poor solvent A seed crystal, stirring and crystallization.
- the good solvent is an alcohol solvent (eg methanol), a ketone solvent (eg acetone), an ester solvent (eg ethyl acetate) ), acetonitrile, dichloromethane, chloroform, toluene, tetrahydrofuran, 2-methyltetrahydrofuran, one, two or more of N,N-dimethylformamide and N,N-dimethylacetamide .
- alcohol solvent eg methanol
- a ketone solvent eg acetone
- an ester solvent eg ethyl acetate
- the poor solvent is an alkane-based solvent, an ether-based solvent (such as isopropyl ether or methyl tert-butyl ether) and a solvent in water One, two or more.
- the molar ratio of pimaserin to pamoic acid in the methods (a1), (a2) and (a3) is (0.5-2):1, for example 0.88:1, 1.8:1 or 1.9:1;
- the mass-volume ratio of the pimaserin to the good solvent is 40-214 mg/mL, for example, 50 mg/mL or 214 mg/mL; when the method (a3) is adopted , the mass-volume ratio of the pimaserin to the good solvent is 416-501 mg/mL, for example, 416.7 mg/mL, 400 mg/mL or 501 mg/mL.
- the volume ratio of the poor solvent to the good solvent is (5-9):1, such as 8:1 or 9:1; when the method (3) is adopted, the The volume ratio of the poor solvent to the good solvent is (4-21):1, for example, 20.8:1, 4:1 or 20:1.
- the temperature for stirring and crystallization is room temperature.
- the stirring and crystallization time is 18 hours to 7 days.
- the stirring and crystallization time is 18-24 hours.
- the preparation method of the pimaserin hemipamoate crystal form B includes the following steps: dispersing pamoic acid in a solvent to obtain a suspension, dissolving pimaserine in a solvent to obtain a free base solution, the free base solution is added dropwise to the suspension and the reaction is stirred; optionally, in the process of stirring the reaction, the crystal form A of the pimaserin hemipamoate as described above is added as a seed crystal.
- the solvent in the method for preparing the crystalline form B of pimaserin hemipamoate is selected from ester solvents, such as ethyl acetate.
- the method for preparing the amorphous form of pimaserin hemipamoate comprises the following steps: dissolving pemaserin hemipamoate in a solvent, and volatilizing the solvent until the solvent is dry to obtain pemaserin Linsemipamoate amorphous.
- the solvent in the amorphous preparation method is an alcohol solvent (eg methanol), a ketone solvent (eg acetone), an ester solvent, an ether solvent (eg tetrahydrofuran, 2-methyltetrahydrofuran), One, two or more of alkane-based solvents, acetonitrile, dichloromethane, chloroform, toluene, N,N-dimethylformamide, N,N-dimethylacetamide, and water.
- an alcohol solvent eg methanol
- a ketone solvent eg acetone
- an ester solvent eg tetrahydrofuran, 2-methyltetrahydrofuran
- an ether solvent eg tetrahydrofuran, 2-methyltetrahydrofuran
- the mass-to-volume ratio of the pimaserin hemipamoate to the solvent may be 1-500 mg/mL, preferably 10-125 mg/mL, such as 90.8 mg/mL, 20.8 mg/mL, 10mg/mL or 125mg/mL.
- the volatilization mode may be normal pressure volatilization or reduced pressure volatilization.
- the volatilization temperature may be 0-60°C, preferably 20-40°C.
- the preparation method of the 1-hydroxy-2-naphthoate crystalline form A of Pimaserin is selected from one of the following methods:
- Method (b1) separately form a solution of pimaserin and 1-hydroxy-2-naphthoic acid in a good solvent, add the acid solution dropwise to the alkali solution under stirring, stir to react, add a poor solvent, and stir to crystallize; or,
- Method (b2) separately form a solution of pimaserin and 1-hydroxy-2-naphthoic acid in a good solvent, add the acid solution dropwise to the alkali solution under stirring, and crystallize by stirring.
- the good solvent is selected from one, two or three kinds of N,N-dimethylformamide, N,N-dimethylacetamide and dimethyl sulfoxide, preferably N,N-dimethylformamide. amide;
- the mass ratio of described pimaserin and 1-hydroxy-2-naphthoic acid is 2:1;
- the poor solvent is selected from one, two or three kinds of alkane solvents, ether solvents and water, preferably water;
- the volume ratio of the poor solvent to the good solvent is (1-20):1, for example, 8:1.
- the temperature of the stirring and crystallization can be room temperature, and the time of stirring and crystallization can be 1-12 hours.
- the good solvent is an alcohol solvent and/or an ester solvent, and the alcohol solvent is preferably isopropanol; the ester solvent is preferably ethyl acetate.
- the volume-to-mass ratio of the good solvent to pemaserin is 1 mL/g to 25 mL/g, for example, 6 mL/g, 15 mL/g or 23.4 mL/g.
- the molar ratio of the described pimaserin and 1-hydroxy-2-naphthoic acid is preferably (0.5 ⁇ 1.5):1, for example 0.83:1;
- the temperature of the stirring and crystallization is room temperature, and the time of stirring and crystallization is 18-24 hours.
- the preparation method of the Pimaserin 1-hydroxy-2-naphthoate monohydrate crystal form B is selected from one of the following methods:
- the good solvent is a ketone solvent, preferably acetone.
- the molar ratio of the pimaserin to the 1-hydroxy-2-naphthoic acid is (0.5-1.5):1, for example, 0.88:1.
- the temperature of the stirring reaction is room temperature, and the time of the stirring reaction is 1-12 hours.
- the poor solvent is one, two or three kinds of alkane solvents, ether solvents and water, preferably water.
- the volume ratio of the poor solvent to the good solvent is (1-20):1, for example, 8:1.
- the temperature of the stirring and crystallization is room temperature, and the time of the stirring and crystallization is 1-12 hours.
- the solvent is one, two or more of alcohol-based solvent, ketone-based solvent, ester-based solvent, ether-based solvent, alkane-based solvent, dichloromethane, chloroform, dimethyl sulfoxide and water.
- the alcohol solvent is preferably methanol.
- the ester solvent is preferably ethyl acetate.
- the ether solvent is preferably tetrahydrofuran.
- the volatilization temperature is room temperature.
- Described solvent is selected from the mixed solvent that water or water and organic solvent form;
- Described organic solvent is selected from one in alcohol solvent, ester solvent, ketone solvent, ether solvent, nitrile solvent and amide solvent.
- the alcohol solvent is preferably one, two or more of methanol, ethanol, n-propanol and isopropanol.
- the ester solvent is preferably ethyl acetate and isopropyl acetate.
- the ketone solvent is preferably acetone.
- the nitrile solvent is preferably acetonitrile.
- the ether solvent is preferably tetrahydrofuran.
- the amide solvent is preferably N,N-dimethylformamide.
- the volume ratio of the water to the organic solvent is preferably (1-5):1, such as 4:1, 5:1, 3.5:1, 2.5:1 or 2:1.
- the solvent is further preferably a mixed solvent of ethanol and water, a mixed solvent of methanol and water, a mixed solvent of acetone and water, a mixed solvent of tetrahydrofuran and water, a mixed solvent of n-propanol and water, a mixed solvent of acetonitrile and water, N , Mixed solvent of N-dimethylformamide and water, isopropanol or ethyl acetate.
- the volume-to-mass ratio of the solvent to pimazoline is preferably 10 mg/mL to 50 mg/mL, for example, 30 mg/mL or 35 mg/mL.
- Described stirring temperature is 10 °C ⁇ 60 °C;
- the stirring time is 3 to 10 days.
- the good solvent is alcohol solvent, ketone solvent, tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, tetrahydrofuran, acetonitrile, 1,4-dioxane One, two or more of hexacyclic, dichloromethane and chloroform;
- the poor solvent is one, two or three kinds of alkane solvents, ether solvents and water.
- the high temperature is 60°C ⁇ 80°C;
- the solvent is selected from alcohol solvents, ketone solvents, ether solvents, ester solvents, dichloromethane, chloroform, tetrahydrofuran, 1,4-dioxane, acetonitrile, toluene, dimethyl sulfoxide and water. One, two or more.
- the present invention also provides the use of the pharmaceutical salt of pemaserin as described above in the preparation of a medicament for preventing, treating or ameliorating the frequency and/or severity of hallucinations, delusions, and/or delusions associated with Parkinson's psychosis.
- the present invention also provides a pharmaceutical composition comprising the pharmaceutically acceptable salt of pimaserin as described above.
- the pharmaceutical composition may further include pharmaceutically acceptable excipients.
- the purpose of the pharmaceutical composition is to facilitate the administration of the compound to a patient in need thereof, such as a human or other mammalian organism.
- the pharmaceutically acceptable adjuvants include one, two or more of physiologically or pharmaceutically acceptable carriers, diluents, vehicles and/or excipients.
- the present invention also provides a pimaserin pharmaceutical preparation, which comprises the pimaserin pharmaceutical salt or the pimaserin pharmaceutical composition.
- the dosage forms of the pharmaceutical preparations of pimaserin include but are not limited to tablets, capsules, solutions, suspensions and semi-solid preparations.
- the pharmaceutical preparation of pimaserin is a pharmaceutically acceptable salt suspension of pimaserin.
- the pimaserin pharmaceutical salt suspension may further include auxiliary materials, and the auxiliary materials may be selected from suspending agents, wetting agents, osmotic pressure regulators, solvents, stabilizers, buffers and One, two or more of the surfactants.
- the concentration of the solid particles of pemaserin in the pimaserin pharmaceutical salt suspension is 62 mg/mL to 124 mg/mL.
- the pimaserin solid particles are pimaserin, pimaserin pharmaceutically acceptable salts, and the pimaserin pharmaceutically acceptable salts include but are not limited to pimaserin hemipamoic acid salt and pimaserin 1-hydroxy-2-naphthoate.
- the concentration of the wetting agent ranges from 1 mg/mL to 10 mg/mL, preferably from 1 mg/mL to 5 mg/mL, such as 1 mg/mL, 1.5 mg/mL, 2.0 mg/mL, 2.5 mg/mL, 3.0 mg/mL, 3.5 mg/mL, 4.0 mg/mL, 4.5 mg/mL or 5.0 mg/mL.
- the wetting agent is selected from one, two or three of Tween 20, Tween 80 and Poloxamer 188, preferably Poloxamer 188.
- the buffering agent is selected from one, two or more of phosphoric acid, phosphate, citric acid, sodium citrate, hydrochloric acid and sodium hydroxide.
- the preparation method of the pharmaceutical salt suspension of pimaserin comprises the following steps:
- step (e3) add the solution prepared by step (e2) to the sieved pimaserin medicinal salt solid particles, fully wet and disperse;
- the present invention also provides a method for preventing, treating or ameliorating the frequency and/or severity of hallucinations, delusions, and/or delusions associated with Parkinson's psychosis, comprising adding a pharmaceutically acceptable salt of pimaserin as described above, or a pharmaceutical composition thereof, Or a pharmaceutical formulation of pimaserin is administered to a patient in need thereof.
- the "crystal” described in the present invention is a structure in which a large number of microscopic material units (atoms, ions, molecules, etc.) are arranged in an orderly manner according to certain rules.
- polymorphism refers to different crystalline forms and other solid-state molecular forms of the same compound, for example, including two or more crystalline forms and/or amorphous forms of the pharmaceutically acceptable salt of pimaserin form of solid.
- Amorphous refers to the constitution of an amorphous solid (amorphous).
- the "carrier”, “diluent”, “vehicle” or “excipient” refers to a substance (or substances) that can be included with a specific agent to form a drug composition, and can be solid or liquid.
- the solid carriers include but are not limited to starch, calcium sulfate dihydrate, terra alba, talc, lactose, sucrose, mica, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like.
- the liquid carrier includes, but is not limited to, syrup, peanut oil, olive oil, saline solution, water, and the like.
- the carrier or diluent may include delayed or timed release materials known in the art, such as monostearic acid alone or in combination with waxes, ethyl cellulose, hypromellose, methyl methacrylate, and the like Glycerides or Glyceryl Distearate.
- the "pharmaceutically acceptable excipients” refer to the following substances, which are suitable for contact with the patient's tissue without inappropriate toxicity, irritation, allergic reaction within the scope of normal medical judgment etc., have a reasonable ratio of pros and cons, and can be effectively used for their intended purpose.
- the "solvate” refers to a molecular complex comprising a drug (eg, pimaserin) and a stoichiometric or non-stoichiometric amount of one or more pharmaceutically acceptable solvent molecules (eg, water).
- a drug eg, pimaserin
- solvent molecules eg, water
- the complex formed has a well-defined stoichiometry independent of humidity.
- the solvent is weakly binding (as in channel solvates and hygroscopic compounds)
- the solvent content is dependent on humidity and drying conditions.
- the complex is generally non-stoichiometric.
- the "hydrate” refers to a solvate containing a drug (eg, pimaserin) and stoichiometric or non-stoichiometric water.
- the “overnight” means that the time is 12 to 24 hours.
- the "patient” includes organisms such as humans or other mammals.
- the reagents and raw materials used in the present invention are all commercially available.
- the room temperature refers to the ambient temperature, which is generally 0°C to 35°C.
- the technical problem to be solved by the present invention is to provide a medicinal salt of pimaserin, a preparation method, The pharmaceutical composition containing it and the application of the pharmaceutical composition.
- the medicinal salt of pimaserin provided by the invention has no pH dependence, has low solubility in water (compared with the existing salt form, its solubility is significantly reduced), good stability, simple and convenient preparation method, and is suitable for industrialization Production.
- the NMR test was carried out on Bruker Advance III 500M nuclear magnetic resonance spectrometer, the measurement frequency was 400Mz/600Mz, and the solvent was deuterated DMSO.
- the TGA measurement was carried out in a TA Instruments model Q2000 device, and the sample (about 2-5 mg) was weighed in a platinum pan and transferred to the instrument for measurement.
- the test parameters are as follows: the instrument is heated to 350°C at a rate of 10°C/min, and the experimental atmosphere is nitrogen.
- XRPD measurements were performed in a Bruker model D8 Advance X-ray powder diffractometer using a circular zero-background single crystal silicon sample stage.
- the scanning parameters are as follows: voltage 40kv, current 40mA, scanning range 3°-45°, scanning step size 0.02°, and scanning mode is continuous scanning.
- the X-ray powder diffraction pattern of pimaserin free base at 2 ⁇ is approximately 6.790°, 8.093°, 12.945°, 13.655°, 14.364°, 14.901°, 17.012°, 17.687°, 19.045°, 19.697°, 20.839°, There are diffraction peaks at 21.036°, 22.219°, 24.531°, 25.219°, 25.733°, 27.133°, 27.922°, 28.971°, 30.669° and 32.935°, with an error range of ⁇ 0.2°.
- DSC Differential scanning calorimetry
- TGA Thermogravimetric analysis
- DSC Differential scanning calorimetry curve
- Thermogravimetric analysis showed that the weight loss of pemaserin hemipamoic acid was 0.2270% at 100°C, see Figure 5 for details.
- PLM Polarized light microscopy
- X-ray powder diffractogram shows that pimaserin hemipamoate has diffraction peaks, and it is judged to be a crystalline form based on PLM, and it is named as pimaserin hemipamoate crystal form A, as shown in the figure for details. 6.
- Embodiment 10 Preparation of amorphous form of pemaserin hemipamoate
- Example 3 Take 25 mg of the Pimaserin crystal form A sample prepared in Example 3, add 2 mL of acetone to dissolve it, and volatilize it to dryness at room temperature and pressure. The obtained sample is characterized by PLM, and it is a non-polarized solid.
- DSC Differential scanning calorimetry
- TGA Thermogravimetric analysis
- DSC Differential scanning calorimetry
- TGA Thermogravimetric analysis
- Pimaserin 1-hydroxy-2-naphthoate The X-ray powder diffraction pattern of Pimaserin 1-hydroxy-2-naphthoate is shown in Figure 14, which has a diffraction peak different from that of Pimaserin 1-hydroxy-2-naphthoate crystal form A, which is a This new crystal form can be determined to be a monohydrate with reference to Figure 13, so it is named Pimaserin 1-hydroxy-2-naphthoate monohydrate crystal form B.
- Pimaserin 1-hydroxy-2-naphthoate crystal form A prepared in Example 16 Take 30 mg of Pimaserin 1-hydroxy-2-naphthoate crystal form A prepared in Example 16, add 1 mL of water and 1 mL of ethanol, stir to dissolve at 60°C, and keep it at room temperature for about 2 minutes and stir for 24 hours. , centrifugation, and drying to obtain the crystalline form B of pimaserin 1-hydroxy-2-naphthoate monohydrate.
- Example 1 in Patent Document CN105924381A also refer to Example 1 in Patent Document CN106008323A
- the crystalline form C of Pimaserin hemitartrate was prepared.
- the crystalline form A of pimaserin hemipamoate, the crystalline form A of pimaserin 1-hydroxy-2-naphthoate salt and the crystalline form A of pimaserin 1-hydroxy-2 -Naphthoate monohydrate crystal form B has lower solubility than pimaserin under both acidic and neutral conditions, and the lower the pH, the greater the difference.
- the crystalline form A of Pimaserin hemipamoate, the crystalline form A of Pimaserin 1-hydroxy-2-naphthoate and the 1-hydroxy-2-naphthalene of Pimaserin of the present invention are shown in Table 2.
- the formate monohydrate crystal form B is relatively stable under various conditions and is suitable for the development of pharmaceutical preparations.
- Example Dv10( ⁇ m) Dv50( ⁇ m) Dv90( ⁇ m) Example 49 1.357 6.219 14.334
- Example 50 0.898 3.294 8.917
- Example 51 0.848 3.292 8.945
- Embodiment 56 Prescription stability investigation
- results are shown in the following table.
- the results show that the prescription samples of pimaserin 1-hydroxy-2-naphthoate monohydrate crystal form B are relatively stable under various conditions, and the pimaserine hemipamoate crystal form A is stable.
- the formulation samples were stable except for slight degradation under long-term light conditions.
Abstract
L'invention concerne un sel pharmaceutiquement acceptable de pimavansérine, un procédé de préparation associé, une composition pharmaceutique la comprenant et une utilisation associée. Le sel pharmaceutiquement acceptable de pimavansérine est un sel formé à partir d'une base libre de pimavansérine et d'un acide organique ayant au minimum six atomes de carbone. Le sel pharmaceutiquement acceptable préparé de pimavansérine présente une bonne solubilité et une bonne stabilité, est pratique à préparer et est approprié pour une production industrielle à grande échelle.
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Citations (7)
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WO2017167180A1 (fr) * | 2016-03-29 | 2017-10-05 | 上海华汇拓医药科技有限公司 | Sel d'acide pamoïque de vortioxétine et sa forme cristalline |
CN107311968A (zh) * | 2016-03-31 | 2017-11-03 | 广州市恒诺康医药科技有限公司 | 西酞普兰帕莫酸盐和其结晶形态及其制备方法和用途 |
WO2018007842A1 (fr) * | 2016-07-08 | 2018-01-11 | Egis Gyógyszergyár Zrt. | Sels de pimavansérine utiles pour l'élaboration d'une préparation pharmaceutique. |
US20200268732A1 (en) * | 2017-11-13 | 2020-08-27 | Texas Tech University System | Compositions and Methods for Treating Cancer |
WO2020234383A1 (fr) * | 2019-05-22 | 2020-11-26 | Zaklady Farmaceutyczne Polpharma S.A. | Intermédiaire pharmaceutique |
WO2021010719A1 (fr) * | 2019-07-12 | 2021-01-21 | 주식회사 지투지바이오 | Formulation à longue durée d'action contenant de la rivastigmine et son procédé de préparation |
CN113274390A (zh) * | 2021-06-04 | 2021-08-20 | 沈阳药科大学 | 哌马色林在制备抗肿瘤药物中的应用 |
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- 2022-03-28 TW TW111111762A patent/TW202304862A/zh unknown
- 2022-03-28 WO PCT/CN2022/083287 patent/WO2022199707A1/fr active Application Filing
Patent Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2017167180A1 (fr) * | 2016-03-29 | 2017-10-05 | 上海华汇拓医药科技有限公司 | Sel d'acide pamoïque de vortioxétine et sa forme cristalline |
CN107311968A (zh) * | 2016-03-31 | 2017-11-03 | 广州市恒诺康医药科技有限公司 | 西酞普兰帕莫酸盐和其结晶形态及其制备方法和用途 |
WO2018007842A1 (fr) * | 2016-07-08 | 2018-01-11 | Egis Gyógyszergyár Zrt. | Sels de pimavansérine utiles pour l'élaboration d'une préparation pharmaceutique. |
US20200268732A1 (en) * | 2017-11-13 | 2020-08-27 | Texas Tech University System | Compositions and Methods for Treating Cancer |
WO2020234383A1 (fr) * | 2019-05-22 | 2020-11-26 | Zaklady Farmaceutyczne Polpharma S.A. | Intermédiaire pharmaceutique |
WO2021010719A1 (fr) * | 2019-07-12 | 2021-01-21 | 주식회사 지투지바이오 | Formulation à longue durée d'action contenant de la rivastigmine et son procédé de préparation |
CN113274390A (zh) * | 2021-06-04 | 2021-08-20 | 沈阳药科大学 | 哌马色林在制备抗肿瘤药物中的应用 |
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