CN116239521A - 一种米力农-己二酸共晶体 - Google Patents
一种米力农-己二酸共晶体 Download PDFInfo
- Publication number
- CN116239521A CN116239521A CN202111484235.9A CN202111484235A CN116239521A CN 116239521 A CN116239521 A CN 116239521A CN 202111484235 A CN202111484235 A CN 202111484235A CN 116239521 A CN116239521 A CN 116239521A
- Authority
- CN
- China
- Prior art keywords
- milrinone
- adipic acid
- crystal
- degrees
- solvent
- 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.)
- Pending
Links
- 239000001361 adipic acid Substances 0.000 title claims abstract description 45
- 230000005496 eutectics Effects 0.000 title abstract description 19
- PZRHRDRVRGEVNW-UHFFFAOYSA-N milrinone Chemical compound N1C(=O)C(C#N)=CC(C=2C=CN=CC=2)=C1C PZRHRDRVRGEVNW-UHFFFAOYSA-N 0.000 claims abstract description 33
- 239000013078 crystal Substances 0.000 claims abstract description 32
- 229960003574 milrinone Drugs 0.000 claims abstract description 32
- WNLRTRBMVRJNCN-UHFFFAOYSA-N adipic acid Chemical compound OC(=O)CCCCC(O)=O WNLRTRBMVRJNCN-UHFFFAOYSA-N 0.000 claims abstract description 20
- 238000000034 method Methods 0.000 claims abstract description 20
- 238000002360 preparation method Methods 0.000 claims abstract description 11
- 235000011037 adipic acid Nutrition 0.000 claims abstract description 10
- 230000005855 radiation Effects 0.000 claims abstract description 8
- 238000002441 X-ray diffraction Methods 0.000 claims abstract description 5
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 27
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 17
- 239000012046 mixed solvent Substances 0.000 claims description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 13
- 238000001914 filtration Methods 0.000 claims description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- 238000001035 drying Methods 0.000 claims description 6
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 5
- RHQDFWAXVIIEBN-UHFFFAOYSA-N Trifluoroethanol Chemical compound OCC(F)(F)F RHQDFWAXVIIEBN-UHFFFAOYSA-N 0.000 claims description 4
- 238000010438 heat treatment Methods 0.000 claims description 4
- 238000003756 stirring Methods 0.000 claims description 4
- 238000001816 cooling Methods 0.000 claims description 2
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 claims description 2
- 239000004615 ingredient Substances 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 238000002425 crystallisation Methods 0.000 abstract description 8
- 230000008025 crystallization Effects 0.000 abstract description 8
- 229910017488 Cu K Inorganic materials 0.000 abstract description 3
- 229910017541 Cu-K Inorganic materials 0.000 abstract description 3
- 230000008569 process Effects 0.000 abstract description 2
- 238000001228 spectrum Methods 0.000 abstract description 2
- 230000000694 effects Effects 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 5
- 206010019280 Heart failures Diseases 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 229910052799 carbon Inorganic materials 0.000 description 5
- 238000004090 dissolution Methods 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- JVTAAEKCZFNVCJ-REOHCLBHSA-N L-lactic acid Chemical compound C[C@H](O)C(O)=O JVTAAEKCZFNVCJ-REOHCLBHSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 238000013112 stability test Methods 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 206010007559 Cardiac failure congestive Diseases 0.000 description 3
- 238000002447 crystallographic data Methods 0.000 description 3
- 238000010586 diagram Methods 0.000 description 3
- 239000004310 lactic acid Substances 0.000 description 3
- 235000014655 lactic acid Nutrition 0.000 description 3
- 238000001179 sorption measurement Methods 0.000 description 3
- 206010067484 Adverse reaction Diseases 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- IVOMOUWHDPKRLL-KQYNXXCUSA-N Cyclic adenosine monophosphate Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=CN=C2N)=C2N=C1 IVOMOUWHDPKRLL-KQYNXXCUSA-N 0.000 description 2
- 229930182843 D-Lactic acid Natural products 0.000 description 2
- JVTAAEKCZFNVCJ-UWTATZPHSA-N D-lactic acid Chemical compound C[C@@H](O)C(O)=O JVTAAEKCZFNVCJ-UWTATZPHSA-N 0.000 description 2
- 229930182555 Penicillin Natural products 0.000 description 2
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 2
- 230000006838 adverse reaction Effects 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- RNLQIBCLLYYYFJ-UHFFFAOYSA-N amrinone Chemical class N1C(=O)C(N)=CC(C=2C=CN=CC=2)=C1 RNLQIBCLLYYYFJ-UHFFFAOYSA-N 0.000 description 2
- 239000006184 cosolvent Substances 0.000 description 2
- 229940022769 d- lactic acid Drugs 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 229940082795 milrinone injection Drugs 0.000 description 2
- 230000002107 myocardial effect Effects 0.000 description 2
- 229940049954 penicillin Drugs 0.000 description 2
- 239000002510 pyrogen Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 208000010444 Acidosis Diseases 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 206010056370 Congestive cardiomyopathy Diseases 0.000 description 1
- 241000208011 Digitalis Species 0.000 description 1
- 201000010046 Dilated cardiomyopathy Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 206010020601 Hyperchlorhydria Diseases 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 229940099471 Phosphodiesterase inhibitor Drugs 0.000 description 1
- 102000004861 Phosphoric Diester Hydrolases Human genes 0.000 description 1
- 108090001050 Phosphoric Diester Hydrolases Proteins 0.000 description 1
- 206010037423 Pulmonary oedema Diseases 0.000 description 1
- 239000000150 Sympathomimetic Substances 0.000 description 1
- 206010047141 Vasodilatation Diseases 0.000 description 1
- 230000007950 acidosis Effects 0.000 description 1
- 208000026545 acidosis disease Diseases 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 229960002105 amrinone Drugs 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000012752 auxiliary agent Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- HOPSCVCBEOCPJZ-UHFFFAOYSA-N carboxymethyl(trimethyl)azanium;chloride Chemical compound [Cl-].C[N+](C)(C)CC(O)=O HOPSCVCBEOCPJZ-UHFFFAOYSA-N 0.000 description 1
- 230000003177 cardiotonic effect Effects 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 238000012937 correction Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000010339 dilation Effects 0.000 description 1
- 229960003638 dopamine Drugs 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000010812 external standard method Methods 0.000 description 1
- 239000010419 fine particle Substances 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 208000030159 metabolic disease Diseases 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 208000031225 myocardial ischemia Diseases 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000003002 pH adjusting agent Substances 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 239000002571 phosphodiesterase inhibitor Substances 0.000 description 1
- 230000009090 positive inotropic effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 208000005333 pulmonary edema Diseases 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 238000011895 specific detection Methods 0.000 description 1
- 230000001975 sympathomimetic effect Effects 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 230000024883 vasodilation Effects 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/84—Nitriles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
-
- 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
- C07C55/00—Saturated compounds having more than one carboxyl group bound to acyclic carbon atoms
- C07C55/02—Dicarboxylic acids
- C07C55/14—Adipic 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
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Health & Medical Sciences (AREA)
- Cardiology (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Heart & Thoracic Surgery (AREA)
- Crystallography & Structural Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Hospice & Palliative Care (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明属于药物化学的技术领域，具体涉及米力农新晶型，具体为米力农与己二酸的共晶体及其制备方法与应用。所述共晶体使用Cu‑Kα辐射，以2θ表示的X射线衍射谱图至少在9.0±0.2°、15.7±0.2°、18.0±0.2°、24.0±0.2°、31.4±0.2°、31.6±0.2°有特征峰。本发明提供的米力农‑己二酸共晶体的制备方法，操作简单，结晶过程易于控制，重现性好。
Description
技术领域
本发明属于药物化学的技术领域，具体涉及米力农新晶型，具体为米力农与己二酸的共晶体及其制备方法与应用。
背景技术
米力农(milrinone，式I)，化学名为1,6-二氢-2-甲基-6-氧-[3,4-双吡啶]-5-甲腈，分子式为C12H9N3O，分子量为211.22，为白色或类白色结晶性粉末，其结构式为：
米力农最早是由美国Sterling公司研制开发成功的抗心力衰竭药物，1987年首次在美国被FDA批准，1992年在美国正式上市，随后相继在英国、法国、德国、荷兰、比利时等国上市销售。
米力农为磷酸二酯酶抑制剂，为氨力农的衍生物，作用机理与氨力农相同。口服和静注均有效，兼有正性肌力作用和血管扩张作用。适用于常规维持治疗无效的严重充血性心力衰竭患者的短期治疗，疗效比氨力农(amirinone)强10～30倍，耐受性较好，不良反应少。本品的正性肌力作用主要是通过抑制磷酸二酯酶，使心肌细胞内环磷酸腺苷(CAMP)浓度增高，细胞内钙增加，心肌收缩力加强，心排血量增加。一般认为是高效、低毒、非洋地黄、非拟交感能的强心药，对缺血性心脏病、扩张型心肌病等所致的严重心衰、肺水肿有显效，优于多巴胺类，不良反应少，不增加心率。因此该药物在治疗充血性心力衰竭(CHF)和外周扩血管等方面发挥了越来越重要的作用。
但是米力农在水中几乎不溶，因此在制备米力农的制剂产品时，需要加入特殊的辅料来改善其溶解性。现有的制剂方法通常采用加入助溶剂及pH调节剂来改善其水溶性，而且用量较大。因此，助溶剂的安全性和助溶效果尤为重要。比如专利CN9151919A公开了使用盐酸、磷酸、硫酸等无机酸成盐后再制备成冻干制剂的方法；专利CN106361710A公开了一种先在乙醇+丙酮+水的溶剂中析出晶体，再使用乳酸作为pH调节剂制备制剂的方法。但是仍未能彻底解决米力农本身溶解性差和稳定性差的问题，比如采用无机酸作为助溶剂，盐酸带入的Cl-有可能引发高氯血症，而磷酸、硫酸等助溶效果不佳；有机酸中，乳酸助溶效果较好，但乳酸是消旋体，由L-乳酸和D-乳酸组成，由于人体内只有代谢L-乳酸的酶且代谢能力有限，如果摄入过量D-乳酸，还会引起代谢紊乱甚至酸中毒。
而且，根据专利CN105663034A公开内容可知，由于米力农几乎不溶于水，在大生产过程中，会带来溶解时间长，溶解不完全，不溶性微粒超标的问题。现有米力农注射液的制备技术，除热原采用活性炭吸附的方法，而活性炭对米力农的吸附量较大，在活性炭使用量为0.05％，吸附米力农可达到约14％，需过量投料才能保证米力农注射液含量符合规定。而过量投料引起生产成本大量增加，且活性炭在吸附热原的同时，本身也会引入过多不明物质，影响产品质量。
基于以上问题，仅仅依靠制剂技术解决米力农溶解性和稳定性的问题，不可避免的会出现辅料和助剂用量过大所带来的临床用药安全隐患。因此，提供一种溶解性好、稳定性高且安全性高的米力农的新晶型，成为了本领域技术人员亟待解决的问题。
发明内容
针对现有技术提供的米力农溶解性不好的缺点，本发明旨在提供一种具有较高溶解性和稳定性的米力农新晶体形式，即米力农-己二酸共晶体。此外本发明提供了一种制备米力农-己二酸共晶体的方法，该方法简单、便捷适合工业化生产。
本发明的具体技术内容如下：
本发明提供了米力农-己二酸共晶体，所述共晶体的晶体单元中含有摩尔比为2：1的米力农-己二酸分子。
一种米力农-己二酸共晶体，其特征在于，使用Cu-Kα辐射，以2θ表示的X射线衍射谱图至少在9.0±0.2°、15.7±0.2°、18.0±0.2°、24.0±0.2°、31.4±0.2°、31.6±0.2°有特征峰。
优选地，所述的米力农-己二酸共晶体，使用Cu-Kα辐射，以2θ表示的X射线衍射谱图至少在9.0±0.2°、12.8±0.2°、15.7±0.2°、18.0±0.2°、24.0±0.2°、25.6±0.2°、31.4±0.2°、31.6±0.2°、32.9±0.2°有特征峰。
优选地，所述的米力农-己二酸共晶使用Cu-Kα辐射，其特征峰符合图1所示的X射线粉末衍射图谱。
优选地，所述的米力农-己二酸共晶体，其分子式为C30H28N6O6，晶体学参数是：单斜晶系，空间群为C2/c，晶胞参数为：
α＝90°、β＝116.580(2)°、γ＝90°，晶胞体积
另一方面，本发明提供一种制备米力农-己二酸共晶体的方法，包括如下步骤：
将米力农和己二酸溶于混合溶剂，加热搅拌，过滤，降温静置挥发析晶，过滤干燥得到米力农-己二酸晶体。
优选地，所述的混合溶剂为甲醇与溶剂A的组合，其中溶剂A选自乙醇、乙腈、水、丙酮或三氟乙醇中的一种或多种；特别优选甲醇与三氟乙醇或丙酮的混合溶剂。
优选地，所述的混合溶剂中甲醇与溶剂A的体积比为1：1～2。
优选地，所述的米力农与混合溶剂质量体积比为7～21:1，mg/mL；优选为8.5～14:1，mg/mL。
优选地，所述的米力农与己二酸的摩尔比为1：0.9～2.0；优选为1：1.1。
优选地，所述的加热温度为50～70℃。
优选地，所述的降温析晶温度为0～30℃；进一步优选地，降温析晶温度为10～15℃。
优选地，所述的析晶时间为6～48小时。
优选地，所述干燥温度为50～60℃，干燥时间为5～24小时。
所述制备方法中所用原料米力农可按照现有技术中的任何方法进行制备或者购买自市售产品。
最后，本发明提供一种药物组合物，所述药物组合物含有本发明所述的米力农-己二酸共晶及其它在药学上可行的组分。
优选地，所述的其它药学上可行的组分可以是可联用的药物活性成分和/或药剂学上接受的辅料成分。
晶体结构的确认
本发明所述米力农-己二酸共晶体测试中X射线晶体数据在日本理学XtaLABSynergy型号仪器上收集，测试温度293(2)K，用Cu-Ka辐射，以ω扫描方式收集数据并进、行Lp校正。用直接法解析结构，差值傅里叶法找出全部非氢原子，所有碳及氮上的氢原子采用理论加氢得到，采用最小二乘法对结构进行精修。
测试及解析本发明制备的米力农-己二酸共晶体结晶形式的晶体学数据(如表1)是:单斜晶系，空间群为C2/c，晶胞参数为：
α＝90°、β＝116.580(2)°、γ＝90°，晶胞体积
表1米力农-己二酸共晶主要晶体学数据
本发明的米力农-己二酸共晶体的ORTEP图表明，该结晶形式中含有两分子米力农和一分子己二酸，如图2所示。本发明的米力农-己二酸共晶的氢键图，如图3所示。依据上述晶体学数据，其对应的X射线粉末衍射图(Cu-Kα)中特征峰详见图1及表2。
表2米力农-己二酸共晶的PXRD峰
与现有技术相比，本发明取得的技术效果是：
本发明提供了一种米力农-己二酸共晶体，该共晶体可显著增强米力农的溶解性，有助于提高口服生物利用度，具有很强的成药价值。本发明提供了米力农-己二酸共晶体的制备方法，该方法操作简单，结晶过程易于控制，重现性好。
附图说明
图1.米力农-己二酸共晶的PXRD谱图。
图2.米力农-己二酸共晶的ORTEP图。
图3.米力农-己二酸共晶的氢键图。
具体实施方式
下面通过实施例来进一步说明本发明，应该正确理解的是：本发明的实施例仅仅是用于说明本发明，而不是对本发明的限制，所以，在本发明的方法前提下对本发明的简单改进均属本发明要求保护的范围。
稳定性实验和溶解性实验中使用的米力农晶体、米力农盐酸盐、米力农甲磺酸盐参照现有文献制备。
实施例1
将211mg米力农和160mg己二酸溶于10mL甲醇和10mL三氟乙醇的混合溶剂中，60℃水浴加热搅拌，过滤收集滤液，10～15℃环境下静置析晶36h，过滤，50℃干燥24h得到米力农-己二酸共晶，收率：94％，纯度：99.91％。
实施例2
将211mg米力农和146mg己二酸溶于15mL甲醇和15mL丙酮的混合溶剂中，55℃水浴加热搅拌，过滤收集滤液，10～15℃环境下静置析晶24h，过滤，50℃干燥24h得到米力农-己二酸共晶，收率：93％，纯度：99.92％。
实施例3
将280mg米力农和194mg己二酸溶于10mL甲醇和10mL丙酮的混合溶剂中，55℃水浴加热搅拌，过滤收集滤液，10～15℃环境下静置析晶48h，过滤，50℃干燥24h得到米力农-己二酸共晶，收率：91％，纯度：99.92％。
实施例4
将106mg米力农和58mg己二酸溶于10mL甲醇和10mL水的混合溶剂中，60℃水浴加热搅拌，过滤收集滤液，15～20℃环境下静置析晶48h，过滤，50℃干燥24h得到米力农-己二酸共晶，收率：83％，纯度：99.91％。
稳定性实验
具体的稳定性试验方法参照《中国药典》第四部有关稳定性考察的指导方法进行，纯度检测用HPLC法进行检测，具体的检测结果见表3。
表3米力农-己二酸共晶的稳定性试验结果
溶解性实验
方法：分别量取10ml的介质(水、0.01mol/LHCl溶液)于西林瓶中，加入过量的待测样品，将西林瓶密封置于25℃恒温水浴中搅拌1小时，经滤膜过滤，取滤液；HPLC检测，按外标法计算饱和溶液的浓度。
表4米力农-己二酸共晶的溶解性(mg/mL)
Claims (9)
1.一种米力农-己二酸共晶体，其特征在于，使用Cu-Kα辐射，以2θ表示的X射线衍射谱图至少在9.0±0.2°、15.7±0.2°、18.0±0.2°、24.0±0.2°、31.4±0.2°、31.6±0.2°有特征峰。
2.如权利要求1所述的共晶体，其特征在于，使用Cu-Kα辐射，以2θ表示的X射线衍射谱图至少在9.0±0.2°、12.8±0.2°、15.7±0.2°、18.0±0.2°、24.0±0.2°、25.6±0.2°、31.4±0.2°、31.6±0.2°、32.9±0.2°有特征峰。
3.如权利要求1所述的共晶体，其特征在于，使用Cu-Kα辐射，其特征峰符合图1所示的X射线粉末衍射图谱。
4.如权利要求1所述的共晶体，其特征在于，所述的米力农-己二酸共晶体，其分子式为C30H28N6O6，晶体学参数是：单斜晶系，空间群为C2/c，晶胞参数为：
α＝90°、β＝116.580(2)°、γ＝90°，晶胞体积
5.一种制备权利要求1-4任一项所述的共晶体的方法，其特征在于，所述方法包括：
将米力农和己二酸溶于混合溶剂，加热搅拌，过滤，降温静置挥发析晶，过滤干燥得到米力农-己二酸晶体。
6.如权利要求5所述的制备方法，其特征在于，所述的混合溶剂为甲醇与溶剂A的组合；其中溶剂A选自乙醇、乙腈、水、丙酮或三氟乙醇中的一种或多种。
7.如权利要求6所述的制备方法，其特征在于，所述的混合溶剂中甲醇与溶剂A的体积比为1：1～2。
8.如权利要求5所述的制备方法，其特征在于，所述的米力农与混合溶剂质量体积比为7～21:1，mg/ml。
9.一种药物组合物，其特征在于，所述药物组合物含有权利要求1-4所述的米力农-己二酸共晶及其它在药学上可行的组分。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111484235.9A CN116239521A (zh) | 2021-12-07 | 2021-12-07 | 一种米力农-己二酸共晶体 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111484235.9A CN116239521A (zh) | 2021-12-07 | 2021-12-07 | 一种米力农-己二酸共晶体 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN116239521A true CN116239521A (zh) | 2023-06-09 |
Family
ID=86622866
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202111484235.9A Pending CN116239521A (zh) | 2021-12-07 | 2021-12-07 | 一种米力农-己二酸共晶体 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN116239521A (zh) |
-
2021
- 2021-12-07 CN CN202111484235.9A patent/CN116239521A/zh active Pending
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN112142679B (zh) | 一种吉非替尼与香草酸共晶甲醇溶剂合物及其制备方法 | |
| CA3211594A1 (en) | Crystal form of pyridine nitrogen oxide compound and use thereof | |
| CN109503475B (zh) | 一种异烟酰胺甲基吡嗪衍生物共晶i | |
| JP6950092B2 (ja) | セタグリプチンの塩及びその製造方法、薬物組成物、並びにその使用 | |
| CN109438371B (zh) | 一种甲基吡嗪衍生物精氨酸水合物 | |
| CN116239521A (zh) | 一种米力农-己二酸共晶体 | |
| CN116239520A (zh) | 一种米力农-酒石酸共晶体 | |
| CN116239525A (zh) | 一种米力农-黄芩素共晶体 | |
| CN116239522A (zh) | 一种米力农-丁二酸共晶体 | |
| CN116239528A (zh) | 一种米力农多元共晶体 | |
| CN116239527A (zh) | 一种米力农-柠檬酸一水共晶体 | |
| CN111518040B (zh) | 一种甲基吡嗪衍生物-哌嗪共晶 | |
| CN116239526A (zh) | 一种米力农与柠檬酸二水共晶体 | |
| CN110078679B (zh) | 一种拉莫三嗪药物共晶及其制备方法和用途 | |
| CN112110865B (zh) | 一种异烟酰胺阿西莫司共晶体ⅱ及其制备方法 | |
| CN115073368B (zh) | 一种米力农-5-磺基水杨酸晶型 | |
| CN109369546B (zh) | 一种甲基吡嗪衍生物茶碱半水合物 | |
| CN115057814A (zh) | 一种米力农苹果酸盐晶体 | |
| CN116813541A (zh) | 米力农药用共晶体及其制备方法 | |
| CN116253680A (zh) | 一种米力农与酮咯酸共晶及其制备方法 | |
| TW201739750A (zh) | 一種鈉依賴性葡萄糖共轉運蛋白抑制劑的胺溶劑合物及其製備方法和應用 | |
| CN117105855A (zh) | 一种米力农-糖精晶型 | |
| CN116813542A (zh) | 米力农的药物多晶体 | |
| CN117105858A (zh) | 一种米力农-3,5-吡啶二甲酸水合物晶型 | |
| CN117069653A (zh) | 一种米力农没食子酸共晶 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination |