JP2022502464A - コンテゾリドアセフォサミルの医薬結晶及びその製造方法並びにその使用 - Google Patents
コンテゾリドアセフォサミルの医薬結晶及びその製造方法並びにその使用 Download PDFInfo
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- JP2022502464A JP2022502464A JP2021519592A JP2021519592A JP2022502464A JP 2022502464 A JP2022502464 A JP 2022502464A JP 2021519592 A JP2021519592 A JP 2021519592A JP 2021519592 A JP2021519592 A JP 2021519592A JP 2022502464 A JP2022502464 A JP 2022502464A
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- 238000004519 manufacturing process Methods 0.000 title claims abstract description 20
- 150000001875 compounds Chemical class 0.000 claims abstract description 28
- 239000000203 mixture Chemical group 0.000 claims abstract description 18
- 239000000126 substance Substances 0.000 claims abstract description 18
- 239000011734 sodium Chemical group 0.000 claims abstract description 12
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical group C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims abstract description 11
- 229910052708 sodium Inorganic materials 0.000 claims abstract description 11
- 239000001257 hydrogen Substances 0.000 claims abstract description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 6
- 239000000047 product Substances 0.000 claims description 46
- 238000000034 method Methods 0.000 claims description 35
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- 238000000634 powder X-ray diffraction Methods 0.000 claims description 28
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 26
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 26
- 239000003960 organic solvent Substances 0.000 claims description 23
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 21
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 15
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 14
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 14
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 13
- 239000012043 crude product Substances 0.000 claims description 9
- 230000008569 process Effects 0.000 claims description 9
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 claims description 9
- 239000008194 pharmaceutical composition Substances 0.000 claims description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical group [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 7
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- 239000003814 drug Substances 0.000 claims description 6
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 6
- JHJLBTNAGRQEKS-UHFFFAOYSA-M sodium bromide Chemical compound [Na+].[Br-] JHJLBTNAGRQEKS-UHFFFAOYSA-M 0.000 claims description 6
- 229940079593 drug Drugs 0.000 claims description 5
- 229910017053 inorganic salt Inorganic materials 0.000 claims description 5
- 238000002844 melting Methods 0.000 claims description 5
- 230000008018 melting Effects 0.000 claims description 5
- 239000011259 mixed solution Substances 0.000 claims description 5
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 4
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 4
- 229940011051 isopropyl acetate Drugs 0.000 claims description 4
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 3
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 3
- 230000003115 biocidal effect Effects 0.000 claims description 3
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 150000004677 hydrates Chemical class 0.000 claims description 3
- 229910000403 monosodium phosphate Inorganic materials 0.000 claims description 3
- 235000019799 monosodium phosphate Nutrition 0.000 claims description 3
- 235000017281 sodium acetate Nutrition 0.000 claims description 3
- 239000001632 sodium acetate Substances 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- 235000017550 sodium carbonate Nutrition 0.000 claims description 3
- 239000011780 sodium chloride Substances 0.000 claims description 3
- 239000001509 sodium citrate Substances 0.000 claims description 3
- 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 claims description 3
- 235000011083 sodium citrates Nutrition 0.000 claims description 3
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 claims description 3
- 235000009518 sodium iodide Nutrition 0.000 claims description 3
- 239000001488 sodium phosphate Substances 0.000 claims description 3
- 229910000162 sodium phosphate Inorganic materials 0.000 claims description 3
- 235000011008 sodium phosphates Nutrition 0.000 claims description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 claims description 3
- 235000011152 sodium sulphate Nutrition 0.000 claims description 3
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 claims description 3
- 239000003242 anti bacterial agent Substances 0.000 claims description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 2
- 235000011121 sodium hydroxide Nutrition 0.000 claims 1
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- 208000035473 Communicable disease Diseases 0.000 description 3
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- SULYVXZZUMRQAX-NSHDSACASA-N (5s)-5-[(1,2-oxazol-3-ylamino)methyl]-3-[2,3,5-trifluoro-4-(4-oxo-2,3-dihydropyridin-1-yl)phenyl]-1,3-oxazolidin-2-one Chemical compound C([C@H]1CN(C(O1)=O)C=1C=C(C(=C(F)C=1F)N1C=CC(=O)CC1)F)NC=1C=CON=1 SULYVXZZUMRQAX-NSHDSACASA-N 0.000 description 2
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- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 2
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical group COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 2
- 241000192125 Firmicutes Species 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
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- JANNTEAGZXJITO-BTQNPOSSSA-M sodium acetyloxy-[1,2-oxazol-3-yl-[[(5R)-2-oxo-3-[2,3,5-trifluoro-4-(4-oxo-2,3-dihydropyridin-1-yl)phenyl]-1,3-oxazolidin-5-yl]methyl]amino]phosphinate Chemical compound [Na+].CC(=O)OP([O-])(=O)N(C[C@H]1CN(C(=O)O1)c1cc(F)c(N2CCC(=O)C=C2)c(F)c1F)c1ccon1 JANNTEAGZXJITO-BTQNPOSSSA-M 0.000 description 2
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- 238000001291 vacuum drying Methods 0.000 description 2
- 239000003039 volatile agent Substances 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- 0 CC(O1)=*=C(N(C2)c(cc(c(N(CC3)C=CC3=O)c3F)F)c3F)O[C@]2CN(c2n[o]cc2)P1(O*)=O Chemical compound CC(O1)=*=C(N(C2)c(cc(c(N(CC3)C=CC3=O)c3F)F)c3F)O[C@]2CN(c2n[o]cc2)P1(O*)=O 0.000 description 1
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- 238000002050 diffraction method Methods 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-M dihydrogenphosphate Chemical compound OP(O)([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-M 0.000 description 1
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- 244000000010 microbial pathogen Species 0.000 description 1
- XONPDZSGENTBNJ-UHFFFAOYSA-N molecular hydrogen;sodium Chemical compound [Na].[H][H] XONPDZSGENTBNJ-UHFFFAOYSA-N 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
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- 238000007911 parenteral administration Methods 0.000 description 1
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Images
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
- C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom
-
- 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
- A61K31/66—Phosphorus compounds
- A61K31/664—Amides of phosphorus acids
-
- 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
- A61K31/66—Phosphorus compounds
- A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- 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
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Oncology (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Communicable Diseases (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
(1)化学式Iを有する化合物の粗生成物を製造する工程と、
(2)化学式Iを有する化合物の粗生成物を有機溶剤と水の混合溶液に溶解させる工程と、
(3)無機塩又は有機溶剤を選択的に添加し、生成物相を分離し、一部又は全部の揮発性物質を除去し、有機溶剤を選択的に添加し、結晶化させて結晶を得る工程と、
(4)化学式Iを有する化合物の結晶を分離する工程とを含む。
用語「約」は、粉末X線回折図のピークの位置に関して使用される場合、ピークの固有変動性を表し、それは、(例えば)使用される設備の校正、多結晶を生成するための方法、結晶化材料の寿命等に依存し、使用される測定器によって決まる。この場合、測定器の測定変動性は約±0.2°2θである。当業者はこの場合の「約」の使用を理解することができる。
コンテゾリドアセフォサミルの構成におけるN-ホスホリル(N-phosphoryl)及びO-アセチルリン酸(O-acetyl phosphoric acid)の特殊性に起因して、プロドラッグとしてのコンテゾリドアセフォサミルはある条件下で不安定になり、よく従来の加熱して溶解する方法や冷却して結晶化させる方法により分解してしまう。本明細は、コンテゾリドアセフォサミル(化学式I)の新規結晶又は結晶複合体を開示している。当該結晶は室温下で安定しており、且つ結晶性質が明らかである。
本明細書は、上記結晶又は結晶複合体の製造方法を開示している。幾つかの実施形態において、化学式Iを有する化合物(化学式Iのコンテゾリドアセフォサミルの粗生成物)を有機溶剤と水の混合溶液に溶解し、無機塩を加え、その後、生成物相を分離し、揮発性物質の一部又は全部を除去し、有機溶剤を加え、結晶化させて結晶を得る。化学式Iのコンテゾリドアセフォサミルの粗生成物を中国専利出願CN105612166Aに開示の方法で製造してもよい。
合成経路:
窒素ガス雰囲気下で、0-10℃ にてトリメチルシリルヨージド(14.4g)を中間体1(10.5g、CN105612166Aの中間体2についての方法によって製造される)のDCM(105 mL)溶液に滴加し、室温で2時間撹拌した。反応液を減圧濃縮し、メチルtert-ブチルエーテルで残留物を洗い(100ml)、濾過及び真空乾燥を行った。得られた生成物をDMSO/MeCN (10.5ml/105ml)に再溶解し、NaOAc (36.7g)及びAc2O(5.9g)を加え、1時間撹拌した。MTBE(700ml)を加え、撹拌、濾過及び真空乾燥を行い、実施例1の化合物粗生成物を得た。
contezolid acefosamil(コンテゾリドアセフォサミル)の先行研究開発では、例えば抽出法、溶剤の減圧除去法のような従来の実験室での処理プロセスによって得られた生成物が、室温貯蔵では不安定である。HPLC精製凍結乾燥法によって得られた生成物であっても安定性が不足するようになり、粉末X線回折において回折ピーク無しを表している。本発明において見出した製造方法によって得られた生成物は意外なことに、粉末X線回折において0-40°2θの間に多くの鋭い回折ピークが表示されており、また示差走査熱量(DSC)分析の結果、狭い融解範囲が示されており、結晶の特徴を有し、特に、得られた結晶生成物は無定形粉末よりも高い安定性を有し、これは重要である。詳しいデータは以下の通りである。
Claims (14)
- 前記結晶又は結晶複合体は、粉末X線回折パターンにおいて約5.0〜40°2θに少なくとも1つの回折ピークを示すことを特徴とする請求項1に記載の結晶又は結晶複合体。
- 前記結晶又は結晶複合体は、粉末X線回折パターンにおいて約20.0〜25°2θに少なくとも2つの回折ピークを示すことを特徴とする請求項1又は2に記載の結晶又は結晶複合体。
- 前記結晶又は結晶複合体は、粉末X線回折パターンにおいて約20.0〜21.0°2θに回折ピークを示すことを特徴とする請求項1乃至3のいずれかに記載の結晶又は結晶複合体。
- 前記結晶又は結晶複合体は、粉末X線回折パターンにおいて約23.0〜24.0°2θに回折ピークを示すことを特徴とする請求項1乃至4のいずれかに記載の結晶又は結晶複合体。
- 前記結晶又は結晶複合体は、粉末X線回折パターンにおいて約6.9°、14.7°、15.5°、16.5°、20.2°、22.9°、23.7°2θに回折ピークを示すことを特徴とする請求項1乃至5のいずれかに記載の結晶又は結晶複合体。
- 前記結晶又は結晶複合体の融点が220±10℃であることを特徴とする請求項1乃至6のいずれかに記載の結晶又は結晶複合体。
- 重量基準で、前記結晶又は結晶複合体におけるナトリウムの含有量が0-6%であることを特徴とする請求項1乃至7のいずれかに記載の結晶又は結晶複合体。
- 請求項1乃至8のいずれかに記載の結晶又は結晶複合体を製造する方法であって、
(1)化学式Iを有する化合物の粗生成物を製造する工程と、
(2)化学式Iを有する化合物の粗生成物を有機溶剤と水の混合溶液に溶解させる工程と、
(3)無機塩又は有機溶剤を添加し、生成物相を分離し、一部又は全部の揮発性物質を除去し、有機溶剤を添加し、結晶化させて結晶を得る工程と、
(4)化学式Iを有する化合物の結晶を分離する工程とを含む方法。 - 工程(2)において、前記有機溶剤はアセトニトリル、アセトン、メタノール、エタノール、プロパノール、イソプロパノール、ブタノール、テトラヒドロフランから選ばれた少なくとも1種であることを特徴とする請求項9に記載の方法。
- 工程(3)において、前記無機塩は塩化ナトリウム、臭化ナトリウム、ヨウ化ナトリウム、クエン酸ナトリウム、りん酸二水素ナトリウム、りん酸水素ジナトリウム、りん酸ナトリウム、硫酸ナトリウム、炭酸ナトリウム、炭酸水素ナトリウム、酢酸ナトリウム及びそれらの水和物から選ばれた少なくとも1種であることを特徴とする請求項9又は10に記載の方法。
- 工程(3)において、前記有機溶剤はアセトニトリル、アセトン、メタノール、エタノール、プロパノール、ブタノール、イソプロパノール、酢酸エチル、酢酸イソプロピル、メチルtert-ブチルエーテル、テトラヒドロフランから選ばれた少なくとも1種であることを特徴とする請求項9乃至11のいずれかに記載の方法。
- 抗生物質薬剤の製造における請求項1乃至8のいずれかに記載の結晶又は結晶複合体の使用。
- 請求項1乃至8のいずれかに記載の結晶又は結晶複合体及び薬学的に許容される担体を含む医薬組成物。
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