WO2016035845A1 - セファロスポリン誘導体の塩、その結晶性固体およびその製造方法 - Google Patents
セファロスポリン誘導体の塩、その結晶性固体およびその製造方法 Download PDFInfo
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- 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
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
- A61K31/545—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine
- A61K31/546—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine containing further heterocyclic rings, e.g. cephalothin
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- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
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- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
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- 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
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- 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
- A61P31/10—Antimycotics
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D227/00—Heterocyclic compounds containing rings having one nitrogen atom as the only ring hetero atom, according to more than one of groups C07D203/00 - C07D225/00
- C07D227/02—Heterocyclic compounds containing rings having one nitrogen atom as the only ring hetero atom, according to more than one of groups C07D203/00 - C07D225/00 with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D227/06—Heterocyclic compounds containing rings having one nitrogen atom as the only ring hetero atom, according to more than one of groups C07D203/00 - C07D225/00 with 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
- C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
- C07D501/38—Methylene radicals, substituted by nitrogen atoms; Lactams thereof with the 2-carboxyl group; Methylene radicals substituted by nitrogen-containing hetero rings attached by the ring nitrogen atom; Quaternary compounds thereof
- C07D501/46—Methylene radicals, substituted by nitrogen atoms; Lactams thereof with the 2-carboxyl group; Methylene radicals substituted by nitrogen-containing hetero rings attached by the ring nitrogen atom; Quaternary compounds thereof with the 7-amino radical acylated by carboxylic acids containing hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/04—Ortho-condensed systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
- A61K2800/80—Process related aspects concerning the preparation of the cosmetic composition or the storage or application thereof
- A61K2800/84—Products or compounds obtained by lyophilisation, freeze-drying
Definitions
- the present invention relates to a salt of a cephalosporin derivative, a crystalline solid thereof, and a method for producing the same, which are excellent in storage stability, solubility, formulation and operability in production.
- Example 12 includes the following compound (I-12): Although compound (IA) is disclosed in the form of betaine, its sodium salt, acid addition salt, and solvate are not specifically disclosed. Also, the crystal is not described.
- the pharmaceutically active ingredient may have substantially different physical properties depending on the respective solid form. Such a difference in physical properties can affect, for example, a method for producing or administering a pharmaceutically active ingredient, formulation, or the like.
- a method for producing or administering a pharmaceutically active ingredient, formulation, or the like As one means for improving physical properties, production of salts and crystalline solids is known. According to studies and analyzes by the present inventors, the compound (IA) synthesized in Patent Document 1 is amorphous. Moreover, it turned out that it is not necessarily satisfactory to use as a pharmaceutical active ingredient or its raw material in terms of purity, storage stability, etc. Therefore, development of a suitable salt or crystalline solid of compound (IA) is desired. The present inventors have tried to crystallize Compound (IA) using various acids or bases, but have not succeeded.
- acids various acids such as hydrochloric acid, sulfuric acid, formic acid, trifluoroacetic acid, phosphoric acid, benzoic acid, methanesulfonic acid, and trifluoromethanesulfonic acid were used, and the solvent, temperature, crystallization method, and the like were changed. Attempts were made to crystallize the acid addition salt of compound (IA) under conditions above that of the examples, but it was found that crystallization was very difficult. It was also found that the solubility of compound (IA) in water was very low, and it was found that improvement of water solubility was also necessary in order to develop compound (IA), particularly as an injection.
- the present inventors used an acid having a substituted or unsubstituted benzenesulfonic acid group such as benzenesulfonic acid and p-toluenesulfonic acid as the compound (IA).
- an acid having a substituted or unsubstituted benzenesulfonic acid group such as benzenesulfonic acid and p-toluenesulfonic acid
- the present invention is as follows.
- Item 3 1) p-toluenesulfonate, 2) benzenesulfonate, or 3) p-toluenesulfonic acid or benzenesulfonic acid and one acid selected from sulfuric acid, hydrochloric acid and hydrobromic acid Item 2.
- the acid addition salt of Item 1 which is a salt formed from a combination, or a hydrate thereof.
- Item 4 1) p-toluenesulfonate, or 3) an acid addition salt according to item 1, which is a salt formed from a combination of p-toluenesulfonic acid and sulfuric acid, or a hydrate thereof.
- (Item 11-1) A crystalline solid of the acid addition salt hydrate according to any one of Items 7 to 11, comprising 1.3 molar equivalents of p-toluenesulfonic acid and 0.5 molar equivalents of sulfuric acid .
- (Item 12) The crystalline solid of the hydrate according to any one of Items 7 to 11, which is an acid addition salt of a mixed acid of 1.3 molar equivalents of p-toluenesulfonic acid and 0.35 molar equivalents of sulfuric acid .
- (Item 18) An acid addition salt or a hydrate thereof according to any one of Items 8 to 16, wherein p-toluenesulfonic acid and sulfuric acid are added to a solution containing the compound (IA).
- a method for producing a crystalline solid (Item 19) About 2.2 to 2.5% by weight of p-toluenesulfonic acid monohydrate and about 5 to 6% by weight of 75% sulfuric acid are added to the column eluate containing the compound (IA). Item 19. The production method according to Item 18, which is added.
- (Item 20) The sodium salt according to item 1, or a hydrate thereof.
- (Item 21) The sodium salt or hydrate thereof according to item 20, which is in an amorphous form.
- (Item 22) A pharmaceutical composition comprising the sodium salt or hydrate thereof according to item 20 or 21.
- (Item 24) A sodium salt of compound (IA) or a hydrate thereof, characterized by using an acid addition salt according to any one of items 1 to 16, a hydrate thereof, or a crystalline solid thereof.
- (Item 25) A compound (IA) characterized by freeze-drying an aqueous solution containing the acid addition salt according to any one of items 1 to 16, its hydrate, or a crystalline solid thereof, and sodium hydroxide ) Of a lyophilized preparation containing the sodium salt or hydrate thereof.
- (Item 26) The process according to item 24 or 25, wherein the acid addition salt is 1) p-toluenesulfonic acid salt, or 3) a salt formed from a combination of p-toluenesulfonic acid and sulfuric acid.
- a pharmaceutical composition comprising compound (IA) or a pharmaceutically acceptable salt, or a hydrate thereof, and further containing sodium p-toluenesulfonate and / or sodium sulfate.
- the pharmaceutical composition according to item 27, comprising a sodium salt of compound (IA) or a hydrate thereof, and further containing sodium p-toluenesulfonate and / or sodium sulfate.
- a pharmaceutical composition for parenteral administration comprising the sodium salt of compound (IA) according to item 1, an acid addition salt thereof, or a solvate thereof, or a crystalline solid thereof.
- (Item 32) A pharmaceutical composition for children or the elderly, comprising a sodium salt of compound (IA) according to item 1, an acid addition salt thereof, or a solvate thereof, or a crystalline solid thereof.
- the present invention provides an acid addition salt, sodium salt, or solvate thereof of compound (IA).
- acid addition salts are preferably provided as crystalline solids.
- the salt, solvate or crystalline solid thereof has at least one of the following characteristics. (1) Good stability to heat, humidity, solvent, light, etc., and high storage stability. (2) Coloring stability is good. (3) Good solubility in water or organic solvent. (4) Fast dissolution rate in water or organic solvent. (5) High purity. (6) The residual rate of the organic solvent is low. (7) Excellent operability such as filtration, centrifugation, and formulation. (8) The specific volume is small. (9) It is difficult to be charged. (10) Manufactured in high yield under conditions with low environmental load, and mass production is possible.
- the crystalline solid of the present invention has high stability even in a wide humidity range (for example, 25 to 99% RH) and harsh environments (for example, under high humidity).
- the type I crystal means a crystalline solid of a hydrate of a mixed salt of 1.3 molar equivalents of p-toluenesulfonic acid and 0.35 molar equivalents of sulfuric acid of the compound (IA).
- 2 shows a powder X-ray diffraction spectrum of a crystalline solid of 8.5 hydrate of 2-molar equivalent of p-toluenesulfonic acid salt of compound (IA) obtained in Example 3.
- the horizontal axis represents the diffraction angle 2 ⁇ (°), and the vertical axis represents the intensity (Count).
- FIG. 1 shows a powder X-ray diffraction spectrum of a crystalline solid of a mixed salt of 1 molar equivalent of p-toluenesulfonic acid and 1 molar equivalent of hydrochloric acid of compound (IA) obtained in Example 4.
- 1 shows a powder X-ray diffraction spectrum of a crystalline solid of a mixed acid salt of 1 molar equivalent of p-toluenesulfonic acid and 1 molar equivalent of hydrobromic acid of compound (IA) obtained in Example 5.
- FIG. 5 shows a powder X-ray diffraction spectrum of the type I crystal D obtained in Example 6-1 and having a water content of 13.5% ⁇ 0.3%.
- Example 7 shows a powder X-ray diffraction spectrum of the type I crystal E obtained in Example 6-2 and having a water content of 13.8% ⁇ 0.3%.
- the powder X-ray-diffraction spectrum of the crystalline solid of 2 molar equivalent benzenesulfonate of the compound (IA) obtained in Example 7 is shown.
- the moisture adsorption-desorption isotherm plot of the type I crystal D carried out in Example 8 is shown.
- the powder X-ray-diffraction spectrum measured on 30% RH conditions of the type-I crystal D implemented in Example 8 is shown.
- the powder X-ray-diffraction spectrum measured on 40% RH conditions of the type-I crystal D implemented in Example 8 is shown.
- the powder X-ray diffraction spectrum measured on 50% RH conditions of the type I crystal D implemented in Example 8 is shown.
- the powder X-ray-diffraction spectrum measured on 60% RH conditions of the type I crystal D implemented in Example 8 is shown.
- the powder X-ray-diffraction spectrum measured on 70% RH conditions of the type-I crystal D implemented in Example 8 is shown.
- the powder X-ray-diffraction spectrum measured on 80% RH conditions of the type I crystal D implemented in Example 8 is shown.
- the powder X-ray-diffraction spectrum measured on 90% RH conditions of the type I crystal D implemented in Example 8 is shown.
- the powder X-ray-diffraction spectrum measured on 95% RH conditions of the type I crystal D implemented in Example 8 is shown.
- a powder X-ray diffraction spectrum of a crystalline solid of a hydrate of a mixed salt of 1.05 molar equivalent of p-toluenesulfonic acid and 0.65 molar equivalent of sulfuric acid of compound (IA) obtained in Example 11 is shown.
- Show. A powder X-ray diffraction spectrum of a crystalline solid of a hydrate of a mixed salt of 1.0 molar equivalent of p-toluenesulfonic acid and 0.5 molar equivalent of sulfuric acid of compound (IA) obtained in Example 12 is shown.
- Show. 2 shows a powder X-ray diffraction spectrum of a crystalline solid of a 2.0 molar equivalent of p-toluenesulfonate hydrate obtained in Example 13 of compound (IA).
- Compound (IA) is represented herein by formula (IA): Substantially having the formula (IA ′): Since both states are possible, both structures are included. For example, the sodium salt of compound (IA) is and Is included.
- Salt formation studies provide a means to change the physicochemical characteristics and resulting biological characteristics of a drug without changing its chemical structure. Salt formation can have dramatic effects on drug properties.
- the selection of an appropriate salt is specified in part by the yield, proportion, and amount of its crystalline structure.
- the hygroscopicity, stability, solubility and processing characteristics of the salt form are also important aspects.
- the solubility of the salt form can affect its suitability for use as a drug. If the aqueous solubility is low, i.e. less than 10 mg / ml, the dissolution rate in in vivo administration is limited by the absorption process and may result in low bioavailability. In addition, low aqueous solubility can make administration by injection difficult, which can limit the choice of an appropriate route of administration.
- Examples of the acid forming the acid addition salt of compound (IA) include acids having a substituted or unsubstituted benzenesulfonic acid group and inorganic acids (eg, sulfuric acid, hydrochloric acid, nitric acid, hydrobromic acid, phosphoric acid, boric acid, etc.
- the acid having a substituted or unsubstituted benzenesulfonic acid group p-toluenesulfonic acid, benzenesulfonic acid, trifluoromethylbenzenesulfonic acid, chlorobenzenesulfonic acid, methoxybenzenesulfonic acid and the like are preferable, and more preferably, Benzenesulfonic acid, p-toluenesulfonic acid and the like.
- the inorganic acid is preferably hydrochloric acid, sulfuric acid or the like.
- the acid addition salt may be a mixed acid salt of two or more combinations selected from these acids, and a mixed acid of a combination of an acid having a substituted or unsubstituted benzenesulfonic acid group and an inorganic acid. Salts are preferred.
- a mixed acid salt of p-toluenesulfonic acid and hydrochloric acid or a mixed acid salt of p-toluenesulfonic acid and sulfuric acid has high stability against humidity and the like, and is excellent in storage stability.
- the acid addition salt is preferably a crystalline solid, but may be a single phase crystal or a mixed crystal.
- the single phase crystal may be a single acid addition salt or a mixed acid salt of two or more acids.
- a mixed crystal is a crystalline solid in which two or more kinds of single-phase crystals exist as a mixture.
- a mixed solid or a crystalline solid of an acid addition salt having a substituted or unsubstituted benzenesulfonic acid group is substituted or unsubstituted.
- a preferable range of the mixed acid of an acid having a substituted or unsubstituted benzenesulfonic acid group and an inorganic acid is about 1.0 to 1.9 molar equivalents of an acid having a substituted or unsubstituted benzenesulfonic acid group and about 0
- it is a mixed acid of any combination of about 1.2 to 1.4 molar equivalents of an acid having a substituted or unsubstituted benzenesulfonic acid group and about 0.3 to 0.7 molar equivalents of an inorganic acid.
- the number of molar equivalents of the acid may include an acid as a residual solvent such as an adhering acid.
- the acid addition salt of the present invention or a solvate thereof, preferably a crystalline solid includes p-toluenesulfonate (non-solvate) of compound (IA), hydrate of p-toluenesulfonate P-toluenesulfonic acid and sulfuric acid mixed acid salt (hereinafter p-toluenesulfonic acid / sulfuric acid mixed acid salt) (non-solvate), p-toluenesulfonic acid / sulfuric acid mixed acid salt hydrate, p- Mixed salt of toluenesulfonic acid and hydrochloric acid (hereinafter p-toluenesulfonic acid / hydrochloric acid mixed acid salt) (non-solvate), hydrate of p-toluenesulfonic acid / hydrochloric acid mixed acid salt, p-toluenesulfonic acid And hydrobromic acid mixed acid salt (hereinafter p-
- the types and contents of acids contained in the acid addition salt, solvate or crystalline solid thereof according to the present invention are as follows: 1) About 1 to 2 molar equivalents of p-toluenesulfone relative to compound (IA) Acid salt, 2) a mixed acid of about 1.0 to 1.9 molar equivalents of p-toluenesulfonic acid and about 0.1 to 0.9 molar equivalents of sulfuric acid, 3) about 1.0 to 1.9 molar equivalents P-toluenesulfonic acid and a mixed acid of about 0.1 to 1.0 molar equivalent of hydrochloric acid, 4) about 1.0 to 1.9 molar equivalent of p-toluenesulfonic acid and about 0.1 to 1.0 A mixed acid of molar equivalents of hydrobromic acid, 5) a mixed acid of about 1.0 to 1.9 molar equivalents of p-toluenesulfonic acid and about 0.1 to 1.0 molar equivalents of n
- a preferred embodiment of the crystalline solid is a mixed acid salt hydrate of any combination of about 1.0 to 1.5 molar equivalents of p-toluenesulfonic acid and about 0.2 to 0.6 molar equivalents of sulfuric acid. It is. More preferably, a mixed salt hydrate of any combination of about 1.2 to 1.3 molar equivalents of p-toluenesulfonic acid and about 0.4 to 0.5 molar equivalents of sulfuric acid, or about 1.
- a mixed salt hydrate of any combination of 1 to 1.4 molar equivalents of p-toluenesulfonic acid and about 0.3 to 0.7 molar equivalents of sulfuric acid More preferred is a mixed salt hydrate of any combination of about 1.3 molar equivalents of p-toluenesulfonic acid and about 0.4 to 0.5 molar equivalents of sulfuric acid.
- Another preferred embodiment is a mixed crystal of a mixed acid hydrate of p-toluenesulfonic acid and sulfuric acid represented by any combination above, or about 1 molar equivalent of p-toluenesulfonic acid and about 0.5 A crystalline solid of a hydrate of a mixed salt of a molar equivalent of sulfuric acid.
- Examples of the solvent for forming the solvate include water, ethanol, 2-propanol, methyl acetate, ethyl acetate, n-propyl acetate, 1,2-dimethoxyethane, methyl isobutyl ketone, acetonitrile and the like.
- water, ethanol or 2-propanol is used. More preferably, it is water.
- the preferred amount of solvate is about 0.5 to 20 molar equivalents, more preferably about 5 to 17 molar equivalents.
- the water of hydrate is preferably crystal water, but water as a residual solvent such as adhering water may be included.
- the water content of the hydrate of the present invention can be selected, for example, from the range of about 5 to 20% by weight, may be about 10 to 20% by weight, and may be about 12 to 17% by weight.
- the hydration content can be selected, for example, from the range of about 0.5 to 20 molar equivalents relative to compound (IA), and may be about 5 to 17 molar equivalents or about 6 to 12 molar equivalents.
- many of the crystalline solids of the present invention have improved stability as the water content increases.
- Acid addition salts, solvates thereof, preferably their crystalline solids are usually required after adding about 0.5 to 50 molar equivalents of acid to a solution of compound (IA) at about 0 ° C. to room temperature. Depending on the temperature, the solution is cooled to about -5 ° C to 5 ° C and crystallized by stirring or standing for several hours to several days.
- a preferred amount of acid is about 5-40 molar equivalents, more preferably about 10-30 molar equivalents.
- Preferred solvents are acetonitrile, acetone, water, ethanol, 2-propanol, or a mixed solvent of two or more selected from them, and more preferred is acetonitrile, water, or a mixed solvent thereof.
- the preparation of the solvate crystalline solid is carried out by dissolving the acid addition salt of Compound (IA) in a soluble solvent containing at least the solvent to be solvated at about 0 ° C. to room temperature, and about 0 ° C. to room temperature for several hours to Perform by stirring or standing for 3 days.
- the crystallized solvate can be separated from the solvent by a usual separation means such as filtration or centrifugation, and can be isolated by a usual purification means such as washing and drying.
- crystalline solid means a solid having a structure in which atoms, ions, molecules, etc. constituting the solid are regularly arranged, and as a result, has a structure having periodicity and anisotropy.
- Single phase crystal means a crystalline solid consisting of a single component and a single structure.
- Multiple crystal means a crystalline solid in which a periodic structure is composed of a mixture of two or more single-phase crystals or two or more substances having different chemical components.
- Crystal solids whose periodic structure is composed of two or more substances with different chemical components include, for example, 1) a mixture of chemical components in various proportions, Is a crystalline solid that forms a uniform solid phase (eg, non-metals or solid solutions consisting of metals and non-metals), 2) part of a periodic structure composed of two or more substances with different chemical components And 3) a crystalline solid in which a solute atom or molecule has entered a gap in a periodic structure composed of two or more substances having different chemical components. That is, “crystalline solid” includes “single phase crystal” and “mixed crystal”. Unless otherwise specified, “crystal” in the present specification has the same meaning as “crystalline solid”.
- the crystallinity of the crystalline form can be measured by many techniques including, for example, powder X-ray diffraction measurement, moisture adsorption / desorption measurement, differential scanning calorimetry, solution colorimetry, and dissolution characteristics.
- the crystalline solid of the present invention may be a single crystal, a twin crystal or a polycrystal, and is usually a single crystal or a mixed crystal thereof in many cases.
- the crystal form (outer shape) is not particularly limited, and examples thereof include triclinic crystals, monoclinic crystals, orthorhombic crystals (rectangular crystals), tetragonal crystals, cubic crystals, trigonal crystals (rhombohedral crystals), hexagonal crystals, and the like.
- the crystal may be a spherulite, a body crystal, a bark crystal, a needle crystal (for example, a beard crystal), or the like.
- the size of the crystal is not particularly limited.
- the average particle diameter of the crystal may be about 0.5 ⁇ m to 1 mm, preferably about 1 to 500 ⁇ m based on a laser diffraction method.
- the crystalline solid of the acid addition salt of compound (IA) or a solvate thereof may adsorb moisture due to a change in relative humidity, and the water of hydration may change. That is, it may be a crystalline solid in which water molecules in the air can easily enter and exit the crystal lattice as crystal water due to external humidity changes. For such crystalline solids, even if the powder X-ray diffraction pattern changes slightly with variation in moisture content, the crystalline solids are substantially the same as long as they have the characteristic peaks described herein. Can be interpreted.
- the water may be any residual solvent such as crystal water or adhering water.
- the crystalline solid may be a single phase crystal or a mixed crystal.
- the crystalline solid of the acid addition salt of compound (IA) or a solvate thereof is preferably characterized by a diffraction peak in a powder X-ray diffraction spectrum.
- the present invention also includes a mixed crystal composed of a crystalline solid containing a plurality of compounds (IA) having diffraction peaks at different diffraction angles in the powder X-ray diffraction spectrum.
- This mixed crystal contains at least a single-phase crystal characterized by the following diffraction peak.
- the diffraction peak may be one sharp peak (singlet shape), one gentle peak (broad shape), or about 2 to 5 multiple peaks (tablet). Shape, triplet shape, quartet shape, quintet shape), etc., but usually one sharp peak in many cases.
- a crystalline solid of 8.5 hydrate of 2-molar equivalent of p-toluenesulfonate of compound (IA) shows a powder X-ray diffraction pattern as shown in FIG. 1, and diffraction angle (2 ⁇ ): 8.1 ⁇ Characteristic peaks are shown at 0.2 °, 13.3 ⁇ 0.2 °, 17.4 ⁇ 0.2 °, 19.1 ⁇ 0.2 ° and 21.3 ⁇ 0.2 °.
- a crystalline solid of a mixed salt of 1 molar equivalent of p-toluenesulfonic acid and 1 molar equivalent of hydrochloric acid of Compound (IA) shows a powder X-ray diffraction pattern as shown in FIG. 2, and a diffraction angle (2 ⁇ ) of 8. Characteristic peaks are shown at 5 ⁇ 0.2 °, 10.2 ⁇ 0.2 °, 20.3 ⁇ 0.2 °, 24.6 ⁇ 0.2 ° and 26.2 ⁇ 0.2 °.
- a crystalline solid of a mixed salt of 1 molar equivalent of p-toluenesulfonic acid and 1 molar equivalent of hydrobromic acid of Compound (IA) shows a powder X-ray diffraction pattern as shown in FIG. 3, and a diffraction angle (2 ⁇ ) : Characteristic peaks at 8.5 ⁇ 0.2 °, 10.3 ⁇ 0.2 °, 16.6 ⁇ 0.2 °, 24.7 ⁇ 0.2 ° and 26.3 ⁇ 0.2 ° Show.
- a crystalline solid of benzenesulfonic acid having 2 molar equivalents of Compound (IA) exhibits a powder X-ray diffraction pattern as shown in FIG. 5, and diffraction angles (2 ⁇ ): 10.3 ⁇ 0.2 °, 13.3 ⁇ 0. Characteristic peaks are shown at .2 °, 16.5 ⁇ 0.2 °, 19.2 ⁇ 0.2 ° and 20.8 ⁇ 0.2 °.
- a crystalline solid of a mixed salt of 1.05 molar equivalent of p-toluenesulfonic acid and 0.65 molar equivalent of sulfuric acid compound (IA) showed a powder X-ray diffraction pattern as shown in FIG. ): Characteristic peaks are shown at 8.4 ⁇ 0.2 °, 10.2 ⁇ 0.2 °, 13.1 ⁇ 0.2 ° and 20.4 ⁇ 0.2 °.
- a crystalline solid of a mixed salt of 1.0 molar equivalent of p-toluenesulfonic acid and 0.5 molar equivalent of sulfuric acid of compound (IA) shows a powder X-ray diffraction pattern as shown in FIG. ): Characteristic peaks at 8.3 ⁇ 0.2 °, 10.1 ⁇ 0.2 °, 13.0 ⁇ 0.2 °, 16.5 ⁇ 0.2 °, and 20.3 ⁇ 0.2 ° Indicates.
- a crystalline solid of a hydrate of p-toluenesulfonic acid with 2 molar equivalents of Compound (IA) shows a powder X-ray diffraction pattern as shown in FIG. 18, and diffraction angle (2 ⁇ ): 5.3 ⁇ 0.2 Characteristic peaks are shown at °, 8.0 ⁇ 0.2 °, 13.0 ⁇ 0.2 °, 19.0 ⁇ 0.2 °, and 20.3 ⁇ 0.2 °.
- Form I crystals (: crystalline solid of a mixed acid hydrate of 1.3 molar equivalents of p-toluenesulfonic acid and 0.35 molar equivalents of sulfuric acid of compound (IA)) are shown in FIG. 15 shows a powder X-ray diffraction pattern such as 15, diffraction angle (2 ⁇ ): 8.2 ⁇ 0.2 °, 8.9 ⁇ 0.2 °, 10.1 ⁇ 0.2 °, 11.4 ⁇ 0. Characteristic peaks are shown at .2 °, 13.0 ⁇ 0.2 °, 20.3 ⁇ 0.2 ° and 26.2 ⁇ 0.2 °. In particular, diffraction angles (2 ⁇ ): 8.2 ⁇ 0.2 °, 10.1 ⁇ 0.2 °, 13.0 ⁇ 0.2 ° and 20.3 ⁇ 0.2 ° are more characteristic peaks. is there.
- the crystalline solid of the acid addition salt of compound (IA) or a solvate thereof preferably has a diffraction angle (2 ⁇ ) of 8.2 ⁇ 0.2 °, 10.1 ⁇ 0.2 °, 13.0 ⁇ . It has at least one peak selected from 0.2 ° and 20.3 ⁇ 0.2 °.
- the crystalline solid of the acid addition salt of compound (IA) or a solvate thereof preferably has a diffraction angle (2 ⁇ ) of 8.2 ⁇ 0.2 °, 8.9 ⁇ 0.2 °, 10.1 At least one peak selected from ⁇ 0.2 °, 11.4 ⁇ 0.2 °, 13.0 ⁇ 0.2 °, 20.3 ⁇ 0.2 ° and 26.2 ⁇ 0.2 °
- a diffraction angle (2 ⁇ ) 8.2 ⁇ 0.2 °, 8.9 ⁇ 0.2 °, 10.1 At least one peak selected from ⁇ 0.2 °, 11.4 ⁇ 0.2 °, 13.0 ⁇ 0.2 °, 20.3 ⁇ 0.2 ° and 26.2 ⁇ 0.2 °
- the crystalline solid of the acid addition salt of compound (IA) or a solvate thereof preferably has a diffraction angle (2 ⁇ ) of 8.2 ⁇ 0.2 °, 8.9 ⁇ 0.2 °, 10.1 ⁇ 0.2 °, 11.4 ⁇ 0.2 °, 13.0 ⁇ 0.2 °, 19.9 ⁇ 0.2 °, 20.3 ⁇ 0.2 °, 21.5 ⁇ 0.2 ° And at least one peak selected from 26.2 ⁇ 0.2 °.
- the crystalline solid of the acid addition salt of compound (IA) or a solvate thereof preferably has a diffraction angle (2 ⁇ ) of 8.2 ⁇ 0.2 °, 8.9 as a diffraction angle represented by 2 ⁇ . ⁇ 0.2 °, 10.1 ⁇ 0.2 °, 13.0 ⁇ 0.2 °, 16.5 ⁇ 0.2 °, 17.0 ⁇ 0.2 °, 17.9 ⁇ 0.2 ° , 19.0 ⁇ 0.2 °, 20.3 ⁇ 0.2 and 26.2 ⁇ 0.2 °.
- the crystalline solid of the present invention is usually prepared by dissolving the compound (IA) in a crystallization solvent and / or an acid and then bringing the compound (IA) into a supersaturated state to crystallize (or crystallize) the compound (IA). Many.
- the crystallization method (method for transitioning to a supersaturated state) is not particularly limited, and for example, an evaporation method (a method for evaporating a crystallization solvent from a crystallization system), a cooling method (a crystallization system (or compound (IA) solution) Cooling method), poor solvent addition method (method of adding poor solvent of compound (IA) to crystallization system), seed crystal addition method (method of adding seed crystal containing compound (IA) to crystallization system) Etc. can be exemplified.
- an evaporation method (a method of evaporating a crystallization solvent from a crystallization system (or solution) containing a compound (IA) and a crystallization solvent to bring it into a supersaturated state, and crystallizing from this supersaturated state) or a cooling method (compound)
- a crystallization system (or solution) containing (IA) and a crystallization solvent After cooling a crystallization system (or solution) containing (IA) and a crystallization solvent to a supersaturated state and crystallizing from this supersaturated state), a seed crystal obtained from the compound (IA) is obtained.
- the crystalline solid of the present invention can be produced by a seed crystal addition method in which a seed crystal is added to a solution dissolved in a crystallization solvent and / or an acid to cause crystallization. According to such a method, the crystalline solid can be produced efficiently.
- crystallization solvent examples include C 1-4 alkanols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol and 2-butanol; C 5-6 alkanes such as pentane and hexane; di-C such as diisopropyl ether.
- Examples include 1-4 alkyl ethers; C 2-4 ketones such as acetone and methyl ethyl ketone; amide solvents such as dimethylacetamide and N-methylpyrrolidone; acetonitrile and water.
- These crystallization solvents can be used alone or as a mixed solvent.
- the amount of the crystallization solvent used is, for example, about 1 to 100 mL, preferably 2 to 60 mL, and more preferably about 5 to 55 mL with respect to 1 g of compound (IA).
- the crystallization operation may be performed once, but may be repeated a plurality of times in order to improve the purity of the crystalline solid.
- the crystallization component obtained by crystallization is usually purified (separated from the non-crystallization component) by a separation means such as filtration or centrifugation.
- the separated crystallization component may be dried.
- the drying method may be any of natural drying, ventilation drying, and vacuum drying.
- vacuum drying for example, drying may be performed at about 1 to 100 hpa, preferably about 1 to 40 hpa (for example, 1.5 to 10 hpa, 10 to 35 hPa).
- the drying temperature may be, for example, room temperature to heating, preferably about 20 to 80 ° C.
- the drying time may be, for example, about 0.5 to 48 hours, preferably about 0.5 to 24 hours (for example, 0.5 to 10 hours).
- the crystalline solid of the acid addition salt or solvate of the present invention can also be synthesized by adding an acid to a solution such as a reaction solution containing the compound (IA) or a column eluate. Specifically, about 2 to 40% by weight of the acid is added to the reaction solution containing the compound (IA), the column eluate, etc., seed crystals are added as necessary, and the mixture is cooled to about ⁇ 5 to 5 ° C. Crystallization is performed by stirring or standing for about 1 hour to about 4 days, and the resulting crystalline solid is washed with cold water or the acid and dried at normal pressure or reduced pressure for about 0.5 to 10 hours. A crystalline solid of the acid addition salt of the present invention can be obtained.
- the acid addition salt crystalline solid of the present invention (for example, Z crystal) is dissolved or suspended in a crystallization solvent, and a salt is exchanged and crystallized by adding a different acid.
- a crystalline solid of an acid addition salt different from the crystal can also be obtained.
- a crystalline solid of 2 molar equivalents of p-toluenesulfonate hydrate of compound (IA) is obtained as follows. That is, an aqueous solution of about 2 to 20 molar equivalents of p-toluenesulfonic acid is added to an acetonitrile solution, an acetone solution, an aqueous solution or a mixed solution thereof containing compound (IA), and dissolved at room temperature or about 0 to 5 ° C.
- a type I crystal of compound (IA) (a mixed crystal of a hydrate of a mixed salt of 1.3 molar equivalents of p-toluenesulfonic acid and 0.35 molar equivalents of sulfuric acid) was obtained as follows. It is done.
- a 2-molar equivalent p-toluenesulfonate hydrate crystalline solid of Compound (IA) is dissolved in a sulfuric acid-water mixture and left to stand for about 1 to 4 days at 0 to 5 ° C. for crystallization.
- the obtained crystalline solid is washed with cold water and air-dried at room temperature for about 0.5 to 2 hours to obtain type I crystals.
- p-toluenesulfonic acid and sulfuric acid are added to an acetonitrile-water mixed solution containing Compound (IA), seed crystals are added as necessary, and the mixture is cooled to about ⁇ 5 to 5 ° C., and about 1 hour to about 4 days Crystallization can be achieved by stirring or standing, and the resulting crystalline solid can be washed with cold water or acid and dried at normal pressure or reduced pressure for about 0.5 to 10 hours to obtain type I crystals.
- Form I crystals may further contain about 0.01 to 0.1 molar equivalents of p-toluenesulfonic acid and / or about 0.01 to 0.1 molar equivalents of sulfuric acid remaining.
- the residual acid may be contained in such a form that it adheres to the crystal or is taken into the crystal.
- the crystalline solid of the acid addition salt of the present invention can be synthesized by salt exchange from acid addition salt crystals of different compositions. For example, 2 molar equivalents of p-toluenesulfonate hydrate crystalline solid is dissolved or suspended in a crystallization solvent and / or acid, the corresponding acid is added and cooled to about ⁇ 5 to 5 ° C., about 1 Crystallization is performed with salt exchange by stirring or standing for about 4 days to about 4 days, and the resulting crystalline solid is washed with cold water or the acid and dried at normal pressure or reduced pressure for about 0.5 to 10 hours Thus, a crystalline solid of the acid addition salt of the present invention can be obtained.
- P-toluenesulfonic acid monohydrate is about 2-3 wt%, more preferably about 2.2-2.5 wt%, and 75% sulfuric acid is contained in the solution containing compound (IA). About 4.5 to 7% by weight, more preferably about 5 to 6% by weight.
- p-toluenesulfonic acid monohydrate is about 1.2 to 1.5 parts by weight with respect to 1 part by weight of compound (IA), and 75% sulfuric acid is about 2.7 to 3.5 parts by weight. Part.
- the crystalline solid of the present invention is clearly identified by spectroscopic probes (eg X-ray diffraction, infrared spectrum, Raman spectrum and solid state NMR).
- spectroscopic probes eg X-ray diffraction, infrared spectrum, Raman spectrum and solid state NMR.
- the crystalline solid of compound (IA), its acid addition salt, or solvate thereof is preferably identified by a powder X-ray diffraction profile.
- the characteristic diffraction peaks are preferably selected from about 10, more preferably about 5, even more preferably about 3 in the diffraction pattern.
- the present invention includes not only a crystalline solid whose diffraction angle of a peak in powder X-ray diffraction completely coincides but also a crystalline solid whose diffraction angle of a peak coincides with an error of about ⁇ 0.2 °.
- the absolute intensity and relative intensity of the peaks shown in the tables and figures below are a number of factors, such as the effect of selective orientation of crystalline solids on the X-ray beam, the influence of coarse particles, the purity of the substance being analyzed. It is also known that it can vary depending on the crystallinity of the sample.
- the peak position can also be shifted based on the variation in sample height.
- a characteristic diffraction peak as used herein is a peak selected from the observed diffraction pattern.
- a peak that is found in the crystalline solid and not seen in other crystalline solids is preferable for identifying the crystalline solid, rather than the size of the peak. It becomes a peak. With such a characteristic peak, even one or two peaks can characterize the crystalline solid.
- Form I crystals can be distinguished from other crystal forms disclosed herein (eg, anhydrides, etc.) by the presence of characteristic diffraction peaks. Moreover, when the charts obtained by measurement are compared and these characteristic peaks coincide, it can be said that the powder X-ray diffraction spectra substantially coincide.
- the moisture content can be changed by changing the relative humidity, and the hydration state can be changed.
- Such type I crystals with different moisture contents have a common characteristic peak as shown in FIG. 4, 5 or 8-15.
- Common characteristic peaks are diffraction angles (2 ⁇ ): 8.2 ⁇ 0.2 °, 8.9 ⁇ 0.2 °, 10.1 ⁇ 0.2 °, 11.4 ⁇ 0.2 °, At least three peaks selected from 13.0 ⁇ 0.2 °, 19.9 ⁇ 0.2 °, 20.3 ⁇ 0.2 °, and 26.2 ⁇ 0.2 °. More preferred common characteristic peaks are diffraction angles (2 ⁇ ): 8.2 ⁇ 0.2 °, 10.1 ⁇ 0.2 °, 13.0 ⁇ 0.2 ° and 20.3 ⁇ 0.2. There are at least three peaks selected from °.
- Single crystal structure analysis (Toshio Sakurai, “Guide for X-ray structure analysis” published by Saika Hobo (1983), Stout & Jensen, X-Ray Structure Determination: A Practical Guide, Macmillan Co., New 68, etc. Reference) is one of methods for specifying a crystal, and crystallographic parameters, crystal coordinates (a value indicating a spatial positional relationship between each atom), and a three-dimensional structure model in the crystal can be obtained.
- Single crystal structure analysis is useful for identifying the crystal structure of a complex as in the present invention.
- the infrared absorption spectrum measurement method is a method for measuring the degree to which infrared rays are absorbed when passing through a sample for each wave number.
- Infrared absorption spectra are usually shown as a graph with the wave number on the horizontal axis and the transmittance or absorbance on the vertical axis.
- the wave number and transmittance (or absorbance) of the absorption peak can be read on a graph, and the output value by the data processing device can be used.
- the infrared absorption spectrum is determined by the chemical structure of the substance. Therefore, the substance can be confirmed or quantified by measuring absorption at various wave numbers.
- Crystal polymorphism is distinguished by functional groups characteristic of the crystal polymorphism, that is, functional groups mainly involved in hydrogen bonds in the crystal structure, such as C ⁇ O bond, OH bond and NH bond, and other characteristic features.
- functional groups characteristic of the crystal polymorphism that is, functional groups mainly involved in hydrogen bonds in the crystal structure, such as C ⁇ O bond, OH bond and NH bond, and other characteristic features.
- absorption bands such as C—X (halogen), C ⁇ C and C ⁇ C. It is selected from about 20 absorption peaks corresponding to characteristic functional groups, more preferably about 10 absorption peaks, most preferably about 5 absorption peaks.
- the absorption spectrum of the sample is measured at a range of wave number 4000cm -1 ⁇ 400cm -1. The absorption spectrum is measured under the same operating conditions as when the resolution of the apparatus, wave number scale and wave number accuracy were confirmed.
- the above absorption peak value includes a value within a range of about ⁇ 2 cm ⁇ 1.
- the present invention includes not only crystals that completely match the peak of the absorption band in the infrared absorption spectrum measurement but also crystals that match the peak of the absorption band with an error of about ⁇ 2 cm ⁇ 1 .
- Infrared absorption spectrum measurement methods include potassium bromide tablet method, solution method, paste method, liquid film method, thin film method, gas sample measurement method, ATR method, and diffuse reflection method.
- the ATR method (Attenuated total reflection) is called a total reflection measurement method and is one of the reflection methods.
- a sample is brought into close contact with the surface of a prism made of a material having a high refractive index such as KRS-5, light is incident on the prism at an angle greater than a critical angle, and the entire surface is reflected at the boundary between the prism and the sample. This is a method of obtaining an absorption spectrum by measuring reflected light.
- the refractive index of the prism is larger than that of the sample, and therefore it is necessary to change the material of the prism depending on the sample.
- the prism and the sample must be in close contact with each other. Therefore, it is suitable for measurement of liquids, powders, plastics, soft rubbers, etc., and has an advantage that the sample can be measured without chemically or physically processing.
- the diffuse reflection method is a method in which a powder sample is measured without making a potassium bromide tablet but in a powder form.
- a Raman spectrum shows the vibration characteristics of a molecule or complex system.
- the deadline lies in inelastic collisions between molecules and photons, which are particles of light containing light. Collisions between molecules and photons result in an exchange of energy that results in a change in energy, which changes the wavelength of the photon. That is, the Raman spectrum is a set of very narrow spectral lines emanating from the molecule of interest when illuminated by incident light. The width of each spectral line is greatly affected by the spectral width of the incident light, and therefore exactly one color light source, such as a laser, is used.
- the wavelength of each Raman line is indicated by a wave number shift from the incident light, which is the difference between the Raman line and the reciprocal of the wavelength of the incident light.
- a Raman spectrum measures the vibrational state of a molecule, which is determined by its molecular structure.
- the absorption band (cm ⁇ 1 ) in the Raman spectrum may cause an error within a range of ⁇ 2 cm ⁇ 1
- the above absorption peak value is understood to include a value within a range of about ⁇ 2 cm ⁇ 1. It is necessary to Therefore, the present invention includes not only crystals whose absorption band peaks in the Raman spectrum completely match but also crystals whose absorption band peaks match with an error of about ⁇ 2 cm ⁇ 1 .
- Solid state 13 C-NMR (nuclear magnetic resonance) has (i) the number of spectra matches the number of carbon atoms of the target compound, (ii) the chemical shift range is wider than 1 H-NMR, and (iii) the signal is solid. It is useful for specifying the crystal form because it is sharper than 1 H-NMR, and (iv) even if an additive is contained, if there is no interaction, the chemical shift does not change. It should be noted that the chemical shift observed depending on the particular spectrometer used and the analyst's use preparation technique is expected to vary slightly. The error range in the solid 13 C-NMR spectrum is approximately ⁇ 0.5 ppm.
- the crystalline solid of the present invention can also be specified by a thermal analysis technique.
- DSC Different Scanning Calorimetry
- DSC is one of the main measurement methods of thermal analysis, and is a method of measuring the thermal properties of a substance as an aggregate of atoms and molecules.
- DSC measures the change in calorie with temperature or time of the pharmaceutically active ingredient and plots the resulting data against temperature or time to obtain a differential scanning calorie curve. From the differential scanning calorimetry curve, it is possible to obtain information on the onset temperature when the pharmaceutically active ingredient is melted, the maximum value of the endothermic peak curve with melting, and the enthalpy.
- the observed temperature can depend on the rate of temperature change as well as the sample preparation technique and specific equipment used.
- the “melting point” in DSC refers to an onset temperature that is not easily affected by sample preparation techniques.
- the error range in onset temperature obtained from the differential scanning calorimetry curve is approximately ⁇ 2 ° C.
- the overall pattern is important, and may vary somewhat depending on the measurement conditions and the measurement equipment.
- TG / DTA differentiated thermothermogravimetric simultaneous measurement
- TG / DTA is one of the main measurement methods of thermal analysis, and is a method of measuring the weight and thermal properties of a substance as an aggregate of atoms and molecules.
- TG / DTA is a method for measuring changes in weight and calorie with temperature or time of a pharmaceutically active ingredient.
- TG thermogravimetric
- DTA differential A heat
- TG / DTA For TG / DTA, it is known that the observed temperature and weight changes can depend on the rate of temperature change as well as the sample preparation technique and the particular equipment used. Therefore, the “melting point” in TG / DTA refers to an onset temperature that is not easily influenced by the sample preparation technique. In the identification of crystal identity, the overall pattern is important and may vary somewhat depending on the measurement conditions and measurement equipment.
- Moisture adsorption / desorption isotherm measurement is a measurement method that measures the adsorption and desorption behavior of moisture by measuring the weight change of each solid to be measured under each relative humidity condition.
- a basic measurement method based on dry weight at 0% RH (relative humidity 0%), increase the relative humidity every 5% or 10%, stabilize the weight at each relative humidity, and then the reference value The amount of adsorbed water can be determined from the weight increase from Similarly, the amount of water desorption can be measured by reducing the relative humidity every 5% or 10% from 100% RH. By plotting the weight change value at each relative humidity, an adsorption / desorption isotherm can be obtained.
- the sodium salt of compound (IA) or a solvate thereof is prepared by adding sodium source such as sodium hydroxide or sodium bicarbonate to a solution containing compound (IA), adjusting the pH to about 5 to 6.5, concentrating under reduced pressure and / Or obtained by freeze-drying.
- the sodium salt or solvate thereof has 1) high solubility in water, 2) good stability to heat, humidity, dissolution and / or light, 3) small specific volume, 4) difficult to charge, 5) Manufactured under conditions with low environmental impact, 6) Mass production possible, 7) Controllable to an appropriate pH range without vascular pain when administered intravenously, 8) Suitable for lyophilized formulations Or 9) has advantageous features such as high dissolution rate in water.
- the sodium salt of compound (IA) is useful as a pharmaceutically active ingredient or a raw material thereof.
- the sodium salt can also be prepared directly from compound (IA), but the acid addition salt of compound (IA) or a solvate thereof, preferably their crystalline solid and sodium hydroxide, and optionally other It can also be obtained by lyophilizing an aqueous solution containing the following additives (eg, sugars, pH adjusters, sodium chloride or magnesium chloride) according to methods well known to those skilled in the art.
- the sodium salt of compound (IA) is preferably in an amorphous, i.e. amorphous form, and very soluble in water.
- the conditions for freezing are about ⁇ 50 to ⁇ 3 ° C. for 0.5 to 5 hours, preferably about ⁇ 40 to ⁇ 5 ° C. for 1 to 4 hours, and the conditions for annealing are about Primary drying at -40 to -20 ° C for 1 to 3 hours, preferably at about -35 to -25 ° C for 1.5 to 2.5 hours, at about -50 to -10 ° C for 0.1 to 150 Time
- vacuum pressure is about 5 to 20 Pa, preferably about ⁇ 40 to ⁇ 20 ° C. for 0.5 to 130 hours
- vacuum pressure is about 7.5 to 15 Pa
- secondary drying conditions are about 15 to 70 ° C.
- the vacuum pressure is about 5 to 20 Pa for 1 to 7 hours, preferably about 20 to 65 ° C. for 1.5 to 6.5 hours, and the vacuum pressure is about 5 to 20 Pa.
- the lyophilized preparation of the present invention is dissolved and administered by adding a solution such as distilled water for injection, physiological saline or glucose solution at the time of use.
- a solution such as distilled water for injection, physiological saline or glucose solution at the time of use.
- the pharmaceutical composition of the present invention exhibits a strong antibacterial spectrum against Gram-positive and negative bacteria, particularly a strong antibacterial activity against ⁇ -lactamase-producing Gram-negative bacteria, and cross resistance with existing cephem and carbapenem drugs. Not shown.
- the compound of the present invention (IA), its sodium salt, its acid adduct, or solvate thereof has a broad antibacterial spectrum, in particular ⁇ -lactamase producing bacteria Gram-negative bacteria (eg, class B type metallo) - ⁇ -lactamase-producing gram-negative bacteria). Therefore, various diseases caused by pathogenic bacteria in various mammals including humans, such as respiratory tract infections, urinary tract infections, respiratory infections, sepsis, nephritis, cholecystitis, oral infections, endocarditis, It is effective for the prevention or treatment of pneumonia, osteomyelitis, otitis media, enteritis, empyema, wound infection, opportunistic infection and the like.
- ⁇ -lactamase producing bacteria Gram-negative bacteria eg, class B type metallo
- the salt of the present invention or a solvate thereof and their crystalline solid are particularly suitable as an injection because of their high solubility.
- the salt of the present invention or a solvate thereof and the crystalline solid thereof have advantages such as high blood concentration, long duration of effect, and / or remarkable tissue migration as pharmacokinetics. Also have.
- the salt of the present invention or a solvate thereof, and a crystalline solid thereof have high stability in human plasma and are very effective as a pharmaceutical product.
- the salt of the present invention or a solvate thereof and the crystalline solid thereof (1) have good stability to heat, humidity, dissolution and / or light, and (2) storage stability and / or coloring.
- the salt of the present invention or a solvate thereof, and the crystalline solid thereof can be administered to a human patient per se, or a pharmaceutical composition in which the above-mentioned crystalline solid is mixed with a suitable simple substance or excipient. Can be administered. Techniques for drug formulation and administration can be found in “Remington ’s Pharmacological Sciences” Mack Publishing Co., Easton, PA.
- parenteral administration When administering the pharmaceutical composition of the present invention, it can be administered either orally or parenterally.
- parenteral administration include transdermal, subcutaneous, intravenous, intraarterial, intramuscular, intraperitoneal, transmucosal, inhalation, nasal, eye drop, ear drop, and intravaginal administration.
- Oral administration is in accordance with conventional methods, such as solid preparations for internal use (eg, tablets, powders, granules, capsules, pills, films, etc.), liquids for internal use (eg, suspensions, emulsions, elixirs, syrups, It may be prepared and administered in any commonly used dosage form such as a limonade agent, an alcoholic agent, an aromatic water agent, an extract, a decoction, a tincture and the like.
- solid preparations for internal use eg, tablets, powders, granules, capsules, pills, films, etc.
- liquids for internal use eg, suspensions, emulsions, elixirs, syrups
- It may be prepared and administered in any commonly used dosage form such as a limonade agent, an alcoholic agent, an aromatic water agent, an extract, a decoction, a tincture and the like.
- the tablet may be a sugar-coated tablet, a film-coated tablet, an enteric-coated tablet, a sustained-release tablet, a troche tablet, a sublingual tablet, a buccal tablet, a chewable tablet or an orally disintegrating tablet, and the powder and granules are dry syrup.
- the capsule may be a soft capsule, a microcapsule or a sustained release capsule.
- Parenteral administration includes injection (eg, intravenous injection, intramuscular injection, infusion, ampoule for subcutaneous injection, vial, liquid, suspension, etc.), topical administration (eg, ear drops, nose drops, eye drops) Agents, ointments, emulsions, sprays, aerosols, inhalants, suppositories, etc.), external preparations (eg lotions, injections, coatings, gargles, enemas, ointments, plasters, jellys) , Creams, patches, cataplasms, powders for external use, suppositories, etc.) and any other commonly used dosage form can be suitably administered.
- injection eg, intravenous injection, intramuscular injection, infusion, ampoule for subcutaneous injection, vial, liquid, suspension, etc.
- topical administration eg, ear drops, nose drops, eye drops
- the injection may be an emulsion of O / W, W / O, O / W / O, W / O / W type and the like.
- the injection can be prepared using a powder-filled preparation or a lyophilized preparation containing the salt of the present invention or a solvate thereof, or a crystalline solid thereof.
- it is a freeze-dried preparation containing the salt of the present invention or a solvate thereof, or a crystalline solid thereof.
- the freeze-dried preparation of the present invention can be used as an aqueous solution for uses such as injections.
- a salt or a crystalline solid having good solubility and dissolution rate in water is preferable.
- it is a sodium salt of compound (IA).
- Various pharmaceutical additives such as excipients, binders, disintegrants, lubricants and the like suitable for the dosage form can be mixed with the effective amount of the compound of the present invention as necessary to obtain a pharmaceutical composition.
- the pharmaceutical composition can be obtained by changing the effective amount, dosage form and / or various pharmaceutical additives of the compound of the present invention as appropriate, so that it can be used for pediatric, elderly, critically ill patients or surgery. You can also
- the pediatric pharmaceutical composition is preferably administered to a patient under the age of 12 or 15 years.
- the pediatric pharmaceutical composition can be administered to patients less than 27 days after birth, 28 to 23 months after birth, 2 to 11 years old, or 12 to 16 years old or 18 years old.
- the elderly pharmaceutical composition is preferably administered to a patient over 65 years of age.
- Suitable routes of administration include, but are not limited to, oral, rectal, transmucosal or enteral administration, or intramuscular, subcutaneous, intrathecal, intrathecal, direct intraventricular, intravenous, intravitreal, intraperitoneal, nasal cavity Internal, intraocular, injection may be included.
- the preferred route of administration is intravenous injection.
- the pharmaceutical composition of the present invention is manufactured by a method well known in the art, for example, conventional mixing, dissolving, granulating, sugar-coating, powdering, emulsifying, encapsulating, inclusion, lyophilization process. Can do.
- the pharmaceutical composition used in the present invention comprises an excipient and an auxiliary agent that facilitate the production of a salt of the present invention or a solvate thereof, or a crystalline solid thereof into a pharmaceutically usable preparation.
- the above-mentioned preparation may contain additives suitable for the administration form; for example, excipients, auxiliaries, stabilizers, wetting agents, emulsifiers, other additives, and the like. They must be pharmaceutically and pharmacologically available and must be substances that do not affect cephalosporin derivatives.
- oral preparations include lactose, stearic acid, magnesium stearate, clay, sucrose, corn starch, talc, gelatin, agar, pectin, peanut oil, olive oil, cocoa butter, ethylene glycol, tartaric acid, citric acid, fumar Contains acids and the like.
- solvent for parenteral preparation, solvent (alcohol, buffer, methyl oleate, water, etc.), buffer, dispersant, solubilizer, stabilizer (methyl p-hydroxybenzoate or ethyl p-hydroxybenzoate) , Sorbic acid, etc.), absorption enhancers (such as glycerin mono- or dioctanoic acid esters), antioxidants, fragrances, analgesics, suspensions, side-effect inhibitors, action-enhancing substances (absorption regulators, enzyme degradation prevention) Agents, ⁇ -lactamase inhibitors, other antibacterial agents, and the like).
- solvent alcohol, buffer, methyl oleate, water, etc.
- dispersant for solubilizer
- stabilizer methyl p-hydroxybenzoate or ethyl p-hydroxybenzoate
- Sorbic acid etc.
- absorption enhancers such as glycerin mono- or dioctanoic acid esters
- antioxidants such
- the salt of the present invention or a solvate thereof, or a crystalline solid thereof is stabilized and listed in the Japanese Pharmacopoeia, the Japanese Pharmacopoeia Standards for Pharmaceuticals, the Standards for Pharmaceutical Additives, and the Food Additives Standard Antioxidants, buffers, soothing agents, preservatives and the like that can be used for injections can be added.
- Specific examples of the antioxidant include sodium bisulfite, sodium pyrosulfite, and ascorbic acid.
- the buffer include citrate, acetate, and phosphate.
- soothing agents include procaine hydrochloride, lidocaine hydrochloride, chlorobutanol, and benzyl alcohol.
- Preservatives include methyl paraoxybenzoate, propyl paraoxybenzoate, phenol, cresol, benzyl alcohol, chlorobutanol, chlorocresol and the like.
- the salt of the present invention or a solvate thereof, or an aqueous solution in which the crystalline solid is dissolved preferably a physiologically compatible buffer solution such as Ringer's solution or physiological saline.
- a physiologically compatible buffer solution such as Ringer's solution or physiological saline.
- a base for adjusting pH for example, sodium hydroxide
- transmucosal administration it can be administered using a penetrant suitable for the barrier to be permeated.
- the penetrant those generally known in the art can be used.
- the simple substance is a known excipient (eg starch, lactose, sucrose, calcium carbonate, calcium phosphate, etc.), binder (eg starch, gum arabic, carboxymethylcellulose, hydroxy) Propyl cellulose, crystalline cellulose, etc.), lubricants (eg, magnesium stearate, talc, etc.).
- excipient eg starch, lactose, sucrose, calcium carbonate, calcium phosphate, etc.
- binder eg starch, gum arabic, carboxymethylcellulose, hydroxy
- lubricants eg, magnesium stearate, talc, etc.
- the pharmaceutical composition containing the salt of the present invention or a solvate thereof, or a crystalline solid thereof can contain a suitable solid or gel phase alone or an excipient.
- suitable solid or gel phase alone or an excipient.
- Such simple substances or excipients include, for example, inorganic salts (eg, sodium chloride, magnesium chloride, calcium carbonate, calcium phosphate, etc.), organic salts (eg, sodium p-toluenesulfonate, sodium gluconate, sodium citrate, etc.) ), Sugar or sugar alcohol (eg, glucose, fructose, sucrose, trehalose, mannitol, etc.), acid (eg, gluconic acid, citric acid, etc.) polymer (eg, starch, cellulose derivative, gelatin, polyethylene glycol, etc.), etc. It is done.
- Preferred are one or more salts selected from inorganic salts and organic salts, and sugars or sugar alcohols.
- the pharmaceutical composition containing the salt of the present invention or a solvate thereof, or a crystalline solid thereof dissolves or suspends the salt of the present invention or a solvate thereof, or a crystalline solid thereof, and an additive in water.
- the drying method may be a drying method in which the salt of the present invention or a solvate thereof, or a crystalline solid thereof is stable. Specific examples include a suction drying method using an evaporator, a spray drying method, a freeze drying method, and the like.
- the freeze drying method is preferred, and the pharmaceutical composition of the present invention is preferably a freeze dried product.
- a pharmaceutical composition containing the salt of the present invention or a solvate thereof, or a crystalline solid thereof 1) The salt of the present invention or a solvate thereof, or a crystalline solid thereof is added to water for injection to prepare an acidic slurry. 2) Add aqueous solution of sodium hydroxide to the slurry of 1) to adjust to pH 5.5-6, and add additives. 3) Additional water for injection was added to adjust the concentration to 5 w / w%, aseptic filtration, to obtain a pharmaceutical solution. 4) A predetermined amount of the preparation solution of 3) is dispensed into vials or ampoules and freeze-dried. A vacuum freeze dryer can be used as the freeze dryer.
- the dose of the salt of the present invention or a solvate thereof, or a crystalline solid thereof is preferably set in consideration of the patient's age, weight, type and degree of disease, route of administration, etc.
- it is usually 1 ⁇ g to 1 g / day, preferably 0.01 to 200 mg / day
- parenteral administration it is usually 1 ⁇ g to 10 g / day, preferably 0.1 mg to 10 mg / day. It is. This may be administered once to several times a day.
- the powder X-ray diffractometry of the crystalline solid obtained in each example is in accordance with the powder X-ray diffractometry described in the general test method of the Japanese Pharmacopoeia under any of the following measurement conditions 1 to 3. went.
- An aluminum plate is used as the sample folder.
- the peak where the 2-Theta (2 ⁇ ) value appears in the vicinity of 38 ° is the peak of aluminum.
- Measurement condition 1 (apparatus) Bruker D-8 Discover (Method of operation) Measurement method: Reflection method
- Light source type Cu tube Use wavelength: CuK ⁇ ray tube current: 40 mA Tube voltage: 40Kv Sample plate: Al Measuring range: 3 ° -40 ° Exposure time: 120s
- Measurement condition 2 (apparatus) RINT TTR III manufactured by Rigaku (Method of operation) The sample was measured under the following conditions. Measurement method: reflection method, parallel beam method Light source type: Cu tube Wavelength: CuK ⁇ tube current: 300 mA Tube voltage: 50Kv X-ray incident angle (2 ⁇ ): 4 ° to 40 ° Sampling width: 0.02 ° Scan speed: 5 ° / min
- Measurement condition 3 (apparatus) RINT2100 Ultimate + from Rigaku (Method of operation) Measurement method: Reflection method
- Light source type Cu tube Use wavelength: CuK ⁇ ray tube current: 40 mA Tube voltage: 40Kv Sample plate: Al Measurement range: 5 ° to 35 ° Sampling width: 0.020 ° Scan speed: 30 ° / min
- Compound (IA) was synthesized.
- Type I Crystal Synthesis of Crystalline Solid of Hydrate of Mixed Acid Salt of 1.3 Molar Equivalent p-Toluenesulfonic Acid and 0.35 Molar Sulfuric Acid of Compound (IA)>
- Example 6-1 Synthesis Step 1 of Type I Crystal D 1: Synthesis of Seed Crystal C Seed A (50 mg) was dissolved in 6 mol / L H 2 SO 4 (3 mL) at room temperature on an ultrasonic bath. The mixture was allowed to stand at 2 ° C. for 2 days. The precipitated crystalline solid was filtered and washed with ice-cold water to obtain seed crystal C (23 mg).
- Step 2 Synthesis of Compound (IA) and Type I Crystal D Under a nitrogen atmosphere, Compound 1 (18.0 kg, 22.6 mol) was dissolved in N, N-dimethylacetamide (41 L) and cooled to 0 ° C. Sodium iodide (6.8 kg, 45.2 mol), compound 2 (13.1 kg, 24.9 mol) and N, N-dimethylacetamide (4 L) were added, and the mixture was stirred at 0 ° C. for 6 hours. The temperature was raised to 7 ° C. and stirred for 16 hours. After cooling to 0 ° C.
- Step 1 Preparation of sample solution About 40 mg of a sample was accurately weighed and dissolved in a sample dilution solvent to make exactly 25 mL. 2 mL of this liquid was accurately weighed and a sample dilution solvent was added to make exactly 20 mL.
- Step 2 Preparation of standard solution About 25 mg of standard p-toluenesulfonate standardized in an environment of 25 ° C./60% RH was accurately weighed and dissolved in a sample dilution solvent to make exactly 100 mL. 5 mL of this solution was accurately weighed and a sample dilution solvent was added to make exactly 50 mL. As the sample dilution solvent, a 5 mmol / L phosphate buffer / acetonitrile mixture for liquid chromatography (9: 1) was used.
- Step 3 Measurement and Quantification The above sample solution and standard solution were measured by liquid chromatography under the following test conditions, and the peak area of p-toluenesulfonic acid was measured by an automatic integration method.
- dehydrated equivalent is a value calculated by subtracting the water content from the total amount as 100%.
- Amount of p-toluenesulfonic acid (%) M S : Weighed amount of standard sodium p-toluenesulfonate (mg) M T : Weighed sample (mg) P: Purity of standard sodium p-toluenesulfonate (%) W T : Sample moisture (%) A T : Peak area of p-toluenesulfonic acid obtained from the sample solution A S : Peak area of p-toluenesulfonic acid obtained from standard solution 172.20: Molecular weight of p-toluenesulfonic acid 194.18: Molecular weight of sodium p-toluenesulfonate
- Step 1 Preparation of standard solution About 50 mg of anhydrous sodium sulfate was accurately weighed and dissolved in the mobile phase to make exactly 25 mL. 2 mL of this liquid was accurately weighed and the mobile phase was added to make exactly 50 mL. Furthermore, 2 mL of this liquid was accurately weighed and the mobile phase was added to make exactly 20 mL. Step 2: Preparation of sample solution About 30 mg of the sample was accurately weighed and dissolved in the mobile phase to make exactly 25 mL. 2 mL of this solution was accurately weighed and the mobile phase was added to make exactly 20 mL.
- Step 3 Measurement and Quantification
- the sample solution and standard solution were measured by liquid chromatography (ion chromatography) under the following test conditions, and the peak area of sulfate ions was measured by an automatic integration method.
- Detector Electrical conductivity detector (Non-suppressor system)
- Mobile phase Bis-Tris approx. 0.67 g, boric acid approx. 3.09 g and ground p-hydroxybenzoic acid approx.
- Amount of sulfuric acid (%) M S / M T ⁇ 100 / (100-W T ) ⁇ A T / A S ⁇ 98.08 / 142.04 ⁇ 1/25 ⁇ 100 M S : Weighed amount of anhydrous sodium sulfate (mg) M T : Weighed sample (mg) W T : Sample moisture (%) A S : Peak area of sulfate ion obtained from standard solution A T : Peak area of sulfate ion obtained from the sample solution 98.08: Molecular weight of sulfuric acid 142.04: Molecular weight of anhydrous sodium sulfate 1/25: Dilution factor (result) p-Toluenesulfonic acid: 22.2 ⁇ 0.2% (dehydrated equivalent) Sulfuric acid: 4.3 ⁇ 0.1% (dehydrated equivalent
- the diffraction angles 2 ⁇ showing characteristic diffraction peaks are 8.3 ⁇ 0.2 °, 9.0 ⁇ 0.2 °, 10.1 ⁇ 0.2 °, 13.0 ⁇ 0.2 °, 16. 3 ⁇ 0.2 °, 17.3 ⁇ 0.2 °, 18.1 ⁇ 0.2 °, 19.1 ⁇ 0.2 °, 20.3 ⁇ 0.2 ° and 26.2 ⁇ 0.2 °.
- they are 8.3 ⁇ 0.2 °, 10.1 ⁇ 0.2 °, 13.0 ⁇ 0.2 °, 16.3 ⁇ 0.2 °, and 20.3 ⁇ 0.2 °. More preferably, they are 8.3 ⁇ 0.2 °, 10.1 ⁇ 0.2 °, 13.0 ⁇ 0.2 °, and 20.3 ⁇ 0.2 °.
- Example 6-2 Synthesis of type I crystal E After suspending type I crystal D (25.0 g) obtained by the method described in Example 6-1 in water (125 mL) cooled to 5 ° C. Stir at 5 ° C. for 26 hours and filter the crystalline solid. The crystalline solid was washed with water (75 mL) cooled to 5 ° C. to obtain type I crystal E (22.92 g) of compound (IA).
- the diffraction angles 2 ⁇ showing characteristic diffraction peaks are 8.3 ⁇ 0.2 °, 9.0 ⁇ 0.2 °, 10.1 ⁇ 0.2 °, 13.0 ⁇ 0.2 °, 16. 3 ⁇ 0.2 °, 17.3 ⁇ 0.2 °, 18.1 ⁇ 0.2 °, 19.1 ⁇ 0.2 °, 20.3 ⁇ 0.2 °, and 26.2 ⁇ 0.2 °.
- Preferred are 8.3 ⁇ 0.2 °, 10.1 ⁇ 0.2 °, 13.0 ⁇ 0.2 °, 16.3 ⁇ 0.2 °, and 20.3 ⁇ 0.2 °. More preferably, they are 8.3 ⁇ 0.2 °, 10.1 ⁇ 0.2 °, 13.0 ⁇ 0.2 °, and 20.3 ⁇ 0.2 °.
- type I crystal D and type I crystal E have different p-toluenesulfonic acid and sulfuric acid contents, but have the same powder X-ray diffraction pattern and thus have the same crystal form. That is, type I crystal D is a crystalline solid in which about 0.02 molar equivalent of p-toluenesulfonic acid and about 0.1 molar equivalent of sulfuric acid remain in type I crystal E.
- Form I crystals may contain about 0.01 to 0.1 molar equivalents of p-toluenesulfonic acid and / or about 0.01 to 0.1 molar equivalents of sulfuric acid remaining. The residual acid may be in a form attached to the crystal or taken into the crystal.
- the preferred p-toluenesulfonic acid content of type I crystals is about 20.2 ⁇ 0.2 to 23.2 ⁇ 0.2% (in terms of dehydrate), and the preferred sulfuric acid content is about 3.5 ⁇ 0.1 to 5.0 ⁇ 0.1% (dehydrated equivalent).
- the more preferable p-toluenesulfonic acid content of the type I crystal is about 21.5 ⁇ 0.2 to 22.3 ⁇ 0.2% (in terms of dehydrate), and the more preferable sulfuric acid content is about 4.2 ⁇ 0.00%. 1 to 4.9 ⁇ 0.1% (dehydrated equivalent).
- the more preferable p-toluenesulfonic acid content of the type I crystal is about 21.5-22.3% (dehydrated equivalent), and the more preferable sulfuric acid content is about 4.2-4.9% (dehydrated equivalent). is there.
- the results of powder X-ray diffraction of type I crystal D measured under measurement condition 3 and held for 3 hours or more under each relative humidity condition are shown below.
- the results of powder X-ray diffraction under 30% RH conditions are shown in FIG.
- the diffraction angles 2 ⁇ showing characteristic diffraction peaks are 8.4 ⁇ 0.2 °, 9.1 ⁇ 0.2 °, 10.2 ⁇ 0.2 °, 11.6 ⁇ 0.2 °, 13.0. ⁇ 0.2 °, 20.1 ⁇ 0.2 °, 20.4 ⁇ 0.2 °, and 26.2 ⁇ 0.2 °. More preferably, they are 8.4 ⁇ 0.2 °, 10.2 ⁇ 0.2 °, 13.0 ⁇ 0.2 °, and 20.4 ⁇ 0.2 °.
- the results of powder X-ray diffraction under 40% RH conditions are shown in FIG.
- the diffraction angle 2 ⁇ showing the characteristic diffraction peak is 8.4 ⁇ 0.2 °, 9.1 ⁇ 0.2 °, 10.2 ⁇ 0.2 °, 11.5 ⁇ 0.2 °, 13. They are 0 ⁇ 0.2 °, 20.0 ⁇ 0.2 °, 20.3 ⁇ 0.2 °, 21.7 ⁇ 0.2 ° and 26.2 ⁇ 0.2 °. More preferably, they are 8.4 ⁇ 0.2 °, 10.2 ⁇ 0.2 °, 13.0 ⁇ 0.2 °, and 20.3 ⁇ 0.2 °.
- the results of powder X-ray diffraction under 50% RH conditions are shown in FIG.
- the diffraction angle 2 ⁇ showing the characteristic diffraction peak is 8.4 ⁇ 0.2 °, 9.1 ⁇ 0.2 °, 10.2 ⁇ 0.2 °, 11.5 ⁇ 0.2 °, 13. They are 0 ⁇ 0.2 °, 20.0 ⁇ 0.2 °, 20.3 ⁇ 0.2 °, 21.7 ⁇ 0.2 ° and 26.2 ⁇ 0.2 °. More preferably, they are 8.4 ⁇ 0.2 °, 10.2 ⁇ 0.2 °, 13.0 ⁇ 0.2 °, and 20.3 ⁇ 0.2 °.
- Diffraction angles 2 ⁇ showing characteristic diffraction peaks are 8.3 ⁇ 0.2 °, 9.1 ⁇ 0.2 °, 10.2 ⁇ 0.2 °, 11.5 ⁇ 0.2 °, 13. They are 0 ⁇ 0.2 °, 19.9 ⁇ 0.2 °, 20.3 ⁇ 0.2 °, 6 ⁇ 0.2 ° and 26.2 ⁇ 0.2 °. More preferably, they are 8.3 ⁇ 0.2 °, 10.2 ⁇ 0.2 °, 13.0 ⁇ 0.2 °, and 20.3 ⁇ 0.2 °.
- the results of powder X-ray diffraction under 70% RH conditions are shown in FIG. 12 and Table 12.
- the diffraction angle 2 ⁇ showing a characteristic diffraction peak is 8.3 ⁇ 0.2 °, 0 ⁇ 0.2 °, 1 ⁇ 0.2 °, 11.5 ⁇ 0.2 °, 13.0 ⁇ 0. 2 °, 19.9 ⁇ 0.2 °, 20.3 ⁇ 0.2 °, 21.6 ⁇ 0.2 ° and 26.2 ⁇ 0.2 °. More preferably, they are 3 ⁇ 0.2 °, 10.1 ⁇ 0.2 °, 13.0 ⁇ 0.2 °, and 20.3 ⁇ 0.2 °.
- the results of powder X-ray diffraction under 80% RH conditions are shown in FIG. 13 and Table 13.
- the diffraction angle 2 ⁇ showing a characteristic diffraction peak is 8.3 ⁇ 0.2 °, 0 ⁇ 0.2 °, 10.1 ⁇ 0.2 °, 11.5 ⁇ 0.2 °, 13.0 ⁇ . 0.2 °, 19.9 ⁇ 0.2 °, 20.3 ⁇ 0.2 °, 21.6 ⁇ 0.2 ° and 26.2 ⁇ 0.2 °. More preferably, they are 8.3 ⁇ 0.2 °, 10.1 ⁇ 0.2 °, 13.0 ⁇ 0.2 °, and 20.3 ⁇ 0.2 °.
- Diffraction angles 2 ⁇ showing characteristic diffraction peaks are 8.2 ⁇ 0.2 °, 9.0 ⁇ 0.2 °, 10.1 ⁇ 0.2 °, 11.5 ⁇ 0.2 °, 13. They are 0 ⁇ 0.2 °, 19.9 ⁇ 0.2 °, 20.3 ⁇ 0.2 °, 5 ⁇ 0.2 ° and 26.2 ⁇ 0.2 °. More preferably, they are 8.2 ⁇ 0.2 °, 10.1 ⁇ 0.2 °, 13.0 ⁇ 0.2 °, and 20.3 ⁇ 0.2 °.
- the I-type crystal adsorbs moisture due to a change in relative humidity and becomes hydrated water, and most of the hydrated water is taken into the crystal lattice as crystal water. That is, the I-type crystal is a crystalline solid in which water molecules can easily enter and leave the crystal lattice as crystal water due to external humidity changes. That is, as shown in FIGS. 7 to 15, type I crystals are crystalline solids in which the number of hydration waters fluctuates as long as they are held for several hours in different humidity environments. Even different compositions can be interpreted as substantially the same crystalline solid as type I crystals.
- the water of hydration may be crystal water, adhering water or a residual solvent.
- the preferred water content of type I crystals is about 12-17%, more preferably about 12-15%.
- the preferred water of hydration for Form I crystals is about 7.5 to 12 moles, more preferably about 8 to 11.5 moles.
- These different moisture content type I crystals have a common characteristic diffraction peak.
- the diffraction angle 2 ⁇ showing a characteristic diffraction peak is 8.2 ⁇ 0.2 °, 8.9 ⁇ 0.2 °, 10.1 ⁇ 0.2 °, 11.4 ⁇ 0.2 °, 13. 0 ⁇ 0.2 °, 19.9 ⁇ 0.2 °, 20.3 ⁇ 0.2 °, 21.5 ⁇ 0.2 ° and 26.2 ⁇ 0.2 °.
- Step 2 Synthesis of Compound 8 Anisole (1.54 L) was cooled in a dry ice-ethanol bath, and aluminum chloride (495.4 g, 3.71 mol) was added followed by dichloromethane (0.93 L). Of the crude product containing Compound 8 obtained in Step 1, 610 g was dissolved in a mixture of dichloromethane (0.51 L) and anisole (1.03 L), and recooled to ⁇ 40 ° C. for 1 hour. Was added dropwise. The container used for the dropwise addition was washed with a mixed solution of dichloromethane (0.36 L) and anisole (0.51 L) and added to the reaction solution. A solution obtained by stirring the reaction solution at ⁇ 20 ° C.
- the aqueous layer was stirred under ice-cooling, and the pH was adjusted to 1.5 by adding a 2 mol / L aqueous sodium hydroxide solution and allowed to stand overnight.
- the aqueous layer was concentrated and purified on a HP20SS column (eluent: 13% acetonitrile water).
- Sodium bicarbonate (8.75 g) was added to the collected fraction containing the desired product, and the mixture was concentrated under reduced pressure to 500 mL. After diluting with water (1.6 L) and filtering with a cotton plug, the filtrate was freeze-dried to obtain Compound 9 (77.8 g).
- Seed crystal A (20 mg) obtained in the same manner as in Example 1 was dissolved in 2 mol / L-HNO 3 aqueous solution (0.3 mL). The solution was left at 4 ° C. for 2 days. The precipitated solid was collected to obtain a crystalline solid. It was confirmed to be a crystalline solid by a microscope. Table 16 shows the result of powder X-ray diffraction measured under Measurement Condition 1.
- the precipitated crystals were collected by filtration, washed with cold water (6 mL) and dried by ventilation to obtain a crystalline solid (1.74 g).
- the obtained crystalline solid (1.5 g) was dissolved in 50% aqueous acetonitrile (7.5 mL), water (30 mL) and 75% sulfuric acid (3.0 g) were added, and the mixture was stirred at 15 ° C. for 3 hr 30 min. . After cooling to 0 ° C. and stirring for 3 hours, the mixture was allowed to stand in a refrigerator for 14 hours and 50 minutes.
- the precipitated crystalline solid was collected by filtration, washed with cold water (4.5 mL), and air-dried to obtain a crystalline solid (1.17 g).
- the diffraction angle 2 ⁇ showing the characteristic diffraction peak is 8.4 ⁇ 0.2 °, 9.1 ⁇ 0.2 °, 10.2 ⁇ 0.2 °, 13.1 ⁇ 0.2 °, 16. They are 3 ⁇ 0.2 °, 17.3 ⁇ 0.2 °, 19.2 ⁇ 0.2 °, 20.4 ⁇ 0.2 °, and 26.3 ⁇ 0.2 °. Preferably, they are 8.4 ⁇ 0.2 °, 10.2 ⁇ 0.2 °, 13.1 ⁇ 0.2 °, 16.3 ⁇ 0.2 °, and 20.4 ⁇ 0.2 °. More preferably, they are 8.4 ⁇ 0.2 °, 10.2 ⁇ 0.2 °, 13.1 ⁇ 0.2 °, and 20.4 ⁇ 0.2 °.
- Type I crystals D obtained by the method described in Example 6-1 were dissolved in a mixture of ethanol (300 mL) and water (200 mL). A solution prepared by mixing 75% sulfuric acid (100 g) in water (500 mL) at room temperature was added, and then water (400 mL) was further added. After cooling to 0 ° C., crystals were precipitated and stirred for 6 hours, and the precipitated crystalline solid was filtered.
- the diffraction angles 2 ⁇ showing characteristic diffraction peaks are 8.3 ⁇ 0.2 °, 9.0 ⁇ 0.2 °, 10.1 ⁇ 0.2 °, 13.0 ⁇ 0.2 °, 16. 5 ⁇ 0.2 °, 17.2 ⁇ 0.2 °, 18.1 ⁇ 0.2 °, 19.1 ⁇ 0.2 °, 20.3 ⁇ 0.2 ° and 26.3 ⁇ 0.2 °.
- they are 8.3 ⁇ 0.2 °, 10.1 ⁇ 0.2 °, 13.0 ⁇ 0.2 °, 16.5 ⁇ 0.2 °, and 20.3 ⁇ 0.2 °. More preferably, they are 8.3 ⁇ 0.2 °, 10.1 ⁇ 0.2 °, 13.0 ⁇ 0.2 °, and 20.3 ⁇ 0.2 °.
- Type I crystal D (25.9 g) obtained by the method described in Example 6-1 was dissolved in a mixture of acetonitrile (40 mL) and water (40 mL). After adding water (259 mL) at room temperature, p-toluenesulfonic acid monohydrate (103.5 g) was added. The mixture was cooled to 5 ° C. and allowed to stand for 65 hours, and the precipitated crystalline solid was filtered. The crystal was washed with water (80 mL) cooled to 5 ° C. to obtain a crystalline solid (15.0 g).
- the diffraction angle 2 ⁇ showing a characteristic diffraction peak is 5.3 ⁇ 0.2 °, 8.0 ⁇ 0.2 °, 8.8 ⁇ 0.2 °, 10.5 ⁇ 0.2 °, 10. 9 ⁇ 0.2 °, 13.1 ⁇ 0.2 °, 17.4 ⁇ 0.2 °, 19.0 ⁇ 0.2 °, 19.7 ⁇ 0.2 °, 20.3 ⁇ 0.2 °, 21.3 ⁇ 0.2 °, 24.4 ⁇ 0.2 ° and 26.3 ⁇ 0.2 °.
- Test example 1 Solid stability test of crystalline solid About 1 g of type I crystal D was put in a polyethylene bag and fastened with a convex. This bag was further put into a polyethylene bag and similarly tightened with a convex. The above specimens under the same storage conditions were collected and placed in a metal can to make a specimen for stability evaluation. The storage conditions, storage period and test items are as follows. It was confirmed that the I-type crystal D was extremely stable under the following storage conditions and storage periods with no change in appearance and no increase in related substances.
- Step 1 Preparation of sample solution About 40 mg of the sample was accurately weighed and dissolved in the sample dilution solvent to make exactly 25 mL.
- the sample dilution solvent a 5 mmol / L phosphate buffer / acetonitrile mixture (9: 1) for liquid chromatography was used.
- Step 2 HPLC measurement of related substances
- the sample solution was measured by liquid chromatography under the following test conditions, and the peak areas of compound (IA) and related substances were measured by an automatic integration method.
- HPLC conditions Column: YMC-UltraHT Pro C18, ⁇ 2.0 ⁇ 100 mm, 2 ⁇ m, YMC Column temperature: 35 ° C UV detection wavelength: 261nm
- Mobile phase [A] 0.1% trifluoroacetic acid solution, [B] acetonitrile for liquid chromatography was gradient as follows. Gradient program Flow rate: 0.5 mL per minute (compound (IA) retention time approximately 5 minutes)
- the amount of related substances in the sample was determined using the following calculation formula.
- Step 3 HPLC measurement of compound (IA) (Preparation of standard solution) About 40 mg of a standard product of type I crystal D of compound (IA) was accurately weighed and dissolved in a sample dilution solvent to make exactly 25 mL. (Preparation of sample solution) About 40 mg of the sample after constant humidity was accurately weighed and dissolved in a sample dilution solvent to make exactly 25 mL. As the sample dilution solvent, a 5 mmol / L phosphate buffer: acetonitrile mixture for liquid chromatography (9: 1) was used.
- the standard solution and the sample solution were measured by liquid chromatography under the following test conditions, and the peak area of the compound (IA) was measured by an automatic integration method.
- Formulation Example 1 After suspending type I crystal D (123.1 g: 82.5 g as compound (IA)) in 1155 g of water for injection and adding 8 wt% aqueous sodium hydroxide solution to pH 6 (added amount: 159.2 g) Then, water for injection for weight adjustment was added to prepare a 50 mg / g solution as compound (IA). At this time, neutralization and dissolution took 2 hours. This solution was sterilized and filtered through a PVDF membrane having a pore size of 0.2 ⁇ m. The obtained filtrate was put into a glass bottle and freeze-dried.
- the freeze-drying conditions are as follows: 1) Cooling at 5 ° C, 2) Cooling at -5 ° C for 1 hour, 3) Freezing at -40 ° C for 4 hours, 4) 123 hours at-° C, primary drying at 10 Pa vacuum, 5) Secondary drying was performed at 60 ° C. for 6 hours at 10 Pa vacuum pressure to produce a freeze-dried product.
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Abstract
Description
本発明者等の検討、分析によれば、特許文献1において合成された化合物(IA)は非結晶である。また純度や保存安定性等の面で医薬活性成分またはその原料として使用するには必ずしも満足のいくものではないことが判明した。よって、化合物(IA)の好適な塩または結晶性固体の開発が望まれている。
本発明者等は、化合物(IA)について、これまでに種々の酸または塩基を用いて結晶化を試みたが成功しなかった。特に酸に関しては、塩酸、硫酸、ギ酸、トリフルオロ酢酸、リン酸、安息香酸、メタンスルホン酸、トリフルオロメタンスルホン酸など種々の酸を用いて、かつ溶媒、温度および晶析方法等を変えて1000例以上の条件下で化合物(IA)の酸付加塩の結晶化を試みたが、結晶化が非常に困難であることが判明した。また、化合物(IA)の水に対する溶解度が非常に低いことがわかり、化合物(IA)を特に注射剤として開発するためには、水溶解度の改善も必要であることが判明した。
で示される化合物の酸付加塩、ナトリウム塩、またはそれらの水和物;但し、該酸は1)置換もしくは非置換のベンゼンスルホン酸基を有する酸または2)置換もしくは非置換のベンゼンスルホン酸基を有する酸と無機酸とからなる混合酸である。
(項目2)項目1記載の酸付加塩またはその水和物。
(項目3)1)p-トルエンスルホン酸塩、2)ベンゼンスルホン酸塩、または3)p-トルエンスルホン酸もしくはベンゼンスルホン酸と、硫酸、塩酸および臭化水素酸から選択される1つの酸の組み合わせから形成される塩である、項目1記載の酸付加塩、またはその水和物。
(項目4)1)p-トルエンスルホン酸塩、または3)p-トルエンスルホン酸および硫酸の組合せから形成される塩である、項目1記載の酸付加塩、またはその水和物。
(項目5)化合物(IA)に対して約1.0~約2.0モル当量のp-トルエンスルホン酸を含有する項目4記載の酸付加塩、またはその水和物。
(項目6)化合物(IA)に対して、約1.0~約1.8モル当量のp-トルエンスルホン酸、および約0.1~約0.5モル当量の硫酸を含有する、項目4記載の酸付加塩、またはその水和物。
(項目7)結晶性固体である、項目1~6のいずれかに記載の酸付加塩またはその水和物。
(項目8)結晶性固体である、項目4~6のいずれかに記載の酸付加塩またはその水和物。
(項目9)単一相結晶または混合結晶である、項目8記載の酸付加塩またはその水和物。
(項目10)水分含量が約12~17%である、項目4~9のいずれかに記載の水和物。
(項目11)2モル当量のp-トルエンスルホン酸塩またはその水和物の単一相結晶、ならびに1モル当量のp-トルエンスルホン酸および0.5モル当量の硫酸を含有する塩またはその水和物の単一相結晶を含有する項目8~10のいずれかに記載の混合結晶。
(項目11-1)1.3モル当量のp-トルエンスルホン酸および0.5モル当量の硫酸を含有する、項目7~11のいずれかに記載の酸付加塩の水和物の結晶性固体。
(項目12)1.3モル当量のp-トルエンスルホン酸および0.35モル当量の硫酸の混合酸の酸付加塩である、項目7~11のいずれかに記載の水和物の結晶性固体。
(項目13)脱水物換算で約20.2~23.2%のp-トルエンスルホン酸および、脱水物換算で約3.5~5.0%の硫酸を含有する、項目7~12のいずれかに記載の酸付加塩の水和物の結晶性固体。
(項目14)粉末X線回折スペクトルにおいて、回折角度(2θ):8.2°±0.2°、10.1°±0.2°、13.0°±0.2°および20.3°±0.2°から選択される少なくとも3本のピークを有する、項目8~13のいずれかに記載の酸付加塩またはその水和物の結晶性固体。
(項目15)粉末X線回折スペクトルにおいて、回折角度(2θ):8.2°±0.2°、8.9°±0.2°、10.1°±0.2°、11.4°±0.2°、13.0°±0.2°、19.9°±0.2°、20.3°±0.2°、21.5°±0.2°および26.2°±0.2°から選択される少なくとも3本のピークを有する、項目8~13のいずれかに記載の結晶性固体。
(項目16)粉末X線回折スペクトルにおいて、回折角度(2θ):8.2°±0.2°、8.9°±0.2°、10.1°±0.2°、13.0°±0.2°、16.5°±0.2°、17.1°±0.2°、17.9°±0.2°、19.0°±0.2°、20.3°±0.2および26.2°±0.2°から選択される少なくとも3本のピークを有する、項目8~13のいずれかに記載の結晶性固体。
(項目17)項目1~16のいずれかに記載の酸付加塩、その水和物、またはそれらの結晶性固体を含む医薬組成物。
(項目18)化合物(IA)を含有する溶液に、p-トルエンスルホン酸および硫酸を添加することを特徴とする、項目8~16のいずれかに記載の酸付加塩、またはその水和物の結晶性固体の製造方法。
(項目19)化合物(IA)を含有するカラム溶出液に対して約2.2~2.5重量%のp-トルエンスルホン酸・1水和物および約5~6重量%の75%硫酸を添加することを特徴とする、項目18記載の製造方法。
(項目20)項目1記載のナトリウム塩、またはその水和物。
(項目21)非晶質形態である、項目20記載のナトリウム塩またはその水和物。
(項目22)項目20または21に記載のナトリウム塩またはその水和物を含有する医薬組成物。
(項目23)凍結乾燥製剤である、項目22記載の医薬組成物。
(項目24)項目1~16のいずれかに記載の酸付加塩、その水和物、またはそれらの結晶性固体を用いることを特徴とする、化合物(IA)のナトリウム塩またはその水和物を含有する凍結乾燥製剤の製法。
(項目25)項目1~16のいずれかに記載の酸付加塩、その水和物、またはそれらの結晶性固体、および水酸化ナトリウムを含む水溶液を凍結乾燥することを特徴とする、化合物(IA)のナトリウム塩またはその水和物を含有する凍結乾燥製剤の製法。
(項目26)酸付加塩が、1)p-トルエンスルホン酸塩、または3)p-トルエンスルホン酸および硫酸の組合せから形成される塩である、項目24または25に記載の製法。
(項目27)化合物(IA)もしくは製薬上許容される塩、またはその水和物を含み、さらにp-トルエンスルホン酸ナトリウムおよび/または硫酸ナトリウムを含有する医薬組成物。
(項目28)化合物(IA)のナトリウム塩またはその水和物を含み、さらにp-トルエンスルホン酸ナトリウムおよび/または硫酸ナトリウムを含有する項目27記載の医薬組成物。
(項目30)経皮、皮下、静脈内、動脈内、筋肉内、腹腔内、経粘膜、吸入、経鼻、点眼、点耳または膣内投与のための、項目29記載の医薬組成物。
(項目31)注射剤、点滴剤、点眼剤、点鼻剤、点耳剤、エアゾール剤、吸入剤、ローション剤、注入剤、塗布剤、含嗽剤、浣腸剤、軟膏剤、硬膏剤、ゼリー剤、クリーム剤、貼付剤、パップ剤、外用散剤または坐剤である、項目29~31のいずれかに記載の医薬組成物。
(項目32)項目1記載の化合物(IA)のナトリウム塩、その酸付加塩、またはそれらの溶媒和物、もしくはそれらの結晶性固体を包含する、小児用または高齢者用の医薬組成物。
当該塩、溶媒和物またはそれらの結晶性固体は、少なくとも以下のいずれかの特徴を有する。
(1)熱、湿度、溶媒、光等に対する安定性が良好であり、保存安定性が高い。
(2)着色安定性が良好である。
(3)水または有機溶媒に対する溶解度が良好である。
(4)水または有機溶媒に対する溶解速度が速い。
(5)高純度である。
(6)有機溶媒の残存率が低い。
(7)濾過、遠心分離、製剤化等の操作性に優れている。
(8)比容積が小さい。
(9)帯電しにくい。
(10)環境負荷が少ない条件下、高収率で製造され、大量製造が可能である。
(11)注射剤等の医薬活性成分またはその製造用原体として有用である。
(12)血管痛を伴わない静脈注射に適したpH範囲に制御できるため、製剤時の液量コントロールや賦形剤の削減などに有利である。
特に本発明の結晶性固体は、広い湿度範囲(例:25~99%RHなど)や過酷な環境下(例:多湿下)においても安定性が高い。
単一相結晶は、1種類の酸付加塩であっても、2種類以上の酸の混合酸塩であってもよい。混合結晶は、2種類以上の単一相結晶が混合物として存在する結晶性固体であるが、例えば、置換もしくは非置換のベンゼンスルホン酸基を有する酸付加塩の結晶性固体と、置換もしくは非置換のベンゼンスルホン酸基を有する酸と無機酸との組み合わせから形成される混合酸塩の結晶性固体との、混合物であってもよく、または、置換もしくは非置換のベンゼンスルホン酸基を有する酸と無機酸との組み合わせから形成される混合酸塩と、前記と異なる組み合わせの置換もしくは非置換のベンゼンスルホン酸基を有する酸と無機酸との組み合わせから形成される混合酸塩の混合物であってもよい。
本発明の結晶性固体は、単結晶、双晶、多結晶などであってもよく、通常、単結晶またはその混合結晶である場合が多い。結晶の形態(外形)は、特に制限されず、例えば、三斜晶、単斜晶、斜法晶(直法晶)、正方晶、立法晶、三方晶(菱面体晶)、六方晶などであってもよく、球晶、骸晶、樹皮状晶、針状晶(例えば、ヒゲ結晶)などであってもよい。結晶のサイズは、特に制限されず、例えば、レーザー回析法に基づいて、結晶の平均粒子径が0.5μm~1mm、このましくは1~500μm程度であってもよい。
例えば、蒸発法(化合物(IA)と晶析溶媒とを含む晶析系(又は溶液)から、晶析溶媒を蒸発して過飽和状態にし、この過飽和状態から結晶化する方法)や冷却法(化合物(IA)と晶析溶媒とを含む晶析系(又は溶液)を冷却して過飽和状態にし、この過飽和状態から結晶化する方法)などから得られた種晶を得た後、化合物(IA)と晶析溶媒および/または酸に溶解させた溶液に種晶を添加して結晶化する種晶添加法などにより本発明の結晶性固体は製造することができる。このような方法によれば、該結晶性固体を効率よく製造することができる。
また、化合物(IA)のI型結晶(:1.3モル当量のp-トルエンスルホン酸および0.35モル当量の硫酸の混合酸塩の水和物の混合結晶)は以下のようにして得られる。すなわち、化合物(IA)の2モル当量のp-トルエンスルホン酸塩水和物の結晶性固体を硫酸‐水混合液に溶解させ、0~5℃で約1~4日静置して晶析させ、得られた結晶性固体を冷水で洗浄し、室温で約0.5~2時間風乾することによりI型結晶を得ることができる。または、化合物(IA)を含むアセトニトリル‐水混合溶液にp-トルエンスルホン酸および硫酸を加え、必要に応じて種晶を加え、約-5~5℃に冷却し、約1時間~約4日間撹拌または静置することにより晶析させ、得られた結晶性固体を冷水または酸で洗浄し、常圧または減圧により約0.5~10時間乾燥させても、I型結晶を得ることができる。I型結晶は、さらに約0.01~0.1モル当量のp-トルエンスルホン酸および/または約0.01~0.1モル当量の硫酸が残留した形で含有される場合もある。該残留酸は結晶に付着または結晶内に取り込まれる形で含有される場合もある。
また、本発明の酸付加塩の結晶性固体は、異なる組成の酸付加塩結晶から塩交換により合成することができる。例えば、2モル当量のp-トルエンスルホン酸塩水和物の結晶性固体を晶析溶媒およびまたは酸に溶解または懸濁させ、対応する酸を加えて約‐5~5℃に冷却し、約1時間~約4日間撹拌または静置することにより塩交換を行いながら晶析させ、得られた結晶性固体を冷水または該酸で洗浄し、常圧または減圧により約0.5~10時間乾燥させることにより、本発明の酸付加塩の結晶性固体を得ることができる。
特に言及がなければ、本明細書中および特許請求の範囲の記載の数値は、おおよその値である。数値の変動は、装置キャリブレーション、装置エラー、物質の純度、結晶サイズ、サンプルサイズ、その他の因子に起因する。
本明細書中で用いる特徴的な回折ピークは、観察された回折パターンから選択されるピークである。複数の結晶性固体を区別する上では、ピークの大きさよりも、その結晶性固体に見られ、他の結晶性固体で見られないピークが、その結晶性固体を特定する上で好ましい特徴的なピークとなる。そういった特徴的なピークであれば、一つ又は二つのピークでも、当該結晶性固体を特徴付けることができる。
共通する特徴的なピークは、回折角度(2θ):8.2±0.2°、8.9±0.2°、10.1±0.2°、11.4±0.2°、13.0±0.2°、19.9±0.2°、20.3±0.2°および26.2±0.2°から選択される少なくとも3本のピークである。より好ましい共通する特徴的なピークは、回折角度(2θ):8.2±0.2°、10.1±0.2°、13.0±0.2°および20.3±0.2°から選択される少なくとも3本のピークである。
赤外吸収スペクトルは通例、横軸に波数を、縦軸に透過率または吸光度をとったグラフで示される。吸収ピークの波数をおよび透過率(または吸光度)はグラフ上で読み取ることができるほか、データ処理装置による産出値を用いることができる。赤外吸収スペクトルはその物質の化学構造によって定まる。したがって、種々の波数における吸収を測定して物質を確認または定量することができる。結晶多形の判別は、その結晶多形に特徴的な官能基、すなわち、主として結晶構造中の水素結合に関与する官能基、例えばC=O結合、OH結合およびNH結合等ならびに、その他特徴的な官能基、例えば、C-X(ハロゲン)、C=CおよびC≡C等の吸収帯を比較することによって行うことができる。特徴的な官能基に対応する約20個の吸収ピーク、より好ましくは約10個の吸収ピーク、最も好ましくは約5個の吸収ピークから選択される。通例、試料の吸収スペクトルは波数4000cm-1~400cm-1 の範囲で測定する。吸収スペクトルの測定は装置の分解能、波数目盛り及び波数精度の確認を行なったときと同一の操作条件の下で行う。
一般に、ラマンスペクトルにおける吸収帯(cm-1)は±2cm-1の範囲内で誤差が生じ得るから、上記の吸収ピークの値は±2cm-1程度の範囲内の数値も含むものとして理解される必要がある。したがって、ラマンスペクトルにおける吸収帯のピークが完全に一致する結晶だけでなく、吸収帯のピークが±2cm-1程度の誤差で一致する結晶も本発明に含まれる。
DSC(示差走査熱量測定)は、熱分析の主要な測定方法のひとつで、原子・分子の集合体としての物質の熱的性質を測定する方法である。DSCにより、医薬活性成分の温度または時間に係る熱量の変化を測定し、得られたデータを温度または時間に対してプロットすることにより示差走査熱量曲線が得られる。示差走査熱量曲線より、医薬活性成分が融解する際のオンセット温度、融解に伴い吸熱ピーク曲線の最大値およびエンタルピーに関する情報を得ることができる。
DSCについて、観察される温度は、温度変化速度ならびに用いる試料調製技法および特定の装置に依存し得ることが知られている。したがって、DSCにおける「融点」とは試料の調製技法の影響を受けにくいオンセット温度のことを指す。示差走査熱量曲線から得られるオンセット温度における誤差範囲はおよそ±2℃である。結晶の同一性の認定においては、融点のみならず全体的なパターンが重要であり、測定条件や測定機器によって多少は変化し得る。
TG/DTAについて、観察される温度、重量変化は、温度変化速度ならびに用いる試料調製技法および特定の装置に依存し得ることが知られている。したがって、TG/DTAにおける「融点」とは試料の調製技法の影響を受けにくいオンセット温度のことを指す。結晶の同一性の認定においては、全体的なパターンが重要であり、測定条件や測定機器によって多少変化し得る。
基本的な測定法として、0%RH(相対湿度0%)での乾燥重量を基準とし、5%、もしくは10%ごとに相対湿度を上げ、それぞれの相対湿度での重量安定化後、基準値からの重量増加から、吸着水の量を求める事が出来る。同様に,100%RHから5%、もしくは10%ごとに相対湿度を下げる事で、水の脱着量を測定する事が可能である。
各相対湿度での重量変化値をプロットする事で、吸脱着等温線を得る事ができる。この結果から、各湿度における付着水分の吸着、脱着現象の考察が可能である。また、無水物結晶が湿度により水和物結晶と相互に結晶転移する場合には、結晶転移が起こる湿度,並びに結晶水の量を計算する事が可能である。
付着水,及び結晶水の吸脱着は粒子径、結晶化度、晶癖等の影響を受けるため、測定結果は多少変化し得る。
化合物(IA)のナトリウム塩は、医薬活性成分またはその原料として有用である。該ナトリウム塩は、化合物(IA)から直接製造することも可能であるが、化合物(IA)の酸付加塩もしくはその溶媒和物、好ましくはそれらの結晶性固体と水酸化ナトリウム、および所望によりその他の添加剤(例:糖類、pH調整剤、塩化ナトリウムまたは塩化マグネシウム)を含む水溶液を当業者周知の方法に従い、凍結乾燥することによっても得られる。化合物(IA)のナトリウム塩は、好ましくは非結晶、すなわち非晶質形態であり、水溶解性が非常に高い。
1)注射用水に本発明の塩もしくはその溶媒和物、またはそれらの結晶性固体を投入し、酸性のスラリー液を調製する、
2)1)のスラリー液に水酸化ナトリウム水溶液を添加してpH5.5~6に調整し、添加物を添加する、
3)注射用水を追加添加して5w/w%に濃度調整、無菌ろ過し、製剤液とする、
4)3)の製剤液の一定量をバイアルまたはアンプル等に分注し、凍結乾燥して製造される。
凍結乾燥機としては、真空凍結乾燥機を用いることができる。
各実施例で得られた結晶性固体の粉末X線回折測定は、日本薬局方の一般試験法に記載された粉末X線回折測定法に従い、以下の測定条件1~3のいずれかの条件で行った。なお、試料フォルダとしてアルミ板を用いている。2-Theta (2θ)値が38°付近にあらわれているピークは、アルミのピークである。
(装置)
Bruker社製D-8Discover
(操作方法)
測定法:反射法
光源の種類:Cu管球
使用波長:CuKα線
管電流:40mA
管電圧:40Kv
試料プレート:Al
測定範囲:3°―40°
露光時間:120s
(装置)
Rigaku社製RINT TTR III
(操作方法)
試料について、以下の条件で測定を行った。
測定法:反射法,平行ビーム法
光源の種類:Cu管球
使用波長:CuKα線
管電流:300mA
管電圧:50Kv
X線の入射角(2θ):4°~40°
サンプリング幅:0.02°
スキャンスピード:5°/min
(装置)
Rigaku社製RINT2100 Ultima+
(操作方法)
測定法:反射法
光源の種類:Cu管球
使用波長:CuKα線
管電流:40mA
管電圧:40Kv
試料プレート:Al
測定範囲:5°~35°
サンプリング幅:0.020°
スキャンスピード:30°/min
各実施例で得られた各結晶性固体約5mgを量り、アルミニウムパンにつめ、開放系にて測定することができる。(測定条件)
装置:SEIKO社製TG/DTA6300
測定温度範囲:25℃-300°
昇温速度:10℃/分
各実施例で得られた結晶性固体の固体13C-NMRスペクトルを、Varian 600MHz NMR Systemsを用いて、以下の条件により測定することができる。
Spectral width:43103.4Hz
Acquisition Time:0.04s
Sequence:tancpx
Recycle Delay:10s
Contact Time: 3ms
外部標準:アダマンタン (38.52ppm)またはグリシン (43.67ppm)
測定温度:10℃
回転速度:20000rps
プローブ:3.2mm T3 HX Probe
各実施例で得られた結晶性固体の水分吸脱着等温線測定を行った.サンプルパンに試料約18.0mgを測り取り測定を行った。測定条件を以下に示す。
装置:Surface Measurement Systems Ltd.社製 DVS Advantage
測定ポイント:95%RHから5%ごとに0%RHまで.
温度:25℃
水分については,日本薬局方 一般試験法 水分(電量滴定)より試験を行った。ただし,陽極液として三菱化学製アクアミクロン(登録商標)AX,陰極液としてアクアミクロン(登録商標)CXUを用いた。カール・フィッシャー法による水分測定は±0.3%の範囲内で誤差が生じ得るので、水分含量の値は±0.3%程度の範囲内の数値も含むものとして理解される必要がある。
キャピラリーゾーン電気泳動技術を用いた手法で,電解質を含む緩衝液中での各試料成分の自由泳動を利用した分離方法である。
pH2.5~11.5に調製した緩衝液が充填されたフューズドシリカキャピラリーに、化合物溶液を注入した後、キャピラリーに高電圧 (Inlet側+,Outlet側-) をかけると、化合物は緩衝液pHにおけるイオン化状態を反映した速度 (+チャージした化合物は速く、-チャージした化合物は遅く) で移動する。この化合物の移動時間と中性分子 (DMSO) の移動時間との差をpHに対してプロットし、フィッティングをかけてpKaを算出した。測定条件を以下に示す。
使用装置:Beckman P/ACEシステムMDQ PDA
泳動液:pH2.5~11.5 Buffer (10vol% MeOH含有)
サンプル溶液: Blank DMSO 10μL+注用水90μL混合
Sample 10mM DMSO stock solution 4uL + DMSO 6uL + 注用水 90uL
(メソッド)
キャピラリー :Fused silica capillary (BECKMAN COULTER,内径50 μm,全長30.2 cm,有効長20.0 cm)
印加電圧 :10kV (331 V/cm)
印加空気圧 :0.7 psi
キャピラリー温度 :25 ℃
電気浸透流マーカー :DMSO
検出 :紫外部多波長吸光検出 (測定波長;215 nm,238 nm)
試料注入 :加圧法 (0.5 psi,5 sec)
本明細書において、pKaは、25℃におけるpKaであり、複数のpKa値を有する酸においては、最も低い値のpKaを意味する。
た。
化合物(IA)は、国際公開第2010/050468号に記載の方法に従って調整し 化合物(IA)のpKaを測定した結果、pKa1=4.2、pKa2=7.2であった。
化合物(IA)(100mg)を1.0 mol/Lのp-トルエンスルホン酸水溶液(2mL)に室温で超音波を用いて溶解し、4℃で4日間静置した。析出物をろ過して種晶A(73mg)を得た。顕微鏡により、針状結晶であることを確認した。
化合物(IA)(2.00g)にp-トルエンスルホン酸1水和物(7.58g)、アセトニトリル(5mL)および水(5mL)を加え溶かした。その溶液中に水をさらに30mL 加えた。その水溶液に種晶Aを一欠片加え、室温で3時間、5℃で16時間静置した。析出物を濾過し、冷水で洗浄した後、乾燥窒素ガスを吹き付けながら45分間乾燥して結晶性固体(2.00g)を得た。
元素分析:(C30H34ClN7O10S2・2.0C7H8O3S・4.0H2Oとして計算)
計算値: C 45.22(%), H 5.00(%),N 8.39(%), C1 3.03(%), S 10.97(%), H2O 6.17(%)
実測値: C 45.22(%), H 4.91(%), N 8.25(%), Cl 2.86(%), S 11.23(%), H2O(KF法) 6.21(%)
測定条件1で測定した粉末X線回折スペクトルにおいて、回折角度(2θ):5.1±0.2 °、8.2±0.2 °、12.1±0.2 °および13.9±0.2 °にピークが認められた。
化合物(IA)(2.00g)をp-トルエンスルホン酸1水和物(7.58g)、アセトン(5mL)および水(5mL)を加え溶かした。その溶液中に水をさらに30mL 加えた。その水溶液に種晶Aを一欠片加え、室温で3時間、5℃で16時間静置した。析出物を濾過し、冷水で洗浄した後、乾燥窒素ガスを吹き付けながら45分間乾燥して結晶性固体(2.30g)を得た。
元素分析:(C30H34ClN7O10S2・2.0C7H8O3S・8.5H2Oとして計算)
計算値: C 42.28(%), H 5.40(%),N 7.84(%), C1 2.84(%), S 10.26(%), H2O 12.25(%)
実測値: C 42.37(%), H 5.26(%), N 7.79(%), Cl2.70(%), S 10.69(%), H2O(KF法) 12.11(%)
測定条件1で測定した粉末X線回折の結果を図1および表1に示す。
(実施例6-1)I型結晶Dの合成
工程1:種晶Cの合成
種晶A(50mg)を室温で6mol/L H2SO4(3mL)に超音波浴上で溶解させ、4℃で2日間静置した。析出した結晶性固体をろ過後、氷冷水で洗浄して種晶C(23mg)を得た。
窒素雰囲気下、化合物1(18.0kg、22.6mol)をN,N-ジメチルアセトアミド(41L)に溶解し、0℃に冷却した。ヨウ化ナトリウム(6.8kg、45.2mol)、化合物2(13.1kg、24.9mol)、N,N-ジメチルアセトアミド(4L)を加え、0℃で6時間撹拌した。7℃に昇温し、16時間撹拌した。0℃に冷却し、ヨウ化ナトリウム(5.1kg、33.9mol)を加えた後、塩化アセチル(8.9kg、113.0mol)を0℃で90分かけて滴下し、0℃で5時間撹拌した。
反応液にアニソール(36L)を加え、この液をメチルエチルケトンおよび亜硫酸水素ナトリウム水溶液の混合液に加え、抽出した。有機層を硫酸と食塩水の混合液で2回洗浄した。アニソール(90L)を加え、15℃に冷却し75%硫酸(36.0kg)を加え、28℃で2時間撹拌した。水(90L)と酢酸エチル(36L)を加え、抽出した。得られた水層を酢酸エチルで2回洗浄した後、クロマト分離用小粒径合成吸着剤(ダイヤイオンTMHP20SS)を用いた逆層カラムクロマトグラフィー(アセトニトリル-硫酸水溶液)により精製した。得られた溶出液に75%硫酸(33.4kg)とp-トルエンスルホン酸一水和物(16.7kg)の水溶液を加えた後、種晶Cを適量加え、固体を析出させた。5℃に冷却し、5℃で10時間撹拌し、析出した結晶性固体をろ過した。その結晶性固体を5℃に冷やした水で洗浄し、その後約33hPaで約3時間減圧乾燥することにより化合物(IA)のI型結晶D(12.7kg、含量換算収率49%)を得た。
(p-トルエンスルホン酸含有量測定方法)
工程1:試料溶液の調製
試料約40mgを精密に量り、試料希釈溶媒に溶かし,正確に25mLとした。この液2mLを正確に量り、試料希釈溶媒を加えて正確に20mLとした。
工程2:標準溶液の調製
25℃/60%RHの環境で恒湿化したp-トルエンスルホン酸ナトリウム標準品約25mgを精密に量り、試料希釈溶媒に溶かし、正確に100mLとした。この液5mLを正確に量り、試料希釈溶媒を加えて正確に50mLとした。
上記の試料希釈溶媒は5mmol/Lリン酸塩緩衝液/液体クロマトグラフィー用アセトニトリル混液(9:1)を用いた。ここでリン酸塩緩衝液は水:0.05mol/Lリン酸二水素ナトリウム試液:0.05mol/Lリン酸水素二ナトリウム試液混液=18:1:1(pHが約7.1)を用いた。
工程3:測定および定量
上記試料溶液および標準溶液を下記試験条件で液体クロマトグラフィーにより測定を行い、p-トルエンスルホン酸のピーク面積を自動積分法により測定した。なお、脱水物換算とは、全量から水分含量を除いたものを100%として計算した値である。
(試験条件)
カラム:Unison UK-C18, φ4.6 × 150 mm, 3 μm,Imtakt製
カラム温度:35℃付近の一定温度
流量:毎分1.0mL (p-トルエンスルホン酸の保持時間 約7分)
検出器:紫外吸光光度計 (測定波長:218nm)
移動相A:0.1%トリフルオロ酢酸溶液
移動相B:液体クロマトグラフィー用アセトニトリル
グラジエントプログラム
以下の計算式を用いて、試料中のp-トルエンスルホン酸の含有量を求めた。
p-トルエンスルホン酸の量 (%)
MS:p-トルエンスルホン酸ナトリウム標準品の秤取量 (mg)
MT:試料の秤取量 (mg)
P:p-トルエンスルホン酸ナトリウム標準品の純度 (%)
WT:試料の水分 (%)
AT:試料溶液から得られるp-トルエンスルホン酸のピーク面積
AS:標準溶液から得られるp-トルエンスルホン酸のピーク面積
172.20:p-トルエンスルホン酸の分子量
194.18:p-トルエンスルホン酸ナトリウムの分子量
工程1:標準溶液の調製
無水硫酸ナトリウム 約50mgを精密に量り、移動相に溶かし正確に25mLとした。この液2mLを正確に量り、移動相を加えて正確に50mLとした。さらにこの液2mLを正確に量り、移動相を加えて正確に20mLとした。
工程2:試料溶液の調製
試料約30mgを精密に量り、移動相に溶かし正確に25mLとした。この液2mLを正確に量り、移動相を加えて正確に20mLとした。
工程3:測定および定量
上記試料溶液および標準溶液を下記試験条件で液体クロマトグラフィー(イオンクロマトグラフィー)により測定を行い、硫酸イオンのピーク面積を自動積分法により測定した。(試験条件)
カラム:Shim-pack IC-A3,φ4.6×150 mm,5 μm,島津製作所
カラム温度:40℃付近の一定温度
流量:毎分1.2mL (硫酸イオンの保持時間 約15分)
検出器:電気伝導度検出器 (ノンサプレッサ方式)
移動相:Bis-Tris約0.67g,ホウ酸約3.09g,及び粉砕したp-ヒドロキシ安息香酸約1.11gを精密に量り,水に溶かし正確に1000mLとした溶液
以下の計算式を用いて、試料中の硫酸の含有量を求めた。
硫酸の量 (%) = MS / MT × 100 / (100-WT) × AT / AS × 98.08 / 142.04 × 1 / 25 × 100
MS:無水硫酸ナトリウムの秤取量 (mg)
MT:試料の秤取量 (mg)
WT:試料の水分 (%)
AS:標準溶液から得られる硫酸イオンのピーク面積
AT:試料溶液から得られる硫酸イオンのピーク面積
98.08:硫酸の分子量
142.04:無水硫酸ナトリウムの分子量
1 / 25:希釈倍率
(結果)
p-トルエンスルホン酸:22.2±0.2%(脱水物換算)
硫酸:4.3±0.1%(脱水物換算)
計算値:C 39.75(%), H 5.39(%),N 8.27(%), C1 2.99(%), S 10.19(%), H2O 13.67(%)
実測値:C 39.73(%), H 5.33(%),N 8.53(%), C1 3.08(%), S 10.11(%), H2O(KF法) 13.69(%)
測定条件2で測定した粉末X線回折の結果を図4および表4に示す。なお、試料フォルダとしてアルミ板を用いている。2-Theta(2θ) 値が38 °付近にあらわれているピークは、アルミのピークである。
実施例6-1記載の方法で得られたI型結晶D(25.0g)を5℃に冷却した水(125mL)に懸濁させた後、5℃で26時間撹拌し、結晶性固体をろ過した。その結晶性固体を5℃に冷却した水(75mL)で洗浄して化合物(IA)のI型結晶E(22.92g)を得た。
(結果)
p-トルエンスルホン酸:21.9±0.2%(脱水物換算)
硫酸:3.9±0.1%(脱水物換算)
計算値:C 40.05(%), H 5.42(%),N 8.36(%), C1 3.02(%), S 9.98(%), H2O 13.82(%)
実測値:C 39.96(%), H 5.32(%),N 8.59(%), C1 2.99(%), S 10.11(%), H2O(KF法) 13.78(%)。
測定条件2で測定した粉末X線回折の結果を図5および表5に示す。なお、試料フォルダとしてアルミ板を用いている。2-Theta(2θ) 値が38 °付近にあらわれているピークは、アルミのピークである。
I型結晶は、約0.01~0.1モル当量のp-トルエンスルホン酸および/または約0.01~0.1モル当量の硫酸が残留した形で含有される場合もある。該残留酸は、結晶に付着した形であっても、結晶内に取り込まれる形であってもよい。
I型結晶の好ましいp-トルエンスルホン酸含量は約20.2±0.2~23.2±0.2%(脱水物換算)であり、好ましい硫酸含量は約3.5±0.1~5.0±0.1%(脱水物換算)である。I型結晶のより好ましいp-トルエンスルホン酸含量は約21.5±0.2~22.3±0.2%(脱水物換算)であり、より好ましい硫酸含量は約4.2±0.1~4.9±0.1%(脱水物換算)である。I型結晶のさらに好ましいp-トルエンスルホン酸含量は約21.5~22.3%(脱水物換算)であり、さらに好ましい硫酸含量は約4.2~4.9%(脱水物換算)である。
化合物(IA)のベタイン(100mg)を1.0mol/Lのベンゼンスルホン酸水溶液(5.5mL)に室温で超音波を用いて溶解した。この溶液に種晶Aを一欠片加え、5℃で4日間静置した。析出物をろ過して、種晶B(27mg)を得た。
化合物(IA)のベタイン(300mg)をアセトニトリル(0.30mL)および水(0.75mL)に溶解させ、ベンゼンスルホン酸(949mg)を加えた。その溶液にさらに水(3.0mL)を加えた後、種晶Bを一欠片加え、5℃で5日間静置した。析出物をろ過して結晶性固体(79.8mg)を得た。
測定条件1で測定した粉末X線回折の結果を図6および表6に示す。
実施例6-1によって得られたI型結晶Dの水分吸脱着等温線測定結果を図7および表7に示す。水分吸脱着等温線測定は±0.5%の範囲内で誤差が生じ得る。水分の増加量(%)は0%RH時におけるI型結晶の重量に対する増加量を表す。
30%RH条件下での粉末X線回折の結果を、図8および表8に示す。
特徴的な回折ピークを示す回折角度2θは8.4±0.2 °,9.1±0.2 °,10.2±0.2 °,11.6±0.2 °,13.0±0.2 °,20.1±0.2 °,20.4±0.2 °および26.2±0.2 °である。より好ましくは、8.4±0.2 °,10.2±0.2 °,13.0±0.2 °および20.4±0.2 °である。
特徴的な回折ピークを示す回折角度2θは、8.4±0.2 °,9.1±0.2 °,10.2±0.2 °,11.5±0.2 °,13.0±0.2 °,20.0±0.2 °,20.3±0.2 °,21.7±0.2 °および26.2±0.2 °である。より好ましくは、8.4±0.2 °,10.2±0.2 °,13.0±0.2 °および20.3±0.2 °である。
特徴的な回折ピークを示す回折角度2θは、8.4±0.2 °,9.1±0.2 °,10.2±0.2 °,11.5±0.2 °,13.0±0.2 °,20.0±0.2 °,20.3±0.2 °,21.7±0.2 °および26.2±0.2 °である。より好ましくは、8.4±0.2 °,10.2±0.2 °,13.0±0.2 °および20.3±0.2 °である。
特徴的な回折ピークを示す回折角度2θは、8.3±0.2 °,9.1±0.2 °,10.2±0.2 °,11.5±0.2 °,13.0±0.2 °,19.9±0.2 °,20.3±0.2 °,6±0.2 °および26.2±0.2 °である。より好ましくは、8.3±0.2 °,10.2±0.2 °,13.0±0.2 °および20.3±0.2 °である。
特徴的な回折ピークを示す回折角度2θは、8.3±0.2 °,0±0.2 °,1±0.2 °,11.5±0.2 °,13.0±0.2 °,19.9±0.2 °,20.3±0.2 °,21.6±0.2 °および26.2±0.2 °である。より好ましくは、3±0.2 °,10.1±0.2 °,13.0±0.2 °および20.3±0.2 °である。
特徴的な回折ピークを示す回折角度2θは、8.3±0.2 °,0±0.2 °,10.1±0.2 °,11.5±0.2 °,13.0±0.2 °,19.9±0.2 °,20.3±0.2 °,21.6±0.2 °および26.2±0.2 °である。より好ましくは、8.3±0.2 °,10.1±0.2 °,13.0±0.2 °および20.3±0.2 °である。
特徴的な回折ピークを示す回折角度2θは、8.3±0.2 °,9.0±0.2 °,10.1±0.2 °,11.5±0.2 °,13.1±0.2 °,19.9±0.2 °,20.3±0.2 °,21.6±0.2 °および26.2±0.2 °である。より好ましくは、8.3±0.2 °,10.1±0.2 °,13.1±0.2 °および20.3±0.2 °である。
特徴的な回折ピークを示す回折角度2θは、8.2±0.2 °,9.0±0.2 °,10.1±0.2 °,11.5±0.2 °,13.0±0.2 °,19.9±0.2 °,20.3±0.2 °,5±0.2 °および26.2±0.2 °である。より好ましくは、8.2±0.2 °,10.1±0.2 °,13.0±0.2 °および20.3±0.2 °である。
I型結晶の好ましい水分含量は約12~17%であり、より好ましくは約12~15%である。I型結晶の好ましい水和水は約7.5~12モルであり、より好ましくは約8~11.5モルである。
これらの異なる水分含量のI型結晶は共通する特徴的な回折ピークを有する。特徴的な回折ピークを示す回折角度2θは、8.2±0.2 °、8.9±0.2 °、10.1±0.2 °、11.4±0.2 °、13.0±0.2 °、19.9±0.2 °、20.3±0.2 °、21.5±0.2 °および26.2±0.2 °である。好ましくは、8.2±0.2 °、8.9±0.2 °、10.1±0.2 °、11.4±0.2 °、13.0±0.2 °、19.9±0.2 °、20.3±0.2 °および26.2±0.2 °である。より好ましくは、8.2±0.2 °、10.1±0.2 °、13.0±0.2 °および20.3±0.2 °である。
工程1 化合物8の合成
化合物6(970g、713mmol、78w/w%純度)をジクロロメタン(7.13L)に溶解し、内温15℃下で化合物7を加えた。この懸濁液を-25℃に冷却し、EDC塩酸塩(150.35g、784mmol)、ピリジン(46mL、570mmol)を加え、反応液を-20℃で3時間撹拌した。この反応液を氷冷撹拌化の2mol/L塩酸(285mL)、冷水(7.2L)、酢酸エチル(2.4L)混合液に加え、ジクロロメタンを減圧留去した。得られた溶液に酢酸エチル(4.5L)を加え、食塩水で2回洗浄した。有機層を減圧濃縮し化合物8を含む粗雑物(1250g)を得た。化合物8を含む粗雑物は精製せずに次の工程で使用した。
アニソール(1.54L)をドライアイス-エタノール浴で冷却し、塩化アルミニウム(495.4g、3.71mol)、次いでジクロロメタン(0.93L)を加えた。工程1で得られた化合物8を含む粗雑物のうち610gをジクロロメタン(0.51L)、アニソール(1.03L)の混液に溶解し、-40℃に再冷却した先の塩化アルミニウム溶液に1時間をかけて滴下した。滴下に用いた容器をジクロロメタン(0.36L)、アニソール(0.51L)の混合液で洗浄し、反応液に加えた。反応液を-20℃下、2時間撹拌して得られた溶液を、氷冷撹拌下のエタノール(7.1L)、1mol/L 塩酸(7.1L)混液に加えた。混合液を氷冷下30分撹拌し、ジクロロメタン(5.14L)、飽和食塩水(257mL)を加え、分離した水層をジクロロメタン(5.14L)で洗浄した。有機層を水(2.57L)、飽和食塩水(100mL)の混液で抽出し、分離した水層は先の水層と合わせた。この水層を氷冷撹拌し、2mol/L 水酸化ナトリウム水溶液を加えることによってpHを1.5に調整し、一晩静置した。水層を濃縮してHP20SSカラムで精製した(溶離液:13%アセトニトリル水)。集めた目的物を含むフラクションに炭酸水素ナトリウム(8.75g)を加えて500mLになるまで減圧濃縮した。水(1.6L)を加えて希釈し、綿栓濾過後、濾液を凍結乾燥し化合物9(77.8g)を得た。
元素分析:(C30H33ClN7O10S2Na・4.5H2Oとして計算)
計算値 C;42.13, H;4.95, N;11.46, S;7.50, Cl;4.14, Na;2.69 (%)
実測値 C;42.22, H;4.88, N;11.24, S;7.01, Cl;4.04, Na;2.74 (%)
得られた化合物9の各種水媒体(注射用水、生理食塩水、ブドウ糖液)に対する溶解度は、いずれも100mg/mL以上であり、非常に高い溶解度であった。
実施例6-1記載の方法によって得られたI型結晶D(2.00g)を50%アセトニトリル水(10mL)に溶解し、水(40mL)、75%硫酸(4.0g)を加え、15℃で5時間20分撹拌した。0℃に冷却し、1時間10分撹拌した後、14時間10分冷蔵庫で静置した.析出した結晶をろ取し、冷水(6mL)で洗浄し通気乾燥することで結晶性固体(1.74g)を得た。
得られた結晶性固体(1.5g)を50%アセトニトリル水(7.5mL)に溶解し、水(30mL)、75%硫酸(3.0g)を加え、15℃で3時間30分撹拌した。0℃に冷却し、3時間撹拌した後、14時間50分冷蔵庫で静置した.析出した結晶性固体をろ取し,冷水(4.5mL)で洗浄し通気乾燥することで結晶性固体(1.17g)を得た。
水分量測定はカール・フィッシャー法により測定した。p-トルエンスルホン酸および硫酸の含量は、実施例6-1に記載と同様の方法で測定した。
(結果)
水分含量:14.0±0.3%
p-トルエンスルホン酸:18.2±0.2%(脱水物換算)
硫酸:6.4±0.1%(脱水物換算)
以上の結果より、本結晶性固体はC30H34N7ClO10S2・1.05C7H8O3S・0.65H2SO4・9.0H2Oである。
測定条件1で測定した粉末X線回折の結果を図16および表17に示す。
実施例6-1記載の方法によって得られたI型結晶D(50.0g)をエタノール(300mL)と水(200mL)の混合液に溶解させた。室温にて75%硫酸(100g)を水(500mL)に混合した溶液を加えた後、さらに水(400mL)を加えた。0℃に冷却し結晶を析出させ6時間撹拌し、析出した結晶性固体をろ過した。その結晶を5℃に冷やした水(600mL)で洗浄して結晶性固体(26.8g)を得た。
得られた結晶性固体のp-トルエンスルホン酸および硫酸の含有量を上記実施例6-1に記載の方法により定量した。
(結果)
p-トルエンスルホン酸:18.3±0.2%(脱水物換算)
硫酸:4.9±0.1%(脱水物換算)
計算値:C 38.52(%), H 5.50(%),N 8.50(%), C1 3.07(%), S 9.73(%), H2O 15.61(%)
実測値:C 38.69(%), H 5.31(%),N 8.67(%), C1 3.04(%), S 9.84(%), H2O(KF法) 15.85(%)。
測定条件2で測定した粉末X線回折の結果を図17および表18に示す。なお、試料フォルダとしてアルミ板を用いている。2-Theta(2θ) 値が38 °付近にあらわれているピークは、アルミのピークである。
実施例6-1記載の方法によって得られたI型結晶D(25.9g)をアセトニトリル(40mL)と水(40mL)の混合液に溶解させた。室温にて水(259mL)を加えた後、p-トルエンスルホン酸一水和物(103.5g)を加えた。5℃に冷却して65時間静置し、析出した結晶性固体をろ過した。その結晶を5℃に冷やした水(80mL)で洗浄して結晶性固体(15.0g)を得た。
得られた結晶性固体中のp-トルエンスルホン酸および硫酸の含有量を上記実施例6-1に記載の方法により定量した。
(結果)
p-トルエンスルホン酸:31.3±0.2%(脱水物換算)
硫酸:0.0±0.1%(脱水物換算)
計算値:C 41.10(%), H 5.57(%),N 7.63(%), C1 2.76(%), S 9.97(%), H2O 14.71(%)
実測値:C 40.82(%), H 5.43(%),N 7.75(%), C1 2.83(%), S 10.05(%), H2O(KF法) 14.91(%)。
測定条件2で測定した粉末X線回折の結果を図18および表19に示す。なお、試料フォルダとしてアルミ板を用いている。2-Theta(2θ) 値が38 °付近にあらわれているピークは、アルミのピークである。
結晶性固体の固体安定性試験
I型結晶D 約1gをポリエチレン袋に入れて、コンベックスで締めた。この袋を更にポリエチレン袋に入れ、同様にコンベックスで締めた。同じ保存条件の上記検体をまとめて、金属缶に入れ、安定性評価用検体とした。保存条件、保存期間及び試験項目は以下の通りである。
I型結晶Dは下記保存条件・保存期間で、外観変化はなく、類縁物質の増加も見られず、極めて安定であることを確認した。
温度:-20±5℃または5±5℃
遮光
包装形態:二重ポリエチレン袋・コンベックス・金属缶
保存期間:0, 3, 6, 9, 12箇月
(測定)
上記保存条件・保存期間で保存したI型結晶Dを用いて、外観変化を目視した後、下記方法により類縁物質および化合物(IA)の含量を測定した。
試料 約40mgを精密に量り、試料希釈溶媒に溶かし、正確に25mLとした。
上記の試料希釈溶媒は5mmol/Lリン酸塩緩衝液/液体クロマトグラフィー用アセトニトリル混液 (9:1)を用いた。ここで、リン酸塩緩衝液は 水:0.05mol/Lリン酸二水素ナトリウム試液:0.05mol/lリン酸水素二ナトリウム試液混液=18:1:1 (pHが約7.1)を用いた。
上記試料溶液を下記試験条件で液体クロマトグラフィーにより測定を行い、化合物(IA)及び類縁物質のピーク面積を自動積分法により測定した。
(HPLC条件)
カラム:YMC-UltraHT Pro C18,φ2.0 × 100 mm,2 μm,YMC
カラム温度:35℃
UV検出波長:261nm
移動相:[A] 0.1%トリフルオロ酢酸溶液、[B]液体クロマトグラフィー用アセトニトリルを以下のようにグラジエントした。
グラジエントプログラム
流量:毎分0.5mL (化合物(IA)の保持時間 約5分)
以下の計算式を用いて、試料中の類縁物質の量を求めた。
Ai:p-トルエンスルホン酸を除く個々の類縁物質のピーク面積
ΣAi:p-トルエンスルホン酸を除く個々の類縁物質のピーク面積の合計
AT:システムピーク及びp-トルエンスルホン酸を除くピーク面積の合計
(標準溶液の調製)
化合物(IA)のI型結晶Dの標準品を 約40mgを精密に量り、試料希釈溶媒に溶かし、正確に25mLとした。
(試料溶液の調製)
恒湿化後の試料 約40mgを精密に量り、試料希釈溶媒に溶かし、正確に25mLとした。
上記の試料希釈溶媒は5mmol/Lリン酸塩緩衝液:液体クロマトグラフィー用アセトニトリル混液 (9:1)を用いた。ここで、リン酸塩緩衝液は、水/0.05mol/Lリン酸二水素ナトリウム試液:0.05mol/Lリン酸水素二ナトリウム試液混液=18:1:1 (pHが約7.1)を用いた。
上記標準溶液及び試料溶液を下記試験条件で液体クロマトグラフィーにより測定を行い、化合物(IA)のピーク面積を自動積分法により測定した。
(HPLC条件)
カラム:YMC-UltraHT Pro C18,φ2.0 × 100 mm,2 μm,YMC
カラム温度:35℃
UV検出波長:261nm
流量:毎分0.5mL (化合物(IA)の保持時間 約5分)
移動相:[A] 0.1%トリフルオロ酢酸溶液、[B]液体クロマトグラフィー用アセトニトリルを以下のようにグラジエントした。
グラジエントプログラム
以下の計算式を用いて、試料中の類縁物質の量を求めた。
化合物(IA) (C30H34ClN7O10S2) の脱水物換算含量 (%)
= MS / MT × C / 1000 × 100 / (100 - WT) × AT / AS × 100
MS:化合物(IA)のI型結晶標準品の秤取量 (mg)
MT:試料の秤取量 (mg)
C:化合物(IA)のI型結晶標準品の含量 (μg/mg)
WT:試料の恒湿化水分 (%)
AS:標準溶液から得られる化合物(IA)のピーク面積
AT:試料溶液から得られる化合物(IA)のピーク面積
I型結晶D(123.1g:化合物(IA)として82.5g)を1155gの注射用水に懸濁させ、8wt%の水酸化ナトリウム水溶液をpH6になるまで添加 (添加量159.2g) した後、重量調整用の注射用水を添加し、化合物(IA)として50mg/gの溶解液を調製した。この際、中和溶解には2時間を要した。この溶液を0.2μm孔径のPVDF膜で滅菌ろ過した。得られたろ液をガラス瓶にいれ、凍結乾燥を行った。凍結乾燥の条件としては、1)5℃冷却、2)-5℃で1時間冷却、3)-40℃で4時間凍結、4)-℃で123時間、10Pa真空圧で一次乾燥、5)60℃で6時間、10Pa真空圧で二次乾燥を行い、凍結乾燥物を製造した。
Claims (28)
- 請求項1記載の酸付加塩またはその水和物。
- 1)p-トルエンスルホン酸塩、2)ベンゼンスルホン酸塩、または3)p-トルエンスルホン酸もしくはベンゼンスルホン酸と、硫酸、塩酸および臭化水素酸から選択される1つの酸の組み合わせから形成される塩である、請求項1記載の酸付加塩、またはその水和物。
- 1)p-トルエンスルホン酸塩、または3)p-トルエンスルホン酸および硫酸の組合せから形成される塩である、請求項1記載の酸付加塩、またはその水和物。
- 化合物(IA)に対して約1.0~約2.0モル当量のp-トルエンスルホン酸を含有する請求項4記載の酸付加塩、またはその水和物。
- 化合物(IA)に対して、約1.0~約1.8モル当量のp-トルエンスルホン酸、および約0.1~約0.5モル当量の硫酸を含有する、請求項4記載の酸付加塩、またはその水和物。
- 結晶性固体である、請求項1~6のいずれかに記載の酸付加塩またはその水和物。
- 結晶性固体である、請求項4~6のいずれかに記載の酸付加塩またはその水和物。
- 単一相結晶または混合結晶である、請求項8記載の酸付加塩またはその水和物。
- 水分含量が約12~17%である、請求項4~9のいずれかに記載の水和物。
- 2モル当量のp-トルエンスルホン酸塩またはその水和物の単一相結晶、ならびに1モル当量のp-トルエンスルホン酸および0.5モル当量の硫酸を含有する塩またはその水和物の単一相結晶を含有する請求項8~10のいずれかに記載の混合結晶。
- 1.3モル当量のp-トルエンスルホン酸および0.35モル当量の硫酸の混合酸の酸付加塩である、請求項7~11のいずれかに記載の水和物の結晶性固体。
- 脱水物換算で約20.2~23.2%のp-トルエンスルホン酸および脱水物換算で約3.5~5.0%の硫酸を含有する、請求項7~12のいずれかに記載の酸付加塩の水和物の結晶性固体。
- 粉末X線回折スペクトルにおいて、回折角度(2θ):8.2°±0.2°、10.1°±0.2°、13.0°±0.2°および20.3°±0.2°から選択される少なくとも3本のピークを有する、請求項8~13のいずれかに記載の酸付加塩またはその水和物の結晶性固体。
- 粉末X線回折スペクトルにおいて、回折角度(2θ):8.2°±0.2°、8.9°±0.2°、10.1°±0.2°、11.4°±0.2°、13.0°±0.2°、19.9°±0.2°、20.3°±0.2°、21.5°±0.2°および26.2°±0.2°から選択される少なくとも3本のピークを有する、請求項8~13のいずれかに記載の結晶性固体。
- 粉末X線回折スペクトルにおいて、回折角度(2θ):8.2°±0.2°、8.9°±0.2°、10.1°±0.2°、13.0°±0.2°、16.5°±0.2°、17.1°±0.2°、17.9°±0.2°、19.0°±0.2°、20.3°±0.2および26.2°±0.2°から選択される少なくとも3本のピークを有する、請求項8~13のいずれかに記載の結晶性固体。
- 請求項1~16のいずれかに記載の酸付加塩、その水和物、またはそれらの結晶性固体を含む医薬組成物。
- 化合物(IA)を含有する溶液に、p-トルエンスルホン酸および硫酸を添加することを特徴とする、請求項8~16のいずれかに記載の酸付加塩、またはその水和物の結晶性固体の製造方法。
- 化合物(IA)を含有するカラム溶出液に対して約2.2~2.5重量%のp-トルエンスルホン酸・1水和物および約5~6重量%の75%硫酸を添加することを特徴とする、請求項18記載の製造方法。
- 請求項1記載のナトリウム塩、またはその水和物。
- 非晶質形態である、請求項20記載のナトリウム塩またはその水和物。
- 請求項20または21に記載のナトリウム塩またはその水和物を含有する医薬組成物。
- 凍結乾燥製剤である、請求項22記載の医薬組成物。
- 請求項1~16のいずれかに記載の酸付加塩、その水和物、またはそれらの結晶性固体を用いることを特徴とする、化合物(IA)のナトリウム塩またはその水和物を含有する凍結乾燥製剤の製法。
- 請求項1~16のいずれかに記載の酸付加塩、その水和物、またはそれらの結晶性固体、および水酸化ナトリウムを含む水溶液を凍結乾燥することを特徴とする、化合物(IA)のナトリウム塩またはその水和物を含有する凍結乾燥製剤の製法。
- 酸付加塩が、1)p-トルエンスルホン酸塩、または3)p-トルエンスルホン酸および硫酸の組合せから形成される塩である、請求項24または25記載の製法。
- 化合物(IA)もしくは製薬上許容される塩、またはその水和物を含み、さらにp-トルエンスルホン酸ナトリウムおよび/または硫酸ナトリウムを含有する医薬組成物。
- 化合物(IA)のナトリウム塩またはその水和物を含み、さらにp-トルエンスルホン酸ナトリウムおよび/または硫酸ナトリウムを含有する請求項27記載の医薬組成物。
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PL15838484T PL3190115T3 (pl) | 2014-09-04 | 2015-09-03 | Sól pochodnej cefalosporyny, jej krystaliczna postać stała i sposób jej wytwarzania |
EA201790522A EA035845B1 (ru) | 2014-09-04 | 2015-09-03 | Соль производного цефалоспорина, ее кристаллическое твердое вещество и способ ее получения |
JP2016546687A JP6120429B2 (ja) | 2014-09-04 | 2015-09-03 | セファロスポリン誘導体の塩、その結晶性固体およびその製造方法 |
SI201531718T SI3190115T1 (sl) | 2014-09-04 | 2015-09-03 | Sol derivata cefalosporina, njene trdne kristalinične oblike in postopek njene izdelave |
AU2015312828A AU2015312828B2 (en) | 2014-09-04 | 2015-09-03 | Salt of cephalosporin derivative, crystalline solid form of same and method for producing same |
US15/508,270 US10004750B2 (en) | 2014-09-04 | 2015-09-03 | Salt of cephalosporin derivative, its crystalline solid and a method of manufacturing thereof |
RS20211278A RS62449B1 (sr) | 2014-09-04 | 2015-09-03 | So derivata cefalosporina, njen kristalni čvrst oblik i postupak njene proizvodnje |
BR112017004166-9A BR112017004166B1 (pt) | 2014-09-04 | 2015-09-03 | Sal de derivado de cefalosporina e seu hidratado, sólido cristalino dos mesmos, seu processo de preparação, composição farmacêutica e método para preparar uma formulação liofilizada |
MX2017002790A MX2017002790A (es) | 2014-09-04 | 2015-09-03 | Sal de un derivado de cefalosporina, forma solida cristalina del mismo y metodo para su produccion. |
CA2959295A CA2959295C (en) | 2014-09-04 | 2015-09-03 | A salt of cephalosporin derivative, its crystalline solid and a method of manufacturing thereof |
LTEPPCT/JP2015/075039T LT3190115T (lt) | 2014-09-04 | 2015-09-03 | Cefalosporino darinio druska, jos kristalinė kietoji forma ir gamybos būdas |
ES15838484T ES2893424T3 (es) | 2014-09-04 | 2015-09-03 | Sal de derivado de cefalosporina, su forma sólida cristalina y método para producirla |
EP15838484.2A EP3190115B1 (en) | 2014-09-04 | 2015-09-03 | Salt of cephalosporin derivative, crystalline solid form of same and method for producing same |
DK15838484.2T DK3190115T3 (da) | 2014-09-04 | 2015-09-03 | Salt af cephalosporinderivat, krystallinsk fast form deraf og fremgangsmåde til fremstilling deraf |
CN201580047079.6A CN106795176B (zh) | 2014-09-04 | 2015-09-03 | 头孢菌素衍生物的盐、其结晶固体及其制造方法 |
HRP20211524TT HRP20211524T1 (hr) | 2014-09-04 | 2015-09-03 | Sol derivata cefalosporina, kristalni kruti oblik istog i postupak za njegovu proizvodnju |
PH12017500435A PH12017500435A1 (en) | 2014-09-04 | 2017-03-08 | A salt of cephalosporin derivative, its crystalline solid and a method of manufacturing thereof |
CY20211100921T CY1124838T1 (el) | 2014-09-04 | 2021-10-21 | Αλας παραγωγου κεφαλοσπορινης, κρυσταλλικη, στερεη μορφη αυτου και μεθοδος παραγωγης αυτου |
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US (1) | US10004750B2 (ja) |
EP (1) | EP3190115B1 (ja) |
JP (1) | JP6120429B2 (ja) |
KR (2) | KR20170043663A (ja) |
CN (1) | CN106795176B (ja) |
AU (1) | AU2015312828B2 (ja) |
BR (1) | BR112017004166B1 (ja) |
CA (1) | CA2959295C (ja) |
CY (1) | CY1124838T1 (ja) |
DK (1) | DK3190115T3 (ja) |
EA (1) | EA035845B1 (ja) |
ES (1) | ES2893424T3 (ja) |
HR (1) | HRP20211524T1 (ja) |
HU (1) | HUE056038T2 (ja) |
LT (1) | LT3190115T (ja) |
MA (1) | MA40585A (ja) |
MX (1) | MX2017002790A (ja) |
MY (1) | MY178017A (ja) |
PH (1) | PH12017500435A1 (ja) |
PL (1) | PL3190115T3 (ja) |
PT (1) | PT3190115T (ja) |
RS (1) | RS62449B1 (ja) |
SI (1) | SI3190115T1 (ja) |
TW (1) | TWI593690B (ja) |
WO (1) | WO2016035845A1 (ja) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2017216765A1 (en) * | 2016-06-17 | 2017-12-21 | Wockhardt Limited | Antibacterial compositions |
WO2020184399A1 (ja) * | 2019-03-08 | 2020-09-17 | 塩野義製薬株式会社 | 抗菌用医薬組成物 |
WO2022025091A1 (ja) | 2020-07-28 | 2022-02-03 | 塩野義製薬株式会社 | カテコール基を有するセファロスポリン類を含有する凍結乾燥製剤およびその製造方法 |
Citations (3)
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WO2010050468A1 (ja) * | 2008-10-31 | 2010-05-06 | 塩野義製薬株式会社 | カテコール基を有するセファロスポリン類 |
WO2011125967A1 (ja) * | 2010-04-05 | 2011-10-13 | 塩野義製薬株式会社 | カテコール基を有するセフェム化合物 |
WO2014068388A1 (en) * | 2012-10-29 | 2014-05-08 | Glaxo Group Limited | 2 substituted cephem compounds |
Family Cites Families (1)
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US9949982B2 (en) * | 2014-09-04 | 2018-04-24 | Shionogi & Co., Ltd. | Preparation containing cephalosporin having a catechol moiety |
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- 2015-09-03 ES ES15838484T patent/ES2893424T3/es active Active
- 2015-09-03 MY MYPI2017700556A patent/MY178017A/en unknown
- 2015-09-03 DK DK15838484.2T patent/DK3190115T3/da active
- 2015-09-03 JP JP2016546687A patent/JP6120429B2/ja active Active
- 2015-09-03 CA CA2959295A patent/CA2959295C/en active Active
- 2015-09-03 KR KR1020187021768A patent/KR102284990B1/ko active IP Right Grant
- 2015-09-03 RS RS20211278A patent/RS62449B1/sr unknown
- 2015-09-04 TW TW104129406A patent/TWI593690B/zh active
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2017
- 2017-03-08 PH PH12017500435A patent/PH12017500435A1/en unknown
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- 2021-10-21 CY CY20211100921T patent/CY1124838T1/el unknown
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WO2010050468A1 (ja) * | 2008-10-31 | 2010-05-06 | 塩野義製薬株式会社 | カテコール基を有するセファロスポリン類 |
WO2011125967A1 (ja) * | 2010-04-05 | 2011-10-13 | 塩野義製薬株式会社 | カテコール基を有するセフェム化合物 |
WO2014068388A1 (en) * | 2012-10-29 | 2014-05-08 | Glaxo Group Limited | 2 substituted cephem compounds |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
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WO2017216765A1 (en) * | 2016-06-17 | 2017-12-21 | Wockhardt Limited | Antibacterial compositions |
CN109310682A (zh) * | 2016-06-17 | 2019-02-05 | 沃克哈特有限公司 | 抗菌组合物 |
WO2020184399A1 (ja) * | 2019-03-08 | 2020-09-17 | 塩野義製薬株式会社 | 抗菌用医薬組成物 |
WO2022025091A1 (ja) | 2020-07-28 | 2022-02-03 | 塩野義製薬株式会社 | カテコール基を有するセファロスポリン類を含有する凍結乾燥製剤およびその製造方法 |
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