WO2011040386A1 - Novel crystal of piperacillin sodium monohydrate - Google Patents

Novel crystal of piperacillin sodium monohydrate Download PDF

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WO2011040386A1
WO2011040386A1 PCT/JP2010/066766 JP2010066766W WO2011040386A1 WO 2011040386 A1 WO2011040386 A1 WO 2011040386A1 JP 2010066766 W JP2010066766 W JP 2010066766W WO 2011040386 A1 WO2011040386 A1 WO 2011040386A1
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crystal
type
crystals
powder
ray diffraction
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勝 毛利
裕司 大西
健太郎 石原
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富山化学工業株式会社
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C07D499/21—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with a nitrogen atom directly attached in position 6 and a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
    • C07D499/44—Compounds with an amino radical acylated by carboxylic acids, attached in position 6
    • C07D499/48—Compounds with an amino radical acylated by carboxylic acids, attached in position 6 with a carbon chain, substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, attached to the carboxamido radical
    • C07D499/58—Compounds with an amino radical acylated by carboxylic acids, attached in position 6 with a carbon chain, substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, attached to the carboxamido radical substituted in alpha-position to the carboxamido radical
    • C07D499/64—Compounds with an amino radical acylated by carboxylic acids, attached in position 6 with a carbon chain, substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, attached to the carboxamido radical substituted in alpha-position to the carboxamido radical by nitrogen atoms
    • C07D499/68—Compounds with an amino radical acylated by carboxylic acids, attached in position 6 with a carbon chain, substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, attached to the carboxamido radical substituted in alpha-position to the carboxamido radical by nitrogen atoms with aromatic rings as additional substituents on the carbon chain
    • 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

Definitions

  • the present invention relates to (2S, 5R, 6R) -6-((2R) -2-((4-ethyl-2,3-dioxopiperazine-1-carbonyl) amino) -2-phenylacetylamino) -3 , 3-Dimethyl-7-oxo-4-thia-1-azabicyclo [3.2.0] heptane-2-carboxylic acid (hereinafter referred to as piperacillin) sodium monohydrate.
  • Piperacillin or its salts are known to have broad antibacterial activity, especially against gram-negative microorganisms, Pseudomonas arginosa, vulgaris, Serratia spp., Intestinal bacteria and other clinically important anaerobes .
  • piperacillin sodium salt is effectively used for the treatment of pneumonia, purulent meningitis and sepsis.
  • drug injections include liquid injections that are pre-dissolved, emulsified or dispersed in liquids such as water, and powders that are dissolved when used in liquids, emulsified or dispersed when used. Injectables are known.
  • piperacillin or a salt thereof is unstable in a solution, and it is difficult to produce a liquid injection of piperacillin or a salt thereof.
  • Piperacillin powder-filled preparations produced using lyophilized powder are known.
  • amorphous solids used in powder-filled preparations are not sufficient in moisture absorption stability and solubility during use.
  • the production by freeze-drying has a problem that it takes a long time and not only increases the production cost but also makes purification difficult.
  • type IV crystals are known as piperacillin sodium solvate (Patent Document 2).
  • a type VI crystal useful as an active pharmaceutical ingredient can be produced from a type III crystal (Patent Document 3).
  • novel crystals of piperacillin sodium monohydrate of the present invention are easy to filter and dry, have a low content of related substances, have high purity, are excellent in moisture absorption stability, and are useful as pharmaceutical active ingredients and production intermediates thereof. It is.
  • each term has the following meaning.
  • Supercritical carbon dioxide means carbon dioxide in a supercritical state of 31.1 ° C. or higher, which is the critical temperature of carbon dioxide, and 7.38 MPa or higher, which is the critical pressure.
  • the type I crystal means a crystal of piperacillin sodium monohydrate having diffraction angles of 3.9, 4.6, 5.6, 6.7, 7.6, and 9.8 ° represented by 2 ⁇ in powder X-ray diffraction.
  • the type II crystal means a crystal of piperacillin sodium monohydrate having diffraction angles of 7.3 and 7.9 ° represented by 2 ⁇ in powder X-ray diffraction.
  • the type III crystal means a crystal of piperacillin sodium monohydrate having diffraction angles of 6.1, 10.2, 12.4, 15.1, 15.8 and 18.6 ° represented by 2 ⁇ in powder X-ray diffraction.
  • Type IV crystal is a crystal of piperacillin sodium monohydrate, 0.5 dioxane adduct having diffraction angles of 5.3, 6.1, 8.7, 10.2, 12.4 and 18.6 ° represented by 2 ⁇ in powder X-ray diffraction. Means.
  • the V-type crystal means a crystal of piperacillin sodium monohydrate having diffraction angles of 3.7, 5.5, 7.3, 11.6, 14.5 and 18.0 ° represented by 2 ⁇ in powder X-ray diffraction.
  • the type VI crystal means a crystal of piperacillin sodium monohydrate having diffraction angles of 5.6, 7.8, 12.3, 15.5, 17.5, 23.3, 24.8 and 28.5 ° represented by 2 ⁇ in powder X-ray diffraction. .
  • the present invention relates to a novel crystal of piperacillin sodium monohydrate having diffraction angles of 6.6, 10.9, 14.6, 17.0, 18.2, 19.8 and 24.9 ° represented by 2 ⁇ in powder X-ray diffraction (hereinafter referred to as ⁇ type). (Referred to as crystals).
  • ⁇ type powder X-ray diffraction
  • the characteristic peak by powder X-ray diffraction may change with measurement conditions.
  • 2 ⁇ has an error within a range of ⁇ 0.2 ° (15th revised Japanese Pharmacopoeia Manual, page B-372, powder X-ray diffraction measurement method (identification and determination), Tokyo Yodogawa Shoten). Therefore, “the diffraction angle of X ° represented by 2 ⁇ ” means “the diffraction angle of ((X ⁇ 0.2) to (X + 0.2)) ° represented by 2 ⁇ ”.
  • 3 to 5 show measurement results of powder X-ray diffraction of freeze-dried powder (hereinafter referred to as amorphous) of ⁇ -type crystal, VI-type crystal and piperacillin sodium.
  • the ⁇ -type crystal of the present invention is also characterized by an absorption wavelength in an infrared absorption spectrum measured under the following conditions.
  • the results of infrared absorption spectrum measurement of ⁇ -type crystal, VI-type crystal and amorphous are shown in FIGS.
  • Infrared absorption spectrum measurement conditions Measurement was performed according to the Japanese Pharmacopoeia, general test method, and infrared absorption spectrum total reflection measurement method (ATR method).
  • Example 2 Purity (related substance content) test ⁇ -type crystals (Example 2) and amorphous (Comparative Example 1) were used as test substances. The purity of the test substance was measured by a high performance liquid chromatography method (Notification of the Pharmaceutical Safety Bureau, Ministry of Health and Welfare No. 340, April 4, 2001).
  • By-product II measurement condition detector UV absorption photometer measurement wavelength: 254nm
  • Flow rate: 1 mL / min The results are shown in Table 1.
  • the ⁇ -type crystal (Example 2) had a similar substance content less than the amorphous (Comparative Example 1).
  • Hygroscopicity test ⁇ -type crystals (Example 2) and amorphous (Comparative Example 1) were used as test substances.
  • the test substance was allowed to stand at 25 ° C. for 1 day under 7 and 22% relative humidity, and the water content was measured according to the Japanese Pharmacopoeia, general test method, and moisture measurement method (Karl Fischer method), and the change in weight was calculated. The results are shown in Table 2.
  • the ⁇ -type crystal (Example 2) had a smaller weight change rate than the amorphous (Comparative Example 1).
  • the ⁇ -type crystal was superior in moisture absorption stability to the amorphous.
  • the ⁇ -type crystal can be produced, for example, by the following production method.
  • ⁇ -type Crystals can be produced by adding methyl acetate to a mixed solvent solution of N, N-dimethylacetamide containing piperacillin sodium and water.
  • the mixing ratio of N, N-dimethylacetamide and water is not particularly limited.
  • the content of N, N-dimethylacetamide is preferably 50 to 99 (v / v)%, and 60 to 90 (v / v). % Is more preferable, and 70 to 80 (v / v)% is more preferable.
  • the amount of the mixed solvent of N, N-dimethylacetamide and water is not particularly limited, but it is preferably 0.5 to 5 times, more preferably 1 to 3 times the amount of piperacillin sodium.
  • the solvent amount of methyl acetate is not particularly limited, but is preferably 2 to 20 times, more preferably 3 to 10 times the amount of piperacillin sodium.
  • the methyl acetate content is not particularly limited, but is preferably 50 to 95 (v / v)%, more preferably 60 to 90 (v / v)%, and still more preferably 70 to 80 (v / v)%.
  • the temperature is not particularly limited, but is preferably 0 to 30 ° C, more preferably 0 to 10 ° C.
  • a seed crystal of ⁇ -type crystal can be used, and the amount thereof is not particularly limited. When using seed crystals, it is preferable to stir.
  • the time required for crystallization is not particularly limited, but is preferably 0.5 to 48 hours, more preferably 1 to 2 hours.
  • the VI type crystal can be produced, for example, by the following production method.
  • a VI type crystal can be manufactured by contacting an ⁇ type crystal with liquefied carbon dioxide or supercritical carbon dioxide.
  • the temperature is preferably 20 to 80 ° C, more preferably 32 to 60 ° C.
  • the pressure is preferably 6 MPa or more, more preferably 7.4 MPa or more, and further preferably 10 to 20 MPa.
  • the reaction time is preferably 0.5 to 20 hours, more preferably 1 to 10 hours.
  • the production method of the VI type crystal from the ⁇ type crystal is extremely excellent in terms of removing the residual solvent. That is, the production method using the ⁇ -type crystal is less than the production method using the III-type crystal (Example 2 and Example 3 of Patent Document 3) and produces a VI-type crystal with less residual solvent at a low carbon dioxide pressure. Can get and is excellent. For example, when a VI-type crystal was produced from an ⁇ -type crystal, a high-purity crystal with little residual solvent was obtained at a pressure of 10 MPa (Example 3). On the other hand, when the VI type crystal was produced from the III type crystal, the residual solvent was not sufficiently removed even at a pressure of 20 MPa (Reference Example 3).
  • the ⁇ -type crystal at the time of manufacturing the VI-type crystal, it is possible to significantly reduce the pressure of carbon dioxide at the time of manufacture compared to the case of using the III-type crystal.
  • the filterability of ⁇ -type crystals is superior to that of III-type crystals, and the time required for production can be shortened by using ⁇ -type crystals.
  • the crystals of piperacillin sodium monohydrate of the present invention can be made into an injection according to a conventional method. Furthermore, the crystal of the present invention can be blended with a known ⁇ -lactamase inhibitor, for example, clavulanic acid, sulbactam and / or tazobactam, to prepare a compounding agent.
  • a preferred ⁇ -lactamase inhibitor includes tazobactam.
  • the compounding ratio of the crystals of piperacillin sodium monohydrate and tazobactam is not particularly limited, but the ratio of titers is preferably piperacillin sodium monohydrate 4-8 relative to tazobactam 1.
  • Example 1 ( ⁇ -type crystal) Piperacillin sodium 1.0 g was added to a mixture of 5.0 mL methyl acetate, 1.7 mL N, N-dimethylacetamide and 0.2 mL water. Subsequently, it left still at 5 degreeC for 2 days. The crystals were collected by filtration, washed successively with a mixed solution of 5.0 mL of methyl acetate, 0.8 mL of N, N-dimethylacetamide and 0.3 mL of water, and a mixed solution of 9.8 mL of methyl acetate and 0.2 mL of water to obtain 0.5 g of ⁇ -type crystals. Got. This was used as a seed crystal of ⁇ -type crystal. Moisture content: 3.2% IR (ATR) 1771, 1715cm -1 The powder X-ray diffraction pattern was consistent with Example 2.
  • Example 2 ( ⁇ -type crystal) Piperacillin sodium (20 g) was added to a mixture of 28 mL of N, N-dimethylacetamide and 8.0 mL of water. After insoluble matter was removed by filtration, 90 mL of methyl acetate was added dropwise, then seed crystals of ⁇ -type crystals were added, and the mixture was stirred at 5 ° C. for 1 hour. Next, 10 mL of methyl acetate was added dropwise, and the mixture was stirred at 5 ° C. for 1 hour. Further, 20 mL of methyl acetate was added dropwise over 1 hour, followed by stirring at 5 ° C. for 1 hour.
  • FIG. 1 shows a scanning electron micrograph
  • FIG. 3 shows a powder X-ray diffraction pattern
  • FIG. 6 shows an infrared absorption spectrum (ATR method).
  • Example 3 (VI type crystal) An ⁇ -type crystal (40 g) was placed in a pressure vessel with a filter (inner diameter: 68 mm, length: 180 mm), and carbon dioxide was introduced at 40 ° C. and 10 MPa for 5 hours (flow rate: 2.7 kg / h). The pressure was released to obtain 36 g of a VI type crystal. Moisture content: 3.1% IR (ATR) 1772, 1716cm -1 The powder X-ray diffraction pattern is shown in FIG. 4, and the infrared absorption spectrum (ATR method) is shown in FIG. When the amount of residual solvent of the obtained crystal was measured by gas chromatography, 41 ppm of methyl acetate was detected.
  • ATR infrared absorption spectrum
  • Example 4 (VI type crystal) In a pressure vessel with a filter (inner diameter: 32 mm, length: 37 mm), 2.0 g of ⁇ -type crystal was put, and carbon dioxide was introduced at 24 ° C. and 10 MPa for 3 hours (flow rate: 48 g / h). The pressure was released to obtain 1.8 g of type VI crystals. Moisture content: 3.2% IR (ATR) 1770, 1716cm -1 The powder X-ray diffraction pattern was consistent with Example 3.
  • Comparative Example 1 (Amorphous) Piperacillin monohydrate 90 g was added to water 180 mL. 14 g of sodium bicarbonate was added at 6-10 ° C. over 2 hours. Insoluble matter was removed by filtration and then lyophilized to obtain 89 g of amorphous substance. Moisture content: 0.5% IR (ATR) 1765, 1713cm -1
  • FIG. 2 shows a scanning electron micrograph
  • FIG. 5 shows a pattern of powder X-ray diffraction
  • FIG. 8 shows an infrared absorption spectrum (ATR method).
  • Reference Example 1 (Type III crystal: Example 1 of Patent Document 2) Piperacillin sodium (2.0 g) was added to a mixed solution of 2-butanone (2 mL), N, N-dimethylformamide (3.8 mL) and water (0.6 mL), and 2-butanone (10 mL) was added dropwise. The insoluble material was removed by filtration, and then allowed to stand at 5 ° C. for 24 hours.
  • the crystals were collected by filtration, washed with a mixed solution of 2-butanone 3 mL, N, N-dimethylformamide 0.9 mL and water 0.1 mL, 2-butanone 6 mL, 99% acetone 6 mL, and piperacillin sodium monohydrate crystals ( 1.7 g of type III crystal was obtained. This was used as a seed crystal of type III crystal.
  • Reference Example 2 (Type III crystal: Example 2 of Patent Document 2) Piperacillin monohydrate (20 g) was added to a mixture of 20 mL of 2-butanone, 28 mL of N, N-dimethylformamide and 6 mL of water. 6.4 g of sodium 2-ethylhexanoate was added at 10 to 20 ° C., and 100 mL of 2-butanone was added dropwise. The insoluble material was removed by filtration, and seed crystals of type III crystals were added, followed by stirring at 15 to 20 ° C. for 1 hour and then at 5 ° C. for 3 hours.
  • the crystals were collected by filtration, washed with a mixed solution of 31 mL of 2-butanone, 7.2 mL of N, N-dimethylformamide and 1.6 mL of water, 60 mL of 2-butanone and 60 mL of 99% acetone, and crystals of piperacillin sodium monohydrate ( 18 g of type III crystal) was obtained.
  • Reference Example 3 (Type VI crystal) 100 g of type III crystal obtained in the same manner as in Reference Example 2 was placed in a pressure vessel with a filter (inner diameter 68 mm, length 180 mm), and carbon dioxide was introduced at 40 ° C. and 20 MPa for 5 hours (flow rate 1.9 kg / h). The pressure was released to obtain 95 g of a VI type crystal. Moisture content: 3.8% As a result of measuring 1 H-NMR spectrum, the obtained crystal contained 6600 ppm of N, N-dimethylformamide.
  • VI type crystal Example 2 of Patent Document 3
  • 200 g of type III crystal was placed in a pressure vessel with a filter (inner diameter 68 mm, length 180 mm), and carbon dioxide was introduced at 40 ° C. and 40 MPa for 4 hours (flow rate 2.4 kg / h). The pressure was released to obtain 200 g of a VI type crystal.
  • ATR method infrared absorption spectrum of an ⁇ -type crystal. It is an infrared absorption spectrum (ATR method) of a VI type crystal. It is an amorphous infrared absorption spectrum (ATR method).
  • novel crystals of piperacillin sodium monohydrate of the present invention are easy to filter and dry, have a low content of related substances, have high purity, are excellent in moisture absorption stability, and are useful as pharmaceutical active ingredients and production intermediates thereof. It is.

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Abstract

Disclosed is a novel crystal of piperacillin sodium monohydrate, which has diffraction angles represented by 2θ of 6.6, 10.9, 14.6, 17.0, 18.2, 19.8 and 24.9° in powder X-ray diffraction. The crystal has a low analogous substance content, high purity, and low hygroscopicity, and is useful as an active ingredient for a drug or an intermediate for the production of an active ingredient for a drug.

Description

ピペラシリンナトリウム・１水和物の新規な結晶Novel crystals of piperacillin sodium monohydrate
　本発明は、（２Ｓ，５Ｒ，６Ｒ）－６－（（２Ｒ）－２－（（４－エチル－２，３－ジオキソピペラジン－１－カルボニル）アミノ）－２－フェニルアセチルアミノ）－３，３－ジメチル－７－オキソ－４－チア－１－アザビシクロ［３．２．０］ヘプタン－２－カルボン酸（以下、ピペラシリンと称する。）ナトリウム・１水和物の新規な結晶に関する。 The present invention relates to (2S, 5R, 6R) -6-((2R) -2-((4-ethyl-2,3-dioxopiperazine-1-carbonyl) amino) -2-phenylacetylamino) -3 , 3-Dimethyl-7-oxo-4-thia-1-azabicyclo [3.2.0] heptane-2-carboxylic acid (hereinafter referred to as piperacillin) sodium monohydrate.
　ピペラシリン又はその塩は、広い抗菌活性、特にグラム陰性微生物、シュードモナスアルギノーサ、尋常変形菌、セラチア種、腸バクテリア及びその他の臨床上重要な嫌気性菌に対し、効果があることが知られている。例えば、肺炎、化膿性髄膜炎及び敗血症等の治療にピペラシリンのナトリウム塩が効果的に使用されている。
　一般に薬物の注射剤としては、水をはじめとする液体に予め溶解、乳化又は分散させて使用する液体注射剤、及び、使用時に液体に溶解、乳化又は分散させて使用する用時溶解型の粉末注射剤が知られている。
　しかし、ピペラシリン又はその塩は、溶液中で不安定であり、ピペラシリン又はその塩の液体注射剤を製造することは難しい。
　凍結乾燥末を用いて製造されたピペラシリンの粉末充填製剤が知られている。しかしながら、粉末充填製剤で使用される非晶質の固形物は、吸湿安定性、用時溶解性が十分ではなかった。さらに、凍結乾燥による製造は、長時間を要し、製造コストを上昇させるだけでなく、精製が困難であるという問題があった。
　一方、ピペラシリンナトリウム・１水和物の結晶として、I型及びII型結晶（特許文献１）、III型（特許文献２）並びにV型及びVI型結晶（特許文献３）が知られている。さらに、ピペラシリンナトリウム・溶媒和物としてIV型結晶が知られている（特許文献２）。また、医薬の原薬として有用なVI型結晶は、III型結晶から製造できることが知られている（特許文献３）。 Piperacillin or its salts are known to have broad antibacterial activity, especially against gram-negative microorganisms, Pseudomonas arginosa, vulgaris, Serratia spp., Intestinal bacteria and other clinically important anaerobes . For example, piperacillin sodium salt is effectively used for the treatment of pneumonia, purulent meningitis and sepsis.
In general, drug injections include liquid injections that are pre-dissolved, emulsified or dispersed in liquids such as water, and powders that are dissolved when used in liquids, emulsified or dispersed when used. Injectables are known.
However, piperacillin or a salt thereof is unstable in a solution, and it is difficult to produce a liquid injection of piperacillin or a salt thereof.
Piperacillin powder-filled preparations produced using lyophilized powder are known. However, amorphous solids used in powder-filled preparations are not sufficient in moisture absorption stability and solubility during use. Furthermore, the production by freeze-drying has a problem that it takes a long time and not only increases the production cost but also makes purification difficult.
On the other hand, as crystals of piperacillin sodium monohydrate, type I and type II crystals (Patent Document 1), type III (Patent Document 2), and V type and VI type crystals (Patent Document 3) are known. Furthermore, type IV crystals are known as piperacillin sodium solvate (Patent Document 2). In addition, it is known that a type VI crystal useful as an active pharmaceutical ingredient can be produced from a type III crystal (Patent Document 3).
特開２００７－０９９７６３号公報JP 2007-099763 A 特開２００７－２４６５１４号公報JP 2007-246514 A 国際公開第２００８／０９３６５０号パンフレットInternational Publication No. 2008/093650 Pamphlet
　本発明は、医薬として優れた作用を有するピペラシリンナトリウム・１水和物の新規な結晶及びそれを充填した注射用製剤を提供することにある。また、医薬の原薬として有用なVI型結晶の製造中間体を提供することにある。 The present invention is to provide a novel crystal of piperacillin sodium monohydrate having an excellent action as a medicine and an injectable preparation filled therewith. Another object of the present invention is to provide an intermediate for producing a type VI crystal useful as a drug substance for pharmaceuticals.
　本発明者らは、上記問題を解決すべく、鋭意研究を重ねた結果、Ｎ，Ｎ－ジメチルアセトアミド、水及び酢酸メチルの混合溶媒を使用することにより、ピペラシリンナトリウム・１水和物の優れた新規な結晶が得られることを見出し、本発明を完成した。
　以下に、本発明を詳細に説明する。 As a result of intensive studies to solve the above-mentioned problems, the present inventors have achieved excellent piperacillin sodium monohydrate by using a mixed solvent of N, N-dimethylacetamide, water and methyl acetate. The inventors found that a new crystal can be obtained and completed the present invention.
The present invention is described in detail below.
　本発明のピペラシリンナトリウム・１水和物の新規な結晶は、濾過及び乾燥が容易で類縁物質含量が少なく、高純度であり、吸湿安定性に優れ、医薬の原薬及びその製造中間体として有用である。 The novel crystals of piperacillin sodium monohydrate of the present invention are easy to filter and dry, have a low content of related substances, have high purity, are excellent in moisture absorption stability, and are useful as pharmaceutical active ingredients and production intermediates thereof. It is.
　本発明において、特にことわらない限り、各用語は、次の意味を有する。
　超臨界二酸化炭素とは、二酸化炭素の臨界温度である31.1℃以上及び臨界圧力である7.38MPa以上の超臨界状態の二酸化炭素を意味する。
　I型結晶とは、粉末Ｘ線回折において、２θで表される3.9、4.6、5.6、6.7、7.6及び9.8°の回折角度を有するピペラシリンナトリウム・１水和物の結晶を意味する。
　II型結晶とは、粉末Ｘ線回折において、２θで表される7.3及び7.9°の回折角度を有するピペラシリンナトリウム・１水和物の結晶を意味する。
　III型結晶とは、粉末Ｘ線回折において、２θで表される6.1、10.2、12.4、15.1、15.8及び18.6°の回折角度を有するピペラシリンナトリウム・１水和物の結晶を意味する。
　IV型結晶とは、粉末Ｘ線回折において、２θで表される5.3、6.1、8.7、10.2、12.4及び18.6°の回折角度を有するピペラシリンナトリウム・１水和物・０．５ジオキサン付加体の結晶を意味する。
　V型結晶とは、粉末Ｘ線回折において、２θで表される3.7、5.5、7.3、11.6、14.5及び18.0°の回折角度を有するピペラシリンナトリウム・１水和物の結晶を意味する。
　VI型結晶とは、粉末Ｘ線回折において、２θで表される5.6、7.8、12.3、15.5、17.5、23.3、24.8及び28.5°の回折角度を有するピペラシリンナトリウム・１水和物の結晶を意味する。 In the present invention, unless otherwise specified, each term has the following meaning.
Supercritical carbon dioxide means carbon dioxide in a supercritical state of 31.1 ° C. or higher, which is the critical temperature of carbon dioxide, and 7.38 MPa or higher, which is the critical pressure.
The type I crystal means a crystal of piperacillin sodium monohydrate having diffraction angles of 3.9, 4.6, 5.6, 6.7, 7.6, and 9.8 ° represented by 2θ in powder X-ray diffraction.
The type II crystal means a crystal of piperacillin sodium monohydrate having diffraction angles of 7.3 and 7.9 ° represented by 2θ in powder X-ray diffraction.
The type III crystal means a crystal of piperacillin sodium monohydrate having diffraction angles of 6.1, 10.2, 12.4, 15.1, 15.8 and 18.6 ° represented by 2θ in powder X-ray diffraction.
Type IV crystal is a crystal of piperacillin sodium monohydrate, 0.5 dioxane adduct having diffraction angles of 5.3, 6.1, 8.7, 10.2, 12.4 and 18.6 ° represented by 2θ in powder X-ray diffraction. Means.
The V-type crystal means a crystal of piperacillin sodium monohydrate having diffraction angles of 3.7, 5.5, 7.3, 11.6, 14.5 and 18.0 ° represented by 2θ in powder X-ray diffraction.
The type VI crystal means a crystal of piperacillin sodium monohydrate having diffraction angles of 5.6, 7.8, 12.3, 15.5, 17.5, 23.3, 24.8 and 28.5 ° represented by 2θ in powder X-ray diffraction. .
　本発明は、粉末Ｘ線回折において、２θで表される6.6、10.9、14.6、17.0、18.2、19.8及び24.9°の回折角度を有するピペラシリンナトリウム・１水和物の新規な結晶（以下、α型結晶と称する。）に関する。なお、粉末Ｘ線回折による特徴的なピークは、測定条件により変動することがある。一般に、２θは、±0.2°の範囲内で誤差が生じる（第十五改正日本薬局方解説書、Ｂ－３７２頁　粉末Ｘ線回折測定法（同定及び判定）、東京廣川書店）。従って、「２θで表されるＸ°の回折角度」は、「２θで表される（（Ｘ－0.2）～（Ｘ＋0.2））°の回折角度」を意味する。 The present invention relates to a novel crystal of piperacillin sodium monohydrate having diffraction angles of 6.6, 10.9, 14.6, 17.0, 18.2, 19.8 and 24.9 ° represented by 2θ in powder X-ray diffraction (hereinafter referred to as α type). (Referred to as crystals). In addition, the characteristic peak by powder X-ray diffraction may change with measurement conditions. In general, 2θ has an error within a range of ± 0.2 ° (15th revised Japanese Pharmacopoeia Manual, page B-372, powder X-ray diffraction measurement method (identification and determination), Tokyo Yodogawa Shoten). Therefore, “the diffraction angle of X ° represented by 2θ” means “the diffraction angle of ((X−0.2) to (X + 0.2)) ° represented by 2θ”.
　α型結晶、VI型結晶及びピペラシリンナトリウムの凍結乾燥末（以下、非晶質と称する。）の粉末Ｘ線回折の測定結果を図３～５に示す。 3 to 5 show measurement results of powder X-ray diffraction of freeze-dried powder (hereinafter referred to as amorphous) of α-type crystal, VI-type crystal and piperacillin sodium.
粉末Ｘ線回折測定条件
使用Ｘ線：ＣｕＫα
加電圧：40kV
加電流：40mA
走査軸：２θ
走査範囲：２θ＝2～40° Powder X-ray diffraction measurement condition use X-ray: CuKα
Applied voltage: 40 kV
Applied current: 40 mA
Scanning axis: 2θ
Scanning range: 2θ = 2-40 °
　本発明のα型結晶は、以下の条件において測定した赤外吸収スペクトルにおける吸収波長によっても特徴付けられる。
　α型結晶、VI型結晶及び非晶質の赤外吸収スペクトル測定結果を図６～８に示す。 The α-type crystal of the present invention is also characterized by an absorption wavelength in an infrared absorption spectrum measured under the following conditions.
The results of infrared absorption spectrum measurement of α-type crystal, VI-type crystal and amorphous are shown in FIGS.
赤外吸収スペクトル測定条件
　日本薬局方、一般試験法、赤外吸収スペクトル全反射測定法（ＡＴＲ法）に従って測定した。 Infrared absorption spectrum measurement conditions Measurement was performed according to the Japanese Pharmacopoeia, general test method, and infrared absorption spectrum total reflection measurement method (ATR method).
　次に、本発明化合物の有用性を明らかにするため、純度試験及び吸湿性試験の結果を説明する。 Next, in order to clarify the usefulness of the compound of the present invention, the results of the purity test and the hygroscopicity test will be described.
（１）純度（類縁物質含量）試験
　被験物質として、α型結晶（実施例２）及び非晶質（比較例１）を用いた。
　被験物質の純度を高速液体クロマトグラフィー法により測定した（平成１３年４月４日医薬発第３４０号厚生省医薬安全局長通知）。 (1) Purity (related substance content) test α-type crystals (Example 2) and amorphous (Comparative Example 1) were used as test substances.
The purity of the test substance was measured by a high performance liquid chromatography method (Notification of the Pharmaceutical Safety Bureau, Ministry of Health and Welfare No. 340, April 4, 2001).
副成物I及び分解物I測定条件
検出器：紫外吸光光度計
測定波長：254nm
カラム：Ｄｅｖｅｌｏｓｉｌ ＯＤＳ－ＨＧ－５、内径4.6×長さ150mm
カラム温度：室温
移動相：21％アセトニトリル緩衝溶液（0.05mol/L酢酸、0.025mol/Lトリエチルアミン）
流量：1mL/分 By-product I and decomposition product I Measurement condition detector: UV absorption photometer Measurement wavelength: 254 nm
Column: Develosil ODS-HG-5, inner diameter 4.6 x length 150 mm
Column temperature: room temperature Mobile phase: 21% acetonitrile buffer solution (0.05 mol / L acetic acid, 0.025 mol / L triethylamine)
Flow rate: 1mL / min
副成物II測定条件
検出器：紫外吸光光度計
測定波長：254nm
カラム：Ｎｕｃｌｅｏｓｉｌ－５Ｃ１８、内径4.6×長さ150mm
カラム温度：室温
移動相：30％アセトニトリル緩衝溶液（0.05mol/L酢酸、0.025mol/Lトリエチルアミン）
流量：1mL/分
　結果を表１に示す。 By-product II measurement condition detector: UV absorption photometer measurement wavelength: 254nm
Column: Nucleosil-5C18, inner diameter 4.6 x length 150 mm
Column temperature: Room temperature Mobile phase: 30% acetonitrile buffer solution (0.05 mol / L acetic acid, 0.025 mol / L triethylamine)
Flow rate: 1 mL / min The results are shown in Table 1.
Figure JPOXMLDOC01-appb-T000001
Figure JPOXMLDOC01-appb-T000001
　α型結晶（実施例２）は、非晶質（比較例１）よりも類縁物質含量が少なかった。 The α-type crystal (Example 2) had a similar substance content less than the amorphous (Comparative Example 1).
（２）吸湿性試験
　被験物質として、α型結晶（実施例２）及び非晶質（比較例１）を用いた。
　被験物質を7及び22％相対湿度下、25℃で１日間放置し、日本薬局方、一般試験法、水分測定法（カール・フィッシャー法）に従って水分含量を測定し、重量変化を算出した。結果を表２に示す。 (2) Hygroscopicity test α-type crystals (Example 2) and amorphous (Comparative Example 1) were used as test substances.
The test substance was allowed to stand at 25 ° C. for 1 day under 7 and 22% relative humidity, and the water content was measured according to the Japanese Pharmacopoeia, general test method, and moisture measurement method (Karl Fischer method), and the change in weight was calculated. The results are shown in Table 2.
Figure JPOXMLDOC01-appb-T000002
Figure JPOXMLDOC01-appb-T000002
　α型結晶（実施例２）は、非晶質（比較例１）よりも重量変化率が小さかった。α型結晶は、非晶質よりも吸湿安定性に優れていた。 The α-type crystal (Example 2) had a smaller weight change rate than the amorphous (Comparative Example 1). The α-type crystal was superior in moisture absorption stability to the amorphous.
　次に、α型結晶の製造法について説明する。α型結晶は、例えば、以下の製造法で製造することができる。 Next, a method for producing an α-type crystal will be described. The α-type crystal can be produced, for example, by the following production method.
［製造法１］α型結晶の製造
　ピペラシリンナトリウムを含むＮ，Ｎ－ジメチルアセトアミド及び水の混合溶媒の溶液に、酢酸メチルを添加することによりα型結晶を製造することができる。 [Production Method 1] Production of α-type Crystals α-type crystals can be produced by adding methyl acetate to a mixed solvent solution of N, N-dimethylacetamide containing piperacillin sodium and water.
　Ｎ，Ｎ－ジメチルアセトアミド及び水の混合比は、特に限定されないが、例えば、Ｎ，Ｎ－ジメチルアセトアミドの含率が50～99（v/v）％が好ましく、60～90（v/v）％がより好ましく、70～80（v/v）％がさらに好ましい。
　Ｎ，Ｎ－ジメチルアセトアミド及び水の混合溶媒の溶媒量は、特に限定されないが、ピペラシリンナトリウムに対し、0.5～5倍量が好ましく、1～3倍量がより好ましい。
　酢酸メチルの溶媒量は、特に限定されないが、ピペラシリンナトリウムに対し、2～20倍量が好ましく、3～10倍量がより好ましい。
　酢酸メチルの含率は、特に限定されないが、50～95（v/v）％が好ましく、60～90（v/v）％がより好ましく、70～80（v/v）％がさらに好ましい。 The mixing ratio of N, N-dimethylacetamide and water is not particularly limited. For example, the content of N, N-dimethylacetamide is preferably 50 to 99 (v / v)%, and 60 to 90 (v / v). % Is more preferable, and 70 to 80 (v / v)% is more preferable.
The amount of the mixed solvent of N, N-dimethylacetamide and water is not particularly limited, but it is preferably 0.5 to 5 times, more preferably 1 to 3 times the amount of piperacillin sodium.
The solvent amount of methyl acetate is not particularly limited, but is preferably 2 to 20 times, more preferably 3 to 10 times the amount of piperacillin sodium.
The methyl acetate content is not particularly limited, but is preferably 50 to 95 (v / v)%, more preferably 60 to 90 (v / v)%, and still more preferably 70 to 80 (v / v)%.
　温度は、特に限定されないが、0～30℃が好ましく、0～10℃がより好ましい。
　この製造において、α型結晶の種晶を使用することもでき、その量は、特に限定されない。種晶を使用する場合、攪拌することが好ましい。
　この製造において、晶出に要する時間は、特に限定されないが、0.5～48時間が好ましく、1～2時間がより好ましい。 The temperature is not particularly limited, but is preferably 0 to 30 ° C, more preferably 0 to 10 ° C.
In this production, a seed crystal of α-type crystal can be used, and the amount thereof is not particularly limited. When using seed crystals, it is preferable to stir.
In this production, the time required for crystallization is not particularly limited, but is preferably 0.5 to 48 hours, more preferably 1 to 2 hours.
　次に、α型結晶からのVI型結晶の製造法について説明する。VI型結晶は、例えば、次に示す製造法により製造することができる。 Next, a method for producing a VI type crystal from an α type crystal will be described. The VI type crystal can be produced, for example, by the following production method.
［製造法２］VI型結晶の製造
　α型結晶を液化二酸化炭素または超臨界二酸化炭素に接触させることにより、VI型結晶を製造することができる。
　この製造において、温度は、20～80℃が好ましく、32～60℃がより好ましい。
　この製造において、圧力は、6MPa以上が好ましく、7.4MPa以上がより好ましく、10～20MPaがさらに好ましい。
　この製造において、反応時間は、0.5～20時間が好ましく、1～10時間がより好ましい。 [Manufacturing method 2] Manufacture of a VI type crystal A VI type crystal can be manufactured by contacting an α type crystal with liquefied carbon dioxide or supercritical carbon dioxide.
In this production, the temperature is preferably 20 to 80 ° C, more preferably 32 to 60 ° C.
In this production, the pressure is preferably 6 MPa or more, more preferably 7.4 MPa or more, and further preferably 10 to 20 MPa.
In this production, the reaction time is preferably 0.5 to 20 hours, more preferably 1 to 10 hours.
　α型結晶からのVI型結晶の製造法は、残留溶媒の除去の点で極めて優れている。すなわち、α型結晶を用いる製造法は、III型結晶を用いる製造法（特許文献３の実施例２及び実施例３など）に比べ、低い二酸化炭素の圧力で、残留溶媒の少ないVI型結晶を得ることができ、優れている。
　例えば、α型結晶からVI型結晶を製造した場合は、圧力10MPaで残留溶媒が少なく純度の高い結晶が得られた（実施例３）。一方、III型結晶からVI型結晶を製造した場合は、圧力20MPaでも残留溶媒が十分に除去されなかった（参考例３）。すなわち、VI型結晶の製造時にα型結晶を使用することにより、III型結晶を使用する場合に比べ、製造時の二酸化炭素の圧力を格段に低減することが可能である。
　加えて、α型結晶の濾過性は、III型結晶より優れ、α型結晶を用いることによって、製造に要する時間を短縮することができる。 The production method of the VI type crystal from the α type crystal is extremely excellent in terms of removing the residual solvent. That is, the production method using the α-type crystal is less than the production method using the III-type crystal (Example 2 and Example 3 of Patent Document 3) and produces a VI-type crystal with less residual solvent at a low carbon dioxide pressure. Can get and is excellent.
For example, when a VI-type crystal was produced from an α-type crystal, a high-purity crystal with little residual solvent was obtained at a pressure of 10 MPa (Example 3). On the other hand, when the VI type crystal was produced from the III type crystal, the residual solvent was not sufficiently removed even at a pressure of 20 MPa (Reference Example 3). That is, by using the α-type crystal at the time of manufacturing the VI-type crystal, it is possible to significantly reduce the pressure of carbon dioxide at the time of manufacture compared to the case of using the III-type crystal.
In addition, the filterability of α-type crystals is superior to that of III-type crystals, and the time required for production can be shortened by using α-type crystals.
　本発明のピペラシリンナトリウム・１水和物の結晶は、常法にしたがって、注射剤にすることができる。さらに、本発明の結晶は、公知のβ－ラクタマーゼ阻害剤、例えば、クラブラン酸、スルバクタム及び／又はタゾバクタム等と配合して、配合剤とすることもできる。好ましいβ－ラクタマーゼ阻害剤としては、タゾバクタムが挙げられる。ピペラシリンナトリウム・１水和物の結晶とタゾバクタムとの配合比は、特に限定されないが、力価の比としては、タゾバクタム１に対し、ピペラシリンナトリウム・１水和物４～８が好ましい。 The crystals of piperacillin sodium monohydrate of the present invention can be made into an injection according to a conventional method. Furthermore, the crystal of the present invention can be blended with a known β-lactamase inhibitor, for example, clavulanic acid, sulbactam and / or tazobactam, to prepare a compounding agent. A preferred β-lactamase inhibitor includes tazobactam. The compounding ratio of the crystals of piperacillin sodium monohydrate and tazobactam is not particularly limited, but the ratio of titers is preferably piperacillin sodium monohydrate 4-8 relative to tazobactam 1.
　以下、代表的な実施例を挙げて本発明を具体的に説明するが、これらの実施例は、本発明を何ら制限するものではない。 Hereinafter, the present invention will be specifically described with reference to representative examples. However, these examples do not limit the present invention in any way.
実施例１（α型結晶）
　ピペラシリンナトリウム1.0gを酢酸メチル5.0mL、Ｎ，Ｎ－ジメチルアセトアミド1.7mL及び水0.2mLの混合液に加えた。次いで5℃で2日間静置した。結晶を濾取し、酢酸メチル5.0mL、Ｎ，Ｎ－ジメチルアセトアミド0.8mL及び水0.3mLの混合液、並びに、酢酸メチル9.8mL及び水0.2mLの混合液で順次洗浄し、α型結晶0.5gを得た。これをα型結晶の種晶とした。
含水率：3.2％
ＩＲ（ＡＴＲ）1771, 1715cm-1
粉末Ｘ線回折のパターンは、実施例２と一致した。 Example 1 (α-type crystal)
Piperacillin sodium 1.0 g was added to a mixture of 5.0 mL methyl acetate, 1.7 mL N, N-dimethylacetamide and 0.2 mL water. Subsequently, it left still at 5 degreeC for 2 days. The crystals were collected by filtration, washed successively with a mixed solution of 5.0 mL of methyl acetate, 0.8 mL of N, N-dimethylacetamide and 0.3 mL of water, and a mixed solution of 9.8 mL of methyl acetate and 0.2 mL of water to obtain 0.5 g of α-type crystals. Got. This was used as a seed crystal of α-type crystal.
Moisture content: 3.2%
IR (ATR) 1771, 1715cm -1
The powder X-ray diffraction pattern was consistent with Example 2.
実施例２（α型結晶）
　ピペラシリンナトリウム20gをＮ，Ｎ－ジメチルアセトアミド28mL及び水8.0mLの混合液に加えた。不溶物を濾去した後、酢酸メチル90mLを滴下し、次いでα型結晶の種晶を添加し、5℃で1時間撹拌した。次いで酢酸メチル10mLを滴下し、5℃で1時間撹拌した。さらに酢酸メチル20mLを1時間で滴下し、5℃で1時間撹拌した。結晶を濾取し、酢酸メチル196mL及び水4.0mLの混合液で洗浄し、α型結晶19gを得た。
含水率：3.2％
ＩＲ（ＡＴＲ）1774, 1715cm-1
　走査型電子顕微鏡写真を図１、粉末Ｘ線回折のパターンを図３、赤外吸収スペクトル（ＡＴＲ法）を図６に示す。 Example 2 (α-type crystal)
Piperacillin sodium (20 g) was added to a mixture of 28 mL of N, N-dimethylacetamide and 8.0 mL of water. After insoluble matter was removed by filtration, 90 mL of methyl acetate was added dropwise, then seed crystals of α-type crystals were added, and the mixture was stirred at 5 ° C. for 1 hour. Next, 10 mL of methyl acetate was added dropwise, and the mixture was stirred at 5 ° C. for 1 hour. Further, 20 mL of methyl acetate was added dropwise over 1 hour, followed by stirring at 5 ° C. for 1 hour. The crystals were collected by filtration and washed with a mixed solution of 196 mL of methyl acetate and 4.0 mL of water to obtain 19 g of α-type crystals.
Moisture content: 3.2%
IR (ATR) 1774, 1715cm -1
FIG. 1 shows a scanning electron micrograph, FIG. 3 shows a powder X-ray diffraction pattern, and FIG. 6 shows an infrared absorption spectrum (ATR method).
実施例３（VI型結晶）
　フィルター付き圧力容器（内径68mm、長さ180mm）にα型結晶40gを入れ、40℃、10MPaで二酸化炭素を5時間導入（流速2.7kg/h）した。脱圧し、VI型結晶36gを得た。
含水率：3.1％
ＩＲ（ＡＴＲ）1772, 1716cm-1
　粉末Ｘ線回折のパターンを図４、赤外吸収スペクトル（ＡＴＲ法）を図７に示す。
　得られた結晶の残留溶媒量をガスクロマトグラフィーで測定したところ、酢酸メチル41ppmを検出した。 Example 3 (VI type crystal)
An α-type crystal (40 g) was placed in a pressure vessel with a filter (inner diameter: 68 mm, length: 180 mm), and carbon dioxide was introduced at 40 ° C. and 10 MPa for 5 hours (flow rate: 2.7 kg / h). The pressure was released to obtain 36 g of a VI type crystal.
Moisture content: 3.1%
IR (ATR) 1772, 1716cm -1
The powder X-ray diffraction pattern is shown in FIG. 4, and the infrared absorption spectrum (ATR method) is shown in FIG.
When the amount of residual solvent of the obtained crystal was measured by gas chromatography, 41 ppm of methyl acetate was detected.
実施例４（VI型結晶）
　フィルター付き圧力容器（内径32mm、長さ37mm）にα型結晶2.0gを入れ、24℃、10MPaで二酸化炭素を3時間導入（流速48g/h）した。脱圧し、VI型結晶1.8gを得た。
含水率：3.2％
ＩＲ（ＡＴＲ）1770, 1716cm-1
粉末Ｘ線回折のパターンは、実施例３と一致した。 Example 4 (VI type crystal)
In a pressure vessel with a filter (inner diameter: 32 mm, length: 37 mm), 2.0 g of α-type crystal was put, and carbon dioxide was introduced at 24 ° C. and 10 MPa for 3 hours (flow rate: 48 g / h). The pressure was released to obtain 1.8 g of type VI crystals.
Moisture content: 3.2%
IR (ATR) 1770, 1716cm -1
The powder X-ray diffraction pattern was consistent with Example 3.
比較例１（非晶質）
　ピペラシリン・１水和物90gを水180mLに加えた。炭酸水素ナトリウム14gを6～10℃で2時間で添加した。不溶物を濾去した後、凍結乾燥し、非晶質89gを得た。
含水率：0.5％
ＩＲ（ＡＴＲ）1765, 1713cm-1
　走査型電子顕微鏡写真を図２、粉末Ｘ線回折のパターンを図５、赤外吸収スペクトル（ＡＴＲ法）を図８に示す。 Comparative Example 1 (Amorphous)
Piperacillin monohydrate 90 g was added to water 180 mL. 14 g of sodium bicarbonate was added at 6-10 ° C. over 2 hours. Insoluble matter was removed by filtration and then lyophilized to obtain 89 g of amorphous substance.
Moisture content: 0.5%
IR (ATR) 1765, 1713cm -1
FIG. 2 shows a scanning electron micrograph, FIG. 5 shows a pattern of powder X-ray diffraction, and FIG. 8 shows an infrared absorption spectrum (ATR method).
参考例１（III型結晶：特許文献２の実施例１）
　ピペラシリンナトリウム2.0gを２－ブタノン2mL、Ｎ，Ｎ－ジメチルホルムアミド3.8mL及び水0.6mLの混合液に加え、２－ブタノン10mLを滴下した。不溶物を濾去した後、5℃で24時間静置した。結晶を濾取し、２－ブタノン3mL、Ｎ，Ｎ－ジメチルホルムアミド0.9mL及び水0.1mLの混合液、２－ブタノン6mL、99％アセトン6mLで洗浄し、ピペラシリンナトリウム・１水和物の結晶（III型結晶）1.7gを得た。これをIII型結晶の種晶とした。 Reference Example 1 (Type III crystal: Example 1 of Patent Document 2)
Piperacillin sodium (2.0 g) was added to a mixed solution of 2-butanone (2 mL), N, N-dimethylformamide (3.8 mL) and water (0.6 mL), and 2-butanone (10 mL) was added dropwise. The insoluble material was removed by filtration, and then allowed to stand at 5 ° C. for 24 hours. The crystals were collected by filtration, washed with a mixed solution of 2-butanone 3 mL, N, N-dimethylformamide 0.9 mL and water 0.1 mL, 2-butanone 6 mL, 99% acetone 6 mL, and piperacillin sodium monohydrate crystals ( 1.7 g of type III crystal was obtained. This was used as a seed crystal of type III crystal.
参考例２（III型結晶：特許文献２の実施例２）
　ピペラシリン・１水和物20gを２－ブタノン20mL、Ｎ，Ｎ－ジメチルホルムアミド28mL及び水6mLの混合液に加えた。10～20℃で２－エチルヘキサン酸ナトリウム6.4gを添加し、２－ブタノン100mLを滴下した。不溶物を濾去した後、III型結晶の種晶を添加し、15～20℃で1時間、次いで5℃で3時間撹拌した。結晶を濾取し、２－ブタノン31mL、Ｎ，Ｎ－ジメチルホルムアミド7.2mL及び水1.6mLの混合液、２－ブタノン60mL、99％アセトン60mLで洗浄し、ピペラシリンナトリウム・１水和物の結晶（III型結晶）18gを得た。 Reference Example 2 (Type III crystal: Example 2 of Patent Document 2)
Piperacillin monohydrate (20 g) was added to a mixture of 20 mL of 2-butanone, 28 mL of N, N-dimethylformamide and 6 mL of water. 6.4 g of sodium 2-ethylhexanoate was added at 10 to 20 ° C., and 100 mL of 2-butanone was added dropwise. The insoluble material was removed by filtration, and seed crystals of type III crystals were added, followed by stirring at 15 to 20 ° C. for 1 hour and then at 5 ° C. for 3 hours. The crystals were collected by filtration, washed with a mixed solution of 31 mL of 2-butanone, 7.2 mL of N, N-dimethylformamide and 1.6 mL of water, 60 mL of 2-butanone and 60 mL of 99% acetone, and crystals of piperacillin sodium monohydrate ( 18 g of type III crystal) was obtained.
参考例３（VI型結晶）
　参考例２と同様にして得られたIII型結晶100gをフィルター付き圧力容器（内径68mm、長さ180mm）に入れ、40℃、20MPaで二酸化炭素を5時間導入（流速1.9kg/h）した。脱圧し、VI型結晶95gを得た。
含水率：3.8％
　1H-NMRスペクトルを測定した結果、得られた結晶は、Ｎ，Ｎ－ジメチルホルムアミド6600ppmを含有した。 Reference Example 3 (Type VI crystal)
100 g of type III crystal obtained in the same manner as in Reference Example 2 was placed in a pressure vessel with a filter (inner diameter 68 mm, length 180 mm), and carbon dioxide was introduced at 40 ° C. and 20 MPa for 5 hours (flow rate 1.9 kg / h). The pressure was released to obtain 95 g of a VI type crystal.
Moisture content: 3.8%
As a result of measuring 1 H-NMR spectrum, the obtained crystal contained 6600 ppm of N, N-dimethylformamide.
参考例４
　ピペラシリンナトリウム1.0gをＮ，Ｎ－ジメチルアセトアミド1.7mL及び水0.2mLの混合液に加えた。不溶物を濾去した後、酢酸エチル5.0mLを添加し、5℃で48時間静置した。結晶は得られなかった。 Reference example 4
Piperacillin sodium 1.0 g was added to a mixture of 1.7 mL N, N-dimethylacetamide and 0.2 mL water. Insoluble material was removed by filtration, 5.0 mL of ethyl acetate was added, and the mixture was allowed to stand at 5 ° C. for 48 hours. Crystals were not obtained.
参考例５～１１
　参考例４と同様にしてＮ，Ｎ－ジメチルアセトアミド及び水の混合溶液に表３に記載の溶媒を添加したが、結晶は得られなかった。 Reference Examples 5 to 11
In the same manner as in Reference Example 4, the solvents listed in Table 3 were added to a mixed solution of N, N-dimethylacetamide and water, but no crystals were obtained.
Figure JPOXMLDOC01-appb-T000003
Figure JPOXMLDOC01-appb-T000003
参考例１２（VI型結晶：特許文献３の実施例２）
　フィルター付き圧力容器（内径68mm、長さ180mm）にIII型結晶200gを入れ、40℃、40MPaで二酸化炭素を4時間導入（流速2.4kg/h）した。脱圧し、VI型結晶200gを得た。 Reference Example 12 (VI type crystal: Example 2 of Patent Document 3)
200 g of type III crystal was placed in a pressure vessel with a filter (inner diameter 68 mm, length 180 mm), and carbon dioxide was introduced at 40 ° C. and 40 MPa for 4 hours (flow rate 2.4 kg / h). The pressure was released to obtain 200 g of a VI type crystal.
α型結晶の走査型電子顕微鏡写真（倍率500倍）である。2 is a scanning electron micrograph (magnification 500 times) of an α-type crystal. 非晶質の走査型電子顕微鏡写真（倍率200倍）である。It is an amorphous scanning electron micrograph (magnification 200 times). α型結晶の粉末Ｘ線回折パターンである。It is a powder X-ray diffraction pattern of α-type crystal. VI型結晶の粉末Ｘ線回折パターンである。It is a powder X-ray diffraction pattern of a VI type crystal. 非晶質の粉末Ｘ線回折パターンである。It is an amorphous powder X-ray diffraction pattern. α型結晶の赤外吸収スペクトル（ＡＴＲ法）である。It is an infrared absorption spectrum (ATR method) of an α-type crystal. VI型結晶の赤外吸収スペクトル（ＡＴＲ法）である。It is an infrared absorption spectrum (ATR method) of a VI type crystal. 非晶質の赤外吸収スペクトル（ＡＴＲ法）である。It is an amorphous infrared absorption spectrum (ATR method).
　本発明のピペラシリンナトリウム・１水和物の新規な結晶は、濾過及び乾燥が容易で類縁物質含量が少なく、高純度であり、吸湿安定性に優れ、医薬の原薬及びその製造中間体として有用である。 The novel crystals of piperacillin sodium monohydrate of the present invention are easy to filter and dry, have a low content of related substances, have high purity, are excellent in moisture absorption stability, and are useful as pharmaceutical active ingredients and production intermediates thereof. It is.

Claims (3)

  1. 粉末Ｘ線回折において、２θで表される6.6、10.9、14.6、17.0、18.2、19.8及び24.9°の回折角度を有する（２Ｓ，５Ｒ，６Ｒ）－６－（（２Ｒ）－２－（（４－エチル－２，３－ジオキソピペラジン－１－カルボニル）アミノ）－２－フェニルアセチルアミノ）－３，３－ジメチル－７－オキソ－４－チア－１－アザビシクロ［３．２．０］ヘプタン－２－カルボン酸ナトリウム・１水和物の結晶。 In powder X-ray diffraction, diffraction angles of 6.6, 10.9, 14.6, 17.0, 18.2, 19.8 and 24.9 ° represented by 2θ are (2S, 5R, 6R) -6-((2R) -2-((4 -Ethyl-2,3-dioxopiperazine-1-carbonyl) amino) -2-phenylacetylamino) -3,3-dimethyl-7-oxo-4-thia-1-azabicyclo [3.2.0] heptane -Crystal of sodium 2-carboxylate monohydrate.
  2. 粉末Ｘ線回折において、２θで表される6.6、10.9、14.6、17.0、18.2、19.8及び24.9°の回折角度を有する（２Ｓ，５Ｒ，６Ｒ）－６－（（２Ｒ）－２－（（４－エチル－２，３－ジオキソピペラジン－１－カルボニル）アミノ）－２－フェニルアセチルアミノ）－３，３－ジメチル－７－オキソ－４－チア－１－アザビシクロ［３．２．０］ヘプタン－２－カルボン酸ナトリウム・１水和物の結晶を、超臨界二酸化炭素に接触させることを特徴とする、粉末Ｘ線回折において、２θで表される5.6、7.8、12.3、15.5、17.5、23.3、24.8及び28.5°の回折角度を有する（２Ｓ，５Ｒ，６Ｒ）－６－（（２Ｒ）－２－（（４－エチル－２，３－ジオキソピペラジン－１－カルボニル）アミノ）－２－フェニルアセチルアミノ）－３，３－ジメチル－７－オキソ－４－チア－１－アザビシクロ［３．２．０］ヘプタン－２－カルボン酸ナトリウム・１水和物の結晶の製造法。 In powder X-ray diffraction, diffraction angles of 6.6, 10.9, 14.6, 17.0, 18.2, 19.8 and 24.9 ° represented by 2θ are (2S, 5R, 6R) -6-((2R) -2-((4 -Ethyl-2,3-dioxopiperazine-1-carbonyl) amino) -2-phenylacetylamino) -3,3-dimethyl-7-oxo-4-thia-1-azabicyclo [3.2.0] heptane 5.6, 7.8, 12.3, 15.5, 17.5, 23.3 represented by 2θ in powder X-ray diffraction, characterized by contacting crystals of sodium 2-carboxylate monohydrate with supercritical carbon dioxide (2S, 5R, 6R) -6-((2R) -2-((4-ethyl-2,3-dioxopiperazine-1-carbonyl) amino) -2- with diffraction angles of 24.8 and 28.5 ° Phenylacetylamino) -3,3-dimethyl-7-oxo-4- A 1-azabicyclo [3.2.0] preparation of crystals of heptane-2-carboxylate monohydrate.
  3. （２Ｓ，５Ｒ，６Ｒ）－６－（（２Ｒ）－２－（（４－エチル－２，３－ジオキソピペラジン－１－カルボニル）アミノ）－２－フェニルアセチルアミノ）－３，３－ジメチル－７－オキソ－４－チア－１－アザビシクロ［３．２．０］ヘプタン－２－カルボン酸ナトリウムを含むＮ，Ｎ－ジメチルアセトアミド及び水の混合溶媒の溶液に、酢酸メチルを添加することを特徴とする、粉末Ｘ線回折において、２θで表される6.6、10.9、14.6、17.0、18.2、19.8及び24.9°の回折角度を有する（２Ｓ，５Ｒ，６Ｒ）－６－（（２Ｒ）－２－（（４－エチル－２，３－ジオキソピペラジン－１－カルボニル）アミノ）－２－フェニルアセチルアミノ）－３，３－ジメチル－７－オキソ－４－チア－１－アザビシクロ［３．２．０］ヘプタン－２－カルボン酸ナトリウム・１水和物の結晶の製造法。 (2S, 5R, 6R) -6-((2R) -2-((4-ethyl-2,3-dioxopiperazine-1-carbonyl) amino) -2-phenylacetylamino) -3,3-dimethyl Adding methyl acetate to a solution of a mixed solvent of N, N-dimethylacetamide and water containing sodium -7-oxo-4-thia-1-azabicyclo [3.2.0] heptane-2-carboxylate; In powder X-ray diffraction characterized by (2S, 5R, 6R) -6-((2R) -2 having diffraction angles of 6.6, 10.9, 14.6, 17.0, 18.2, 19.8 and 24.9 ° represented by 2θ -((4-Ethyl-2,3-dioxopiperazine-1-carbonyl) amino) -2-phenylacetylamino) -3,3-dimethyl-7-oxo-4-thia-1-azabicyclo [3.2 .0] Heptane-2-carboxylic acid A method for producing sodium monohydrate crystals.
PCT/JP2010/066766 2009-09-30 2010-09-28 Novel crystal of piperacillin sodium monohydrate WO2011040386A1 (en)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030028016A1 (en) * 2001-08-03 2003-02-06 Alberto Brandt Process for the preparation of the sodium salt of 6[D-(-)alpha-4-(ethyl-2,3-dioxo-1-piperazinocarbonylamino) phenylacetamido]penicillanic acid
JP2007099763A (en) * 2005-09-08 2007-04-19 Toyama Chem Co Ltd New crystal of piperacillin sodium-1 hydrate and method for producing the same
JP2007246514A (en) * 2006-02-14 2007-09-27 Toyama Chem Co Ltd Novel crystal of piperacillin sodium
WO2008093650A1 (en) * 2007-01-31 2008-08-07 Toyama Chemical Co., Ltd. Novel crystal of piperacillin sodium

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030028016A1 (en) * 2001-08-03 2003-02-06 Alberto Brandt Process for the preparation of the sodium salt of 6[D-(-)alpha-4-(ethyl-2,3-dioxo-1-piperazinocarbonylamino) phenylacetamido]penicillanic acid
JP2007099763A (en) * 2005-09-08 2007-04-19 Toyama Chem Co Ltd New crystal of piperacillin sodium-1 hydrate and method for producing the same
JP2007246514A (en) * 2006-02-14 2007-09-27 Toyama Chem Co Ltd Novel crystal of piperacillin sodium
WO2008093650A1 (en) * 2007-01-31 2008-08-07 Toyama Chemical Co., Ltd. Novel crystal of piperacillin sodium

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