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WO2020100911A1 - Procédé de production d'hydrate de citrate ferrique - Google Patents

Procédé de production d'hydrate de citrate ferrique Download PDF

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Publication number
WO2020100911A1
WO2020100911A1 PCT/JP2019/044384 JP2019044384W WO2020100911A1 WO 2020100911 A1 WO2020100911 A1 WO 2020100911A1 JP 2019044384 W JP2019044384 W JP 2019044384W WO 2020100911 A1 WO2020100911 A1 WO 2020100911A1
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Prior art keywords
ferric citrate
water
ferric
citric acid
organic solvent
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PCT/JP2019/044384
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English (en)
Japanese (ja)
Inventor
隆行 宮奥
康平 齋藤
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Tokuyama Corp
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Tokuyama Corp
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Priority to CN201980070605.9A priority Critical patent/CN112969456B/zh
Priority to JP2020556122A priority patent/JP7335268B2/ja
Publication of WO2020100911A1 publication Critical patent/WO2020100911A1/fr
Anticipated expiration legal-status Critical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/41—Preparation of salts of carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/235—Saturated compounds containing more than one carboxyl group
    • C07C59/245—Saturated compounds containing more than one carboxyl group containing hydroxy or O-metal groups
    • C07C59/265—Citric acid
    • 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
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/194—Carboxylic acids, e.g. valproic acid having two or more carboxyl groups, e.g. succinic, maleic or phthalic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
    • C07F15/02—Iron compounds

Definitions

  • the present invention relates to a novel method for producing ferric citrate hydrate.
  • Ferric citrate is a compound containing ferric iron that is trivalent iron and a molecular structure derived from citric acid, and the molar ratio of the molecular structure derived from citric acid to ferric iron has a constant value. It is said that it will not be taken. It is also called ferric citrate hydrate because it contains a certain amount of water. It is known that the ferric citrate hydrate can be suitably used as a therapeutic agent for hyperphosphatemia in renal failure patients, in addition to reagents and food additives. Such ferric citrate hydrate for pharmaceutical use preferably has a large BET specific surface area and excellent solubility as compared with ferric citrate for food additive use. It is known that the specific surface area is preferably 16 m 2 / g or more. (See Patent Document 1 or 2).
  • ferric citrate hydrate having a BET specific surface area of 16 m 2 / g or more
  • a base such as sodium hydroxide
  • ferric hydroxide is reacted with a base such as sodium hydroxide
  • Obtaining ferric hydroxide then reacting ferric hydroxide with citric acid in water to obtain a solution containing ferric citrate, and dropping the solution into a water-soluble organic solvent such as acetone
  • a method for producing ferric citrate hydrate by depositing it as a solid is disclosed.
  • Patent Document 3 as a method for producing ferric citrate hydrate having excellent solubility, after ferric citrate is dissolved in water, an organic solvent is added to the solution to prepare ferric citrate. A method of depositing iron hydrate as a solid is disclosed.
  • ferric citrate hydrate is known to cause ulcerative gastrointestinal side effects, and in order to reduce the occurrence of side effects, the dose of ferric citrate hydrate should be reduced. It is necessary to further improve the BET specific surface area in order to improve the dissolution rate and solubility in blood.
  • the production methods of Patent Documents 1 and 2 can produce ferric citrate hydrate having a BET specific surface area of 16 m 2 / g or more, but the BET specific surface area is about 45 m 2 / g at the maximum. Yes, it is not possible to produce ferric citrate hydrate with a larger BET specific surface area.
  • Patent Document 3 the production method of Patent Document 3 is difficult to dissolve ferric citrate, which is a raw material, in water.
  • the ferric acid citrate is not completely dissolved, the production yield of the ferric citrate hydrate to be produced is low, and the BET specific surface area of the ferric citrate hydrate is described in Patent Documents 1 and 2.
  • the above dissolution operation was carried out at a high temperature, all the raw materials were dissolved, and the production yield and BET specific surface area were improved, but a decrease in purity was observed due to the decomposition of ferric citrate and / or citric acid. ..
  • an object of the present invention is to provide a production method for efficiently obtaining ferric citrate hydrate having high purity and various BET specific surface areas regardless of the raw materials used.
  • ferric citrate which is a raw material when the BET specific surface area of the ferric citrate hydrate produced is reduced
  • the ferric citrate contains elements other than iron, hydrogen, carbon, and oxygen, which are the constituent elements of ferric citrate, such as magnesium (Mg), calcium (Ca), and silicon (Si).
  • Mg magnesium
  • Ca calcium
  • Si silicon
  • ferric citrate containing such an element was used as a raw material
  • a method for increasing the BET specific surface area of the ferric citrate hydrate produced was earnestly studied, and it was found that When contacting a solution in which ferric chloride and ferric citrate are dissolved and a water-soluble organic solvent, by containing ferric chloride in the solution of ferric citrate, in the raw material It was found that a ferric citrate hydrate having a high BET specific surface area can be obtained regardless of the type and amount of the above-mentioned elements contained. Furthermore, they have found that the BET specific surface area can be adjusted to an arbitrary value by adjusting the amount of ferric chloride contained in the ferric citrate solution, and have completed the present invention.
  • the present invention comprises a modified ferric citrate hydrate including a step 2 of contacting a solution containing water, ferric chloride and a raw material ferric citrate with a water-soluble organic solvent. It is a method of manufacturing a product.
  • the present invention can preferably adopt the following aspects. 1)
  • the solution contains citric acid.
  • the water-soluble organic solvent is a solvent containing at least ketones or alcohols. 3) Using 5 to 40 g (5 to 40 parts by mass) of ferric chloride with respect to 100 g (100 parts by mass) of the anhydrous ferric citrate equivalent to the raw material.
  • the method further comprises a step 1 of preparing the raw material ferric citrate by mixing the mixture with an organic solvent. 5) In the step 1, the amount of the water is 2.0 to 8.5 mL with respect to 1 g of the citric acid. 6) In the step 1, the ferric chloride is 1.0 to 2.5 equivalents with respect to the citric acid.
  • ferric citrate hydrate having a large BET specific surface area of 10 m 2 / g or more can be obtained.
  • the ferric citrate as a raw material may contain elements such as magnesium and calcium depending on the production method, but the ferric citrate stably has a large BET specific surface area regardless of the kind and amount of these elements.
  • a hydrate can be obtained.
  • the BET specific surface area can be arbitrarily adjusted by adjusting the amount of ferric chloride, and a ferric citrate hydrate having a maximum BET specific surface area of 165 m 2 / g is obtained. You can also Further, the obtained ferric citrate hydrate contains almost no impurities, has high purity, and is expected to be suitably used for pharmaceutical applications.
  • the BET specific surface area of the modified ferric citrate hydrate and 100 parts by mass of ferric chloride with respect to 100 g (100 parts by mass) of anhydrous ferric citrate as a raw material It is a graph which shows the relationship with. 13 is an X-ray diffraction chart of ferric citrate hydrate obtained in Example 13. 9 is an X-ray diffraction chart of ferric citrate hydrate obtained in Comparative Example 8. 11 is an X-ray diffraction chart of ferric citrate hydrate obtained in Comparative Example 9.
  • the present invention comprises a modified ferric citrate hydrate, which comprises a step 2 of contacting a solution containing water, ferric chloride and the raw material ferric citrate with a water-soluble organic solvent. It is a manufacturing method.
  • the raw material ferric citrate or a hydrate thereof is hereinafter referred to as "raw material ferric citrate", which is obtained by bringing the solution and the water-soluble organic solvent into contact with each other.
  • Ferric citrate hydrate is also referred to as "modified form”. The manufacturing method of the present invention will be described in detail below.
  • Step 2 is a step of contacting a solution containing water, ferric chloride and raw material ferric citrate with a water-soluble organic solvent.
  • step 2 will be described.
  • ferric citrate as a raw material to be dissolved in the solution is not particularly limited, and is commercially available as a reagent or food additive, prepared by step 1 described below, or known. What was manufactured by the method of can be used. Examples of known methods include the methods described in Patent Documents 1 and 2. Specifically, ferric chloride hexahydrate is first dissolved in water and then hydrolyzed with sodium hydroxide to obtain ferric hydroxide. Ferric citrate is produced by reacting the obtained ferric hydroxide with citric acid in water. Ferric citrate as a raw material can be produced by precipitating ferric citrate using an organic solvent, and then separating and drying the solution containing the ferric citrate.
  • the quality of commercially available ferric citrate usually has a BET specific surface area of about 0.2 to 3 m 2 / g.
  • the purity by high performance liquid chromatography (HPLC) is about 60.0 to 75.0%, aconitic acid is 25.0 to 35.0%, citraconic acid is 0.2 to 3.0%, and itaconic acid is About 0.1 to 1.0% is included.
  • the ferric citrate which is a raw material produced by the known methods described in Patent Documents 1 and 2, has a BET specific surface area of about 16 to 45 m 2 / g.
  • the purity by high performance liquid chromatography is about 90.0 to 98.5%, aconitic acid is 0.5 to 5.0%, citraconic acid is 0.05 to 2.0%, and itaconic acid is About 0.1 to 2.0% is included.
  • ferric citrate water improved to a purity acceptable for use as a drug substance It is possible to produce Japanese products.
  • ferric citrate as a raw material having a purity of about 90.0 to 98.5% by HPLC from the viewpoint that a highly pure ferric citrate hydrate can be obtained. It is more preferable to use the prepared raw material ferric citrate.
  • ferric citrate as a raw material may contain elements such as sodium, magnesium, calcium and silicon in addition to iron, hydrogen, carbon and oxygen which are the constituent elements of ferric citrate.
  • commercially available ferric citrate for food additive use includes those containing 0.6% by mass of magnesium and 0.5% by mass of calcium, and those containing 0.4% by mass of silicon.
  • a modified product having a large BET specific surface area can be obtained even when ferric citrate containing many elements other than the constituent elements is used as a raw material. It is preferable that the content of the element contained in is small, and at least the content of magnesium in ferric citrate as a raw material is preferably 3.0% by mass or less.
  • Such contained elements are analyzed by inductively coupled plasma mass spectrometry (ICP-MS), inductively coupled plasma optical emission spectroscopy (ICP-OES), fluorescent X-ray (XRF), scanning electron microscope / energy dispersive X-ray spectroscopy. (SEM / EDS) and the like.
  • ICP-MS inductively coupled plasma mass spectrometry
  • ICP-OES inductively coupled plasma optical emission spectroscopy
  • XRF fluorescent X-ray
  • SEM / EDS scanning electron microscope / energy dispersive X-ray spectroscopy.
  • Water used for the solution containing ferric chloride and the raw material ferric citrate in step 2 is not particularly limited, and tap water, ion-exchanged water, distilled water, or the like can be used.
  • the amount of water used is 50 with respect to 100 g (100 parts by mass) of 100 g (100 parts by mass) of the amount converted to the anhydrous ferric citrate as a raw material (hereinafter referred to as the “anhydrous equivalent amount of ferric citrate as a raw material”) It is preferably about 500 mL (50 to 500 parts by volume).
  • the anhydrous equivalent amount of ferric citrate of the raw material from the weight of ferric citrate of the raw material, the weight obtained by subtracting the weight of water and organic solvent contained in ferric citrate of the raw material Show.
  • the amount of water and organic solvent contained in the raw material ferric citrate varies depending on the production conditions, storage conditions and the like. Therefore, in order to control the quality such as the BET specific surface area of the modified product and the production yield more highly, the amount of water contained in the ferric citrate as a raw material is determined by Karl Fischer titration (KF) or the like.
  • the amount of the organic solvent was measured using gas chromatography (GC), etc., and the amount of water used was calculated based on the anhydrous equivalent amount of ferric citrate as the raw material calculated from the amount of the water or the organic solvent. It is preferable to determine.
  • the amounts of ferric chloride, citric acid, and a water-soluble organic solvent described below are also preferably calculated based on the anhydrous equivalent amount of ferric citrate as a raw material for the same reason as above.
  • the amount of water used is 50 mL (50 parts by volume) or more per 100 g (100 parts by mass) of anhydrous ferric citrate as a raw material, ferric citrate or chloride as a starting material It is preferable in that all the ferric iron can be dissolved, the viscosity of the produced solution is low, and the handling is easy.
  • the amount is 500 mL (500 parts by volume) or less, the amount of the water-soluble organic solvent used can be further reduced in order to precipitate the modified product, and the production yield is high, which is preferable.
  • 75 to 450 mL (75 to 450 parts by volume) is preferable for 100 g (100 parts by mass) of anhydrous ferric citrate as a raw material, and 100 It is more preferably up to 400 mL (100 to 400 parts by volume).
  • the water used in step 2 may contain other solvent.
  • the other solvent include water-soluble organic solvents such as acetone.
  • the amount of the water-soluble organic solvent is preferably 50 g (50 parts by mass) or less with respect to 100 g (100 parts by mass) of a solution containing ferric chloride and ferric citrate as a raw material. In this case, the amount of water used does not include the amount of the other solvent.
  • the water-soluble organic solvent used here is used separately from the water-soluble organic solvent that is brought into contact with a solution containing ferric chloride and the raw material ferric citrate described below.
  • the amount of the water-soluble organic solvent described below that is, the amount of the water-soluble organic solvent to be contacted with the solution containing ferric chloride and the raw material ferric citrate, is actually used to precipitate ferric citrate hydrate. It is the amount used for.
  • the ferric chloride dissolved in the solution is not particularly limited, and reagents, industrial products, etc. can be used.
  • the form of the solid or solution of ferric chloride is not particularly limited, and the solid form may be dissolved in water or a water-soluble organic solvent and used as a solution.
  • ferric chloride may be in the form of a hydrate as well as an anhydride, but any form may be used.
  • the amount of water contained in them must be included in the amount of water used.
  • the amount of the water-soluble organic solvent contained therein needs to be included in the amount of the water-soluble organic solvent that may be contained in the above solution.
  • the amount of ferric chloride used may be appropriately determined according to the desired BET specific surface area of the modified body, but with respect to 100 g (100 parts by mass) of the ferric citrate as a raw material in terms of anhydride. It is preferably 2.5 to 50 g (2.5 to 50 parts by mass).
  • the BET specific surface area of the reformed product By using 2.5 g (2.5 parts by mass) or more of ferric chloride with respect to 100 g (100 parts by mass) of anhydrous ferric citrate as a raw material, the BET specific surface area of the reformed product The BET specific surface area of the obtained modified product tends to increase as the amount of use increases.
  • the amount of ferric chloride is 50 g (50 parts by mass) or less with respect to 100 g (100 parts by mass) of anhydrous ferric citrate as a raw material, ferric chloride remains in the reformed body. Without it, more accurately, the reformed body does not contain ferric chloride or the ferric chloride remaining in the reformed body is small, and a highly purified reformed body can be obtained.
  • the residual amount of ferric chloride can be measured by X-ray powder diffraction (XRD) or the like.
  • the solution containing water, ferric chloride and the raw material ferric citrate further contains citric acid, because the raw material ferric citrate is easily dissolved.
  • the molecular structure derived from ferric and citric acid in the resulting modified body when ferric citrate is Fe (C 6 H 5 O 7 ) (C 6 H 5 O 7 ) 3- ) content ratio, that is, the molar ratio of the molecular structure derived from citric acid to the ferric iron in the modified body (hereinafter, "modified iron and citric acid molecule The "molar ratio with the structure”) can be varied.
  • the molar ratio of the modified product can be set to a desired value by adjusting the amount of citric acid contained in the solution.
  • the content thereof is preferably 5 to 200 g (5 to 200 parts by mass) with respect to 100 g (100 parts by mass) of the anhydrous ferric citrate as a raw material.
  • the citric acid used is not particularly limited, and industrially available grade citric acid can be used.
  • impurities such as aconitic acid, citraconic acid, and itaconic acid contained in the modified product are impurities derived from citric acid, and from the viewpoint of obtaining a highly purified modified product, the above-mentioned impurities contained in citric acid are included.
  • the content of impurities by HPLC is preferably 0.5% or less.
  • citric acid exists in the form of anhydrate as well as the form of a monohydrate, but the form is not particularly limited, and may be in the form of a solid, for example, a solution of water or a water-soluble organic solvent. ..
  • the amount converted to the pure content of citric acid contained in each should be within the above range. Is preferable, and the amount of water contained in each is preferably included in the amount of water used. Further, also in the case of the solution form of the water-soluble organic solvent, the amount of the water-soluble organic solvent contained therein is preferably included in the amount of the water-soluble organic solvent that may be contained in the above solution.
  • molar ratio of the citric acid-derived molecular structure to ferric iron in the ferric iron citrate (hereinafter, referred to as “molar ratio of the raw material iron and citric acid molecular structure”), for example, Using ferric iron citrate as a raw material having a ferric citrate content of 15.0% and a citric acid-derived molecular structure content of 60.0%, that is, a raw material molar ratio of 1.16, When 10 g (10 parts by mass) of acid is used with respect to 100 g (100 parts by mass) of anhydride of ferric citrate as a raw material, the modified iron and The molar ratio with the citric acid molecular structure is usually about 0.90, and when 20 g (20 parts by mass) of citric acid is used, the molar ratio
  • the solution containing water, ferric chloride and the raw material ferric citrate may be prepared by dissolving ferric chloride and the raw material ferric citrate in water.
  • the preparation method is not particularly limited, but water, ferric chloride, and raw materials can be obtained by using a container made of glass, stainless steel, Teflon (registered trademark), glass lining, or the like, and further using a mechanical stirrer, a magnetic stirrer, or the like. From the viewpoint of uniformity and operability, it is preferable to mix the ferric citrate of (1) under stirring and dissolve the ferric chloride and the raw material ferric citrate in water.
  • the order of mixing water, ferric chloride and the raw material ferric citrate is not particularly limited, but it is preferable to sequentially add ferric chloride and the raw material ferric citrate to water and mix them.
  • citric acid is added to the solution, the order of mixing is not limited, but after mixing water and citric acid to form an aqueous citric acid solution, ferric chloride and the second citric acid starting material are mixed.
  • ferric chloride and the second citric acid starting material are mixed.
  • the preparation temperature of the solution depends on the manufacturing conditions such as the type of ferric citrate used as a raw material and the amount of water used, so the temperature at which ferric chloride and the ferric citrate raw material are dissolved is appropriately adjusted. It may be adjusted, but it is usually 0 to 80 ° C. However, ferric citrate and / or citric acid decomposes under high temperature, and the purity of the modified product tends to decrease, and at low temperature, the time required for dissolution tends to increase, so the preparation temperature Is preferably 5 to 70 ° C., more preferably 10 to 60 ° C.
  • the time required for dissolution may be appropriately determined by visually confirming the disappearance of ferric chloride and the raw material ferric citrate. Depending on the dissolution temperature, the amount of impurities such as aconitic acid derived from the decomposition of ferric citrate and / or citric acid tends to increase as the holding time of the dissolution liquid increases.
  • the time required for dissolution is preferably within 2 hours. Further, it is preferable that after confirming the disappearance of solids (ferric citrate, ferric chloride, citric acid as raw materials), it is promptly contacted with a water-soluble organic solvent.
  • step 2 a solution containing water, ferric chloride, and ferric citrate as a raw material prepared as described above is contacted with a water-soluble organic solvent.
  • Ferric citrate in the solution is insoluble in the water-soluble organic solvent, and thus ferric citrate hydrate is precipitated by the operation.
  • the water-soluble organic solvent in step 2 is an organic solvent that mixes with water at an arbitrary ratio. That is, it is an organic solvent having a solubility of 20 g (20 parts by mass) or more in 100 g (100 parts by mass) of water at 25 ° C.
  • the water-soluble organic solvent examples include alcohols such as methanol, ethanol, 1-propanol, 2-propanol and allyl alcohol, esters such as methyl acetate, ethers such as tetrahydrofuran and dioxane, acetone, methyl ethyl ketone and acetylacetone. , Ketones such as diacetone alcohol, and nitriles such as acetonitrile. Among these, ketones or alcohols are preferable from the viewpoint of the quality and yield of the modified product, and particularly acetone, 2-propanol, methanol or ethanol is preferable.
  • the ratio of the ketone or the alcohol in the mixed solvent is 50% by mass or more. Is preferred.
  • the amount of the water-soluble organic solvent to be used may be appropriately determined in consideration of the capacity of the production apparatus, etc., but from the viewpoint of the quality of the reformed product and the yield, the equivalent amount of ferric citrate as the anhydride is 100 g ( It may be appropriately determined within the range of 200 to 4000 mL (200 to 4000 volume parts) with respect to 100 parts by weight.
  • the amount of the water-soluble organic solvent used is 200 mL (200 parts by volume) or more, it is preferable in terms of the production yield of the modified product, solid-liquid separation property, and the like, and when it is 4000 mL (4000 parts by volume) or less, per batch It is preferable in terms of yield.
  • the amount of the water-soluble organic solvent used is 100 g (100 parts by mass) of the ferric citrate as a raw material in terms of the anhydride.
  • 300 to 3000 mL (300 to 3000 parts by volume) is preferable, 350 to 2000 mL (350 to 2000 parts by volume) is more preferable, and 350 to 1000 mL (350 to 1000 parts by volume) is the most preferable.
  • the equipment used for the contact operation between the solution containing water, ferric chloride and the raw material ferric citrate in step 2 and the water-soluble organic solvent is not particularly limited, and the equipment used for producing the solution is not limited. Can be done using. Further, the method of contacting the solution and the water-soluble organic solvent is not particularly limited, after the solution is produced, a water-soluble organic solvent may be added thereto, or in a water-soluble organic solvent, You may add the said solution.
  • the method of dropping the above-mentioned solution into the water-soluble organic solvent is preferable.
  • the dropping rate of the above-mentioned solution may be appropriately determined while confirming the working time and the degree of dispersion of the precipitated reforming substance in the solvent, but it is usually determined within the range of 5 minutes to 5 hours.
  • the temperature at the time of contact may be appropriately determined in consideration of the boiling point of the water-soluble organic solvent to be used, but if the temperature is too low, the modified body tends to agglomerate, and if it is too high, ferric citrate water is used. It is preferable to carry out the treatment in the range of ⁇ 20 to 70 ° C. because there is a concern that impurities such as aconitic acid will be produced as a by-product due to decomposition of the hydrate and / or citric acid. Considering operability such as solid-liquid separation of the precipitated ferric citrate hydrate and volatilization of the water-soluble organic solvent, the temperature is preferably -10 to 65 ° C, more preferably 0 to 60 ° C.
  • the modified product can be isolated by solid-liquid separation using vacuum filtration or pressure filtration of the suspension, solid-liquid separation using centrifugal separation, or the like to obtain a modified wet product, and drying the wet product. it can.
  • the wet body of the modified product refers to the water-containing product and the water-containing organic solvent product of the modified product obtained by the production method of the present invention, and in particular, the amount converted to the anhydride of the modified product.
  • a wet body containing 5 to 45 g (5 to 45 parts by mass) of water with respect to 100 g (100 parts by mass) of the converted anhydrous product is referred to as a low water content wet body.
  • a step of drying the low hydrous product after obtaining the low hydrous product is included.
  • the modified product obtained by the production method of the present invention is subjected to solid-liquid separation from the above suspension using vacuum filtration, pressure filtration, centrifugal separation or the like to obtain a modified wet body of ferric citrate. It is preferable to isolate the modified product by dispersing it in a water-soluble organic solvent to obtain the low-moisture-content wet body and drying it.
  • the wet body after solid-liquid separation and the low-moisture content body have hygroscopicity, and the BET specific surface area of the modified body may decrease due to dissolution of the solid surface due to an increase in water content.
  • the BET specific surface area may decrease during the drying operation depending on the conditions of the drying operation of the wet body and the low water content wet body. This phenomenon is speculated to be because the solid surface of ferric citrate hydrate is dissolved by water. Therefore, during the solid-liquid separation and the drying operation, it is preferable to suppress the mixing of water from the external atmosphere into the wet body of ferric citrate hydrate and the low water content wet body.
  • solid-liquid separation and drying operations are preferably performed under a vacuum, a dry air atmosphere, or an atmosphere of an inert gas such as nitrogen or argon.
  • an inert gas such as nitrogen or argon.
  • the wet body and the low water content wet body are washed with a water-soluble organic solvent or a mixed solvent with water, and the mother liquor as a dispersion solvent in the suspension is sufficiently removed.
  • the washing method is not particularly limited, but it may be performed by bringing the wet body and the washing liquid into contact with each other in the apparatus used for the solid-liquid separation.
  • the wet body after the solid-liquid separation and the cleaning liquid may be mixed to form a suspension, and then the solid-liquid separation may be performed again, that is, a reslurry cleaning operation may be used.
  • the amount of the solvent used for washing is 50 to 1000 g (50 to 1000 parts by mass) with respect to 100 g (100 parts by mass) of ferric citrate as a raw material, so that a sufficient cleaning effect can be obtained.
  • the high production yield of the modified product is preferable.
  • the wet body and the low water content wet body of the modified body are dried under normal pressure, reduced pressure, or aeration of an inert gas such as nitrogen or argon to obtain a modified body containing no water-soluble organic solvent. It can be isolated.
  • the drying temperature is ⁇ 80 ° C. or higher and lower than 60 ° C., and the time may be appropriately determined while checking the residual amount of the water-soluble organic solvent and the like, but it is usually 0.5 to 100 hours. Further, in the drying process, when it becomes a lump and the reduction efficiency of the water-soluble organic solvent is low, it can be dried more efficiently by making it into a powder using a hammer mill, a pin mill or the like.
  • the water-soluble organic solvent can be reduced by bringing it into contact with an atmosphere containing water.
  • the reformer may be held in the atmosphere or an atmosphere in which temperature and relative humidity are adjusted.
  • the BET specific surface area of the modified product tends to decrease when it comes into contact with water, it is dried in advance in an atmosphere not containing water to reduce the water-soluble organic solvent as much as possible. It is preferable to shorten the drying time under an atmosphere containing water.
  • the decrease width of the BET specific surface area changes depending on the temperature and the relative humidity. Therefore, considering the decrease width of the BET specific surface area, the temperature is 5 to 60 ° C. and the relative humidity is 20 to 95 RH%. Is preferred.
  • the time required for the drying may be appropriately determined while confirming the residual amount of the water-soluble organic solvent and the like as in the above, but is usually 0.5 to 100 hours.
  • modified ferric citrate hydrate having a large BET specific surface area can be produced regardless of the ferric citrate used as a raw material. Further, by adjusting the amount of ferric chloride used, modified ferric citrate hydrate having various BET specific surface areas in the range of 10 to 165 m 2 / g of BET specific surface area by nitrogen adsorption method. You can get things. As a result, it has excellent solubility in a solvent such as water. Furthermore, since the purity can be further increased as compared with ferric citrate as a raw material, it can be suitably used as a drug or a food additive.
  • Step 1 of preparing a ferric citrate hydrate used as the raw material ferric citrate will be described.
  • citric acid, ferric chloride, and hydroxide or carbonate of magnesium are mixed in water to obtain a mixture, and then the mixture is mixed with an organic solvent to prepare aqueous ferric citrate solution.
  • This is a step of preparing a Japanese product.
  • the magnesium hydroxide or carbonate is 0.30 to 0.95 equivalent to ferric chloride.
  • citric acid can be used without any particular limitation, such as reagents and industrial products. Also, the form thereof is not particularly limited, and a form such as an aqueous solution may be used in addition to the solid form. In the case of the solid form, citric acid may be in the form of hydrate as well as anhydride, but any form may be used.
  • step 1 the amount of other raw materials such as ferric chloride used is calculated based on the amount of citric acid used in step 2. Therefore, the amount of citric acid used may be appropriately determined according to the preparation scale of ferric citrate hydrate. When a hydrate, an aqueous solution, or the like is used, the amount of citric acid contained in them is converted to a pure content. When citric acid and its hydrate, aqueous solution and the like are used in combination, the sum of the amount of citric acid used and the amount of the citric acid converted to pure content is the standard. Further, the amount of water contained in the form is included in the amount of water used in the present invention.
  • the pure content of citric acid may be calculated by a known method such as high performance liquid chromatography (HPLC) or a quantification method using a titrator.
  • HPLC high performance liquid chromatography
  • KF Karl Fischer titration method
  • Citric acid may contain impurities such as aconitic acid and citraconic acid derived from the decomposition of citric acid depending on the production conditions.
  • impurities such as aconitic acid and citraconic acid derived from the decomposition of citric acid depending on the production conditions.
  • citric acid having a low content of the impurities it is preferable to use citric acid having a low content of the impurities.
  • the purity of citric acid is preferably 98.0 to 99.9%, and impurities such as aconitic acid and citraconic acid are 0.01 to 1 respectively. It is preferably 0.0%.
  • ferric chloride can be used without any particular limitation, such as reagents and industrial products.
  • the form thereof is not particularly limited, and in addition to the solid form, a form such as an aqueous solution may be used.
  • ferric chloride may be in the form of a hydrate as well as an anhydride, but any form may be used.
  • the amount of ferric chloride used is preferably 1.0 to 2.5 equivalents of ferric chloride with respect to the citric acid used in step 1. By setting it as the said range, the manufacturing yield of ferric citrate hydrate can be improved more. Furthermore, in the range, the molar ratio of the raw material iron and the citric acid molecular structure can be adjusted by the amount used. Specifically, usually, when ferric chloride is 1.0 equivalent to citric acid, the molar ratio of the obtained raw material is 0.8 to 1.1, and when it is 1.5 equivalent, it is 0.7. It is ⁇ 1.0, and when it is 2.0 equivalents, it is 0.6 to 0.9. Therefore, the amount of ferric chloride used may be appropriately determined according to the desired molar ratio of the raw materials.
  • the amount used is based on the amount converted to the pure content of ferric chloride contained therein (the amount converted to the pure content of ferric chloride). Further, the amount of water contained in the form is included in the amount of water used in step 1.
  • magnesium hydroxide or carbonate (hereinafter referred to as "magnesium hydroxide or the like") is used as a base. Specifically, magnesium hydroxide or magnesium carbonate is used. These bases may be used alone or in combination of two or more. Further, these can be used without particular limitation, such as reagents and industrial products. Among these, magnesium hydroxide is more preferable in consideration of reactivity.
  • the amount of the base used is 0.30 to 0.95 equivalent to the ferric chloride used in Step 1, that is, 0.30 to 2.38 equivalent to the citric acid used in Step 1.
  • the BET specific surface area of ferric citrate hydrate can be 16 m ⁇ 2 > / g or more. Within this range, the BET specific surface area of ferric citrate hydrate tends to increase as the amount of base used decreases. On the other hand, as the amount of the base used increases, the production yield of ferric citrate hydrate tends to increase. Therefore, the amount of the base used may be appropriately determined within the above range according to the desired BET specific surface area and the like.
  • the amount of the base used is 1 More preferably 0.40 to 0.90 equivalents to ferric chloride, that is, 0.40 to 2.25 equivalents to the citric acid used in step 1, 0.50 to 0.85 equivalents, 0.50 to 2.13 equivalents relative to the citric acid used in step 1 are more preferable.
  • step 1 the water is not particularly limited, and tap water, ion-exchanged water, distilled water or the like can be used.
  • the amount of water used in step 1 is preferably 2.0 to 8.5 mL with respect to 1 g of citric acid used in step 1.
  • the generated by-product salt can be sufficiently removed, and the by-product salt in the ferric citrate hydrate produced. The remaining amount of can be reduced.
  • the amount of ferric citrate hydrate dissolved in the mother liquor (dispersion solvent in the suspension containing ferric citrate hydrate described below) It is possible to reduce and increase the production yield of ferric citrate hydrate.
  • 2.5 to 7.5 mL is more preferable, and 3.0 to 6.5 mL per 1 g of citric acid used in Step 1. More preferable.
  • the ferric citrate hydrate obtained when using less than 2.5 mL of water tends to be granular, but when it is 2.5 mL or more, the obtained ferric citrate becomes powdery. Tend to be.
  • the incorporation of the by-product salt into the ferric citrate hydrate is reduced, and the residual amount of the by-product salt can be more highly reduced.
  • the amount of water contained in the form is included in the amount of water used in step 1.
  • step 1 citric acid, ferric chloride, and hydroxide of magnesium are mixed in water to obtain a mixture.
  • the mixing operation is not particularly limited and may be carried out by a known method, but a container made of glass, stainless steel, Teflon (registered trademark), glass lining or the like is used, and further, a mechanical stirrer, a magnetic stirrer or the like is used. It is preferable to mix each raw material with stirring from the viewpoint of uniformity and operability.
  • the mixing order of each raw material is not particularly limited, but when only other raw materials except for citric acid are mixed, ferric hydroxide is once precipitated in the system.
  • ferric hydroxide may be converted into other iron compounds such as ⁇ , ⁇ or ⁇ iron oxide hydroxide and iron oxide depending on the temperature and the like.
  • the iron compound has a significantly lower solubility in water or an aqueous citric acid solution than ferric hydroxide, and as a result, it remains as an insoluble solid even after the subsequent addition of citric acid, and the prepared citric acid
  • the production yield of diiron hydrate may decrease and the iron compound may remain in the ferric citrate hydrate.
  • each raw material it is preferable to mix water and citric acid before mixing ferric chloride, hydroxide of magnesium, and the like. Furthermore, when magnesium hydroxide or the like is mixed with a mixture containing ferric chloride, magnesium hydroxide or the like becomes a lump and it may take a long time to dissolve, so ferric chloride is mixed. It is more preferable to previously mix magnesium hydroxide or the like. Considering the above, specifically, it is more preferable to mix ferric chloride in the order of citric acid, water, hydroxide of magnesium and the like. In the mixing order, there is no problem even if the mixing order of citric acid and water is reversed.
  • the temperature of the above mixing operation is preferably 35 to 80 ° C. when all the raw materials are mixed. At the time of mixing all the raw materials, the solid raw materials are dissolved in water and reacted to produce ferric citrate hydrate. Ferric citrate hydrate may precipitate due to the high solids concentration in it. By setting the temperature to 35 ° C. or higher, precipitation of ferric citrate hydrate can be avoided and the solution state can be stably maintained. On the other hand, if the temperature is 80 ° C. or lower, decomposition of ferric citrate hydrate and / or citric acid can be suppressed, and the purity of the prepared ferric citrate hydrate can be further increased.
  • the temperature is particularly Not limited.
  • ferric citrate hydrate will proceed instantaneously, so after mixing all the raw materials, visually confirm the dissolution of each solid and set the time for mixing. It may be determined appropriately. It is usually sufficient to mix for at least 5 minutes after adding the last raw material. However, depending on the mixing temperature, as the mixing time increases, the decomposition of ferric citrate hydrate and / or citric acid tends to proceed, so as soon as dissolution is confirmed, mixing with an organic solvent, which is the next operation, is performed. It is preferable to carry out the operation.
  • step 1 the mixture obtained as described above and an organic solvent are mixed. By the mixing operation, ferric citrate hydrate is precipitated, and a suspension containing ferric citrate hydrate can be obtained.
  • the organic solvent is not particularly limited as long as it is an organic solvent in which ferric citrate hydrate is precipitated by mixing with the mixture, but usually, the mixture has a high solid concentration, and therefore the organic solvent Depending on the type, when mixed with the mixture, it may be separated into an organic solvent and may not be uniformly mixed, and ferric citrate hydrate may not be precipitated. Irrespective of the manufacturing conditions of the mixture, examples of the organic solvent in which ferric citrate hydrate precipitates include methanol, ethanol, 1-propanol, and 2-propanol.
  • the amount of the organic solvent used is preferably 3 to 20 mL with respect to 1 g of citric acid used in step 1. By setting it as the said range, a ferric citrate hydrate will precipitate after mixing with an organic solvent. Among the above ranges, considering the production yield of ferric citrate hydrate, operability, etc., the amount of the organic solvent used is more preferably 4 to 15 mL with respect to 1 g of citric acid used in step 1. 5 to 13 mL is more preferable.
  • organic solvent when 3 to 20 mL of the above organic solvent is used with respect to 1 g of citric acid used in step 1, if the content is 1 mL or less with respect to 1 mL of the organic solvent, an organic solvent other than the above may be contained. I do not care.
  • the organic solvent other than the above is an organic solvent which is miscible with the above organic solvent and water, and specifically, alcohols such as 1-butanol, 2-butanol, t-butanol, allyl alcohol, propargyl alcohol, acetone, Ketones such as methyl ethyl ketone, acetylacetone and diacetone alcohol, cyclic ethers such as tetrahydrofuran and dioxane, nitriles such as acetonitrile, N, N-dimethylacetamide, N, N-dimethylformamide, N-methyl-2-pyrrolidone and the like
  • examples thereof include nitrogen-containing compounds and sulfur-containing compounds such as dimethyl sulfoxide.
  • alcohols such as 1-butanol, 2-butanol, t-butanol, allyl alcohol, and propargyl alcohol, acetone, etc. are taken into consideration in view of their relatively low boiling point, easy removal, production yield, and the like.
  • Ketones such as methyl ethyl ketone, acetylacetone and diacetone alcohol, cyclic ethers such as tetrahydrofuran and dioxane, and nitriles such as acetonitrile are more preferable, and ketones such as acetone, methyl ethyl ketone, acetylacetone and diacetone alcohol are more preferable.
  • step 1 the mixture and the organic solvent may be mixed as long as the mixing operation can be carried out, and the method for carrying out the mixing is not particularly limited, but similar to the preparation of the above mixture, glass, stainless steel, Teflon (registered trademark) From the viewpoint of uniformity and operability, it is preferable to mix the mixture and the organic solvent with stirring by using a container for manufacturing, glass lining or the like, and further using a mechanical stirrer, a magnetic stirrer or the like.
  • the order of mixing the mixture and the organic solvent is not particularly limited, and the organic solvent may be added to the mixture after it is produced, or the mixture may be added to the organic solvent.
  • the method of dropping the mixture into the organic solvent is preferable from the viewpoint of operability and production yield.
  • the dropping rate of the above mixture may be appropriately determined while confirming the working time and the degree of dispersion of the precipitated ferric citrate hydrate in the solvent, but usually it is determined within the range of 5 minutes to 5 hours. Good.
  • the temperature at the time of mixing may be appropriately determined in consideration of the boiling point of the organic solvent to be used, but if it is too low, ferric citrate hydrate tends to agglomerate, and if it is too high, the citric acid no. Since decomposition of diiron hydrate and / or citric acid may cause by-production of impurities such as aconitic acid, it is preferably carried out in the range of 20 to 80 ° C. Considering operability such as solid-liquid separation of the precipitated ferric citrate hydrate and volatilization of the organic solvent, the temperature is more preferably 25 to 70 ° C, further preferably 30 to 60 ° C.
  • the mixture After mixing the above mixture with an organic solvent, it is preferable to hold the mixture for a certain period of time with stirring in order to sufficiently precipitate ferric citrate hydrate.
  • the holding time varies depending on the temperature at the time of mixing, etc., but it is usually sufficient to hold for 15 minutes to 50 hours. Further, the temperature in the operation is preferably in the same range as in the mixing for the same reason as in the mixing. As described above, a suspension containing ferric citrate hydrate can be obtained.
  • the ferric citrate hydrate obtained in step 1 is subjected to solid-liquid separation from the above suspension using vacuum filtration, pressure filtration, centrifugation or the like to obtain ferric citrate hydrate and an organic solvent.
  • the isolated wet body of ferric citrate hydrate is preferably washed with an organic solvent or a mixed solvent of an organic solvent and water. By this washing, the mother liquor (dispersing solvent in the suspension) remaining in the wet body can be removed, and the residual amount of the by-product salt in the ferric citrate hydrate can be further reduced.
  • the mixing ratio is 0.2 to 2 mL of water with respect to 1 mL of the organic solvent, since it is possible to suppress the decrease in the production yield due to the dissolution of ferric citrate hydrate in the washing solution and the precipitation of by-product salts. Is preferred. From the viewpoint of cleaning efficiency, it is preferable that the amount of the cleaning liquid used is 0.5 to 5 mL with respect to 1 g of citric acid as the raw material used in step 1.
  • the mother liquor may remain in the wet body depending on the method of solid-liquid separation or the preparation scale.
  • the mixture may be mixed with an organic solvent and a mixed solvent of water to prepare a suspension again (hereinafter, referred to as “resuspension”), and then solid-liquid separation may be performed for washing.
  • suspension an organic solvent and a mixed solvent of water to prepare a suspension again (hereinafter, referred to as “resuspension”), and then solid-liquid separation may be performed for washing. According to this operation, the residual amount of the mother liquor in the wet body can be further reduced, and the residual amount of the by-product salt in the ferric citrate hydrate produced as a result can be further reduced.
  • the organic solvent in the mixed solvent used for washing by preparing the resuspension is an organic solvent having a solubility of 0.2 g or more in 1 g of water at 25 ° C.
  • Specific examples include alcohols such as methanol, ethanol, 1-propanol, 2-propanol and allyl alcohol, esters such as methyl acetate, ethers such as tetrahydrofuran and dioxane, acetone, methyl ethyl ketone, acetylacetone and diacetone alcohol.
  • Examples include ketones and nitriles such as acetonitrile.
  • alcohols such as methanol, ethanol, 1-propanol, 2-propanol, and allyl alcohol, and acetone, methyl ethyl ketone, and acetylacetone are used from the viewpoint of solubility and easy removal of ferric citrate hydrate in a cleaning solution.
  • Ketones such as diacetone alcohol and the like are more preferable, and methanol, ethanol, 1-propanol, 2-propanol, acetone and methyl ethyl ketone are more preferable.
  • these may use a single type and may use multiple types.
  • the mixing ratio of the organic solvent and water is preferably 0.1 to 2 mL of water to 1 mL of the organic solvent.
  • the amount of the mixed solvent used is preferably 0.5 to 20 mL with respect to 1 g of citric acid as a raw material used in Step 1, from the viewpoint of operability and cleaning efficiency. ⁇ 15 mL is more preferred, and 1.5-10 mL is even more preferred.
  • the method for carrying out the resuspension is not particularly limited as long as the resuspension can be prepared.
  • the wet body, the organic solvent and water are mixed.
  • the mixed solvent may be mixed with stirring.
  • the mixed solvent of the organic solvent and water is preferably prepared before mixing with the wet body.
  • the temperature of the mixing operation is preferably in the range of ⁇ 20 to 75 ° C. in consideration of the stirring efficiency and the production yield, and the operability of the mixing operation and the solid-liquid separation operation after mixing and the boiling point of the organic solvent are considered. Then, 0 to 70 ° C. is more preferable, and 10 to 60 ° C. is further preferable.
  • mixing it is preferable from the viewpoint of uniformity and the like that mixing is performed in the temperature range for a certain time or more with stirring. It cannot be specified unconditionally because it depends on the production scale, etc., but it is usually sufficient to maintain the mixed state for 15 minutes to 2 hours.
  • the resuspension prepared as described above is subjected to solid-liquid separation using vacuum filtration, pressure filtration, centrifugal separation, etc. in the same manner as the above suspension to obtain a wet solution of ferric citrate hydrate.
  • the body may be isolated. Also in the solid-liquid separation operation, the wet body after solid-liquid separation is preferably washed with an organic solvent or a mixed solvent of an organic solvent and water.
  • the wet body of ferric citrate hydrate thus isolated can be made into ferric citrate hydrate from which the organic solvent and the like have been removed by drying as described below.
  • the solid surface of the ferric citrate hydrate is dissolved in the water contained in the wet body during the drying operation to hydrate the ferric citrate.
  • the BET specific surface area of the product may decrease. Therefore, it is preferable to reduce the content of water in the wet body before drying.
  • the amount converted to the anhydrous ferric citrate hydrate contained in the wet body (hereinafter, referred to as "anhydrous equivalent amount of ferric citrate hydrate in the wet body")
  • the content of water is preferably 0.05 to 0.5 g per 1 g.
  • the anhydrous equivalent amount of ferric citrate hydrate in the wet body is determined by measuring the contents of water and the organic solvent in the wet body by KF, gas chromatography (GC), etc. It is calculated by subtracting the content of the organic solvent from the weight of the wet body.
  • the washing at the time of solid-liquid separation is finally carried out only with the organic solvent.
  • washing with an organic solvent may be performed plural times, or washing may be performed by preparing a suspension again from the wet body after solid-liquid separation and the organic solvent.
  • the wet body of the prepared ferric citrate hydrate is dried, and excess water and organic solvent contained in the wet body are removed, thereby ferric citrate hydrate.
  • the drying operation may be carried out by a known method, for example, using a shelf dryer or a conical dryer, under vacuum, under a dry air atmosphere, or under an inert gas atmosphere such as nitrogen or argon, It should be carried out. Further, the temperature of the drying operation is preferably ⁇ 80 to 80 ° C. in consideration of the stability of ferric citrate hydrate.
  • the drying time may be appropriately determined while confirming the residual amount of the organic solvent and the like, but is usually 0.5 to 100 hours. Furthermore, in the drying process, when the resin becomes lumpy and the reduction efficiency of the organic solvent is low, it can be dried more efficiently by making it into a powder using a hammer mill, a pin mill or the like.
  • the ferric citrate hydrate prepared by the step 1 has a low content of organic impurities derived from the decomposition of ferric citrate and / or citric acid, and the by-product salt.
  • the content of inorganic impurities derived from the like is also low, and a high purity equal to or higher than that of ferric citrate produced by a known method and commercially available ferric citrate used in Examples described later, and Since it has a BET specific surface area of more than 16 m 2 / g, it can be suitably used as ferric citrate as a raw material used in step 2.
  • the purity and the citric acid content of the ferric citrate and the modified ferric citrate hydrates of the raw materials of Examples and Comparative Examples were measured by high performance liquid chromatography (HPLC).
  • HPLC high performance liquid chromatography
  • the BET specific surface areas of the ferric citrate and the modified ferric citrate hydrates of the examples and comparative examples were measured by the nitrogen adsorption method.
  • the iron content of ferric citrate as a raw material and the modified ferric citrate hydrate of Examples and Comparative Examples was measured by a redox titration method.
  • the water content of ferric citrate as a raw material in Examples and Comparative Examples is respectively Karl Fischer titration method (KF), gas chromatography (GC), inductively coupled plasma. It was measured by optical emission spectroscopy (ICP-OES).
  • the content of citric acid in the ferric citrate raw material and the modified ferric citrate hydrate was calculated by the calibration curve method from the peak area value of citric acid measured under the conditions, It is the ratio of the mass of citric acid to the mass of the raw material ferric citrate and the modified ferric citrate hydrate.
  • Liquid chromatograph device manufactured by Waters Corporation
  • Detector Ultraviolet absorptiometer (manufactured by Waters Corporation) Measurement wavelength: 210 nm
  • Column A stainless tube having an inner diameter of 4.6 mm and a length of 250 mm packed with 5 ⁇ m octadecylsilylated silica gel for liquid chromatography.
  • Mobile phase A mixed solution prepared by adding 12.0 g of sodium dihydrogen phosphate to 2000 mL of water and dissolving it, and then adding phosphoric acid to adjust the pH to 2.2.
  • the iron content of the ferric citrate hydrate by the redox titration method was measured under the following conditions. In the following Examples and Comparative Examples, the iron content of ferric citrate hydrate is the ratio of the mass of iron to the mass of ferric citrate hydrate measured under the conditions.
  • Gas Chromatograph (Agilent Technologies, Inc.)
  • Detector Hydrogen flame ionization detector (Agilent Technologies, Inc.)
  • Introduction method Headspace method
  • Column A fused silica tube having an inner diameter of 0.53 mm and a length of 30 m, which is coated with polyethylene glycol for gas chromatography in a thickness of 1 ⁇ m.
  • the ferric citrate as a raw material used in Examples and Comparative Examples is a commercially available ferric citrate manufactured by Company A and Company B, and is prepared in Production Example 1 below. Was used. The results of analysis of the water content and the content of the organic solvent in the ferric citrate of these raw materials are shown in Table 1 below.
  • the molar ratio of the iron and citric acid molecular structure of the modified body and the molar ratio of the iron and citric acid molecular structure of the raw material, the modified body and ferric citrate of the raw material measured by the method described above.
  • the contents of the molecular structures derived from iron and citric acid and the molecular weights of iron and citric acid were calculated by the following formulas, respectively.
  • the solid After stirring at 20 to 30 ° C for 1 hour, the solid was filtered by pressure filtration, and the filtered solid was washed twice with 80 mL of acetone.
  • the obtained wet body and 400 mL of acetone were stirred at 20 to 30 ° C. for 30 minutes, the solid was filtered by pressure filtration, and the solid after filtration was washed twice with 80 mL of acetone.
  • the obtained wet body was dried under reduced pressure at 30 ° C for 15 hours to obtain 30.1 g of ferric citrate as a raw material.
  • Example 1 In a 100-mL four-necked flask equipped with a stirring blade and a thermometer, 0.33 g of citric acid monohydrate (9.1 g of citric acid per 100 g of anhydrous ferric citrate as a raw material) and water. 8 mL was added and stirred to prepare an aqueous citric acid solution. Next, 4.0 g of ferric citrate manufactured by Company A (an amount of ferric citrate equivalent to an anhydride: 3.3 g) as ferric citrate as a raw material was added little by little over 15 minutes and stirred. After stirring at 50 to 60 ° C. for 30 minutes and further at 20 to 30 ° C.
  • the solid After stirring at 20 to 30 ° C. for 1 hour, the solid was filtered by pressure filtration, and the filtered solid was washed twice with 8 mL of acetone.
  • the obtained wet body and 20 mL of acetone were stirred at 20 to 30 ° C. for 30 minutes, the solid was filtered by pressure filtration, and the solid after filtration was washed twice with 8 mL of acetone.
  • the obtained wet body was dried under reduced pressure at 30 ° C. for 15 hours, and further kept in an atmosphere at 40 ° C. and 40 RH% for 12 hours to obtain a modified ferric citrate hydrate. 3.7 g of iron hydrate was obtained.
  • the production yield of the modified ferric citrate hydrate based on the weight of the raw material ferric citrate was 92.0%.
  • the BET specific surface area of the modified ferric citrate hydrate determined by the nitrogen adsorption method was 32.6 m 2 / g, and the purity determined by HPLC was 82.78%.
  • the contents of iron and citric acid in the modified ferric citrate hydrate were 19.2% by mass and 57.9% by mass, respectively, and the molar ratio of citric acid to iron was 0.88. Met.
  • Example 2 Same as Example 1 except that the amount of ferric chloride hexahydrate and / or citric acid monohydrate used was changed or ferric chloride hexahydrate was not used. It was carried out. The conditions and results are shown in Table 2.
  • Example 5 when ferric citrate as a raw material was added and stirred for 30 minutes at 50 to 60 ° C., the ferric citrate as a raw material was not completely dissolved. After stirring for 1.5 hours, it was confirmed that the whole amount was dissolved.
  • Examples 10 and 11 The same procedure as in Example 1 was carried out except that the ferric citrate used as the starting material was changed. The conditions and results are shown in Table 3.
  • Example 12 To a 500 mL four-necked flask equipped with a stirring blade and a thermometer, 40.0 g (190.3 mmol) of citric acid monohydrate and 140 mL of water (3.8 mL per 1 g of citric acid) were added and stirred, and the mixture was stirred. An aqueous acid solution was prepared. Then, 17.7 g of magnesium hydroxide (303.3 mmol, 0.85 equivalent to ferric chloride) was added over 15 minutes, and then heated up to around 40 ° C. to confirm that the magnesium hydroxide was dissolved. confirmed. Ferric chloride hexahydrate 64.3 g (237.9 mmol, 1.25 equivalents relative to citric acid) was added at 40 ° C.
  • the obtained wet body and 250 mL of acetone were added to a 500 mL four-necked flask equipped with a stirring blade and a thermometer, and stirred at 25 to 35 ° C for 30 minutes.
  • the obtained suspension was filtered by pressure filtration, and the solid after filtration was washed twice with 80 mL of acetone.
  • the obtained wet body was dried under reduced pressure at 30 ° C. for 15 hours to obtain 41.1 g of ferric citrate hydrate (production yield 102.8% based on the weight of citric acid monohydrate). It was
  • the BET specific surface area of the obtained ferric citrate hydrate by the nitrogen adsorption method was 17.8 m 2 / g, and the purity by HPLC was 99.84%.
  • the contents of iron and citric acid in the ferric citrate hydrate were 19.4% and 54.0%, respectively, and the molar ratio of the citric acid-derived molecular structure to iron was 0.81. It was Further, according to the analysis by ICP-OES, the residual amount of magnesium, which is an element derived from the by-product salt, was 2.4%.
  • the water content of ferric citrate hydrate was 16.0% as analyzed by KF.
  • Example 13 To a 500 mL four-necked flask equipped with a stirring blade and a thermometer, 40.0 g (190.3 mmol) of citric acid monohydrate and 140 mL of water (3.8 mL for 1 g of citric acid) were added and stirred, and the mixture was stirred. An aqueous acid solution was prepared. Then, 17.7 g of magnesium hydroxide (303.3 mmol, 0.85 equivalent with respect to ferric chloride) was added over 15 minutes, and then warmed up to around 40 ° C. to dissolve magnesium hydroxide. confirmed. After adding 64.3 g (237.9 mmol, 1.25 equivalents to citric acid) of ferric chloride hexahydrate at 40 ° C.
  • the obtained suspension was filtered by pressure filtration, and the solid after filtration was washed twice with 80 mL of acetone.
  • the obtained wet body was dried under reduced pressure at 30 ° C. for 15 hours to obtain 40.0 g of ferric citrate hydrate (production yield 100.0% based on the weight of citric acid monohydrate). It was
  • the BET specific surface area of the obtained ferric citrate hydrate by the nitrogen adsorption method was 18.2 m 2 / g, and the purity by HPLC was 99.85%.
  • the contents of iron and citric acid in the ferric citrate hydrate were 19.8% and 54.9%, respectively, and the molar ratio of the citric acid-derived molecular structure to iron was 0.81.
  • the X-ray diffraction chart shown in FIG. 2 was obtained by the analysis by XRD, and only the halo pattern peculiar to ferric citrate hydrate was shown, and each raw material such as citric acid and ferric chloride and sub-materials No peak derived from raw salt such as magnesium chloride was detected.
  • the residual amount of magnesium which is an element derived from the by-product salt, was 1.1%.
  • the water content of ferric citrate hydrate was 16.9% as analyzed by KF.
  • Example 14 to 21 Comparative Examples 5 to 7
  • the procedure of Example 13 was repeated, except that the amounts of magnesium hydroxide and ferric chloride hexahydrate used were changed.
  • the conditions and results are shown in Table 4.
  • Example 13 was carried out in the same manner as in Example 13 except that the amount of water used was changed. The conditions and results are shown in Table 5.
  • Example 26 To a 500 mL four-necked flask equipped with a stirring blade and a thermometer, 40.0 g (208.2 mmol) of citric acid anhydride and 116 mL of water (2.9 mL per 1 g of citric acid) were added and stirred to obtain an aqueous citric acid solution. Was prepared. Then, 18.2 g of magnesium hydroxide (312.3 mmol, 0.67 equivalents relative to ferric chloride) was added over 15 minutes, and then heated to around 45 ° C. to confirm that magnesium hydroxide was dissolved. confirmed. Ferric chloride hexahydrate (84.4 g, 312.3 mmol, 1.5 equivalents based on citric acid) was added at 40 ° C.
  • the obtained wet body and 180 mL of acetone were added to a 500 mL four-necked flask equipped with a stirring blade and a thermometer, heated to about 40 ° C., and then stirred at 35 to 45 ° C. for 30 minutes. Then, 140 mL of water was added, and the mixture was stirred at 35 to 45 ° C. for 30 minutes.
  • the obtained suspension was filtered by pressure filtration, the solid after filtration was washed twice with a mixed solvent of 60 mL of acetone and 20 mL of water, and further, the solid after filtration was washed once with 80 mL of acetone.
  • the obtained wet body was dried under reduced pressure at 45 ° C. for 15 hours to obtain ferric citrate hydrate 46.0 g (production yield 115.0% based on the weight of citric anhydride).
  • the BET specific surface area of the obtained ferric citrate hydrate by the nitrogen adsorption method was 19.8 m 2 / g, and the purity by HPLC was 99.85%.
  • the contents of iron and citric acid in the ferric citrate hydrate were 20.5% and 54.6%, respectively, and the molar ratio of the citric acid-derived molecular structure to iron was 0.77. It was Further, according to the analysis by ICP-OES, the residual amount of magnesium, which is an element derived from the by-product salt, was 0.9%. Further, the water content of the ferric citrate hydrate was 19.8% as analyzed by KF.
  • the total amount of water in the solution was 68 mL, 1.9 mL for 1 g of sodium citrate, and 2.6 mL for converted 1 g of citric acid.
  • After cooling to around 30 ° C. it was obtained.
  • the obtained solution was added dropwise to 300 mL of methanol at 20 to 30 ° C. over 15 minutes.
  • the mixture was stirred at 20 to 30 ° C. for 1 hour to obtain a suspension containing the precipitated ferric citrate hydrate.
  • the obtained suspension was filtered by pressure filtration, and the solid after filtration was washed twice with 30 mL of methanol.
  • the obtained wet body and 250 mL of acetone were added to a 500 mL four-necked flask equipped with a stirring blade and a thermometer, and stirred at 25 to 35 ° C for 30 minutes.
  • the obtained suspension was filtered by pressure filtration, and the solid after filtration was washed twice with 80 mL of acetone.
  • the obtained wet body was dried under reduced pressure at 30 ° C. for 15 hours to obtain 33.2 g of ferric citrate hydrate (manufacturing yield 83.0% based on the weight of sodium citrate dihydrate). Obtained.
  • the BET specific surface area of the obtained ferric citrate hydrate by the nitrogen adsorption method was 1.9 m 2 / g, and the purity by HPLC was 98.77%.
  • the contents of iron and citric acid in the ferric citrate hydrate were 13.8% and 48.9%, respectively, and the molar ratio of the citric acid-derived molecular structure to iron was 1.03.
  • the X-ray diffraction chart shown in FIG. 3 was obtained by the XRD analysis, and in addition to the halo pattern peculiar to ferric citrate hydrate, the diffraction angles 2 ⁇ were 27.5 °, 31.8 °, Peaks were shown at 45.5 °, 54.0 ° and 56.6 °.
  • the peak is a characteristic peak of sodium chloride, which is a by-product salt. Furthermore, according to the analysis by ICP-OES, the residual amount of sodium, which is an element derived from the by-product salt, was 15.3%. Further, the water content of the ferric citrate hydrate was 10.1% as analyzed by KF.
  • the total amount of water in the solution was 124 mL, which was 3.4 mL for 1 g of citric acid.
  • the obtained solution was added to 600 mL of methanol at 20 to 30 ° C. It dripped over 15 minutes. The mixture was stirred at 20 to 30 ° C. for 1 hour to obtain a suspension containing the precipitated ferric citrate hydrate. The obtained suspension was filtered by pressure filtration, and the solid after filtration was washed twice with 60 mL of methanol.
  • the obtained wet body and 250 mL of acetone were added to a 500 mL four-necked flask equipped with a stirring blade and a thermometer, and stirred at 25 to 35 ° C for 30 minutes.
  • the obtained suspension was filtered by pressure filtration, and the solid after filtration was washed twice with 80 mL of acetone.
  • the obtained wet body was dried under reduced pressure at 30 ° C. for 15 hours to obtain 35.9 g of ferric citrate hydrate (manufacturing yield 89.8% based on the weight of sodium citrate dihydrate). Obtained.
  • the BET specific surface area of the obtained ferric citrate hydrate by a nitrogen adsorption method was 4.5 m 2 / g, and the purity by HPLC was 98.26%.
  • the contents of iron and citric acid in the ferric citrate hydrate were 15.1% and 52.2%, respectively, and the molar ratio of the citric acid-derived molecular structure to iron was 1.00.
  • the X-ray diffraction chart shown in FIG. 4 was obtained by the XRD analysis. In addition to the halo pattern peculiar to ferric citrate hydrate, the diffraction angles 2 ⁇ were 31.8 °, 45.6 ° and It showed a peak at 56.6 °.
  • This peak is a characteristic peak of sodium chloride, which is a by-product salt. Furthermore, the analysis by ICP-OES revealed that the residual amount of sodium, which is an element derived from the by-product salt, was 7.7%. The water content of ferric citrate hydrate was 11.3% as analyzed by KF.
  • Example 27 Example 1 was carried out in the same manner as in Example 1 except that the raw material ferric citrate used was changed to the raw material ferric citrate hydrate obtained in Example 13. The conditions and results are shown in Table 6.
  • Comparative Example 10 The same procedure as in Comparative Example 1 was carried out except that the raw material ferric citrate used was changed to the raw material ferric citrate hydrate obtained in Example 13. The conditions and results are shown in Table 6.
  • Examples 28 to 34 It carried out like Example 27 except having changed the usage-amount of ferric chloride hexahydrate and / or citric acid monohydrate. The conditions and results are shown in Table 6.

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Abstract

La présente invention concerne un procédé de production permettant d'obtenir efficacement un hydrate de citrate ferrique qui présente diverses surfaces spécifiques BET et un degré élevé de pureté indépendamment du matériau de départ qui est utilisé. La présente invention concerne un procédé de production d'un hydrate de citrate ferrique modifié, qui comprend une seconde étape de mise en contact d'un solvant organique soluble dans l'eau et d'une solution contenant de l'eau, du chlorure ferrique et du citrate ferrique, qui est un matériau de départ.
PCT/JP2019/044384 2018-11-14 2019-11-12 Procédé de production d'hydrate de citrate ferrique Ceased WO2020100911A1 (fr)

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CN1600302A (zh) * 2003-09-22 2005-03-30 宝龄富锦生技股份有限公司 含有柠檬酸铁的医药组合物以及药用级柠檬酸铁及其制法和含有药用级柠檬酸铁的膳食营养品
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CN117534122B (zh) * 2024-01-10 2024-04-05 华能国际电力股份有限公司德州电厂 基于微尺度反应层面、用于电解水制氢的导电颗粒及应用

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