JP2024010302A - Method for producing polyvinyl pyrrolidone-iodine complex - Google Patents

Method for producing polyvinyl pyrrolidone-iodine complex Download PDF

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JP2024010302A
JP2024010302A JP2022111563A JP2022111563A JP2024010302A JP 2024010302 A JP2024010302 A JP 2024010302A JP 2022111563 A JP2022111563 A JP 2022111563A JP 2022111563 A JP2022111563 A JP 2022111563A JP 2024010302 A JP2024010302 A JP 2024010302A
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iodine
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hydrogen iodide
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利光 石井
Toshimitsu Ishii
池 祥雅
Yoshimasa Ike
紘一 田上
Koichi Tagami
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GODO SHIGEN CO Ltd
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Abstract

To provide a method for producing a polyvinyl pyrrolidone-iodine complex that satisfies all the specifications in the pharmacopoeial standards of various countries, offering high quality and stability.SOLUTION: A method for producing a polyvinyl pyrrolidone-iodine complex includes mixing polyvinyl pyrrolidone with iodine in a solid-phase state and then adding hydrogen iodide for a reaction.SELECTED DRAWING: None

Description

本発明は、ポリビニルピロリドン-ヨウ素複合体の製造方法に関する。 The present invention relates to a method for producing a polyvinylpyrrolidone-iodine complex.

ポリビニルピロリドン-ヨウ素複合体(以下、「PVP-I」とも記す。)は、ポビドンヨードとも称され、ポリビニルピロリドン(以下、「PVP」とも記す。)とヨウ素とが結合したヨウ素複合体である。PVP-Iは褐色粉末状製品として市販され、水やエタノール等に溶解し、その水溶液は殺菌剤又は消毒剤として広く用いられている。
PVP-Iの殺菌又は消毒作用は、PVP内に取り込まれて複合体を形成しているヨウ素(I)が徐々に遊離し、その酸化作用によって、微生物表面の膜タンパク質を構成するアミノ酸の酸化等で膜機能が阻害されることで発揮されると考えられる。
Polyvinylpyrrolidone-iodine complex (hereinafter also referred to as "PVP-I") is also referred to as povidone-iodine, and is an iodine complex in which polyvinylpyrrolidone (hereinafter also referred to as "PVP") and iodine are bonded. PVP-I is commercially available as a brown powder product and is dissolved in water, ethanol, etc., and its aqueous solution is widely used as a disinfectant or disinfectant.
The bactericidal or disinfecting action of PVP-I is due to the gradual release of iodine (I 2 ) incorporated into PVP to form a complex, and its oxidizing action leads to the oxidation of amino acids that constitute membrane proteins on the surface of microorganisms. It is thought that this is achieved by inhibiting membrane function.

PVP-Iの従来の製造方法として、以下が提案されている。
(1)PVPの水溶液にヨウ化水素ガス又はアルカリ金属ヨウ素塩を添加し、この溶液を乾燥して得られた粉末状PVP-ヨウ化物混合物を、ヨウ素と反応させる方法(特許文献1)。
(2)無水有機溶媒中で特定開始剤の存在下に重合して得た粉末状PVPを粉末状ヨウ素と室温で混合する方法(特許文献2)。
(3)PVP及びヨウ素を、ギ酸、シュウ酸又は炭酸、ギ酸又はシュウ酸のアンモニウム塩の存在下で、水溶液中で反応させる方法(特許文献3)。
(4)粉末状のPVPをヨウ素と混合後、熱処理を行う方法(特許文献4)。
(5)水素添加されたPVPをヨウ素と固相で反応させる方法(特許文献5)。
(6)特定含水率のPVPを用いて、ヨウ素と共に加熱する方法(特許文献6)。
(7)乾燥PVP粉末と、ヨウ素粉末と、ヨウ化水素ガス又はアルカリ金属ヨウ素塩から選択されるヨウ化物とを、特定量比で、室温で24時間混合する方法(特許文献7)。
(8)粉末状PVPとヨウ素とを、ギ酸、シュウ酸又は炭酸、ギ酸又はシュウ酸のアンモニウム塩又はアミドの存在下、70~100℃で固相で反応させる方法(特許文献8)。
(9)粉末状PVPをHClガスと接触させて(PVP)HCl錯体を形成し、次いでヨウ素と反応させて水溶性のPVP/HCl/I錯体を得る方法(特許文献9)。
(10)特定濃度のPVP水溶液とヨウ素を混合し、ギ酸、シュウ酸、それらのエステル、塩又はアミドから選択される還元剤の存在下、50~110℃で30分~15時間加熱する方法(特許文献10)
The following has been proposed as a conventional manufacturing method for PVP-I.
(1) A method in which hydrogen iodide gas or an alkali metal iodine salt is added to an aqueous solution of PVP, and a powdered PVP-iodide mixture obtained by drying this solution is reacted with iodine (Patent Document 1).
(2) A method in which powdered PVP obtained by polymerization in an anhydrous organic solvent in the presence of a specific initiator is mixed with powdered iodine at room temperature (Patent Document 2).
(3) A method in which PVP and iodine are reacted in an aqueous solution in the presence of formic acid, oxalic acid, or carbonic acid, or an ammonium salt of formic acid or oxalic acid (Patent Document 3).
(4) A method in which powdered PVP is mixed with iodine and then heat treated (Patent Document 4).
(5) A method of reacting hydrogenated PVP with iodine in a solid phase (Patent Document 5).
(6) A method of heating PVP with a specific water content together with iodine (Patent Document 6).
(7) A method in which dry PVP powder, iodine powder, and iodide selected from hydrogen iodide gas or alkali metal iodine salt are mixed in a specific ratio at room temperature for 24 hours (Patent Document 7).
(8) A method in which powdered PVP and iodine are reacted in a solid phase at 70 to 100°C in the presence of formic acid, oxalic acid, carbonic acid, ammonium salt or amide of formic acid or oxalic acid (Patent Document 8).
(9) A method of contacting powdered PVP with HCl gas to form a (PVP) 2 HCl complex, and then reacting with iodine to obtain a water-soluble PVP/HCl/I 2 complex (Patent Document 9).
(10) A method in which a PVP aqueous solution of a specific concentration and iodine are mixed and heated at 50 to 110°C for 30 minutes to 15 hours in the presence of a reducing agent selected from formic acid, oxalic acid, their esters, salts, or amides ( Patent document 10)

特開昭50-035318号公報Japanese Unexamined Patent Publication No. 50-035318 特開昭51-046393号公報Japanese Unexamined Patent Publication No. 51-046393 特開昭56-065006号公報Japanese Unexamined Patent Publication No. 56-065006 独国特許第1037075号公報German Patent No. 1037075 特開昭56-061405号公報Japanese Unexamined Patent Publication No. 56-061405 米国特許第2900305号公報US Patent No. 2900305 米国特許第3028300号公報US Patent No. 3,028,300 特開昭54-143495号公報Japanese Unexamined Patent Publication No. 54-143495 特表平5-502660号公報Special Publication No. 5-502660 特表2003-509347号公報Special Publication No. 2003-509347

特許文献1の方法では、ヨウ化物(I)としてヨウ化水素ガスを添加すると、水溶液中で強酸であるヨウ化水素酸となるため、乾燥工程において強い腐食性が問題となる。また、ヨウ化物(I)としてヨウ化ナトリウムのようなアルカリ金属ヨウ素塩を添加する場合、製品としてのPVP-I中の灰分量が増加する問題がある。
特許文献2の方法は安定性に優れたPVP-Iの製造に適するとされるが、90~95℃で10時間以上の加熱(熱処理)が必要である。特許文献3の方法も7~32時間と長時間の反応を要する。特許文献4の方法も90~100℃で18~64時間の熱処理を、特許文献5の方法も室温で5時間、その後90℃で20時間の加熱を要し、特許文献6の方法も95℃で22時間の加熱を要している。このように長時間の加熱や含水率が高いPVPを用いると、生成物が塊状となったり、PVPに焦げ付きが発生しやすく、作業性や品質の面で問題がある。
特許文献7の方法では、加熱処理が省略されているものの、強いヨウ素臭のある不純物が生成し、生成物中の灰分量も問題となる。
特許文献8の方法は熱処理時間を短縮できるが、得られたPVP-Iを水溶液とすると、短時間でヨードを遊離してしまい、保存期間が制限される。
特許文献9の方法で得られる生成物の分配係数は20未満と低く、保存安定性に問題がある。
特許文献10の方法では、生成物中の灰分量が問題となるほか、粉末状又は顆粒状PVP-Iを取得する場合に水を除去する必要がある。
In the method of Patent Document 1, when hydrogen iodide gas is added as iodide (I ), it becomes hydroiodic acid, which is a strong acid in an aqueous solution, and therefore strong corrosivity becomes a problem in the drying process. Further, when an alkali metal iodine salt such as sodium iodide is added as iodide (I - ), there is a problem that the ash content in the PVP-I product increases.
Although the method of Patent Document 2 is said to be suitable for producing PVP-I with excellent stability, it requires heating (heat treatment) at 90 to 95° C. for 10 hours or more. The method of Patent Document 3 also requires a long reaction time of 7 to 32 hours. The method of Patent Document 4 also requires heat treatment at 90 to 100°C for 18 to 64 hours, the method of Patent Document 5 also requires heating at room temperature for 5 hours and then 20 hours at 90°C, and the method of Patent Document 6 also requires heat treatment at 95°C. This requires 22 hours of heating. When heating for such a long time or using PVP with a high moisture content, the product tends to become lumpy and the PVP tends to burn, which poses problems in terms of workability and quality.
In the method of Patent Document 7, although heat treatment is omitted, impurities with a strong iodine odor are generated, and the amount of ash in the product is also a problem.
Although the method of Patent Document 8 can shorten the heat treatment time, when the obtained PVP-I is made into an aqueous solution, iodine is liberated in a short period of time, which limits the storage period.
The product obtained by the method of Patent Document 9 has a low distribution coefficient of less than 20, and has a problem in storage stability.
In the method of Patent Document 10, the amount of ash in the product is a problem, and water must be removed when obtaining powdered or granular PVP-I.

一方、PVP-Iは、一般に有効ヨウ素、すなわちチオ硫酸ナトリウムで滴定し得る活性ヨウ素及びヨウ化物を含有する褐色粉末として市販されており、その品質評価の指標として、第18改正日本薬局方、及び特許文献7等に開示される「分配係数(DC:distribution coefficient)」や、「ヨウ素損失」等がある。
「分配係数」は、PVP-Iの水溶液をへプタンで抽出してそのヨウ素(I)抽出量から算出するものである。かかる分配係数が200以上であると、PVP表面に単純に付着したヨウ素量が少なく、PVP内にヨウ素が多く取り込まれ複合体を形成していることを意味する。
「ヨウ素損失」は、加速安定性試験とも称され、PVP-Iの水溶液の、室温における有効ヨウ素量と、所定温度で所定時間加温した後の水溶液中における有効ヨウ素量とを測定し、その差を評価する。すなわちPVP-Iの水溶液中での安定性の指標であり、差が6%以下であれば、水溶液中にPVPから遊離ヨウ素として放出(遊離)される時間が遅く、PVP-Iとしての安定性が良好であることを意味する。
特許文献1~10の方法では、上述した問題点に加え、得られるPVP-Iが、前記した品質評価の指標に関する全項目を満たすのが困難という問題点がある。
On the other hand, PVP-I is generally commercially available as a brown powder containing active iodine, i.e., active iodine and iodide that can be titrated with sodium thiosulfate. There are "distribution coefficient (DC)" and "iodine loss" disclosed in Patent Document 7 and the like.
The "partition coefficient" is calculated from the amount of iodine (I 2 ) extracted by extracting an aqueous solution of PVP-I with heptane. A distribution coefficient of 200 or more means that the amount of iodine simply attached to the PVP surface is small, and that a large amount of iodine is incorporated into the PVP to form a complex.
"Iodine loss" is also called an accelerated stability test, and measures the effective iodine amount of an aqueous solution of PVP-I at room temperature and the effective iodine amount in the aqueous solution after heating at a predetermined temperature for a predetermined time. Assess the difference. In other words, it is an indicator of the stability of PVP-I in an aqueous solution, and if the difference is 6% or less, the time for release (liberation) of free iodine from PVP in an aqueous solution is slow, indicating the stability of PVP-I. means that it is good.
In addition to the above-mentioned problems, the methods of Patent Documents 1 to 10 have the problem that it is difficult for the obtained PVP-I to satisfy all the items regarding the quality evaluation indicators described above.

本発明者らは、品質評価の指標の全項目を満たすPVP-Iを簡便に製造する方法について検討した。その結果、固相状態でPVPとヨウ素とを予め混合し、次いでこの混合物にヨウ素供給源としてヨウ化水素を添加し、固相にて好適には加熱下に混合することで、日本薬局方に加え、分配係数やヨウ素損失等の品質評価指標を満たす、高品質かつ安定なPVP-Iを製造できることを見出し、本発明を完成した。
本発明の目的は、各国薬局方の規格値の全項目を満足し、高品質で安定なポリビニルピロリドン-ヨウ素複合体水溶液(ポビドンヨード製剤)を得ることができる、ポリビニルピロリドン-ヨウ素複合体の製造方法を提供することである。
The present inventors investigated a method for easily producing PVP-I that satisfies all of the quality evaluation indicators. As a result, by premixing PVP and iodine in the solid state, then adding hydrogen iodide as an iodine source to this mixture and mixing in the solid state, preferably under heating, the Japanese Pharmacopoeia In addition, they discovered that it is possible to produce high-quality and stable PVP-I that satisfies quality evaluation indicators such as partition coefficient and iodine loss, and completed the present invention.
The purpose of the present invention is to obtain a polyvinylpyrrolidone-iodine complex aqueous solution (povidone-iodine preparation) that satisfies all the specification values of each country's pharmacopoeia and is of high quality and stable. The goal is to provide the following.

本発明は、下記の態様を有する。
[1] ポリビニルピロリドンとヨウ素を固相状態で混合し、次いでヨウ化水素を添加して反応させる、ポリビニルピロリドン-ヨウ素複合体の製造方法。
[2] 前記ヨウ化水素を添加後に100℃以下で熱処理を行う、[1]に記載の製造方法。
[3] 前記ヨウ素及び前記ヨウ化水素の全ヨウ素量の前記ポリビニルピロリドンに対する質量比が、前記ポリビニルピロリドンの乾燥質量に対して18質量%以上である、[1]又は[2]に記載の製造方法。
[4] 前記ヨウ素及び前記ヨウ化水素の使用質量比が、ヨウ素換算で、ヨウ素:ヨウ化水素=50:50から90:10の範囲である、[1]~[3]のいずれかに記載の製造方法。
[5] さらに、ヨウ素塩の共存下で反応を行う、[1]~[4]のいずれかに記載の製造方法。
[6] 前記ヨウ素、前記ヨウ化水素及び前記ヨウ素塩の全ヨウ素量の前記ポリビニルピロリドンに対する質量比が、前記ポリビニルピロリドンの乾燥質量に対して18質量%超である、[5]に記載の製造方法。
[7] 前記ポリビニルピロリドンの含水量が4~6質量%である、[1]~[6]のいずれかに記載の製造方法。
The present invention has the following aspects.
[1] A method for producing a polyvinylpyrrolidone-iodine complex, in which polyvinylpyrrolidone and iodine are mixed in a solid state, and then hydrogen iodide is added and reacted.
[2] The manufacturing method according to [1], wherein heat treatment is performed at 100° C. or lower after adding the hydrogen iodide.
[3] The production according to [1] or [2], wherein the mass ratio of the total iodine amount of the iodine and hydrogen iodide to the polyvinylpyrrolidone is 18% by mass or more with respect to the dry mass of the polyvinylpyrrolidone. Method.
[4] Any one of [1] to [3], wherein the mass ratio of the iodine and the hydrogen iodide used is in the range of iodine:hydrogen iodide = 50:50 to 90:10 in terms of iodine. manufacturing method.
[5] The production method according to any one of [1] to [4], wherein the reaction is further carried out in the presence of an iodine salt.
[6] The production according to [5], wherein the mass ratio of the total iodine amount of the iodine, the hydrogen iodide, and the iodine salt to the polyvinylpyrrolidone is more than 18% by mass with respect to the dry mass of the polyvinylpyrrolidone. Method.
[7] The production method according to any one of [1] to [6], wherein the polyvinylpyrrolidone has a water content of 4 to 6% by mass.

本発明によれば、各国薬局方の規格値の全項目を満足し、高品質で安定なポリビニルピロリドン-ヨウ素複合体の製造方法を提供できる。 According to the present invention, it is possible to provide a method for producing a high-quality and stable polyvinylpyrrolidone-iodine complex that satisfies all the standard values of each country's pharmacopoeia.

本発明のポリビニルピロリドン-ヨウ素複合体(PVP-I)の製造方法は、ポリビニルピロリドン(PVP)とヨウ素(I)を固相状態で混合し、次いでヨウ化水素を添加して反応させることが特徴である。 The method for producing the polyvinylpyrrolidone-iodine complex (PVP-I) of the present invention includes mixing polyvinylpyrrolidone (PVP) and iodine (I 2 ) in a solid state, and then adding hydrogen iodide to cause the reaction. It is a characteristic.

本発明の製造方法において、PVPは、公知の方法で得られたものを使用できる。例えば、水、イソプロパノール又はトルエン等の溶媒中で、過酸化水素、ペルオキソ二硫酸ナトリウム、ジアルキルペルオキシド等の過酸化物やアゾイソブチロニトリル等のアゾ化合物等のラジカル重合開始剤の存在下で重合したPVPを使用できる。
また、重合後に水素又は錯体水素化物により水素化処理したPVP、特表2003-509347号公報に開示される末端変性されたPVP、特開昭51-142094号公報等に開示される(メタ)アクリル酸誘導体等が共重合されたPVP等を、本発明の製造方法に用いてもよい。
In the production method of the present invention, PVP obtained by a known method can be used. For example, polymerization is carried out in a solvent such as water, isopropanol, or toluene in the presence of a radical polymerization initiator such as a peroxide such as hydrogen peroxide, sodium peroxodisulfate, or dialkyl peroxide, or an azo compound such as azoisobutyronitrile. PVP can be used.
In addition, PVP hydrogenated with hydrogen or a complex hydride after polymerization, terminal-modified PVP disclosed in Japanese Patent Publication No. 2003-509347, (meth)acrylic disclosed in JP-A-51-142094, etc. PVP or the like copolymerized with an acid derivative or the like may be used in the production method of the present invention.

本発明の製造方法に用いるPVPは、溶状、重金属、アルデヒド、N-ビニルピロリドンモノマー、過酸化物、ヒドラジン、ギ酸、ピロリドン、強熱残分等の各不純物含有量が、第十八改正日本薬局方における「ポビドン」(1-ビニル-2-ピロリドン重合物=PVP)の規格値をクリアしているものを用いることが好ましい。なお、かかる規格値は、その大部分が日本薬局方、欧州薬局方(The European Pharmacopoeia)及び米国薬局方(The United States Pharmacopeia)の「三薬局方」での調和合意に基づき規定されている。 The PVP used in the production method of the present invention has a content of impurities such as soluble state, heavy metals, aldehydes, N-vinylpyrrolidone monomer, peroxide, hydrazine, formic acid, pyrrolidone, and ignition residues, according to the Japanese Pharmacopoeia 18th Edition. It is preferable to use one that meets the standard values for "povidone" (1-vinyl-2-pyrrolidone polymer = PVP) in the above. Note that most of these standard values are defined based on harmonization agreements among the "Three Pharmacopoeia" of the Japanese Pharmacopoeia, the European Pharmacopoeia, and the United States Pharmacopeia.

PVPのK値は10~100の範囲で適宜選択できるが、20~50が好ましく、25~35が好ましく、25~33がより好ましい。K値が前記した範囲であればPVPとして取り扱いやすく、またPVP-Iにおけるヨウ素の安定性が保たれる傾向となる。ここでK値とは、H.Fikentscher,Cellulose-Chemie,13,38-64及び71-74(1932)により提案された、重合度を表す定数であり、水溶液中にて測定される。 The K value of PVP can be appropriately selected within the range of 10 to 100, preferably 20 to 50, preferably 25 to 35, and more preferably 25 to 33. If the K value is within the above range, it will be easy to handle as PVP, and the stability of iodine in PVP-I will tend to be maintained. Here, the K value is H. It is a constant representing the degree of polymerization proposed by Fikentscher, Cellulose-Chemie, 13, 38-64 and 71-74 (1932), and is measured in an aqueous solution.

PVPは、取扱いの容易さ、及び本製造方法の実施中に、PVPが水分により凝集した塊状物の生成を抑制する観点から、その含水量が4~6質量%の範囲であるのが好ましい。なお、PVPの含水量は必要に応じ、室温(30℃)~90℃の範囲の温度雰囲気で、好適には撹拌しながら大気圧下又は減圧条件下で乾燥することで前記した範囲に調整可能である。 The water content of PVP is preferably in the range of 4 to 6% by mass from the viewpoint of ease of handling and suppressing the formation of lumps of PVP agglomerated by water during implementation of the present production method. The water content of PVP can be adjusted to the above-mentioned range if necessary by drying it in a temperature atmosphere ranging from room temperature (30°C) to 90°C, preferably under atmospheric pressure or reduced pressure with stirring. It is.

PVP及びヨウ素の固相状態での混合は、窒素、アルゴン等の不活性ガス雰囲気下で行うのが好ましい。また、混合は、好適には10℃~35℃の範囲で行うのが好ましい。混合時間は、PVPとヨウ素とが充分に混合されれば特に制限はない。 Mixing of PVP and iodine in a solid state is preferably carried out under an atmosphere of an inert gas such as nitrogen or argon. Further, the mixing is preferably carried out at a temperature in the range of 10°C to 35°C. The mixing time is not particularly limited as long as PVP and iodine are sufficiently mixed.

混合の手段は、PVPと固体状のヨウ素とが十分に撹拌され混合でき、また好適には混合器内の温度制御が可能である限り特に制限はない。PVPとヨウ素という比重の異なる両者の混合効率をより高めること、及び付着箇所を減らし取出し収量を高める観点から、例えば撹拌翼を有しない、コニカルドライヤー等の混合装置が好ましい。 The mixing means is not particularly limited as long as the PVP and solid iodine can be sufficiently stirred and mixed and the temperature within the mixer can preferably be controlled. From the viewpoint of further increasing the mixing efficiency of PVP and iodine, which have different specific gravities, and from the viewpoint of reducing the number of adhesion sites and increasing the extraction yield, a mixing device such as a conical dryer, which does not have stirring blades, is preferable.

PVPとヨウ素を固相状態で混合して調製した混合物に、次いでヨウ化水素を添加する。ヨウ化水素は、前記混合物を調製した混合容器に導入するのが好ましい。 Hydrogen iodide is then added to a mixture prepared by mixing PVP and iodine in a solid state. Preferably, hydrogen iodide is introduced into the mixing vessel in which the mixture was prepared.

ヨウ化水素の導入量は、前記混合物の調製に用いたPVPの乾燥PVP換算質量に対する、ヨウ素とヨウ化水素中のヨウ素合計量(全ヨウ素量)として、18質量%以上であるのが好ましく、20質量%超であるのがより好ましく、21質量%以上であるのがさらに好ましい。かかる全ヨウ素量は、乾燥PVPに対し25質量%以下であるのが好ましい。
また、ヨウ素供給源としてのヨウ素及びヨウ化水素の使用質量比が、ヨウ素換算で、ヨウ素:ヨウ化水素=50:50から90:10の範囲となるようにヨウ化水素を添加するのが好ましく、60:40から80:20の範囲がより好ましい。
全ヨウ素量、及び前記使用質量比が前記した範囲内であると、得られるPVP-Iが日本薬局方等の各国薬局方の定める品質基準を満足しやすく、かつ後述する分配係数、ヨウ素損失等の評価値を目標水準に到達させやすい。
The amount of hydrogen iodide introduced is preferably 18% by mass or more as the total amount of iodine in iodine and hydrogen iodide (total iodine amount) based on the dry PVP equivalent mass of PVP used for preparing the mixture, More preferably, the content is more than 20% by mass, and even more preferably 21% by mass or more. The total amount of iodine is preferably 25% by weight or less based on dry PVP.
Further, hydrogen iodide is preferably added so that the mass ratio of iodine and hydrogen iodide used as an iodine source is in the range of iodine:hydrogen iodide=50:50 to 90:10 in terms of iodine. , the range of 60:40 to 80:20 is more preferable.
When the total iodine amount and the mass ratio used are within the ranges described above, the obtained PVP-I will easily satisfy the quality standards set by each country's pharmacopoeia, such as the Japanese Pharmacopoeia, and will have a good distribution coefficient, iodine loss, etc. as described below. It is easy to make the evaluation value reach the target level.

PVP及びヨウ素を固相状態で、好適には室温で予め混合させる際に、さらにヨウ素塩を添加してもよい。かかるヨウ素塩としては、例えばヨウ化リチウム、ヨウ化ナトリウム、ヨウ化カリウム、ヨウ化マグネシウム、ヨウ化バリウム等の無機ヨウ素塩:ヨウ化アンモニウム、ヨウ化テトラアルキルアンモニウム等の有機ヨウ素塩が挙げられる。
中でも、ヨウ化ナトリウム、ヨウ化カリウム、ヨウ化アンモニウムが好ましい。これらのヨウ素塩は1種類を単独で用いても、2種以上を併用してもよい。2種以上を併用する場合、ヨウ素塩としての使用量比には特に制限はない。
When PVP and iodine are premixed in solid phase, preferably at room temperature, an iodine salt may also be added. Examples of such iodine salts include inorganic iodine salts such as lithium iodide, sodium iodide, potassium iodide, magnesium iodide, and barium iodide; and organic iodine salts such as ammonium iodide and tetraalkylammonium iodide.
Among these, sodium iodide, potassium iodide, and ammonium iodide are preferred. These iodine salts may be used alone or in combination of two or more. When two or more types are used in combination, there is no particular restriction on the usage ratio of the iodine salts.

PVPとヨウ素を混合させる際にさらにヨウ素塩を添加する場合、乾燥PVPに対する、ヨウ素とヨウ化水素とヨウ素塩中のヨウ素合計量(全ヨウ素量)が18質量%以上であるのが好ましく、20質量%超であるのがより好ましく、21質量%以上であるのがさらに好ましい。かかる全ヨウ素量は、乾燥PVPに対し25質量%以下であるのが、得られるPVP-Iが、日本薬局方等の各国薬局方の定める品質基準を満足できる観点から好ましい。
また、ヨウ素供給源としての、ヨウ素、ヨウ化水素及びヨウ素塩の使用質量比が、ヨウ素換算で、ヨウ素:[ヨウ化水素とヨウ素塩]=50:50から90:10の範囲となるようにヨウ素塩を添加するのが好ましく、60:40から80:20の範囲がより好ましい。また、この場合において、ヨウ化水素とヨウ素塩の使用質量比は、ヨウ素換算で、ヨウ化水素:ヨウ素塩=10:90から90:10の範囲であるのが好ましく、15:85から85:15の範囲がより好ましい。各使用質量比が前記した範囲内であると、得られるPVP-Iが日本薬局方等の各国薬局方の定める品質基準を満足しやすく、かつ後述する分配係数、ヨウ素損失等の評価値を目標水準に到達させやすい。
When iodine salt is further added when mixing PVP and iodine, it is preferable that the total amount of iodine (total iodine amount) in the iodine, hydrogen iodide, and iodine salt is 18% by mass or more, and 20% by mass, based on the dry PVP. More preferably, it is more than 21% by mass, and even more preferably 21% by mass or more. It is preferable that the total iodine amount is 25% by mass or less based on the dry PVP, from the viewpoint that the obtained PVP-I can satisfy the quality standards set by the pharmacopoeia of each country, such as the Japanese Pharmacopoeia.
In addition, the mass ratio of iodine, hydrogen iodide, and iodine salt used as an iodine source is in the range of iodine: [hydrogen iodide and iodine salt] = 50:50 to 90:10 in terms of iodine. Preferably, iodine salt is added, more preferably in the range of 60:40 to 80:20. Further, in this case, the mass ratio of hydrogen iodide and iodine salt used is preferably in the range of hydrogen iodide:iodine salt=10:90 to 90:10, and 15:85 to 85:1 in terms of iodine. A range of 15 is more preferred. If the mass ratio of each used is within the above range, the obtained PVP-I will easily satisfy the quality standards set by the pharmacopoeia of each country such as the Japanese Pharmacopoeia, and will aim for the evaluation values of partition coefficient, iodine loss, etc. described later. Easy to reach standards.

本発明の製造方法は、好適には、混合装置にPVP及びヨウ素、必要に応じてさらにヨウ素塩をまず投入し、室温(30℃程度)で予め混合する。次いで、装置内にヨウ化水素をガスとして導入して混合して行うことで実施できる。
PVPとヨウ素の混合物にヨウ化水素を添加後、さらに昇温して加熱条件下で混合を行い、熱処理するのが、反応を円滑にかつ速やかに進行させ、安定なPVP-Iを生産性良く得られる観点から好ましい。
昇温温度の上限に厳密な意味での制限はないが、PVPそれ自体、及び得られるPVP-Iの熱安定性の観点から、通常、100℃以下で設定するのが好ましく、95℃以下を設定温度として昇温するのがより好ましい。
In the manufacturing method of the present invention, preferably, PVP and iodine, and if necessary, further iodine salt are first charged into a mixing device and mixed in advance at room temperature (about 30° C.). Next, hydrogen iodide can be introduced as a gas into the apparatus and mixed.
After adding hydrogen iodide to the mixture of PVP and iodine, the temperature is further raised, the mixture is heated, and the heat treatment is performed to allow the reaction to proceed smoothly and quickly, and to produce stable PVP-I with good productivity. It is preferable from the viewpoint of the obtained results.
There is no strict limit to the upper limit of the heating temperature, but from the viewpoint of thermal stability of PVP itself and the resulting PVP-I, it is usually preferable to set it at 100°C or lower, and 95°C or lower. It is more preferable to raise the temperature as the set temperature.

昇温は、ヨウ化水素を導入後に、設定温度まで一段階で昇温しても、段階的に昇温してもよい。昇温速度には特に制限はない。熱処理の時間にも厳密な意味での制限はないが、PVP自体及び得られるPVP-Iの熱安定性、並びに反応を円滑に完結させる観点からは、通常、設定温度に昇温後、10時間以内であるのが好ましく、6時間以内がより好ましい。
より具体的には、PVP及びヨウ素、必要に応じてさらにヨウ素塩を含有する前記混合物にヨウ化水素を導入後、例えば50℃で2時間、次いで70℃で2時間、さらに90℃で5時間、のように段階的に昇温しながら混合して熱処理を行うことができる。あるいは、PVPとヨウ素の混合物にヨウ化水素を添加後、例えば90℃まで一段階で昇温して混合して熱処理を行なってもよい。
なお、前記混合物へのヨウ化水素ガスの導入は、調製した混合物にヨウ化水素を導入せず設定温度までいったん昇温し、冷却後に行ってもよい。
After introducing hydrogen iodide, the temperature may be raised to a set temperature in one step or in steps. There is no particular restriction on the heating rate. There is no strict limit to the heat treatment time, but from the viewpoint of thermal stability of PVP itself and the resulting PVP-I, and from the viewpoint of completing the reaction smoothly, it is usually 10 hours after raising the temperature to the set temperature. It is preferably within 6 hours, and more preferably within 6 hours.
More specifically, after introducing hydrogen iodide into the mixture containing PVP and iodine, and optionally an iodine salt, the mixture is heated, for example, at 50°C for 2 hours, then at 70°C for 2 hours, and then at 90°C for 5 hours. The heat treatment can be performed by mixing and increasing the temperature in stages as shown in . Alternatively, after adding hydrogen iodide to a mixture of PVP and iodine, heat treatment may be performed by heating the mixture in one step to, for example, 90° C. and mixing.
Note that hydrogen iodide gas may be introduced into the mixture after the mixture is heated to a set temperature without introducing hydrogen iodide into the mixture and then cooled.

熱処理終了後、自然冷却又は冷媒等により混合装置を室温(30℃付近)まで冷却し、PVP-Iを褐色粉末として取り出す。 After the heat treatment is completed, the mixing device is cooled to room temperature (around 30° C.) by natural cooling or a refrigerant, and PVP-I is taken out as a brown powder.

本発明の製造方法で得られるPVP-Iは、有効ヨウ素量が好ましくは10.0%~12.0%の範囲であり、ヨウ化物イオンに対する有効ヨウ素の比(有効ヨウ素/ヨウ化物イオン)が1.8~2.4の範囲にある。また、分配係数は好ましくは200以上、より好ましくは200~250の範囲であり、ヨウ素損失が好ましくは6.3以下、より好ましくは4.0~6.3の範囲である。
なお、有効ヨウ素量、有効ヨウ素/ヨウ化物イオン、分配係数、ヨウ素損失の評価方法については、実施例にて後述する通りである。
The PVP-I obtained by the production method of the present invention preferably has an effective iodine content in the range of 10.0% to 12.0%, and a ratio of effective iodine to iodide ions (effective iodine/iodide ion). It is in the range of 1.8 to 2.4. Further, the distribution coefficient is preferably 200 or more, more preferably in the range of 200 to 250, and the iodine loss is preferably 6.3 or less, more preferably in the range of 4.0 to 6.3.
The methods for evaluating the effective iodine amount, effective iodine/iodide ion, partition coefficient, and iodine loss are as described later in Examples.

以下、実施例及び比較例を挙げて本発明を具体的に説明するが、本発明はこれらの実施例等により限定されない。得られた生成物の分析は以下のようにして行った。 EXAMPLES Hereinafter, the present invention will be specifically explained with reference to Examples and Comparative Examples, but the present invention is not limited by these Examples and the like. The obtained product was analyzed as follows.

[有効ヨウ素量、ヨウ化物イオン量]
第十八改正日本薬局方の一般試験法「2.物理的試験法 2.50 滴定終点検出法」に従い、「ポビドンヨード」の項に記載の要領で定量した。
[Effective iodine amount, iodide ion amount]
It was determined in accordance with the general test method "2. Physical test method 2.50 Titration end point detection method" of the 18th edition of the Japanese Pharmacopoeia, and as described in the section of "Povidone-iodine".

[分配係数]
各実施例及び比較例で得られた生成物を用いて、有効ヨウ素濃度が約1%となるように試料を調製し、0.1mol/Lのチオ硫酸ナトリウム水溶液で滴定して、分配試験に付す前の有効ヨウ素量を求めた。
この試料1mLを精秤して三角フラスコに分取し、次いでヘプタン25mLをホールピペットで計り入れて、25℃で1時間激しく振り混ぜた。静置後、ヘプタン相を採取して石英セルに入れ、520nmでの吸光度を測定した。ヘプタンのみの520nmの吸光度をブランク値として、ヘプタン相のヨウ素量を算出した。かかる値より、水相のヨウ素量を算出し、ヘプタン相と水相の各ヨウ素量より、分配係数を算出した。
[Partition coefficient]
Using the products obtained in each example and comparative example, samples were prepared so that the effective iodine concentration was approximately 1%, titrated with a 0.1 mol/L sodium thiosulfate aqueous solution, and subjected to a partition test. The effective amount of iodine before addition was determined.
1 mL of this sample was accurately weighed and dispensed into an Erlenmeyer flask, and then 25 mL of heptane was measured out using a whole pipette, and the mixture was vigorously shaken at 25° C. for 1 hour. After standing still, the heptane phase was collected and placed in a quartz cell, and the absorbance at 520 nm was measured. The amount of iodine in the heptane phase was calculated using the absorbance at 520 nm of heptane alone as a blank value. From this value, the amount of iodine in the aqueous phase was calculated, and the distribution coefficient was calculated from the amounts of each iodine in the heptane phase and the aqueous phase.

[ヨウ素損失]
各実施例及び比較例で得られた生成物を用いて、有効ヨウ素濃度が約1%となるように試料を調製し、その10mLを精秤して(M:g)、0.1mol/Lのチオ硫酸ナトリウム水溶液で滴定した(滴定量:L(mL))。
調製した試料100mLを回転子を入れたナスフラスコに分取して栓をし、80℃で15時間加温した。25℃まで冷却後、試料から10mLを精秤(M:g)して、0.02mol/Lのチオ硫酸ナトリウム水溶液で滴定した(滴定量:M(mL))。
以上の値を用いて、ヨウ素損失(%)を下式にて算出した。
ヨウ素損失(%)=100×(M/L)×[(L/M)-(M/M)]
[Iodine loss]
Using the products obtained in each example and comparative example, a sample was prepared so that the effective iodine concentration was about 1%, and 10 mL of the sample was accurately weighed ( ML : g), and 0.1 mol/ It was titrated with L aqueous sodium thiosulfate solution (titration amount: L (mL)).
100 mL of the prepared sample was placed in an eggplant flask equipped with a rotor, the flask was stoppered, and the flask was heated at 80° C. for 15 hours. After cooling to 25° C., 10 mL of the sample was accurately weighed (M M :g) and titrated with a 0.02 mol/L aqueous sodium thiosulfate solution (titration amount: M (mL)).
Using the above values, iodine loss (%) was calculated using the following formula.
Iodine loss (%) = 100 x (M L /L) x [(L/M L ) - (M/M M )]

<実施例1>
含水率4.0%のPVP118.5g(乾燥PVP換算量113.8g)とヨウ素17.1gとを容量500mLのナス型フラスコに入れ、ロータリーエバポレーターにて、30℃でナス型フラスコを回転させて内容物を混合した。
次いで、ナス型フラスコ内にヨウ化水素7.3gを5分かけて導入した。ここで、乾燥PVP質量に対する、ヨウ素及びヨウ化水素中のヨウ素合計量(全ヨウ素量)は21.4質量%であり、ヨウ素とヨウ化水素のヨウ素換算での使用質量比は70:30であった。
ヨウ化水素導入後の内容物を30℃で2時間、次に50℃に昇温して2時間、さらに70℃に昇温して2時間、そして90℃に昇温して5時間、いずれもロータリーエバポレーターにてナス型フラスコを回転させて混合した。内容物を30℃に冷却して、141.7gのPVP-Iを褐色粉末状生成物として得た(取り出し収量99.1%)。
<Example 1>
118.5 g of PVP with a moisture content of 4.0% (113.8 g in terms of dry PVP) and 17.1 g of iodine were placed in a 500 mL eggplant-shaped flask, and the eggplant-shaped flask was rotated at 30°C using a rotary evaporator. The contents were mixed.
Next, 7.3 g of hydrogen iodide was introduced into the eggplant-shaped flask over 5 minutes. Here, the total amount of iodine in iodine and hydrogen iodide (total iodine amount) with respect to the mass of dry PVP is 21.4% by mass, and the mass ratio of iodine and hydrogen iodide in terms of iodine is 70:30. there were.
After introducing hydrogen iodide, the contents were heated at 30°C for 2 hours, then heated to 50°C for 2 hours, further heated to 70°C for 2 hours, and then heated to 90°C for 5 hours. The mixture was also mixed by rotating the eggplant-shaped flask in a rotary evaporator. The contents were cooled to 30° C. to obtain 141.7 g of PVP-I as a brown powder product (99.1% yield).

<実施例2>
含水率4.9%のPVP118.5g(乾燥PVP換算量112.7g)と、ヨウ素17.0gと、ヨウ化アンモニウム2.76gとを容量500mLのナス型フラスコに入れ、ロータリーエバポレーターにて、30℃でナス型フラスコを回転させて内容物を混合した。
次いで、ナス型フラスコ内にヨウ化水素4.85gを5分かけて導入した。ここで、乾燥PVP質量に対する、ヨウ素とヨウ化水素とヨウ化アンモニウム中のヨウ素合計量(全ヨウ素量)は21.5質量%であり、ヨウ素とヨウ化水素とヨウ化アンモニウムのヨウ素換算での使用質量比は70:20:10であった。
ヨウ化水素導入後の内容物を30℃で2時間、次に50℃に昇温して2時間、さらに70℃に昇温して2時間、そして90℃に昇温して5時間、いずれもロータリーエバポレーターにてナス型フラスコを回転させて混合した。内容物を30℃に冷却して、123.9gのPVP-Iを褐色粉末状生成物として得た(取り出し収量87%)。
<Example 2>
118.5 g of PVP with a moisture content of 4.9% (112.7 g in terms of dry PVP), 17.0 g of iodine, and 2.76 g of ammonium iodide were placed in a 500 mL eggplant-shaped flask, and heated in a rotary evaporator for 30 g. The contents were mixed by rotating the eggplant flask at °C.
Next, 4.85 g of hydrogen iodide was introduced into the eggplant-shaped flask over 5 minutes. Here, the total amount of iodine in iodine, hydrogen iodide, and ammonium iodide (total iodine amount) with respect to the mass of dry PVP is 21.5% by mass, and the amount of iodine, hydrogen iodide, and ammonium iodide in terms of iodine is 21.5% by mass. The mass ratio used was 70:20:10.
After introducing hydrogen iodide, the contents were heated at 30°C for 2 hours, then heated to 50°C for 2 hours, further heated to 70°C for 2 hours, and then heated to 90°C for 5 hours. The mixture was also mixed by rotating the eggplant-shaped flask in a rotary evaporator. The contents were cooled to 30° C. to yield 123.9 g of PVP-I as a brown powder product (87% yield).

<実施例3>
含水率4.9%のPVP118.5g(乾燥PVP換算量112.7g)と、ヨウ素17.0gと、ヨウ化アンモニウム5.5gとを容量500mLのナス型フラスコに入れ、ロータリーエバポレーターにて、30℃でナス型フラスコを回転させて内容物を混合した。次いで、ナス型フラスコ内にヨウ化水素2.4gを導入した。ここで、乾燥PVP質量に対する、ヨウ素とヨウ化水素とヨウ化アンモニウム中のヨウ素合計量(全ヨウ素量)は21.5質量%であり、ヨウ素とヨウ化水素とヨウ化アンモニウムのヨウ素換算での使用質量比は70:10:20であった。
ヨウ化水素導入後の内容物を50℃に昇温して4時間、さらに70℃に昇温して4時間、そして90℃に昇温して10時間、いずれもロータリーエバポレーターにてナス型フラスコを回転させて混合した。内容物を30℃に冷却して、139.4gのPVP-Iを褐色粉末状生成物として得た(取り出し収量97.2%)。
<Example 3>
118.5 g of PVP with a moisture content of 4.9% (112.7 g of dry PVP), 17.0 g of iodine, and 5.5 g of ammonium iodide were placed in a 500 mL eggplant-shaped flask, and heated in a rotary evaporator for 30 g. The contents were mixed by rotating the eggplant flask at °C. Next, 2.4 g of hydrogen iodide was introduced into the eggplant-shaped flask. Here, the total amount of iodine in iodine, hydrogen iodide, and ammonium iodide (total iodine amount) with respect to the mass of dry PVP is 21.5% by mass, and the amount of iodine, hydrogen iodide, and ammonium iodide in terms of iodine is 21.5% by mass. The mass ratio used was 70:10:20.
After introducing hydrogen iodide, the contents were heated to 50°C for 4 hours, further heated to 70°C for 4 hours, and then heated to 90°C for 10 hours, all in a round-bottomed flask using a rotary evaporator. was mixed by rotating. The contents were cooled to 30° C. to obtain 139.4 g of PVP-I as a brown powder product (97.2% yield).

<実施例4>
含水率5.0%のPVP118.5g(乾燥PVP換算量112.6g)とヨウ素15.8gとを容量500mLのナス型フラスコに入れ、ロータリーエバポレーターにて、30℃でナス型フラスコを回転させて内容物を混合した。
次いで、ナス型フラスコ内にヨウ化水素6.8gを5分かけて導入した。ここで、乾燥PVP質量に対する、ヨウ素及びヨウ化水素中のヨウ素合計量(全ヨウ素量)は20.0質量%であり、ヨウ素とヨウ化水素のヨウ素換算での使用質量比は70:30であった。
ヨウ化水素導入後の内容物を30℃で2時間、次に50℃に昇温して2時間、さらに70℃に昇温して2時間、そして90℃に昇温して5時間、いずれもロータリーエバポレーターにてナス型フラスコを回転させて混合した。内容物を30℃に冷却して、123.3gのPVP-Iを褐色粉末状生成物として得た(取り出し収量87.5%)。
<Example 4>
118.5 g of PVP with a water content of 5.0% (112.6 g in terms of dry PVP) and 15.8 g of iodine were placed in a 500 mL eggplant-shaped flask, and the eggplant-shaped flask was rotated at 30°C using a rotary evaporator. The contents were mixed.
Next, 6.8 g of hydrogen iodide was introduced into the eggplant-shaped flask over 5 minutes. Here, the total amount of iodine in iodine and hydrogen iodide (total iodine amount) with respect to the mass of dry PVP is 20.0% by mass, and the mass ratio of iodine and hydrogen iodide in terms of iodine is 70:30. there were.
After introducing hydrogen iodide, the contents were heated at 30°C for 2 hours, then heated to 50°C for 2 hours, further heated to 70°C for 2 hours, and then heated to 90°C for 5 hours. The mixture was also mixed by rotating the eggplant-shaped flask in a rotary evaporator. The contents were cooled to 30° C. to obtain 123.3 g of PVP-I as a brown powder product (87.5% withdrawal yield).

<実施例5>
含水率5.0%のPVP118.5g(乾燥PVP換算量112.6g)とヨウ素14.6gとを容量500mLのナス型フラスコに入れ、ロータリーエバポレーターにて、30℃でナス型フラスコを回転させて内容物を混合した。
次いで、ナス型フラスコ内にヨウ化水素6.3gを5分かけて導入した。ここで、乾燥PVP質量に対する、ヨウ素及びヨウ化水素中のヨウ素合計量(全ヨウ素量)は18.5質量%であり、ヨウ素とヨウ化水素のヨウ素換算での使用質量比は70:30であった。
ヨウ化水素導入後の内容物を30℃で2時間、次に50℃に昇温して2時間、さらに70℃に昇温して2時間、そして90℃に昇温して5時間、いずれもロータリーエバポレーターにてナス型フラスコを回転させて混合した。内容物を30℃に冷却して、133.76gのPVP-Iを褐色粉末状生成物として得た(取り出し収量96.0%)。
<Example 5>
118.5 g of PVP with a water content of 5.0% (112.6 g in terms of dry PVP) and 14.6 g of iodine were placed in a 500 mL eggplant-shaped flask, and the eggplant-shaped flask was rotated at 30°C using a rotary evaporator. The contents were mixed.
Next, 6.3 g of hydrogen iodide was introduced into the eggplant-shaped flask over 5 minutes. Here, the total amount of iodine in iodine and hydrogen iodide (total iodine amount) with respect to the mass of dry PVP is 18.5% by mass, and the mass ratio of iodine and hydrogen iodide in terms of iodine is 70:30. there were.
After introducing hydrogen iodide, the contents were heated at 30°C for 2 hours, then heated to 50°C for 2 hours, further heated to 70°C for 2 hours, and then heated to 90°C for 5 hours. The mixture was also mixed by rotating the eggplant-shaped flask in a rotary evaporator. The contents were cooled to 30° C. to obtain 133.76 g of PVP-I as a brown powder product (96.0% yield).

<実施例6>
含水率5.0%のPVP118.5g(乾燥PVP換算量112.6g)とヨウ素16.9gとを容量500mLのナス型フラスコに入れ、ロータリーエバポレーターにて、30℃でナス型フラスコを回転させて内容物を混合した。
次いで、ナス型フラスコ内にヨウ化水素7.3gを5分かけて導入した。ここで、乾燥PVP質量に対する、ヨウ素及びヨウ化水素中のヨウ素合計量(全ヨウ素量)は21.4質量%であり、ヨウ素とヨウ化水素のヨウ素換算での使用質量比は70:30であった。
ヨウ化水素導入後の内容物を30℃から6時間30分かけて90℃に昇温し、90℃で5時間、ロータリーエバポレーターにてナス型フラスコを回転させて混合した。内容物を30℃に冷却して、128.7gのPVP-Iを褐色粉末状生成物として得た(取り出し収量90.2%)。
<Example 6>
118.5 g of PVP with a moisture content of 5.0% (112.6 g in terms of dry PVP) and 16.9 g of iodine were placed in a 500 mL eggplant-shaped flask, and the eggplant-shaped flask was rotated at 30°C using a rotary evaporator. The contents were mixed.
Next, 7.3 g of hydrogen iodide was introduced into the eggplant-shaped flask over 5 minutes. Here, the total amount of iodine in iodine and hydrogen iodide (total iodine amount) with respect to the mass of dry PVP is 21.4% by mass, and the mass ratio of iodine and hydrogen iodide in terms of iodine is 70:30. there were.
After hydrogen iodide was introduced, the contents were heated from 30°C to 90°C over 6 hours and 30 minutes, and mixed at 90°C for 5 hours by rotating the eggplant-shaped flask in a rotary evaporator. The contents were cooled to 30° C. to obtain 128.7 g of PVP-I as a brown powder product (90.2% yield).

<比較例1>
含水率4.8%のPVP118.5g(乾燥PVP換算量112.8g)とヨウ素24.25gとを容量500mLのナス型フラスコに入れ、ロータリーエバポレーターにて、30℃でナス型フラスコを回転させて内容物を混合した。ここで、乾燥PVP質量に対するヨウ素量は21.5質量%であった。次いで、50℃に昇温して2時間、さらに70℃に昇温して2時間、そして90℃に昇温して5時間、いずれもロータリーエバポレーターにてナス型フラスコを回転させて混合した。内容物を30℃に冷却して、130.6gのPVP-Iを褐色粉末状生成物として得た(取り出し収量91.5%)。
<Comparative example 1>
118.5 g of PVP with a water content of 4.8% (112.8 g in terms of dry PVP) and 24.25 g of iodine were placed in a 500 mL eggplant-shaped flask, and the eggplant-shaped flask was rotated at 30°C using a rotary evaporator. The contents were mixed. Here, the amount of iodine based on the mass of dry PVP was 21.5% by mass. Next, the mixture was mixed by increasing the temperature to 50° C. for 2 hours, further increasing the temperature to 70° C. for 2 hours, and increasing the temperature to 90° C. for 5 hours by rotating the eggplant-shaped flask in a rotary evaporator. The contents were cooled to 30° C. to yield 130.6 g of PVP-I as a brown powder product (91.5% yield).

<比較例2>
含水率4.5%のPVP118.5g(乾燥PVP換算量113.2g)とヨウ素23.20gとを容量500mLのナス型フラスコに入れ、ロータリーエバポレーターにて、30℃でナス型フラスコを回転させて内容物を混合した。
次いで、ナス型フラスコ内にヨウ化水素1.13gを5分かけて導入した。ここで、乾燥PVP質量に対する、ヨウ素及びヨウ化水素中のヨウ素合計量(全ヨウ素量)は21.5質量%であり、ヨウ素とヨウ化水素のヨウ素換算での使用質量比は95:5であった。
ヨウ化水素導入後の内容物を30℃で2時間、次に50℃に昇温して2時間、さらに70℃に昇温して2時間、そして90℃に昇温して5時間、いずれもロータリーエバポレーターにてナス型フラスコを回転させて混合した。内容物を30℃に冷却して、134.4gのPVP-Iを褐色粉末状生成物として得た(取り出し収量94.1%)。
<Comparative example 2>
118.5 g of PVP with a moisture content of 4.5% (113.2 g of dry PVP equivalent) and 23.20 g of iodine were placed in a 500 mL eggplant-shaped flask, and the eggplant-shaped flask was rotated at 30 ° C. using a rotary evaporator. The contents were mixed.
Next, 1.13 g of hydrogen iodide was introduced into the eggplant-shaped flask over 5 minutes. Here, the total amount of iodine in iodine and hydrogen iodide (total iodine amount) with respect to the mass of dry PVP is 21.5% by mass, and the mass ratio of iodine and hydrogen iodide in terms of iodine is 95:5. there were.
After introducing hydrogen iodide, the contents were heated at 30°C for 2 hours, then heated to 50°C for 2 hours, further heated to 70°C for 2 hours, and then heated to 90°C for 5 hours. The mixture was also mixed by rotating the eggplant-shaped flask in a rotary evaporator. The contents were cooled to 30° C. to obtain 134.4 g of PVP-I as a brown powder product (94.1% yield).

実施例1~6、及び比較例1~2で得られたPVP-Iのそれぞれにつき、有効ヨウ素量(質量%)、有効ヨウ素/ヨウ化物イオンの比、分配係数、及びヨウ素損失を上記した評価方法で求めた。結果を表1にまとめて示す。 For each of PVP-I obtained in Examples 1 to 6 and Comparative Examples 1 to 2, the effective iodine amount (mass%), effective iodine/iodide ion ratio, partition coefficient, and iodine loss were evaluated as described above. I found it by method. The results are summarized in Table 1.

実施例1~6で得られたPVP-Iは、有効ヨウ素量及び有効ヨウ素/ヨウ化物イオンの値が日本薬局方の基準を満たし、分配係数が好ましくは200以上、ヨウ素損失が好ましくは5.2%以下であって品質に優れ、保存安定性にも優れる。また、本法によれば、ヨウ素の供給源として、ヨウ化水素の供給に先立ってPVPとヨウ素塩を共存させても、品質に優れるPVP-Iを得ることができる。 The PVP-I obtained in Examples 1 to 6 has an effective iodine amount and an effective iodine/iodide ion value that meet the standards of the Japanese Pharmacopoeia, a partition coefficient of preferably 200 or more, and an iodine loss of preferably 5. It is 2% or less and has excellent quality and storage stability. Furthermore, according to the present method, PVP-I with excellent quality can be obtained even if PVP and iodine salt are coexisting as an iodine source prior to supplying hydrogen iodide.

<実施例7>
含水率5.8%のPVP36.0kg(乾燥PVP換算量33.9kg)とヨウ素5.0kgとを容量150Lのコニカル乾燥機に入れ、回転数を12回/分として、30℃で17時間内容物を混合した。
次いで、コニカル乾燥機内にヨウ化水素ガス2.14kgを3時間かけて導入した。ここで、乾燥PVP質量に対する、ヨウ素及びヨウ化水素中のヨウ素合計量(全ヨウ素量)は21.0質量%であり、ヨウ素とヨウ化水素のヨウ素換算での使用質量比は70:30であった。
ヨウ化水素導入後の内容物を、コニカル乾燥機の回転数を12回/分として、30℃で2時間混合し、次に50℃に昇温して2時間混合し、さらに70℃に昇温して2時間、そして90℃に昇温して5時間混合した。内容物を30℃に冷却して、42.2kgのPVP-Iを褐色粉末状生成物として得た(取り出し収量99.5%)。
得られたPVP-Iの有効ヨウ素量は11.3質量%、有効ヨウ素/ヨウ化物イオンの比は2.0、分配係数は230以上、ヨウ素損失は5.5%以下であった。
<Example 7>
36.0 kg of PVP with a moisture content of 5.8% (33.9 kg of dry PVP equivalent) and 5.0 kg of iodine were placed in a conical dryer with a capacity of 150 L, and the rotation speed was set to 12 times/min at 30°C for 17 hours. mixed things.
Next, 2.14 kg of hydrogen iodide gas was introduced into the conical dryer over a period of 3 hours. Here, the total amount of iodine in iodine and hydrogen iodide (total iodine amount) with respect to the mass of dry PVP is 21.0% by mass, and the mass ratio of iodine and hydrogen iodide in terms of iodine is 70:30. there were.
After introducing hydrogen iodide, the contents were mixed at 30°C for 2 hours with the conical dryer rotating at 12 times/min, then heated to 50°C and mixed for 2 hours, and further heated to 70°C. The mixture was heated for 2 hours, then heated to 90°C and mixed for 5 hours. The contents were cooled to 30° C. to obtain 42.2 kg of PVP-I as a brown powder product (99.5% yield).
The effective iodine amount of the obtained PVP-I was 11.3% by mass, the effective iodine/iodide ion ratio was 2.0, the partition coefficient was 230 or more, and the iodine loss was 5.5% or less.

本発明の製造方法で得られるポリビニルピロリドン-ヨウ素複合体は、ポリビニルピロリドン-ヨウ素複合体水溶液(ポビドンヨード製剤)の原体として、殺菌剤や消毒剤等の用途に有用である。

The polyvinylpyrrolidone-iodine complex obtained by the production method of the present invention is useful as a raw material for an aqueous polyvinylpyrrolidone-iodine complex solution (povidone-iodine preparation) for uses such as bactericidal agents and disinfectants.

Claims (7)

ポリビニルピロリドンとヨウ素を固相状態で混合し、次いでヨウ化水素を添加して反応させる、ポリビニルピロリドン-ヨウ素複合体の製造方法。 A method for producing a polyvinylpyrrolidone-iodine complex, which comprises mixing polyvinylpyrrolidone and iodine in a solid phase state, and then adding hydrogen iodide to cause a reaction. 前記ヨウ化水素を添加後に100℃以下で熱処理を行う、請求項1に記載の製造方法。 The manufacturing method according to claim 1, wherein a heat treatment is performed at 100° C. or lower after adding the hydrogen iodide. 前記ヨウ素及び前記ヨウ化水素の全ヨウ素量の前記ポリビニルピロリドンに対する質量比が、前記ポリビニルピロリドンの乾燥質量に対して18質量%以上である、請求項1に記載の製造方法。 The manufacturing method according to claim 1, wherein a mass ratio of the total iodine amount of the iodine and the hydrogen iodide to the polyvinylpyrrolidone is 18% by mass or more based on the dry mass of the polyvinylpyrrolidone. 前記ヨウ素及び前記ヨウ化水素の使用質量比が、ヨウ素換算で、ヨウ素:ヨウ化水素=50:50から90:10の範囲である、請求項1に記載の製造方法。 The manufacturing method according to claim 1, wherein the mass ratio of the iodine and the hydrogen iodide used is in the range of iodine:hydrogen iodide=50:50 to 90:10 in terms of iodine. さらに、ヨウ素塩の共存下で反応を行う、請求項1に記載の製造方法。 The manufacturing method according to claim 1, wherein the reaction is further carried out in the presence of an iodine salt. 前記ヨウ素、前記ヨウ化水素及び前記ヨウ素塩の全ヨウ素量の前記ポリビニルピロリドンに対する質量比が、前記ポリビニルピロリドンの乾燥質量に対して18質量%超である、請求項5に記載の製造方法。 The manufacturing method according to claim 5, wherein a mass ratio of the total iodine amount of the iodine, the hydrogen iodide, and the iodine salt to the polyvinylpyrrolidone is more than 18% by mass with respect to the dry mass of the polyvinylpyrrolidone. 前記ポリビニルピロリドンの含水量が4~6質量%である、請求項1~6のいずれか1項に記載の製造方法。

The manufacturing method according to any one of claims 1 to 6, wherein the polyvinylpyrrolidone has a water content of 4 to 6% by mass.

JP2022111563A 2022-07-12 2022-07-12 Method for producing polyvinyl pyrrolidone-iodine complex Pending JP2024010302A (en)

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