WO1999015512A1

WO1999015512A1 - Isothiazolone preparation and process for producing the same

Info

Publication number: WO1999015512A1
Application number: PCT/JP1998/004168
Authority: WO
Inventors: Shigeru Nakano; Takamasa Yoshida; Masayuki Harada; Masayuki Morita; Kazuyoshi Tsuchiya
Original assignee: Chemicrea Inc.
Priority date: 1997-09-19
Filing date: 1998-09-17
Publication date: 1999-04-01
Also published as: JPH11171712A

Abstract

An isothiazolone preparation stabilized at a high concentration in water, which is prepared without using an organic solvent or the like by adding to an aqueous solution of an isothiazolone compound a 5-bromo-5-nitro-1,3-dioxane derivative and a surfactant in such a small amount as to be enough for dissolving or dispersing the derivative in the solution.

Description

BACKGROUND OF THE INVENTION 1. Field of the Invention

TECHNICAL FIELD The present invention relates to an isothiazolone preparation and a method for producing the same, and in particular, has improved stability in water without containing a metal salt such as magnesium ion or calcium ion or an organic solvent which causes latex shock. Things. Background of the Invention

Conventionally, many compounds have been used as industrial fungicides. Among these, one of the advantages such as relatively simple processing method and excellent cost-effectiveness is 5-chloro-opening 2-methylisothiazoline-1-one or 2-methyl. And isothiazolone compounds such as isothiazolin-3-one. This isothiazolone compound is widely known as an industrial bactericide, preservative, and fungicide, especially a slime control agent for pulp and paper, a bactericidal and fungicide for water treatment, a preservative for cutting oil, It is useful and widely used as a fungicide for paints, natural rubber latex, synthetic rubber latex, acryl-based emulsion, vinyl acetate-based emulsion, and as a preservative and power-proofing agent for aqueous dispersions of these polymers.

The isothiazolone compound is usually used as a liquid preparation because it can be easily added to the target system. However, isotizazolone compounds are known to be very unstable in water and easily decompose in water.

Therefore, a method for stabilizing the isothiazolone compound by dissolving it in water or a water-soluble solvent together with a magnesium salt, a calcium salt, and the like has been found and has been distributed on the market for many years.

However, when the above formulation is used as a preservative or fungicide in latex emulsions and various resin emulsion phases, which are part of the intended use, the emulsion phase is destroyed due to the presence of metal salts such as magnesium salts and calcium salts. Phase separation and solidification occurred (so-called emulsion shock). As one method of stabilizing the type of isothiazolone compound that does not cause such emulsion shock, a method of dissolving it in a hydrophilic organic solvent and preparing it has been invented and put to practical use.

In recent years, however, the effects of volatile organic solvents on the human body and the environment in the final product or in manufacturing and formulation operations have been recognized. For example, see European Chemical News (Vol. 66, No. 1740). , 11-17). Therefore, there is a need for formulations that take this point into account. This is a so-called VOC (volatile organic compound) countermeasure problem.

In other words, the development of a stable isotisoazolone formulation that does not cause the so-called emulsion shock and is taking measures against VOCs has become a new issue.

In order to solve the above problems, a method has been proposed in which a large amount of anionic and nonionic surfactants are added to an aqueous solution of a metal salt-free isothiazolone compound to stabilize the isothiazolone compound in water. However, the stability of the drug product originally intended is not sufficient.

On the other hand, several methods using various organic compounds as stabilizers have been disclosed. For example, a method using a cyclic ester (JP-A-6-87705), a method using an orthoester (US Pat. No. 4,096,274), a method using hexamethylenetetramine (US Pat. No. 5,248,893) ) Has been proposed, but in any of the methods, an organic solvent such as ethylene glycol is used, and the above-mentioned problem of the preparation containing the organic solvent still remains.

In recent years, a method for stabilizing an isothiazolone compound by combining 5-promo-5-nitro-1,3-dioxane with hexamethylenetetramine as a second component has been disclosed as another stabilizer. (EP 686 347) Although this method has also achieved the purpose of stabilization, the use of a mixed solvent of diprovylene glycol and water as the solvent cannot avoid the use of organic solvents.

On the other hand, as an example that does not use an organic solvent, it is soluble in water or water and water due to two components such as a 5-bromo-5-nitro-1,3-dioxane derivative and an amide or potassium hydrogen fluoride. A method for stabilizing isothiazolone compounds in a mixed solvent of organic solvents has been proposed. According to this method, the temperature of 50 ° C It exhibits a storage stability of 60 days under conditions, and is a method that can withstand practical use in terms of stability.

However, in the case of using a 5-bromo-5-twotro 1,3-dioxane derivative, there is no description of an example in which stabilization was performed using only water.

A method for stabilization in water using only 5-promote 5—two-row 1,3—dioxane (Japanese Patent Laid-Open No. 193,055) has been proposed, but an example without using an organic solvent is also described. Not listed.

As described above, although various methods for stabilizing the isothiazolone compound have been proposed, a wide concentration range can be obtained without using a metal salt such as magnesium ion or calcium ion or an organic solvent which may cause emulsion shock. However, a method for stabilizing an isotizazolone compound in water has not been completed.

The present invention has been made under such circumstances, and has been used to convert metal salts such as magnesium ions and calcium ions, which cause latex emulsion shock, into metal salts and organic compounds that cause latex emulsion shock in a wide concentration range that has not been achieved so far. The aim is to provide Isothia Vlone products that have excellent product stability over a long period of time and have little impact on the environment without using solvents.

Another object of the present invention is to provide a method for producing this isotizazolone preparation. Disclosure of the invention

From the above viewpoints, the present inventors have conducted intensive studies and as a result, have found that a 5-bromo-5-nitro-11,3-dioxane derivative and a solubilized or solubilized solution in an aqueous solution of an unstable isothiazolone compound. It has been found that by adding a very small amount of a surfactant sufficient to disperse and prepare the surfactant, it is possible to obtain practically no problematic stability without using an organic solvent.

The organic solvent is a liquid organic compound used when a solute is dissolved to form a solution. In the present invention, acetic acid is sometimes used to prepare a buffered aqueous solution, but it is not an organic solvent because the amount of addition is extremely small. The same applies to stabilizers and surfactants. Therefore, in the present invention, although the preparation contains an organic compound, it is substantially an organic solvent. Is not used.

Thus, the Isotia Vron preparation according to the present invention

(A) General formula (1)

—General formula (1)

(However, X and Y in the formula are the same or different, and represent a hydrogen atom or a halogen atom, R represents an alkyl group having 1 to 8 carbon atoms, and the alkyl group may be straight-chain or branched.) An isothiazolone compound represented by or a mixture of any ratio thereof,

(B) an amount of water or a buffered aqueous solution sufficient to at least dissolve the compound of the general formula (1),

(C) The following general formula (2) blended as a stabilizing component

General formula ( ² )

(Wherein and R ₂ are the same or different, and represent a hydrogen atom or a lower alkyl group having 1 to 5 carbon atoms) At least one of the 5-bromo-5-nitro-1,3-dioxane derivatives represented by Type and

(D) a surfactant in an amount sufficient to dissolve the dioxane derivative,

As described above, it is characterized by comprising four components.

The substituents X and Y of the isothiazolone compound of the formula (1) used in the present invention are the same or different and represent a hydrogen atom or a halogen atom. Examples of the halogen atom include a chlorine atom, a bromine atom and an iodine atom, and a chlorine atom is preferred. R represents an alkyl group having 1 to 8 carbon atoms, and may be linear or branched. Further, a mixture irrespective of these ratios may be used.

Specific examples of the isothiazolone compounds of the formula (1) include 5-chloro-2-methylisothiazolin-3-one, 2-methylisothiazoline-1-one, and 2-isothiazolone. n-octylisothiazoline-3-one, 4,5-dichloro-2-n-octylisothiazoline-3-one, 2-ethylisothiazoline-3-one, 5-methyl-2-ethylisothiazoline-3-one And preferably 5-chloro-2-methylisothiazoline-1-one, 2-methylisothiazoline-1-one, 2-n-octylisothiazoline-3-one, and 4,5-dichloro-2-n-one. Luisothiazolin-1-one is more preferable, and 2-methylisothiazolin-13-one and 5-chloro-2-methylisothiazolin-13-one are more preferable. These isothiazolone compounds may be used in a mixture regardless of the ratio. These isothiazolone compounds can be synthesized, for example, according to the method of GA Mi 11er et al. (J. Heterocyclic Chem., 8, 581-586 (1971)).

In the present invention, the 5-bromo-5-nitro-1,3-dioxane derivative of the formula (2) is used as a stabilizer (C) for a preparation. In this compound (2), R! And R ₂ are the same or different and represent a hydrogen atom or a lower alkyl group. The lower alkyl group refers to an alkyl group having 1 to 5 carbon atoms, which may be linear or branched, such as a methyl group, an ethyl group, a normal propyl group, an isopropyl group, a normal butyl group, an isobutyl group, and a butyl group. Butyl group, normal pentyl group and the like.

Specific examples of the compound of the above formula (2) include 5-bromo-5-nitro-1,3-dioxane, 5-promo-2-methyl-15-nitro-1,3-dioxane, 5-promo-1, 2-dimethyl-5-nitro-1,3-dioxane, 5-promo 2-ethyl-5-nitro-1,3-dioxane, 5-promo 5-nitro-1 2-normalprovir 1,3-dioxane, 5-bromo-2,2-getyl-1-5-nitro-1,3-dioxane; 5-bromo-12-ethyl-2-methyl-5-nitro-1,3-dioxane; These may be used not only in one kind but also in combination of two or more kinds.

These compounds have the formula (3)

Equation (3) 2-promo 2-nitro-1,3-propanediol represented by

General formula (4)

〇

R, ^ F¾ General formula (4)

(Wherein, and R ₂ have the same meanings as in the general formula (2)) and the method of STAN LEY R. et al. (J. Soc. Cosmet. Chem., 35) , 73-93 (1984)).

Among the stabilizers thus obtained, 5-bromo-5-nitro-1,3, -dioxane, 5-bromo-2-methyl-5-nitro-1,3 —Dioxane is particularly preferred. Although these compounds have bactericidal properties, they are known to be compounds with very little irritation to the human body and the environment, and also meet the purpose of the present invention.

Further, in the present invention, a surfactant is used for solubilizing or dispersing the stabilizing component (C) which is hardly soluble in the aqueous solution of the isothiazolone compound to obtain a predetermined concentration of the stabilizing agent in the preparation. As the surfactant, anionic, cationic, or nonionic surfactants can be used, and among them, anionic or nonionic surfactants are preferable in terms of economic efficiency and formulation stability. Alkyl benzene sulfonic acid and its salts, alkyl (phenyl) ether sulfate, and polyolefin sulfonic acid salt can be used as the anionic surfactant, and the higher alcohol surfactant is used as the nonionic surfactant. Agents and alkylphenol-based surfactants can be used. In particular, sodium tetradecenesulfonic acid salt is preferred from the viewpoint of the stability of the preparation. This surfactant is also used as a raw material for cosmetics and is a surfactant that is less irritating to the human body.

In the isothiazolone preparation provided by the present invention, in addition to water, a buffered aqueous solution in an amount necessary to maintain the liquid property at ρΗ2 to 6 can be used.

The stability of the isothiazolone compound is also affected by ρΗ. When ρ Η2 or less, the stability becomes very poor and decomposition proceeds. The isothiazolone compound decomposes The pH is further reduced to produce hydrochloric acid, and the degradation is further accelerated below pH 1.

The isotizazolone compound is stable even in this formulation using water, but a decrease in pH is inevitable. The present inventors have found that the use of various buffered aqueous solutions can alleviate the decrease in pH and improve the stability of the isothiazolone preparation as compared with water.

As the kind of the buffer aqueous solution used here, acetic acid / sodium acetate system, fluoric acid / hydrogen phthalate power system, phosphoric acid / sodium phosphate system and the like can be used. Particularly, an aqueous solution of acetic acid / sodium acetate buffer is most preferred in terms of formulation stability and economy.

The concentration of the aqueous buffer solution may be an amount sufficient to maintain pH within a predetermined range. Specifically, 0.1 N to 2.0 N is preferable. If the concentration is higher than this, not only will there be no economic advantage, but also the stability of the preparation may be impaired.

The preparation of the present invention is prepared by diluting the isothiazolone compound represented by the formula (1) with water or a buffered aqueous solution so as to obtain a desired concentration, and preparing a predetermined amount of the above-mentioned stabilizing component (C ) And its stabilizing component can be prepared by adding a surfactant (D) in an amount sufficient to solubilize the same in a solution. When the stabilizing component (C) is difficult to dissolve, heating for a short time can solubilize the stabilizing component (C) without impairing the stability of the preparation.

The compounding amount of the compound of the general formula (1) in the preparation of the present invention is preferably 0.5 to 40% by weight from the viewpoint of storage stability, 0.5 to 30% by weight, and more preferably 1 to 20% by weight. % Is particularly preferable from the viewpoint of economical advantage in storage and transportation ゃ storage stability. The amount of the 5-bromo-5-nitro-1,3-dioxane derivative represented by the general formula (2) as the stabilizing component (C) is 0.1 to 5% by weight of the preparation in terms of storage stability. From the viewpoint of stabilizing effect and economical aspect, the amount of use is preferably 0.5 to 2% by weight.

When the stabilizing component (C) and the surfactant (D) are contained together, the preparation can be stably maintained for a longer period of time than when only the stabilizing component (C) (dioxane derivative) is used. If the surfactant (D) is not added, stabilize this aqueous solution of isothiazolone. Minute (c) is difficult to dissolve or disperse and it is difficult to add a predetermined concentration. In addition, it has been confirmed that the surfactant (D) alone cannot stabilize the aqueous solution presented in the present invention to practical use within a predetermined concentration range. Therefore, the remarkable stabilizing effect of the preparation presented by the present invention is due to the combined use of the stabilizing component (C) and the surfactant (D). Preferred implementation of the departure date

Next, the present invention will be described in more detail with reference to Examples and Comparative Examples, but the present invention is not limited to these.

(A) Preparation of formulation (1): Examples 1 to 6

The corresponding germicidal composition was prepared. One example of the preparation method is shown below.

Hereinafter, 2-methylisothiazolin-1-one is referred to as MT, and 5-methyl-2-thiocyanone-Vin-3-one is referred to as CMT.

1.0 Og of the stabilizer, 5-promo-2-methyl-5-nitro-1,3-dioxane, and 2.00 g of the surfactant, Triton X were placed in a container. Separately, 55.05 g of a buffer solution obtained by mixing a 0.2 N aqueous acetic acid solution and a 0.2 N aqueous sodium acetate solution at a volume ratio of 4: 1 has a CMT of 91.53% by weight and an MT of 8. 89.57 g of a mixture of two kinds of isothiazoopene compounds consisting of 47% by weight was added to prepare an aqueous solution of isothiazoopene. 100.03 g of this aqueous solution was added to the above-mentioned container, and the mixture was stirred until it became uniform, whereby Preparation 1 was prepared. Similarly, Formulations 2 to 6 were prepared as shown in Table 1.

1. Preparation of drug product (1)

Example 1 2 3 4 5 6

Formulation 1 2 3 4 5 6

CMT 12.01 12.24 18.66 18.87 1.185 0.813

MT 1.22 1.13 1.73 1.75 0.109 0.075

Stabilizer (2) (1) (2) (1) (2) (2)

0.971 0.972 0.973 0.972 0.971 0.973

Surfactant 1.946 1.954 1.949 1.947 1.943 0.2009

• As the stabilizer, (1) represents 5-bromo-5-nitro-1,3-dioxane, and (2) represents 5-bromo-12-methyl-5-nitro-1,3-dioxane.

• In Examples 1 to 6, the surfactant is U C. Using Triton X-100 manufactured by Azbil Corporation and using a 0.2 N aqueous solution of acetic acid and a 0.2 N aqueous solution of sodium acetate in a 4: 1 volume ratio to obtain a buffer solution of pH 4.1. did.

(B) Heat-stabilizing punch test and test results of preparation (1): 卖 Examples ₇ to 1

The six preparations prepared in (A) were left in a thermostat at 55 ° C, and the content of the isothiazolone compound was analyzed at regular intervals by high performance liquid chromatography. Table 2 shows the results. Thermal stability test results of preparations (1)

Example 7 8 9 10 11 12 Formulation 1 2 3 4 5 6

97.3 98.8 99.7 99.9 101 100

1 week 97.3 99.1 99.4 98.9 102 100 Pale yellow transparent Pale yellow transparent Pale yellow transparent Pale yellow transparent Colorless transparent Colorless transparent

99.2 97.2 4.5 0 99.8 101

2 weeks 100 98.2 56.9 5.7 100 102 Transparent pale yellow Transparent pale yellow

18.1 27.0 99.9 100

3 weeks 96.2 91.2 100 102 Heavy precipitation Heavy precipitation Very pale yellow

102 101

4 weeks 100 102 Very pale yellow

• The numerical values indicate the residual ratio (%) obtained from the analysis results using Watanabe Liquid Chromatography.

'The upper row shows the CMT residual rate, the middle row shows the MT residual rate, and the lower row shows the appearance observed visually. As is evident from Table 2, the residual amount of isotizazolone in the drug product is related to the appearance of the aqueous solution. This product was colorless and transparent at the time of preparation, but gradually turned yellow when heated. At that time, more than 95% of the isothiazolone remained. Thereafter, the color slowly increased and at some point a large amount of sedimentation occurred. At this time, the isothiazolone remaining in the solution was less than 40%, and it was judged that isothiazolone had decomposed at this point.

(C) Preparation of preparation (2): Example 13 to 18

The corresponding germicidal composition was prepared. Table 3. Preparation of drug product (2)

Example 13 14 15 16 17 18

Formulation 7 8 9 10 11 12

Stabilizer (2) (1) (2) (1) (2) (2)

Dilution buffer Buffer water Water Buffer Buffer Buffer

For the isothiazolone compound, a mixture of CMT, 91.5% by weight and MT, 8.5% by weight was used, and the concentrations in the preparation were adjusted to 11.6% by weight and 1.1% by weight, respectively.

The concentration of all stabilizers is 1.0% by weight, and the surfactant is Triton from UCC.

X-100 was used and the concentration was 2.0% by weight.

As the stabilizer, (1) is 5-bromo-5-nitro-1,3-dioxane, and (2) is 5-promo-2-methyl-5-twotro 1,3-dioxane.

As the buffer aqueous solution, a 0.2 M acetic acid aqueous solution and a 0.2 M sodium acetate aqueous solution were mixed at a volume ratio of 4: 1 to obtain a pH of 4.1.

In Example 17, 4.6% by weight of sodium chloride was added.

In Example 18, the preparation 11 of Example 17 was diluted 100-fold with water.

(D) Coagulated cattle. Test: conducted, Example 1 9-24

Using the formulations 7 to 12 shown in Table 3, an emulsion shock test was performed on the synthetic polymer aqueous dispersion styrene-butadiene polymer latex.

The test method was performed as follows. About 5 ml of the synthetic polymer aqueous dispersion styrene-butadiene polymer latex was added to a Petri dish, and 4 to 5 drops of the preparation shown in Table 3 was added thereto, and thoroughly mixed with a spoon. As a comparative example, Zone C manufactured by Takakawa Synthetic Chemical Company was similarly tested. Table 4. Emulsion shock test results

Example 19 20 21 22 23 24

Formulation Comparative Example 1 7 8 9 10 11 12

Emulsi, yeon

SB5028 X 〇〇〇〇〇〇〇

SB1341 X X 〇〇〇〇 X 〇

SBR0591 X X 〇〇〇〇〇〇〇

Awake 1561 X X 〇〇〇 X 〇 In this table, 〇 indicates that no aggregation occurred, X indicates that a small amount of aggregation occurred, and XX indicates that severe aggregation occurred.

Zonen C, shown as a comparative example, is widely used as a fungicide, but contains a magnesium salt to stabilize isotizazolone. Normally, it is used after being diluted to a concentration of several hundred ppm, but in this comparative example, the stock solution was used as it was. As a result, aggregation occurred in all the dispersions. On the other hand, when the buffer solution was used as in Examples 19 to 22, no aggregation occurred in this formulation.

In Example 23, to examine the effect of the addition of sodium chloride, the composition 7 was tested with a composition containing 4.6% by weight of a salt. The addition of salt resulted in mixed results, with small amounts of aggregation occurring at SB1341 and NBR1561. However, no coagulation was observed in the composition of Example 24, which was prepared by diluting this 100-fold and using the formulation 12 having a practical concentration. It is clear that the addition of salt has no practical problem.

E (3) of (E): Example 25-54

Formulations 13 to 42 shown in Table 5 were prepared.

5 in Table 5 indicates the total concentration of 5-chloro-2-methylisothiazolin-3-one (CMT) and 2-methylisothiazolin-3-one (MT). CMT: MT The ratio is 9: 1. A thermostability test was performed at 55 ° C using this formulation. Table 5. Preparation of drug product (3)

Example Formulation A I Stabilizer Surfactant Not yet

Concentration Dark / Also

25 13 9.7 (1 \

U · 0 A Λ

I U

26 14 9.7 (9 u.

0 A 1. U No

27 15 9.3 (\

\ u) 1 Π A 0. O 7

28 16 7.8 (1 \ Λ

, 丄 me u .0 iy .y

29 17 7.8 \) J Λ

· 0 A i 1 Ωy.

30 18 7.8) u.

0 A iy · y no Λ

31 19 13.3 丄 1, n u A (Λ

32 20 12.8 L) U.0 A 1.0 7

33 21 12 fi L) 1.U A 2.0 Male

34 22 198 L) 1 uA 3.8 ";

H

35 23 \) 1 U 7.4

36 24 14 \

\ L) 1V Fiphono LH_200 1.0 (3.)

37 25 L) 1 · U Sanonol JLMr— 1430 5.6

38 26 14 9 L) 1. U Leo Jor SC — 90 2.9

39 14 1) 1.u Rehonox OC— 100 2.0 v „\

40 28 1 R l

(L) 1 u h

Liho Knox NC—500F 3.8

41 0 1 Λ

* J * <J L) 1.u B 7.4 la

42 30 1 9 ά) 1.UA 2.0

45 33 q fi \

L) 1.U A 3.8

46 34 13 uRu (9) 1 0 A 1 q

47 35 13.2 (2) 1.0 A 2.0 (a)

48 36 13.6 (2) 1.0 A 2.0 (c)

49 37 13.4 (2) 1.0 A 2.0 (a)

50 38 13.2 (2) 1.0 A 1.9 (a)

51 39 20.4 (2) 1.0 A 1.9 (a)

52 40 1.3 (2) 1.0 A 0.2 (a)

53 41 13.4 (2) 1.0 A 2.0 (a)

54 42 20.6 (2) 1.0 A 1.9 (a)

Promote 5-dioxane, (2) is 5-bromo-2-methyl-1-5-dioxane, 13-dioxane,

(3) represents 5-promo 2,2-dimethyl 5-nitro-1,1,3-dioxane, and the concentration is by weight.

As for the type of surfactant, A uses Triton X-100 from UCC, B uses Lipolan LB-440 from Lion, and all others use Lion's surfactant ₍ concentration is% by weight).

Solvents (a) are 0.2M, (b) is 2M, (c) is 0.02Μ, acetic acid / sodium acetate aqueous solution, (d) is 0.2M potassium hydrogen phosphate and 0.2M caustic It is a mixture of aqueous soda solutions at a volume ratio of 20: 1. (F) Results of heat stability punch test of drug product (2): Example 5 5-84 Table 6. Results of heat stability test of drug product (2)

Example Formulation Stability test results

υ Η 10 days 20 days 30 days 40 days 50 days

55 13 〇 Δ Δ x (21) X X

56 14 〇〇 x (12) X X X

57 15 〇〇 x (14) X X X

58 16 〇 x (7) X X X X

59 17 〇 x (5) X X X X

60 18 〇 x (7) X X X X

61 19 〇〇 x (say 20) X X X

62 20 〇 ι (say ιο) X X X X

63 21 〇〇 x (14) X X X

64 22 〇〇 x (13) X X X

65 23 〇〇 x (20) X X X

66 24 〇 △ x (17) X X X

67 25 〇〇〇 Δ x (39 days) X

68 26 〇〇〇 x (24) X X

69 27 〇〇 x (18) X X X

70 28 〇〇 △ x (25 days) X X

71 29 〇〇〇〇〇 x (48 days)

72 30 〇〇 x (say i8) X X X

73 31 〇〇 x (19) X X X

74 32 〇〇 x (17) X X X

75 33 〇〇 x (18) X X X

76 34 〇 x (9) X X X X

77 35 〇〇 x (18) X X X

78 36 〇 Δ x (ll) X X X

79 37 〇〇 x (18) X X X

80 38 〇〇 Δ x (21) X X

81 39 〇 x (9) X X X X

82 40 〇〇 Δ Δ △ △

83 41 〇〇 △ x (say 21) X X

84 42 X XXX で外観 ι ι XXX XXX XXX XXX 結果 XXX 結果結果結果 XXX XXX XXX 結果 XXX 結果 XXX XXX XXX XXX 結果 XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX 結果 XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX XXX. 〇 indicates that the appearance of the aqueous isothiazolone formulation is colorless and transparent to pale yellow and transparent, は indicates that a very small amount of turbidity has occurred, and X indicates that a large amount of precipitation has occurred and the isothiazolone seems to be completely decomposed. State.

(G) Preparation of drug product (4)

Formulations 43 to 50 shown in Table 7 were prepared.

A heat stability test at 55 ° C was performed using a preparation having the same meaning as AI in Table 7 above.

〇〇〇〇〇〇〇 X

Preparation of drug product: (4) 5

Say

Examples Formulation AI Stabilizer; (2) Liho. Run LB-440 NaCl

Concentration △ 〇〇〇〇〇 X X Concentration

85 43 12.7 0.9 7.0 4.4

86 44 13.4 0.9 9 6.8 0

87 45 13.5 says

0.9 5.9 0

88 46 13.6 0.9 5.2 0

89 47 14.1 1.0 1.7 0

90 48 13.7 0.7 5.2 0

91 49 13.9 0.4 3.6 0

92 50 14.2 0.2 1.8 0

5-Bromo-1-methyl-5-nitro-1

3-Dioxane was used.

All figures in the table are% by weight.

Lipolan LB-440 is a Lion surfactant.

(H) Results of heat stability test of drug product (3): Example 9 3-1100 Table 8. Results of heat stability test of drug product (3)

Example Formulation Stability test results

0 says 10 says 20 days 30 days 40 days 50 days

93 43 〇〇 x (39 days) X

94 44 〇〇〇 x (48)

95 45 〇〇〇 x (45 days)

96 46 〇〇 x (39 days) X

97 47 〇 x (30 days) X X

98 48 〇〇 x (34 days) X

99 49 〇 X X X

100 50 〇 X X X The meanings of △, △, X in the table are the same as in Table 6 above

(I) Preparation of preparation (5): Example of sushi application Table 9 · Preparation of formulation (5)

Examples Formulation Stabilizer Surfactant

101 51 (1) 6.8% by weight

102 52 (2) 6.8% by weight

'The compound used was a mixture of CMT, 78.5% by weight, MT, 21.5% by weight, and the concentration in the preparation was adjusted to 11.0% by weight and 3.0% by weight, respectively. A thermal stability test at 55 ° C. was performed using this formulation. AI in Table 9 indicates the total concentration of CMT and MT.

The stabilizing agent (1) is 5-promo 5-nitro-1,3-dioxane, and (2) is 5-bromo-12-methyl-1-5-nitro-11,3-dioxane. 1.0% by weight.

The surfactant used was Lipolan LB-440 manufactured by Lion Corporation.

All contain 6.3% salt by weight in the formulation.

(J Thermostability of formulation † Cattle test. I Closure () m 1 n ^ 104 Table 10. Results of thermal stability test of formulation (4)

Example Formulation Stability test results

0 days 10 days 20 days 25 days

103 51 〇〇 △ x (21)

104 52 〇〇 x (17th) X △, △, X in the table have the same meaning as in Table 6 above.

(K) Preparation of formulation (6): Example 105, 10R Table 11 1. Preparation of formulation (6)

Examples Formulation AI Stabilizer; (2) Liho. Run LB-440

% By weight% by weight% by weight

105 53 25.0 1.0 6.8

106 54 30.0 1.0 6.8 For the isothiazolone compound, a mixture of 91.5% by weight of CMT and 8.5% by weight of MT was used. AI in Table 11 indicates the total concentration of CMT and MT. 55 with this formulation. A thermal stability test at C was performed.

(L) formulation of thermostable袢試驗結罢_(5):卖施Example 1 0 ₇ 1 0 8 Table 1 2. Results of thermal stability test of drug product (5)

Example Formulation Stability test results

0 days 10 days 15 days 20 days 25 days

107 53 〇〇〇 x (18) X

108 54 〇〇〇〇 x (25) 〇, △, and X in the table have the same meaning as in Table 6 above.

(M) Preparation of Formulation (7) Examples 109 to 115 Table 1 3. Preparation of Formulation (7)

Examples Formulation A I Stabilizer; (1) Liho. Run LB-440

% By weight% by weight% by weight

109 55 20.0 11.1 1.7

110 56 25.0 13.9 2.1

111 57 30.0 16.7 2.5

112 58 35.0 6.7 1.0

113 59 35.0 19.5 2.9

114 60 40.0 6.7 1.0

115 61 40.0 22.3 3.3

A mixture of CMT, 91.5% by weight and MT, 8.5% by weight was used as the isothiazolone compound. AI in Table 13 indicates the total concentration of CMT and MT. A thermal stability test at 55 ° C was performed using this formulation.

(N) Results of heat stability test of drug product (5): Example 11 fi-1 2 2 Table 1 4. Results of heat stability test of drug product (6)

Example Formulation Stability test results

0 says 10 days 20 days 30 days 40 days

116 55 〇〇〇〇 x (40 days)

117 56 〇〇〇 x (29) X

118 57 〇〇 x (20 days) X X

119 58 〇〇 x (13) X X

120 59 〇〇 x (17 days) X X

121 60 〇 ι (ιο says) X X X

122 61 〇〇 x (16) XX △, △, X in the table have the same meaning as in Table 6 above.

(P) Comparative example: Comparative examples 2 to 6

As a comparative example, the compositions shown in Table 15 below were prepared and subjected to a stability test at 55 ° C. I got it. The results are shown in Table 16. Table 15. Preparation of drug product

μμ * Λ / 5ll, ¾¾ sweet

Surfactant

Concentration type

Δ9.8 water

Q 0 10 Lithium acetate-^

λ

49.7 A1.0 Water

5 8.9 A 10 water

n

0 13.4 B 7.4 Acetic acid, nota ',

Table 16 6. Thermal stability test results

Comparative example Stability test result

4 hours 1 2 3 3 4

2 Δ X X X X

3 Δ X X X X

4 〇 X X X X

5 〇〇 △ X X

6 〇〇〇〇 X In the table, 〇, 、, and X have the same meaning as in Table 6 above.

The preparation of the present invention does not contain metal salts such as calcium salts and magnesium salts and has been conventionally used for stabilization of an isothiazolone compound in an aqueous solution. Has stability. In addition, since this drug formulation provides stability without using any organic solvent, there is little environmental pollution or adverse effects on the human body due to the organic solvent. Furthermore, it is economically inexpensive and has excellent characteristics as a pharmaceutical preparation.

Claims

General formula (1)

General formula (1)

. Chief

(Wherein X and Y in the formula are the same or different and represent hydrogen or a halogen atom, R represents an alkyl group having 1 to 8 carbon atoms, and the alkyl group is a straight-chain alkyl group.

But it may be branched. ) Or a mixture of any of the isothiazolone compounds represented by

General formula (2) Open

General formula (2)

(Wherein, R and R ₂ in the formula are the same or different and each represent a hydrogen atom or a lower alkyl group having 1 to 5 carbon atoms) at least one of a 5-nitro-5-nitro-1,3-dioxane derivative represented by An isothiazolone preparation comprising one type, a surfactant necessary for dissolving or dispersing the dioxane derivative, and water or a buffered aqueous solution, and containing substantially no organic solvent.

The isothiazolone compound represented by the general formula (1) is a compound in which R is a methyl group, X is a hydrogen atom, and Y is a chlorine atom; 5-methyl-2-methylisothiazolin-3-one; or R is a methyl group; 2. The isothiazolone preparation according to claim 1, which is 2-methylisothiazolin-3-one in which X and Y are hydrogen atoms, or a mixture of any kind thereof.

The isothiazolone preparation according to claim 12, wherein the dioxane derivative is contained in the preparation in an amount of 0.1 to 5% by weight.

4. The isothiazolone preparation according to claim 1, wherein the surfactant is an anionic surfactant or a nonionic surfactant.

5. The isothiazolone preparation according to claim 1, wherein the preparation contains an amount of a buffered aqueous solution necessary for maintaining the pH of the solution at pH 2 to 6.

6. The isothiazolone preparation according to claim 5, wherein the buffer aqueous solution is an acetic acid / sodium acetate aqueous solution.

7. The isothiazolone preparation according to any one of claims 1 to 6, wherein the isothiazolone compound of the general formula (1) is contained in the preparation in an amount of 0.5 to 40% by weight.

8. The isotizazolone preparation according to any one of claims 1 to 7, wherein the dioxane derivative represented by the general formula (2) is 5-bromo-2-methyl-5-two 1,3-dioxane.

9. The isothiazolone preparation _{c according} to any one of claims 1 to 7, wherein the dioxane derivative of the general formula (2) is 5-promo-5-ditro 1,3-dioxane.

10. General formula (1)

-Throw ceremony

(However, X and Y in the formula are the same or different and each represents hydrogen or a halogen atom, R represents an alkyl group having 1 to 8 carbon atoms, and the alkyl group may be linear or branched. ) And a mixture of any of the isothiazolone compounds represented by the general formula (2)

General formula (2)

(Wherein R> and R ₂ in the formula are the same or different and represent a hydrogen atom or a lower alkyl group having 1 to 5 carbon atoms). 5-Promote 5-Nitro-1,3-dioxane derivative A method for producing an IsothiaVlone preparation, comprising dissolving at least one kind of surfactant and a surfactant necessary for dissolving or dispersing the dioxane derivative in water or a buffered aqueous solution.

11. In the above isothiazolone compound of the general formula (1), R is a methyl group, and X is a hydrogen atom. 5 -chloro-2-methylisothiazolin-3-one where Y is a chlorine atom, or 2-methylisothiaV-lin-3-one where R is a methyl group and X and Υ are hydrogen atoms, or the ratio of the types The method for producing an isothiazolone preparation according to claim 10, wherein the mixture is any mixture.

12. The method according to claim 10, wherein the amount of the dioxane derivative represented by the general formula (2), which is dissolved in water or an aqueous buffer solution, is 0.1 to 5% by weight of the isothiazolone preparation to be produced. A method for producing an isothiazolone preparation.

13. The method for producing an isothiazolone preparation according to any one of claims 10 to 12, wherein an anionic surfactant or a nonionic surfactant is used as the surfactant.

14. The process for producing an isothiazolone preparation according to any one of claims 10 to 13, wherein an amount of a buffered aqueous solution necessary for maintaining the liquid property at ρΗ2 to 6 is used.

15. The method for producing an isothiazolone preparation according to claim 14, wherein an aqueous solution of acetic acid / sodium acetate is used as the buffer aqueous solution.

16. Claims 10 to 15 wherein the amount of the isothiazolone compound of the general formula (1) dissolved in the water or the aqueous buffer solution is 0.5 to 40% by weight of the isothiazolone preparation to be produced. A method for producing the isotizazolone preparation according to the above.

17. The method for producing an isothiazolone preparation according to any one of claims 10 to 16, wherein the dioxane derivative represented by the general formula (2) is 5-promo 2-methyl-5-ditro-1,3-dioxane. .

18. The method for producing an isothiazolone preparation according to claim 10, wherein the dioxane derivative represented by the general formula (2) is 5-bromo-5-nitro-1,1-dioxane.