KR101946928B1 - A solid composition comprising iodide and sodium chloride with improved water solubility - Google Patents

Abstract

The present invention relates to a solid composition containing an iodine agent and sodium chloride having improved water solubility. The solid composition contains the iodine agent and sodium chloride, or a mixture of the iodine agent, sodium chloride and a flavoring agent, and is excellent in storage stability and water solubility, as a dissolution rate thereof for water is 30 seconds or less.

Description

[0001] The present invention relates to a solid composition comprising iodine and sodium chloride having improved water solubility, and a solid composition comprising iodide and sodium chloride with improved water solubility,

The present invention relates to a solid composition comprising iodine and sodium chloride with improved water solubility.

Disinfectants are drugs that have a wide range of activity against a number of pathogens causing infection, and they do not exhibit resistance while destroying bacteria and viruses as well as many other microorganisms. Particularly, among the disinfectants, iodine disinfectants are known to exhibit a wide range of activity against various viruses and bacteria in a short time.

Povidone iodine is a chemical combination of polyvinylpyrrolidone (povidone, PVP) and iodine, usually containing 9 to 12% iodine. It has been widely used as an antiseptic disinfectant for the prevention and treatment of wound infections, and is also effective for yeast, fungi, fungi, viruses and protozoa. However, povidone iodine has been produced and sold mostly in solution, despite its excellent activity and wide application.

The high concentration of povidone iodine solution at 10% is relatively stable, but when used for disinfection of the eye, nasal cavity, or oral cavity, high povidone iodine can not be used for the ciliary mucosal layer or epithelium layer because it damages the cilia. Only low concentration povidone iodine solution is available. However, when the povidone iodine solution is flowed in a dilute solution of low concentration to provide convenience of use, the activity of the iodine agent is rapidly lowered, and the lifetime of the product is shortened. Therefore, low concentrations of povidone-iodine are difficult to circulate or store for long-term, and to date no products have been marketed with less than 0.3% of povidone-iodine-containing disinfectants.

When a low concentration povidone iodine solution is to be used, it is required to dilute the high concentration solution just before use. However, it is inconvenient to dilute the high concentration solution, and the concentration of the high povidone iodine solution on the market is not constant, There is a problem that a general person or a patient can not make a solution of a precise concentration suitable for the purpose immediately before use.

Compared to the unstable solution of low concentration of povidone iodine, solid povidone iodine has very stable characteristics. Solid povidone iodine is stable at room temperature as well as at room temperature when stored in sealed condition, and iodine loss is effective at 0.5% for 3 years at a temperature of 65 ° C. Therefore, povidone iodine in a solid state is a very stable substance that does not lose activity, and can be a good solution to the storage stability problem because it can be stored for a long period of time.

However, when the solid povidone iodine is practically used in a home or a hospital, it takes a long time to dissolve in water. Povidone iodine is water-soluble, but when it dissolves in water, it forms a lump on the surface of water, sticks to the surface of the container and does not come off easily. It takes a long time to dissolve completely.

U.S. Patent No. 04950653 discloses that it takes 45 minutes to dissolve povidone iodine in water. In addition, when povidone iodine is mixed with urea and sugar alcohol, it takes more than 2 minutes to dissolve in water, but the application is limited due to problems such as stability and safety including urea.

Therefore, there is no prior literature disclosing a composition which uses solid povidone iodine for storage stability, but which has improved solubility during use and is convenient for use.

U.S. Patent No. 04950653 (Solid iodophor composition, registered on Aug. 21, 1990) United States Patent No. 05126127 (Stabilized PVP-I solutions, registered on June 30, 1992)

The present invention is to provide a solid composition comprising an iodine agent and sodium chloride having improved water solubility.

The present invention relates to a solid composition comprising a mixture of 0.2 to 50 parts by weight of iodine and 100 parts by weight of sodium chloride, wherein the dissolution rate in water is 30 seconds or less, 0.4 to 25 parts by weight of iodine and 100 parts by weight of sodium chloride, and the dissolution rate in water is 15 seconds or less.

Further, when the solid composition having a dissolution rate in water of 30 seconds or less is dissolved in 100 ml of water, 0.01 to 0.5 w / v% of iodine and 1 to 5 w / v% of sodium chloride are contained. Particularly, in the case of iodine-containing povidone-iodine, the lowest concentration capable of exerting a pharmacological effect is 0.01 w / v%, and even when containing a solid composition of 0.2 to 50 parts by weight of iodine and 100 parts by weight of sodium chloride, If the final concentration is less than 0.01 w / v%, the pharmacological effect is low and it is not preferable for use. In addition, if the final concentration of povidone-iodine dissolved in water exceeds 0.5 w / v%, it is not suitable for use because it is too stimulating when applied to the respiratory system.

The iodine agent is selected from the group consisting of povidone iodine, cadexomer iodine and poloxamer iodine, and it is preferable to use povidone iodine with excellent antiviral and antibacterial effect.

The sodium chloride is a water-soluble solid salt, which is a salt of a cation selected from the group consisting of sodium, potassium, ammonium, lithium or zinc and an anion selected from the group consisting of chloride, bromide or iodide in 0.2 to 50 parts by weight of iodine It is also possible to mix at least one kind of salt selected from the resulting salts in 100 parts by weight, but it is preferable to use 100 parts by weight of sodium chloride.

The solid composition is preferably in the form of powder, more preferably 30 mesh or more (600 mu m or less) in powder size, and most preferably 60 mesh or more (250 mu m or less) in powder particle size.

In addition, the solid composition may further comprise 0.001 to 2 parts by weight of fragrance. The fragrance is used for shielding the odor and taste of iodine. The fragrance can be selected from among the fragrances listed in the International Flavors Association (IFRA), and it is preferable to use the fragrance and the fragrance, It is preferable to use a stable substance which does not react with iodine. It is preferable to use a compound having a functional group such as saturated alkyl, acid, alcohol, ester, ether, lactone, ketone or aromatic.

Specifically, the perfume can be selected from the group consisting of butyl acetate, amyl acetate, isoamyl acetate, hexyl acetate, 2-hexyl acetate, ethyl propionate ethyl propionate, butyl propionate, isobutyl propionate, isoamyl propionate, ethyl butyrate, ethyl 2-methylbutyrate, Butyl isobutyrate, ethyl hexanoate, ethyl pivalate, methyl 4-methylvalerate, ethyl valerate, ethyl isobutyrate, ethyl isobutyrate, But are not limited to, ethyl isovalerate, isopropyl isovalerate, ethyl lactate, 2-pentanone, heptanoic acid, 3-heptanone, ), 2,3-hexanedione ( 2,3-hexanedione, d-camphor, p-methyl anisole, 2-methoxy-6-methyl pyrazine, But are not limited to, 1,8-cineole, 1,4-cineole, benzyl methyl ether, 3-heptanol, isoamyl isovalerate but are not limited to, isoamyl isovalerate, butyl valerate, butyl lactate, methyl benzoate, ethyl benzoate, propyl benzoate, butyl benzoate, benzoate, isobutyl benzoate, amyl benzoate, isoamyl benzoate, methyl phenylacetate, ethyl phenylacetate, benzyl acetate, , Sasafras acetate, isobornyl acetate, ethyl 3-phenylpropionate, 2-methyl- 2-methyl-5-ethoxypyrazine, 2-methyl-6-ethoxypyrazine, 2,3-diethyl- diethyl-5-methylpyrazine, 5-methyl-6,7-dihydro-5H-cyclopentapyrazine, 2-acetyl pyrazine, Acetylpyridine, 2-acetyl pyridine, 3-acetyl pyridine, 2-t-butyl cyclohexanone, p-dimethyl- P-dimethyl-hydroquinone, isoquinoline, 2,3-dimethyl-benzofuran, 3,6-dimethyl benzofuranone, Ambernaphthofuran, pt-butyl-cyclohexanone, thymol methyl ether, 3-phenylpropyl alcohol, 2,6-dimethoxy 2-t-butyl-6-methyl-phenol, l-menthol, dl- Such as dl-menthol, d-neomenthol, menthone lactone, p-ethyl acetophenone, skatole, diphenyl ether, such as? -naphthyl methyl ether,? -naphthyl ethyl ether, saffron indenone, ambroxide, (-) - ambroside ( - -) - ambroxide, phenylacetic acid, watermelon ketone, dihydroactinidiolide, 3-butyl phthalide, borneol, dl-isoborneol, thymol, exaltolide, exaltone, menthyl lactate, methyl dihydrojasmonate, ethylenebis Ethylene brassylate, t-hydrofurfuryl phenylacetate, 2- (3-phenylpropyl) pyridine, (±) -mus (±) -muscone, (-) - muscone, isomuscone, normuscone, cyclohexadecanone, celestolide, , Sandal cyclopropane, aniseed oil, eucalyptus oil, and peppermint oil. In the present invention,

The solid composition comprising 0.2 to 50 parts by weight of the iodine of the present invention and 100 parts by weight of sodium chloride does not deteriorate even after long-term storage, has a high storage stability, is kept in a moisture-proof, light-shielded and airtight state, USP grade water for injection, distilled water, purified water, physiological saline, tap water or sterilized water). Further, if the solid composition is dissolved in physiological saline immediately before use, the sodium chloride concentration of the final aqueous solution composition is used so as not to exceed 5 w / v%.

In another aspect, the present invention provides an antiviral agent for the respiratory tract of the eye, nasal cavity, oral cavity, pharynx, larynx, bronchus and lung, comprising a solid composition comprising a mixture of 0.2 to 50 parts by weight of iodine and 100 parts by weight of sodium chloride, To an antimicrobial composition. In particular, in the case of an aqueous solution in which the above solid composition is dissolved in water, it is possible to sterilize all tissues of the respiratory system such as eyes, nasal cavity, oral cavity, pharynx, larynx, bronchus, Do.

The present invention relates to a solid composition comprising iodine and sodium chloride with improved water solubility. The solid composition comprises an iodine agent and a sodium chloride or a mixture of an iodine agent, sodium chloride and a flavoring agent and is excellent in water solubility not only in storage stability but also in a water dissolution rate of 30 seconds or less.

Hereinafter, preferred embodiments of the present invention will be described in detail. However, the present invention is not limited to the embodiments described herein but may be embodied in other forms. Rather, the intention is to provide an exhaustive, complete, and complete disclosure of the principles of the invention to those skilled in the art.

≪ Example 1: Preparation of mixed solid composition of povidone iodine and sodium chloride with improved stability and solubility >

Sodium chloride and fragrance pulverized to 30 mesh or more (not more than 600 mu m) were put into a mortar and poured into a mortar for 5 minutes, To prepare a solid composition in powder form having improved stability and solubility.

Condition Povidone iodine (g) Chloride
Sodium (g) Fragrance (g) Spices used (g) Total usage
Perfume amount (g) Example 1 0.2 1.5 - - Example 2 0.2 2.5 - - Example 3 0.2 3.5 - - Example 4 0.1 1.5 - - Example 5 0.1 3.5 - - Example 6 0.3 1.5 - - Example 7 0.3 3.5 - - Example 8 0.01 2.5 - - Example 9 0.5 2.0 - - Example 10 0.5 1.5 - - Example 11 0.1 2.5 Isoamyl acetate 0.001,
l-menthol 0.002,
(-) - Ambroside 0.0006,
Exaltolide 0.0003 0.0039 Example 12 0.1 2.5 d-camphor 0.001,
1,8-cineol 0.005,
l-menthol 0.002,
(-) - Ambroside 0.0004,
Exaltolide 0.0002 0.0086 Example 13 0.2 2.5 Isoamyl acetate 0.001,
l-menthol 0.002,
(-) - Ambroside 0.0006,
Exaltolide 0.0003 0.0039 Example 14 0.2 2.5 d-camphor 0.001,
1,8-cineol 0.005,
l-menthol 0.002,
(-) - Ambroside 0.0006,
Exaltolide 0.0003 0.0089 Example 15 0.2 2.5 2-hexyl acetate 0.0005,
Butyl propionate 0.0005,
Butyl isobutyrate 0.0005,
Ethyl valerate 0.0005,
2-pentanone 0.0005,
l-menthol 0.001,
(-) - Ambroside 0.0004,
Exaltolide 0.0002 0.0041 Example 16 0.2 2.5 Isoamyl acetate 0.001,
Butyl valerate 0.0005,
Isobornyl acetate 0.0005,
Isoquinoline 0.0003,
Ambernaphthofuran 0.0003,
Exaltolide 0.0002 0.0028 Example 17 0.3 2.5 Isoamyl acetate 0.001,
l-menthol 0.002,
(-) - Ambroside 0.0006,
Exaltolide 0.0003 0.0039

< Comparative Example  1. Compared to Povidone  Preparation of mixed solid composition of iodine and sodium chloride &gt;

The solid compositions of Comparative Examples 1 to 11 were prepared in the same manner as in Example 1, with reference to Table 2 below.

Condition Povidone iodine (g) Chloride
Sodium (g) Spices Spices used (g) Total usage
Perfume amount (g) Comparative Example 1 0.2 - - - Comparative Example 2 2.5 2.5 - - Comparative Example 3 5 2.5 - - Comparative Example 4 0.2 0.2 - - Comparative Example 5 0.2 0.1 - - Comparative Example 6 0.2 - Isoamyl acetate 0.001,
l-menthol 0.002,
(-) - Ambroside 0.0006,
Exaltolide 0.0003 0.0039 Comparative Example 7 0.2 Sodium sulfate
Anhydride 2.5 - - Comparative Example 8 0.2 Ammonium chloride
2.5 - - Comparative Example 9 0.2 Potassium chloride
2.5 - - Comparative Example 10 0.2 Potassium bromide
2.5 - - Comparative Example 11 0.2 D-mannitol
2.5 - -

< Experimental Example  1. Check storage stability>

To confirm the storage stability of the solid composition of the present invention, Examples 2 and 11 were placed in a mortar and ground for 3 minutes to prepare a uniform mixture. The mixture was placed in a 5 ml brown glass vial and the lid was closed The samples were stored in a 60 ° C incubator for 2 weeks, and the loss of iodine was measured at intervals of one week. Examples 2 and 11 were repeated three times, and the temperature condition of 60 ° C was a severe condition for the relative stability of the drug.

In order to measure the amount of iodine lost, each sample was taken out at intervals of one week, and the mixture, which was contained in 5 ml of glass vial, was dissolved in distilled water (100 ml) and titrated with 0.01 N sodium thiosulfate standard solution Respectively. The amount of iodine lost was calculated as 1.269 mg of iodine per 1 ml of 0.01 N sodium thiosulfate standard solution, and is shown in Table 3.

Condition Amount of iodine lost (%) Early After 1 week after 2 weeks Example 2 0 0.67 1.04 Example 11 0 0.75 1.30 Example 2 was dissolved in 100 ml of water
Dissolved aqueous solution 0 33.0 65.5

Referring to Table 3, the solid compositions of Examples 2 and 11 of the present invention showed very little amount of iodine lost within 2 weeks at a high temperature of 60 캜, within 1.5%. However, when the aqueous solution in which the solid composition of Example 2 was dissolved in water was measured at high temperature of 60 캜 for 2 weeks, the amount of iodine lost was 50 times or more as compared with the solid composition, and the concentration of povidone iodine remaining was 0.1% And the storage stability was very low.

Thus, it can be confirmed that the solid composition comprising a low concentration of the iodine agent and the sodium chloride as in the present invention remains effective even after long-term storage, and does not deteriorate its activity and has high storage stability.

Experimental Example 2. Determination of dissolution rate in water [

The compositions of Examples 1 to 17 and Comparative Examples 1 to 11 were placed in a 100 ml glass bottle and 100 ml of distilled water at 25 ° C (± 0.5 ° C) was added and stirred at 300 rpm in a magnetic stirrer, And the comparative example was repeated three times. In the case of the time required for complete dissolution of povidone iodine in water, the time from when the residual povidone iodine completely disappeared from the vessel wall in the solution containing distilled water was measured and shown in Table 4 below.

Condition Complete dissolution time (seconds) Example 1 12 Example 2 10 Example 3 7 Example 4 8 Example 5 ≤ 5 Example 6 13 Example 7 8 Example 8 ≤ 5 Example 9 15 Example 10 23 Example 11 ≤ 5 Example 12 ≤ 5 Example 13 10 Example 14 10 Example 15 10 Example 16 10 Example 17 12 Comparative Example 1 900 Comparative Example 2 640 Comparative Example 3 650 Comparative Example 4 600 Comparative Example 5 630 Comparative Example 6 930 Comparative Example 7 1044 Comparative Example 8 60 Comparative Example 9 60 Comparative Example 10 120 Comparative Example 11 80

As shown in Table 4, it was confirmed that the solid composition of the present invention was a composition which dissolves very rapidly in water, because the dissolution rate in water is 30 seconds or less.

However, as in Comparative Example 1 and Comparative Example 6, it was found that the dissolution rate in water was 900 seconds or more, that is, 15 minutes or more in the absence of sodium chloride. In addition, in Comparative Example 7 using sodium sulfate instead of sodium chloride, the dissolution rate to water was very slow and the time required was 1044 seconds (about 17 minutes). Comparative Example 8 using ammonium chloride, Comparative Example 9 using potassium chloride, In Comparative Example 10 using D-mannitol and 60 to 120 seconds in Comparative Example 11 using D-mannitol, the dissolution rate in water was significantly lower than in the examples of the present invention.

In addition, although not shown in Table 4, when the amount of povidone iodine contained in the solid composition is less than 0.2 part by weight based on 100 parts by weight of sodium chloride, the dissolution rate in water is fast, but the effective amount for exhibiting antiviral and antimicrobial effects And it was confirmed that it is not suitable for use .

Therefore, the solid composition including the iodine agent and the sodium chloride mixture as in the present invention is not affected by activity even when stored for a long period of time and has high storage stability, is not affected by places such as home or hospital, There was no inconvenience at all.

Claims (10)

0.2 to 50 parts by weight of povidone iodine and 100 parts by weight of sodium chloride, wherein the dissolution rate in water is 30 seconds or less. The method according to claim 1,
Wherein said solid composition comprises a mixture of 0.4 to 25 parts by weight of povidone iodine and 100 parts by weight of sodium chloride and wherein the dissolution rate in water is 15 seconds or less. delete delete 3. The method according to claim 1 or 2,
Wherein the solid composition is in powder form and has a powder particle size of at least 30 mesh. 3. The method according to claim 1 or 2,
Wherein the mixture further comprises 0.001 to 2 parts by weight of fragrance. The method according to claim 6,
The perfume can be selected from the group consisting of butyl acetate, amyl acetate, isoamyl acetate, hexyl acetate, 2-hexyl acetate, ethyl propionate ), Butyl propionate, isobutyl propionate, isoamyl propionate, ethyl butyrate, ethyl 2-methylbutyrate, But are not limited to, butyl isobutyrate, ethyl hexanoate, ethyl pivalate, methyl 4-methylvalerate, ethyl valerate, ethyl isovalerate ethyl isovalerate, isopropyl isovalerate, ethyl lactate, 2-pentanone, heptanoic acid, 3-heptanone, 2,3-hexanedione d-camphor, p-methyl anisole, 2-methoxy-6-methyl pyrazine, 1,8-cineole (1 , 8-cineole, 1,4-cineole, benzyl methyl ether, 3-heptanol, isoamyl isovalerate, butyl But are not limited to, butyl valerate, butyl lactate, methyl benzoate, ethyl benzoate, propyl benzoate, butyl benzoate, Isopropyl benzoate, isobutyl benzoate, amyl benzoate, isoamyl benzoate, methyl phenylacetate, ethyl phenylacetate, benzyl acetate, sassafras acetate, isobornyl acetate, ethyl 3-phenylpropionate, 2-methyl-5-ethoxy 2-methyl-5-ethoxypyrazine, 2-methyl-6-ethoxypyrazine and 2,3-diethyl-5- methylpyrazine, 5-methyl-6,7-dihydro-5H-cyclopentapyrazine, 2-acetylpyrazine, acetylpyridine pyridine, 2-acetyl pyridine, 3-acetyl pyridine, 2-t-butyl cyclohexanone, p-dimethyl- dimethyl-hydroquinone, isoquinoline, 2,3-dimethyl-benzofuran, 3,6-dimethyl benzofuranone, ambernaphthofuran, ambernaphthofuran, pt-butyl-cyclohexanone, thymol methyl ether, 3-phenylpropyl alcohol, 2,6-dimethoxyphenol (2, 6-dimethoxyphenol, 2-t-butyl-6-methyl-phenol, 1-menthol, dl- menthol, d-neomenthol, menthone lactone, p-ethyl acetophenone, skatole, diphenyl ether,? -naphthyl methyl ether ( ? -naphthyl methyl ether,? -naphthyl ethyl ether, saffron indenone, ambroxide, (-) - ambroxide, phenyl But are not limited to, phenylacetic acid, watermelon ketone, dihydroactinidiolide, 3-butyl-phthalide, borneol, dl-isoborneol (dl isoborneol, thymol, exaltolide, exaltone, menthyl lactate, methyl dihydrojasmonate, ethylene brassylate, t-hydrofurfuryl phenylacetate, 2- (3-phenylpropyl) pyridine, (±) -mucone ((±) -muscone), (-) - muscone, isomuscone, normuscone, cyclohexadecanone, celestolide, sandal cyclopropane, and the like. Wherein the solid composition comprises at least one selected from aniseed oil, eucalyptus oil and peppermint oil. An antiviral and antimicrobial composition for the respiratory tract of the eye, nasal cavity, oral cavity, pharynx, larynx, bronchus and lung, comprising a solid composition containing povidone iodine and sodium chloride of claim 1 or 2. An antiviral and antimicrobial composition for the respiratory tract of the eye, nasal cavity, oral cavity, pharynx, larynx, bronchus and lung, comprising a solid composition comprising povidone iodine, sodium chloride and a flavoring according to claim 6. 10. The method of claim 9,
The perfume can be selected from the group consisting of butyl acetate, amyl acetate, isoamyl acetate, hexyl acetate, 2-hexyl acetate, ethyl propionate ), Butyl propionate, isobutyl propionate, isoamyl propionate, ethyl butyrate, ethyl 2-methylbutyrate, But are not limited to, butyl isobutyrate, ethyl hexanoate, ethyl pivalate, methyl 4-methylvalerate, ethyl valerate, ethyl isovalerate ethyl isovalerate, isopropyl isovalerate, ethyl lactate, 2-pentanone, heptanoic acid, 3-heptanone, 2,3-hexanedione d-camphor, p-methyl anisole, 2-methoxy-6-methyl pyrazine, 1,8-cineole (1 , 8-cineole, 1,4-cineole, benzyl methyl ether, 3-heptanol, isoamyl isovalerate, butyl But are not limited to, butyl valerate, butyl lactate, methyl benzoate, ethyl benzoate, propyl benzoate, butyl benzoate, Isopropyl benzoate, isobutyl benzoate, amyl benzoate, isoamyl benzoate, methyl phenylacetate, ethyl phenylacetate, benzyl acetate, sassafras acetate, isobornyl acetate, ethyl 3-phenylpropionate, 2-methyl-5-ethoxy 2-methyl-5-ethoxypyrazine, 2-methyl-6-ethoxypyrazine and 2,3-diethyl-5- methylpyrazine, 5-methyl-6,7-dihydro-5H-cyclopentapyrazine, 2-acetylpyrazine, acetylpyridine pyridine, 2-acetyl pyridine, 3-acetyl pyridine, 2-t-butyl cyclohexanone, p-dimethyl- dimethyl-hydroquinone, isoquinoline, 2,3-dimethyl-benzofuran, 3,6-dimethyl benzofuranone, ambernaphthofuran, ambernaphthofuran, pt-butyl-cyclohexanone, thymol methyl ether, 3-phenylpropyl alcohol, 2,6-dimethoxyphenol (2, 6-dimethoxyphenol, 2-t-butyl-6-methyl-phenol, 1-menthol, dl- menthol, d-neomenthol, menthone lactone, p-ethyl acetophenone, skatole, diphenyl ether,? -naphthyl methyl ether ( ? -naphthyl methyl ether,? -naphthyl ethyl ether, saffron indenone, ambroxide, (-) - ambroxide, phenyl But are not limited to, phenylacetic acid, watermelon ketone, dihydroactinidiolide, 3-butyl-phthalide, borneol, dl-isoborneol (dl isoborneol, thymol, exaltolide, exaltone, menthyl lactate, methyl dihydrojasmonate, ethylene brassylate, t-hydrofurfuryl phenylacetate, 2- (3-phenylpropyl) pyridine, (±) -mucone ((±) -muscone), (-) - muscone, isomuscone, normuscone, cyclohexadecanone, celestolide, sandal cyclopropane, and the like. A respiratory machine of the eye, nasal cavity, oral cavity, pharynx, larynx, bronchus and lung, characterized in that it comprises at least one selected from aniseed oil, eucalyptus oil and peppermint oil. An antiviral and antimicrobial composition for institutions.