JP2001302576A - Method for adjusting evaporation rate of aromatic compound by utilization of crystallization characteristic with surfactant - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for simply controlling the evaporation of a fragrant, a medicine or the like at low cost to impart a controlled release property. SOLUTION: This method for adjusting the evaporation rate of the aromatic compound, comprising the formation of the crystals of the molecular complex of the aromatic compound with a surfactant.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a molecular complex crystal of a surfactant and an aromatic compound, and a method for controlling the vaporization rate of the aromatic compound by forming the crystal. By using such a crystal and a method, the vaporization rate of a volatile aromatic compound can be adjusted cheaply and easily, and a medicine, a pesticide, an insecticide, an anthelmintic, a disinfectant, a disinfectant,
It is possible to stably store medicines such as cosmetics or fragrances or give them sustained release.

[0002]

2. Description of the Related Art Generally, a stationary fragrance or an insecticide is prepared by dissolving a fragrance or a bactericidal / insecticidal component in a liquid or the like in an open container or by opening an opening in order to control the vaporization rate. Place the product in a container shaped so as to suppress the vaporization of the active ingredient and install it in a room, etc., so that the active ingredient evaporates gradually and the active ingredient gas is released into the atmosphere. As a result, its long-lasting and sustained-release properties are maintained.

Further, as another method for controlling the vaporization or sustained release of a fragrance or an insecticide, another solid substance is impregnated with a liquid in which the active ingredient is dissolved, or the active ingredient itself is reacted with another compound. Or forming a clathrate compound. On the other hand, in the field of medicine or cosmetics, for example, in external preparations or cosmetics applied to the skin, there is a need for a drug exhibiting a sustained release action such that the effect can be maintained for a long time with one application. , For this purpose,
Porous films and hydrogels are used. Furthermore,
For example, in the case of inhalants, a drug having a sustained release action is required for the purpose of simple and long-term continuous administration.

[0004] In any of the above cases, however, in order to suppress vaporization or impart a sustained release effect, a compound or device specific to a specific active compound requiring the sustained release effect is required. Therefore, there are drawbacks that the production is troublesome and the cost is high. Also,
There is a drawback that it is difficult to control the degree of the vaporization / sustained release action.

[0005]

SUMMARY OF THE INVENTION Accordingly, an object of the present invention is to easily and inexpensively suppress the vaporization of compounds such as fragrances, insecticides, and medicines, or to provide a sustained-release property, and It is an object of the present invention to develop a method capable of controlling the vaporization / sustained release action.

[0006]

Means for Solving the Problems The inventors of the present invention have conducted intensive studies in order to solve such a problem, and as a result, the molecular complex crystal formed between the surfactant and the aromatic compound has been described above. The present inventors have found that the vaporization of an aromatic compound can be suppressed or a sustained release property can be given, and that the vaporization rate can be easily adjusted, and based on this, the present invention has been completed.

The present inventors have previously shown that a surfactant can form a crystal as a molecular complex with various aromatic compounds, and have conducted X-ray crystallographic analysis to analyze the three-dimensional structure of this molecular complex crystal. Successful (Bull.Chem.Soc.Jap.,
71, 2109-2118 (1998)). The present invention is based on the finding that the formed molecular complex crystal can control the volatility of an aromatic compound.

Accordingly, the present invention provides a molecular complex crystal formed between a surfactant and the aromatic compound, and an aromatic compound formed by forming a molecular complex crystal between the surfactant and the aromatic compound. The present invention relates to a method for adjusting the vaporization rate of a group III compound. Note that, as generally recognized, a “crystal” is a solid substance having a spatially periodic atomic arrangement and having a spatial lattice structure, which is different from a micelle and a suspension. Or, it is also different from an emulsion. The “molecular complex crystal” refers to a crystal of a molecular complex, and refers to a crystal formed of a surfactant having a fixed composition ratio and an aromatic compound.

[0009]

DETAILED DESCRIPTION OF THE INVENTION In the molecular complex crystal and method according to the present invention, a surfactant and an aromatic compound are used. The surfactant is not particularly limited as long as it can form a molecular complex crystal with the aromatic compound according to the purpose of the present invention, and generally commercially available surfactants can be used. For example, when used as a medicine, it must be a physiologically acceptable surfactant. The surfactant is preferably an ionic surfactant having an ionic group, based on the results of the structure analysis described below. The ionic surfactant may be anionic, cationic or zwitterionic.

Examples of the surfactant include cationic surfactants such as quaternary ammonium salts, aliphatic amine salts, and alkylpyridinium salts, alkylquinolinium salts, and alkylisoquinolinium salts. Fatty acid salts, higher alcohol sulfates, liquid fatty oil sulfates, sulfates of aliphatic amines and aliphatic amides, fatty alcohol phosphates,
Examples include dibasic fatty acid ester sulfonates, fatty acid amide sulfonates, and alkylaryl sulfonates.

Specifically, the following surfactants:

[0012]

Embedded image Wherein R, R ′, R ¹ , R ² , R ³ , and R ⁴ are each independently hydrogen or an optionally substituted alkyl group, X is halogen, for example chlorine or bromine, Y is preferably an alkali metal, such as sodium or potassium.

Particularly preferred types of surfactants include alkyltrimethylammonium salts, dialkyldimethylammonium salts, alkyldimethylbenzylammonium salts, alkylpyridinium salts, fatty acid monocarboxylates, alkylbenzene sulfonates, dialkyl sulfosuccinates, and alkyl sulfates. Salts, alkyl sulfate polyoxyethylene salts and alkyl phosphate salts.

In addition, from the results of the structural analysis of the above-mentioned alkyl group by the experiments described below, from the viewpoints of packing of molecular complex crystals, formation of spaces in the crystals, and interaction with aromatic compounds, etc. The activator comprises at least one
It is preferable to have a linear or branched alkyl group having 8 or more carbon atoms, or a group obtained by substituting one or more positions of the alkyl group with a hydrophobic group. Preferably, the surfactant comprises at least one ionic group attached to the ionic group.
Has a straight-chain alkyl group having 8 or more carbon atoms. In particular, the alkyl group is an octyl group, a nonyl group, a decyl group, an undecyl group, a dodecyl group, a tridecyl group, a tetradecyl group, a pentadecyl group, a hexadecyl group, a heptadecyl group, an octadecyl group, a nonadecyl group, or an icosyl group.
Preferred alkyl groups have from 8 to 30, more preferably from 8 to 20, most preferably from 10 to 16 carbon atoms.

However, as will be apparent from the experiments described below, the larger the carbon number of the alkyl chain, the stronger the bond in the crystal. Thus, the aromatic compound becomes more stable, and its vaporization rate decreases. Therefore,
The number of carbon atoms of the alkyl group can be freely determined depending on the vaporization or sustained release required for a given aromatic compound. In addition, a desired vaporization rate and sustained release can be obtained.

Particularly preferred surfactants are decyltrimethylammonium, dodecyltrimethylammonium,
It is a halide of tetradecyltrimethylammonium or hexadecyltrimethylammonium. The aromatic compound that forms a crystal with the surfactant may be a fragrance, a biocide, or a medicine, and is required to control its vaporization rate, that is, to have a sustained release property, a storage property, and the like. It is not particularly limited as long as it is a compound capable of forming a crystal as a molecular complex with a surfactant. Here, biocides include insecticides, acaricides, fungicides, fungicides, anthelmintics, disinfectants, and the like, and are used particularly for eliminating or killing harmful organisms.

However, from the results of the structural analysis by the experiments described below, considering the packing of the molecular complex crystal, the interaction with the surfactant, the occupied space, etc., the number of aromatic compounds is less than three in total. And an aromatic compound having a carbon ring or a heterocyclic ring. Preferably, the rings are substantially linear. Preferably, the molecular weight of the aromatic compound is between 78 and 300, more preferably between 78 and 200, and most preferably between 78 and 150. Preferably, the aromatic compound has 6 to 30 carbon atoms, more preferably 6 to 20,
Most preferably, it is 6-10.

As a specific example, the aromatic compound is
o-iodophenol, m-iodophenol, p-iodophenol, p-cresol, m-cyanophenol, o-hydroxybenzoic acid, m-hydroxybenzoic acid, p-hydroxybenzoic acid, o-toluic acid, m-toluyl Acid, p-toluic acid, o-phthalic acid, m-phthalic acid, p-phthalic acid, hydroquinone, 1,4-dimethoxybenzene, p-benzoquinone, 1,4-cyclohexanediol, naphthalene, 1-naphthol, 2- Naphthol, indole, 7-hydroxycoumarin, coumarin,
2-aminopyridine, 3-aminopyridine, 4-aminopyridine, 2-hydroxypyridine, 3-hydroxypyridine, 4-hydroxypyridine, 3-cyanotolpyridine, 4-cyanosipyridine, 4-dimethylaminopyridine, 2-dimethylpyridine Phenylpyridine, 3-phenylpyridine,
4-phenylpyridine, 2,2′-bipyridine, 2,4
-Bipyridine, 4,4'-bipyridine, anthracene,
Acridine, phenanthrene, benzo [h] quinoline, benzo [f] quinoline, 1,1′-biphenyl-4-ol, dibenzyl, biphenyl, carbazole dibenzofuran, and diphenylamine, particularly, flopropion and 4-chloro-m- It is selected from the group consisting of cresol, guaiacol, 2-methylindole and skatole as a fragrance.

The molecular complex crystal according to the present invention can be produced by a conventional crystallization method. For example, a surfactant and an aromatic compound are dissolved in a suitable solvent in a suitable molar ratio and left at a suitable temperature. Thus, the compound can be easily produced by isolating the precipitate. Further, the molecular complex crystal according to the present invention can be produced by simply mixing these solids in a mortar or the like, depending on the surfactant and the aromatic compound. This is confirmed by X-ray crystallography of the product that it is a crystal of a molecular complex.

The method and crystals of the present invention can control the vaporization of aromatic compounds using inexpensive and very common surfactants. Thus, reagents or agents such as medicaments, insecticides, anthelmintics, bactericides, disinfectants, or fragrances can be used to store or impart a sustained release action to them.

[0021]

EXAMPLES In the following experiments, hexadecyltrimethylammonium bromide (CTA) was used as a surfactant.
B; Wako), tetradecyltrimethylammonium bromide (MTAB; Wako), dodecyltrimethylammonium bromide (LTAB; Tokyo Chemical), and decyltrimethylammonium bromide (DTAB; Tokyo Chemical):

[0022]

Embedded image Was used. <Example 1> Crystal of surfactant and pharmaceutical compound Materials As aromatic compounds used as pharmaceuticals, flopropion (antispasmodic) (IGMA) and 4-chloro-m-cresol (bactericide) (Tokyo Kasei):

[0023]

Embedded image Was used. These were recrystallized by a conventional method and used for molecular complex crystallization. CTAB and MTAB were each crystallized from a methanol-acetone solution and then recrystallized from water, which was used for the following molecular complex crystallization.

2. Preparation of Molecular Complex Crystals To a methanol solution containing CTAB or MTAB, an equimolar amount of each of 4-chloro-m-cresol or flopropion was added, and the mixture was warmed with hot water to form a homogeneous solution, and then left in a cool place for about one week. The precipitate formed was isolated to obtain two molecular complex crystals 1-I and 1-II.

Using an ordinary solubilization method, an equimolar amount of flopropion was added to an aqueous solution containing CTAB, solubilized until a homogeneous solution was obtained, and then left in a cool place for about one week to form a solution. The precipitate is isolated and one molecular complex crystal 1-I
II was obtained. After the obtained molecular complex crystals are sufficiently dried, they are dissolved in a methanol solution, and the absorption wavelength is measured using an ultraviolet-visible spectrophotometer (UV160A, Shimadzu). The formation of a molecular complex was confirmed by comparison with.

Crystals 1-I, 1-II and 1-III were all colorless plate-like crystals. 3. X-ray structural analysis of molecular complex crystal X-ray crystallographic analysis was performed on crystals 1-I, 1-II, and 1-III. The crystal was cooled to -50 ° C using a nitrogen spray type cooling device, and then cooled by a CCD diffractometer (SMART-
CCD; Simens) or four-axis automatic diffractometer (AF)
C-5R; Rigaku) using MoKα or CuK
Monochromatic X-rays of α were used. SADABS for absorption correction
Or, using psi-scan, program SIR-92
The phase was determined by the direct method using [111] and refined by the least-squares method program SHELXL-97 [109]. The respective experimental conditions and crystallographic data are shown in Table 1 below.

[0027]

[Table 1] The structural diagrams of these crystals are shown in FIGS. Here, FIG.
2 are for crystal 1-I, and FIGS. 3 and 4 are for crystal 1-I.
For I, FIGS. 5 and 6 show the crystal structure for Crystal 1-III. Crystal 1-I has 1 in the asymmetric unit.
The molecule CTAB and 0.5 molecule of 4-chloro-m-cresol are present, and the crystal 1-II has two MTABs and one molecule of flopropion in the asymmetric unit, and the crystal 1-III Has two molecules of CTAB and two molecules of flopropion in the asymmetric unit. It is clear that all these form molecular complex crystals.

4. Measurement of dissolution rate To confirm the formation of the molecular complex, the solubility was measured. As a sample, a single substance of flopropion, a mixture of CTAB and flopropion powder, and a molecular complex crystal of CTAB and flopropion were used. 80me for each sample
sh and then 40 mesh sieving and used for dissolution rate measurements. Dissolution rate measuring device U. S. P. (NF) NTR
-5S3 (Toyama) at 25 ° C., 50 r.
p. m. Under the conditions of the above, the sample was dissolved in 500 mL of degassed distilled water, and 10 mL was collected at regular intervals,
After filtration using a 0.45 μm membrane filter, the dissolved amount of flopropion was measured using an ultraviolet-visible spectrophotometer (U
V-160A, Shimadzu).

FIG. 7 shows the results. From this figure, CTAB
It can be seen that the dissolution rate of the molecular complex crystal of と and flopropion is much faster than the other two. This suggests that a molecular complex is present and that the contact between the flopropion molecule and water as a solvent is prevented. In addition, it has been found that the molecular complex crystal according to the present invention also has a further effect of improving the solubility of a water-insoluble aromatic compound. This is particularly advantageous in pharmaceutical applications.

5. Measurement of sustained-release action Using Rigaku TG8120, the amount of decrease of 4-chloro-m-cresol in the molecular complex crystal accompanying the temperature rise was measured at a temperature rise rate of 10 K / min in a temperature range of 25 to 160 ° C. under a nitrogen stream. By comparing this with that of 4-chloro-m-cresol alone,
The sustained release effect on chloro-m-cresol was measured.

FIG. 8 shows the results. From this figure, it can be seen that the molecular complex crystal suppresses vaporization of a single drug. Further, it can be seen that the vaporization rate of the aromatic molecules crystallized together depends on the chain length of the surfactant, and the longer the chain length of the surfactant, the more the vaporization rate is suppressed. Furthermore, depending on the chain length of the surfactant, it can be seen that the surfactant and the molecule complex crystals are more stable than the drug molecule alone when compared with the surfactant. <Example 2> Crystal of surfactant and fragrance compound As aromatic compounds used as material fragrances, guaiacol (Tokyo Kasei), 2-methylindole (Aldr)
ich), and Skatole (Aldrich):

[0032]

Embedded image Was used. Since guaiacol is liquid at room temperature, a commercially available product was used as it is for crystallization of a molecular complex, and the other product was recrystallized by a conventional method and used for crystallization of a molecular complex. CTAB, MTAB, LTAB, and DTAB
Was crystallized from a methanol-acetone mixed solution and then recrystallized from water, which was used for the following molecular complex crystallization.

When the molar ratios of these complexes were calculated using a UV spectrum, it was found that for each of the complexes,
The molar ratio of surfactant: fragrance compound was 1: 2.
2. Preparation of Molecular Complex Crystals CTAB / guaiacol molecular complex crystals are prepared by adding an equimolar amount of guaiacol to 0.5 × 10 ⁻² mol / L of an aqueous CTAB solution, solubilizing the solution, and then homogenizing the solution at 2-3 ° C.
, And the precipitate was isolated to give a molecular complex crystal 2-VII.

A molecular complex of CTAB, MTAB or LTAB with 2-methylindole, and CTAB, MTA
The molecular complex of B, LTAB or DTAB and skatole is prepared by dissolving these surfactants in an equimolar amount of a fragrance in methanol to prepare 0.5 × 10 ⁻² mol / L, and then adding the surfactant at about 10 ° C. Let stand for about a week, isolate the precipitate,
Molecular complex crystals 2-I, 2-II, 2-III, 2-I
V, 2-V and 2-VI were obtained.

After the obtained molecular complex crystals are sufficiently dried, they are dissolved in a methanol solution, and the absorption wavelength is measured using an ultraviolet-visible spectrophotometer (UV160A, Shimadzu). The formation of a molecular complex was confirmed by comparison with the absorption wavelength. 3. X-ray structure analysis of molecular complex crystal X-ray crystal analysis was performed on crystals 2-I to VII. The crystal was cooled to −50 ° C. using a nitrogen spray type cooling device, and then cooled by a CCD diffractometer (SMART-CCD; Simen).
s), and MoKα monochromatic X-rays were used. The phase is determined by the direct method using the program SIR-92 [111], and the least square method program SHELXL-97 [1]
09]. The respective experimental conditions and crystallographic data are shown in Tables 2 to 4 below.

[0036]

[Table 2]

[0037]

[Table 3]

[0038]

[Table 4] The structural diagrams of these crystals are shown in FIGS. 9 and 10 show the crystal 2-I, and FIGS. 11 and 12 show the crystal 2-I.
FIGS. 13 and 14 show the crystal structures of crystals 2-VI, V and VI, and FIG. 15 shows the crystal structures of crystal 2-VII. It is clear that all these form molecular complex crystals.

4. Measurement of sustained release action Using a Rigaku TG8120, the amount of decrease in the fragrance compound in the molecular complex crystal due to the temperature rise in a temperature range of 25 to 160 ° C. at a temperature rising rate of 10 K / min under a nitrogen stream is measured, and this is measured for fragrance. It was compared with the agent alone. CTAB / 2
FIG. 16 shows the results of experiments performed with three types of molecular complex crystals of -methylindole, MTAB / 2-methylindole and LTAB / methylindole, and 2-methylindole alone as a control.

Further, CTAB / skatole, MTAB /
FIG. 17 shows the results of experiments performed on skatole, LTAB / skatole, and four kinds of molecular complex crystals of DTAB / skatole, and skatole alone as a control. From these figures, it is understood that the molecular complex crystal suppresses the vaporization of the fragrance depending on the chain length of the surfactant, as in Example 1. Further, it can be seen that the stability when a molecular complex is formed with a surfactant is higher than that of a simple substance and depends on the chain length. That is, the molecular complex crystal according to the present invention controls the vaporization rate of an aromatic compound, and thus can be applied to medicines, fragrances, insecticides, and the like.

Further, in order to thermodynamically prove the stability of these molecular complex crystals, the crystal structure data is used to obtain Le.
The van der Waals energy was calculated for each molecular complex using the nnard-Jones potential. The calculations were performed only for CC interactions located within 5 ° between the alkyl chains of adjacent surfactants. Here, since the hydrogen atom of the alkyl chain of the surfactant is geometrically determined by the position of the carbon atom, C-
Only the calculation of the C interaction can be sufficiently estimated. In addition, the electrostatic energy was ignored because the bromide anion and ammonium cation of the surfactant occupy almost the same position in each crystal.

Table 5 below shows CTAB, MTAB, LT
Van der of molecular complex crystal formed between AB or DTAB and 2-methylindole or skatole
5 shows the waals energy.

[0043]

[Table 5] As seen in FIGS. 9 and 11 and the like, when the length of the alkyl chain decreases, the number of contacts of the alkyl chain located within 5 ° decreases. This is, as evident from Table 5, the van
This is due to a decrease in der waals energy. In addition, it could be explained that the molecular complex of 2-methylindole having a large vander waals energy was more stably incorporated into the surfactant crystal lattice than skatole, and had a lower vaporization rate and higher stability.

As described above, the formation of a molecular complex crystal of a surfactant and an aromatic compound slows down the vaporization rate of the aromatic compound, and the vaporization rate can be controlled by the chain length of the surfactant used.

[0045]

The crystal and the method according to the present invention are simple and inexpensive for aromatic compounds such as fragrances and insecticides, cosmetics,
It is possible to suppress the vaporization of a drug or the like, impart sustained release properties, and easily adjust the sustained release action.

[Brief description of the drawings]

FIG. 1 is an a-axis projection view and b) b-axis projection view of a crystal structure of a crystal 1-I.

FIG. 2 is a view showing the molecular structure of crystal 1-I.

FIG. 3 is a b-axis projection view of the crystal structure of crystal 1-II.

FIG. 4 is a view showing the molecular structure of crystal 1-II.

FIG. 5 is a c-axis projection view of the crystal structure of crystal 1-III.

FIG. 6 is a diagram showing a molecular structure of crystal 1-III.

FIG. 7 is a graph showing the results of a dissolution rate measurement experiment.

FIG. 8 is a graph showing the results of an experiment for measuring the removal property and stability.

FIG. 9 shows a) a-axis projection view and b) b-axis projection view of the crystal structure of crystal 2-I.

FIG. 10 is a view showing the molecular structure of crystal 2-I.

FIG. 11 is a b-axis projection view of the crystal structures of crystals 2-II (a) and III (b).

FIG. 12 is a diagram showing a molecular structure of crystal 2-II (a) and III (b).

FIG. 13 is a b-axis projection view of the crystal structure of crystal 2-IV.

FIG. 14: Crystals 2-IV (a), V (b), and VI
It is a figure which shows the molecular structure of (c).

FIG. 15 shows the molecular structure of Crystal 2-VII.

FIG. 16 is a graph showing the results of a sustained release / stability measurement experiment performed on 2-methylindole.

FIG. 17 is a graph showing the results of a sustained release / stability measurement experiment performed with skatole.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) C07B 63/00 C07B 63/00 E H C07C 39/28 C07C 39/28 41/46 41/46 43/23 43/23 Z 45/86 45/86 49/825 49/825 C09K 3/00 110 C09K 3/00 110C // A61L 9/12 A61L 9/12 C07D 209/08 C07D 209/08 (72) Inventor Hirata Hirotaka 5-13-2, Kamishinei-cho, Niigata City, Niigata F-term in Niigata University of Pharmacy (reference) 4C002 AA06 4C204 AB20 BB09 CB03 DB03 EB02 FB01 GB01 4H006 AA05 AD40 FC52 FE13 FE73 FE75 GP03 GP12 4H011 AA01 AA02 AA01 AC04 BC04 BC06 DF02

Claims (8)

[Claims] 1. A method for suppressing the vaporization rate of an aromatic compound by forming crystals of a molecular complex of a surfactant and an aromatic compound. 2. The method according to claim 1, wherein the surfactant is an ionic surfactant comprising an ionic group and at least one straight-chain alkyl group having 8 or more carbon atoms bonded to the ionic group. The method of claim 1. 3. The method according to claim 2, wherein the vaporization rate is controlled by the length of the chain of the alkyl group of the surfactant. 4. The ionic surfactant comprises a quaternary ammonium salt, an aliphatic amine salt, an alkylpyridinium salt, an alkylquinolinium salt, an alkylisoquinolinium salt, a fatty acid salt, a higher alcohol sulfate salt, Liquid fatty acid sulfate, aliphatic amine and aliphatic amide sulfate, fatty alcohol phosphate, dibasic fatty acid ester sulfonate, fatty acid amide sulfonate, and alkylaryl sulfonate The method according to claim 1, wherein the method is selected from: 5. The method according to claim 1, wherein the aromatic compound is a fragrance.
The method according to any one of claims 1 to 4. 6. The method according to claim 1, wherein the aromatic compound is a biocide. 7. The method according to claim 1, wherein the aromatic compound is a medicine.
The method according to any one of claims 1 to 4. 8. A molecular complex crystal comprising a volatile aromatic compound and an ionic surfactant comprising at least one alkyl group having at least 8 carbon atoms and an ionic group bonded to the alkyl group.