AQUEOUS SOLUTIONS OF POORLY SOLUBLE ACTIVE INGREDIENTS USING POLYALKYOXYLATED AMINO ALCOHOLS

Abstract

Disclosed is the use a polyalkoxylated amino alcohol to solubilize active compounds that are poorly soluble in water, including particularly agricultural actives or pharmaceutical actives. Also disclosed are compositions comprising such actives, water and the polyalkoxylated aminoalcohol.

Claims

1. A composition comprising biologically active compound that is insoluble or poorly soluble in water and a polyalkoxylated amino alcohol of the formula ##STR00006## where Ri, R.sub.2, R.sub.3, and R.sub.4 are independently selected from alkyl, alkenyl, aryl, aralkyl, or heterocyclic groups having 1-25 carbons, R.sub.5 is a divalent alkyl, alkenyl, aryl, aralkyl, or heterocyclic group having 4-25 carbons, and where each AO is a polyoxyalkylene chain having oxypropylene (PO) and oxyethylene (EO) groups, where m is the average number of PO groups per AO group and n is the average number of the average number of EO groups per AO group, and m is at least 1, n is at least 2, and m+n is at least 20 no more than 400, wherein the composition is solid or comprises water.

2. The composition of claim 1 wherein Ri, R.sub.2, R.sub.3, and R.sub.4 are independently selected alkyl groups having 3-12 carbon atoms.

3. The composition of claim 1 wherein Ri, R.sub.2, R.sub.3, and R.sub.4 are butyl or 2-ethylhexyl.

4. The composition of claim 1 wherein R.sub.5 is 2,2-isopropylidenediphenylene, 2,2-isopropylidenedicyclohexylidene, or 1,4-butylene.

5. The composition of claim 1 wherein m is at least 10 and n is at least 15.

6. The composition of claim 1 wherein m/n is less than 1.

7. The composition of claim 1 wherein m is at least 10 and n is at least 15 and m+n is less than 300.

8. The composition of claim 1 wherein AO is a block copolymer of PO and EO.

9. The composition of claim 1 wherein at least one AO has an EO rich block and a PO rich block.

10. The composition of claim 1 further comprising a solvent that is at least partially miscible with water.

11. The composition of claim 1 which is an aqueous solution.

12. The composition of claim 1 wherein the weight ratio of the biologically active compound to the polyalkoxylated amino alcohol is in the range of 2:1 to 1:100.

13. The composition of claim 1 wherein the biologically active compound is an agricultural active ingredient.

14. The composition of claim 1 wherein the biologically active compound is an active pharmaceutical ingredient.

15. A method comprising diluting the composition of claim 13 with water and applying it to an area to prevent pests by spraying.

Description

EXAMPLES

Synthesis of Amino Alcohol Starter

[0031] This synthesis of amino alcohol starter BA-DGE/DBA described below is representative of the synthesis of all of the amino alcohol starters. The other starters can be synthesized according to similar procedures. To a 30 mL vial containing a cross-shaped stir bar was added bisphenol-A diglycidyl ether (D.E.R. 331 epoxy resin, 7.40 g of epoxide equivalent weight=185 g/mol epoxide, 40.0 millimole (mmol) epoxide) and dibutylamine (5.16 g, 40.0 mmol, 40.0 mmol N—H). The vial was capped with an inverted 14/20 septum that was secured with copper wire. A syringe needle was inserted through the septum to vent the reaction. The reaction mixture was heated at 75° C. for 30 min, 130° C. for 2 h, and 150° C. for 2 h. The product was a clear, light yellow, viscous liquid. .sup.1H and .sup.13C NMR analysis of the product was consistent with the structure of amino alcohol BA-DGE/DBA. The yield was quantitative.

Synthesis of Polyalkoxylated Amino Alcohols.

[0032] The reactions are carried out in a parallel port reactor (PPR) setup containing a plate with 48 (6×8) small reactors 24 of which located in three separate modules were utilized. Propylene oxide (PO) and ethylene oxide (EO) are delivered via an ISCO syringe pump equipped with a robotically controlled needle and compressed gas micro-valve.

[0033] A glass insert along with a removable poly(ether ether ketone) (PEEK) stir paddle for each cell are dried in a vacuum oven at 125° C. The stock solutions of the starters which are listed below were prepared in o-xylene. Potassium hydride (KH) was added to each solution with stirring overnight to produce >50 mol % of the alkoxyde as shown below:

TABLE-US-00001 Amount o-Xylene Total KH KH (g) (g) (g) (mg) (mmol) BA-DGE/DBA 2.85 3.18 6.03 100 2.5 BA-DGE/2EHA 2.84 3.51 6.35 80 2 h-BA-DGE/DBA 2.85 3.36 6.21 100 2.5 BD-DGE/DBA 2.9 2.79 5.69 150 3.75

[0034] The stock solutions of the starters are charged manually using a pipette into the glass inserts under nitrogen. The amounts of the stock solutions range from 1.0 to 2.0 ml for all cells.

[0035] The glass inserts along with the stir paddles are loaded to the corresponding PPR wells and the reactors were sealed. The cells are charged with calculated amounts of propylene oxide. The temperature is increased to 150° C. and reaction mixtures are stirred for 4 hours after reaching the process temperature. The pressure profile indicated when the reactions were completed. The cells are vented and purged with nitrogen to remove residual propylene oxide. The system is left overnight.

[0036] Next day, reactor modules are heated to 70° C., ethylene oxide is introduced, the temperature was increased to 150° C. and the reactors were stirred for 4 hrs. The pressure curves were consistent with reaction completion. After cooling and venting as described above, the mixtures are quenched with 10 wt % acetic acid in o-xylene. Then small samples were taken from each reactor for NMR analyses from which is determined the average number of PO and EO units.

##STR00003##

Examples 1-15 and Comparative Examples 1 and 2

[0037] A concentrate solution of 1 wt % difenoconazole and with no additive (Comparative 1 and 2) or either 10 wt % or 1 wt % polyalkoxylated amino alcohols is prepared. This is diluted with water such that the amount of the difenoconzole is 500 ppm and the amount of the polyalkyoxylated amino alcohol is either 500 ppm or 5000 ppm. The mixtures are measured for light transmission for 25 hours using a Turbiscan™ tower. The height averaged transmission over the bottom ⅓ of the solution, normalized using the height averaged from the bottom ⅓ of the control transmission (which is made up of the alkyoxylated amino alcohol and solvent (if any) and water in concentrations in the same range as when tested with the active present). Results are shown in Table 1.

[0038] Difenoconazole Structure

##STR00004##

TABLE-US-00002 TABLE 1 Difenoconazole Results Additive Average number of PO groups/average number of Amount EO groups on of Type a per molecule additive Time (hours) Example Starter of AO basis (ppm) 0 1 2 4 20 1 BA-DGE/ block  82/151 5000 99 99 99 99 99 DBA 2 BA-DGE/ block 48/63 5000 96 95 95 95 94 DBA 3 BA-DGE/ block 48/63 5000 100 100 100 99 98 DBA 4 BA-DGE/ block 105/162 5000 98 98 98 98 98 2EHA 5 BA-DGE/ block 41/66 5000 98 98 98 98 98 2EHA 6 h-BA-DGE/ block  55/115 5000 100 101 101 101 101 DBA 7 h-BA-DGE/ block 33/50 5000 100 100 100 100 100 DBA 8 BD-DGE/ block 41/69 5000 97 98 98 98 98 DBA 9 BD-DGE/ block 23/36 5000 97 97 97 97 97 DBA 10 BA-DGE/ block 105/162 500 49 19 15 12 20 2EHA 11 BA-DGE/ block 41/66 500 90 90 90 90 90 2EHA 12 h-BA-DGE/ block  55/115 500 79 61 54 47 35 DBA 13 h-BA-DGE/ block 33/50 500 79 79 78 77 75 DBA 14 BD-DGE/ block 41/69 500 70 65 64 62 56 DBA 15 BD-DGE/ block 23/36 500 39 36 35 34 31 DBA CE1 — — — — 1 0 0 0 1 CE2 — — — — 1 0 0 0 1

Examples 16-37 and Comparative 3

[0039] The process of for Examples 1-15 and Comparative 1 and 2 was repeated using this time pyraclostrobin instead of the Difenoconazole. The results are shown in Table 2.

[0040] Pyraclostrobin Structure

##STR00005##

TABLE-US-00003 TABLE 2 Pyraclostrobin Results Additive Amount of additive Time (hours) Example Starter Type PO/EO (ppm) 0 1 2 4 20 24 BA-DGE/ block 105/162 5000 87 92 92 92 93 2EHA 25 BA-DGE/ block  82/151 5000 96 96 96 96 96 DBA 26 BA-DGE/ block 48/63 5000 97 97 97 96 95 DBA 27 BD-DGE/ block 41/69 5000 90 93 94 94 93 DBA 28 h-BA-DGE/ block  55/115 5000 83 83 86 89 92 DBA 29 BA-DGE/ block 41/66 5000 94 95 95 95 94 2EHA 30 h-BA-DGE/ block 33/50 5000 96 97 97 97 97 DBA 31 BD-DGE/ block 23/36 5000 85 89 89 88 85 DBA 32 BA-DGE/ block 105/162 500 38 6 2 1 0 2EHA 33 BA-DGE/ block 41/66 500 45 11 5 2 0 2EHA 34 h-BA-DGE/ block  55/115 500 69 46 35 24 7 DBA 35 h-BA-DGE/ block 33/50 500 84 82 81 79 71 DBA 36 BD-DGE/ block 41/69 500 47 37 33 28 15 DBA 37 BD-DGE/ block 23/36 500 53 25 18 12 3 DBA CE3 — — — — 2 0 0 0 0

[0041] The compositions and methods can alternatively comprise, consist of, or consist essentially of, any appropriate materials, steps, or components herein disclosed. The compositions, methods, and articles can additionally, or alternatively, be formulated so as to be devoid, or substantially free, of any materials (or species), steps, or components, that are otherwise not necessary to the achievement of the function or objectives of the compositions, methods, and articles.

[0042] For ranges, stated upper and lower limits can be combined to form ranges (e.g. “at least 1 or at least 2 weight percent” and “up to 10 or 5 weight percent” can be combined as the ranges “1 to 10 weight percent”, or “1 to 5 weight percent” or “2 to 10 weight percent” or “2 to 5 weight percent”). The terms “first,” “second,” and the like, do not denote any order, quantity, or importance, but rather are used to distinguish one element from another. The terms “a” and “an” and “the” do not denote a limitation of quantity and are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. “Or” means “and/or” unless clearly stated otherwise.

[0043] Unless specified to the contrary herein, all test standards are the most recent standard in effect as of the filing date of this application, or, if priority is claimed, the filing date of the earliest priority application in which the test standard appears.

[0044] The term “alkyl” means a branched or straight chain, unsaturated aliphatic hydrocarbon group, e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, s-pentyl, and n- and s-hexyl, or a cycloalkyl, such as cyclohexyl, or alkyls including cyclic groups and straight or branched chains. “Alkenyl” means a straight or branched chain, monovalent hydrocarbon group having at least one carbon-carbon double bond (e.g., ethenyl (—HC═CH.sub.2)). “Alkoxy” means an alkyl group that is linked via an oxygen (i.e., alkyl-O—), for example methoxy, ethoxy, and sec-butyloxy groups. “Aryl” means an aromatic hydrocarbon group containing the specified number of carbon atoms, such as phenyl, tropone, indanyl, or naphthyl. The prefix “hetero” means that the compound or group includes at least one ring member that is a heteroatom (e.g., 1, 2, or 3 heteroatom(s)), wherein the heteroatom(s) is each independently N, O, S, Si, or P. The number of carbon atoms indicated in a group is exclusive of any substituents. For example —CH.sub.2CH.sub.2CN is a C.sub.2 alkyl group substituted with a nitrile.