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NZ765172B2 - Process for preparing large size isoxazoline particles - Google Patents
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NZ765172B2 - Process for preparing large size isoxazoline particles - Google Patents

Process for preparing large size isoxazoline particles Download PDF

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Publication number
NZ765172B2
NZ765172B2 NZ765172A NZ76517218A NZ765172B2 NZ 765172 B2 NZ765172 B2 NZ 765172B2 NZ 765172 A NZ765172 A NZ 765172A NZ 76517218 A NZ76517218 A NZ 76517218A NZ 765172 B2 NZ765172 B2 NZ 765172B2
Authority
NZ
New Zealand
Prior art keywords
isoxazoline compound
particles
isoxazoline
crystallizer vessel
temperature
Prior art date
Application number
NZ765172A
Other versions
NZ765172A (en
Inventor
Aaron Cote
Athanas Koynov
Luke Ryan Schenck
George X Zhou
Original Assignee
Intervet International Bv
Filing date
Publication date
Application filed by Intervet International Bv filed Critical Intervet International Bv
Priority claimed from PCT/EP2018/080230 external-priority patent/WO2019091940A1/en
Publication of NZ765172A publication Critical patent/NZ765172A/en
Publication of NZ765172B2 publication Critical patent/NZ765172B2/en

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    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/72—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms
    • A01N43/80—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms five-membered rings with one nitrogen atom and either one oxygen atom or one sulfur atom in positions 1,2
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/14—Ectoparasiticides, e.g. scabicides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/04—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member

Abstract

The application relates to a process to produce large isoxazoline compound particles which comprises initiating crystallization and then maintaining the temperature of the crystallization in the metastable region by removing, reheating and recycling a portion of the solvent thereby allowing the existing crystals to grow larger while minimizing the formation of newer smaller crystals. In one embodiment, the isoxazoline compound is fluralaner.

Claims (25)

Claims
1. A process for preparing isoxazoline compound particles wherein the isoxazoline compound is a compound of Formula (I) R 2 O N (R 1 ) n T Q 5 (Formula I) wherein R1 = halogen, CF3, OCF3, or CN; n = integer from 0 up to and including 3; R2 = C1-C3 haloalkyl; 10 T = ring structure: 5-, or 6-membered, or bicyclic, which is optionally substituted by one or more radicals Y; Y = methyl, halomethyl, n, CN, NO2, NH2-C=S, or two adjacent radicals Y together form a chain; 15 Q = X-NR3R4, NR5-NR6-X-R3, X-R3, or a 5-membered roaryl ring, which is optionally substituted by one or more radicals selected from ZA, ZB and ZD; X = CH2, ), CH(CN), CO, CS; R3 = hydrogen, methyl, hyl, halopropyl, halobutyl, methoxymethyl, methoxyethyl, halomethoxymethyl, ethoxymethyl, hoxymethyl, propoxymethyl, 20 ethylaminocarbonylmethyl, ethylaminocarbonylethyl, dimethoxyethyl, propynylaminocarbonylmethyl, N-phenyl-N-methyl-amino, haloethylaminocarbonylmethyl, haloethylaminocarbonylethyl, tetrahydrofuryl, methylaminocarbonylmethyl, (N,N-dimethylamino)-carbonylmethyl, aminocarbonylmethyl, cyclopropylaminocarbonylmethyl, 5 propenylaminocarbonylmethyl, haloethylaminocarbonylcyclopropyl, alkylsulfanylalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, cycloalkyl, 3 * * O CH O 3 N N N N * * S R3-1 R3-2 R3-3 R3-4 * * N N N H C N * Z * 3 N N N R3-5 R3-6 R3-7 R3-8 N N Z A NH 2 * * Z A * * O N S O CH 3 CH R3-9 R3-10 R3-11 R3-12 S S S O * * * R3-13 R3-14 R3-15 R3-16 R3-17 or R3-18; 5 wherein ZA = hydrogen, n, cyano, or halomethyl (CF3); * * * * * N O ZB-1 ZB-2 ZB-3 ZB-4 ZB-5 * F N O F O F F N F O F N * * * ZB-6 ZB-7 ZB-8 ZB-9, O N * O N O * * F N * N 15 F F O O ZD-1 ZD-2 ZD-3 ZD-4 N N * * ZD-5 ZD-6, R4 = hydrogen, ethyl, methoxymethyl, halomethoxymethyl, ethoxymethyl, 5 haloethoxymethyl, propoxymethyl, methylcarbonyl, arbonyl, propylcarbonyl, cyclopropylcarbonyl, methoxycarbonyl, methoxymethylcarbonyl, aminocarbonyl, ethylaminocarbonylmethyl, ethylaminocarbonylethyl, dimethoxyethyl, propynylaminocarbonylmethyl, haloethylaminocarbonylmethyl, cyanomethylaminocarbonylmethyl, or haloethylaminocarbonylethyl; 10 R5 = H, alkyl, or haloalkyl; R6 = H, alkyl, or haloalkyl; or wherein R3 and R4 together form a substituent ed from the group ting of: or salt or solvate thereof, comprising a) Dissolving the isoxazoline compound in a crystallizer vessel with a solvent which has a temperature dependent solubility of the isoxazoline compound to create a batch of isoxazoline compound solution; b) Initiating crystallization by 5 i) cooling the crystallizer vessel to supersaturation or ii) vibrating the crystallizer vessel or iii) adding crystalline seed of the isoxazoline compound to the crystallizer vessel or iv) a combination of one or more of the above; 10 c) Removing a portion of the batch, heating the removed portion to fully dissolve the isoxazoline nd particles in the t and returning the dissolved isoxazoline compound solution to the crystallizer vessel; wherein the rate of return is equal to the rate of removal and is 0.25 to 0.75 batch volumes per hour; and wherein the batch volume is the volume of the isoxazoline compound solution d in step a); 15 and d) Cooling the crystallizer vessel to achieve isoxazoline compound les.
2. A process for preparing isoxazoline compound les wherein the isoxazoline compound is a compound of Formula (I) R 2 O N (R1) n T Q (Formula I) wherein R1 = halogen, CF3, OCF3, or CN; n = integer from 0 up to and including 3; R2 = C1-C3 haloalkyl; 5 T = ring structure: 5-, or 6-membered, or bicyclic, which is optionally substituted by one or more radicals Y; Y = methyl, thyl, halogen, CN, NO2, S, or two adjacent radicals Y together form a chain; 10 Q = X-NR3R4, NR5-NR6-X-R3, X-R3, or a 5-membered N-heteroaryl ring, which is optionally substituted by one or more radicals selected from ZA, ZB and ZD; X = CH2, CH(CH3), CH(CN), CO, CS; R3 = hydrogen, methyl, haloethyl, halopropyl, halobutyl, methoxymethyl, methoxyethyl, halomethoxymethyl, ethoxymethyl, haloethoxymethyl, propoxymethyl, 15 ethylaminocarbonylmethyl, ethylaminocarbonylethyl, dimethoxyethyl, ylaminocarbonylmethyl, N-phenyl-N-methyl-amino, haloethylaminocarbonylmethyl, haloethylaminocarbonylethyl, tetrahydrofuryl, methylaminocarbonylmethyl, (N,N-dimethylamino)-carbonylmethyl, propylaminocarbonylmethyl, cyclopropylaminocarbonylmethyl, 20 ylaminocarbonylmethyl, hylaminocarbonylcyclopropyl, alkylsulfanylalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, cycloalkyl, 3 * * O CH O 3 N N N N * * S R3-1 R3-2 R3-3 R3-4 * * N N N H C N * * 3 N N N 5 R3-5 R3-6 R3-7 R3-8 N A N Z NH 2 * * * * O N S O CH 3 CH R3-9 R3-10 R3-11 R3-12 S S S O * * * 10 R3-13 R3-14 R3-15 R3-16 R3-17 or R3-18; wherein ZA = hydrogen, halogen, cyano, or thyl (CF3); * * * * * N O 5 ZB-1 ZB-2 ZB-3 ZB-4 ZB-5 * F N O F O F F N F O F N * * * ZB-6 ZB-7 ZB-8 ZB-9, 10 ZD = O N * O N O * * F N * N F F O O ZD-1 ZD-2 ZD-3 ZD-4 N N * * 15 ZD-5 ZD-6, R4 = hydrogen, ethyl, methoxymethyl, halomethoxymethyl, ethoxymethyl, haloethoxymethyl, propoxymethyl, methylcarbonyl, ethylcarbonyl, propylcarbonyl, cyclopropylcarbonyl, ycarbonyl, methoxymethylcarbonyl, aminocarbonyl, ethylaminocarbonylmethyl, ethylaminocarbonylethyl, dimethoxyethyl, propynylaminocarbonylmethyl, haloethylaminocarbonylmethyl, cyanomethylaminocarbonylmethyl, or haloethylaminocarbonylethyl; 5 R5 = H, alkyl, or haloalkyl; R6 = H, alkyl, or haloalkyl; or wherein R3 and R4 together form a substituent ed from the group consisting of: or salt or solvate thereof 15 comprising a) Combining the isoxazoline compound in a crystallizer vessel with a solvent which has a temperature dependent lity of the isoxazoline compound; b) g the crystallizer vessel until the isoxazoline compound is dissolved in the solvent; 20 c) Cooling the crystallizer vessel to 48-55oC to form a batch of supersaturated isoxazoline compound in the solvent; i) adding crystalline seed of the isoxazoline compound to the crystallizer vessel to initiate crystallization and particle growth; ii) Forming a slurry of isoxazoline compound particles and solvent in the llizer vessel; 5 d) Maintaining the temperature of the crystallizer vessel to 48-55oC; e) Removing a portion of the batch and g the removed portion to fully dissolve the isoxazoline compound particles in the solvent; wherein the rate of removal is at a rate of 0.25 to 0.75 batch volumes per hour; and wherein the batch volume is the volume of the supersaturated isoxazoline compound on created in step c); 10 f) Returning the dissolved oline compound solution to the crystallizer vessel; wherein the rate of return is equal to the rate of removal of step e); and g) Cooling the crystallizer vessel to achieve isoxazoline compound particles.
3. The process of any one of claims 1-2, wherein the particles have a volume weighted particle size distribution (d50) as measured by a static light ring 15 instrument of between 50 and 150 µm and an average particle thickness as measured by scanning electron microscopy (SEM) of greater than 10 µm, or greater than 20 µm.
4. The process of any one of claims 1-3, wherein the isoxazoline compound is aner.
5. The process of any one of claims 1-4, wherein the solvent is isopropanol. 20
6. The process of any one of claims 2-5, wherein the crystallizer of step b is heated to a temperature greater than 60oC, or 65 oC.
7. The s of any one of claims 1-6, wherein the removed portion is heated to a temperature greater than 60oC, or 65 oC.
8. The process of any one of claims 1-7, wherein the d portion is heated via 25 a heat exchanger or in a second vessel.
9. The process of any one of claims 2-8, wherein the rate of removal in step e) is 0.40 to 0.46 batch s per hour.
10. The process of any one of claims 1-9, wherein the rate of l is maintained for 4 to 24 hours, or 6 hours. 5
11. The process of any one of claims 2-10, wherein the crystallizer vessel of step g) is cooled to a temperature of 0oC or less, or -10 oC.
12. The process of any one of claims 1-11, where the crystallizer vessel is cooled over 10-48 hours, or 12-20 hours.
13. The process of any one of claims 2-12, further comprising a step of filtering the 10 isoxazoline nd particles of step g).
14. The process of claim 13, wherein the temperature of the filtering is maintained at a temperature of 0oC or less, or at -10 oC.
15. The process of any one of claims 13-14, wherein the filtered isoxazoline particles are dried. 15
16. A fluralaner particle composition comprising particles having a volume weighted particle size distribution (d50) as measured by a static light ring instrument of between 50 and 150 µm and with a ess of greater than 10µm, or greater than 20µm as measured by scanning electron microscopy (SEM).
17. The fluralaner particle ition of claim 15, wherein, the volume weighted 20 particle size distribution (d50) as measured by a static light ring instrument of the particles does not decrease by more than 40% when the mechanical resiliency as measured by a pressure titration is sed from 1 to 3 bar dispersion pressure.
18. The fluralaner particle composition of any one of claims 16-17 wherein the particle size distribution (d50) of the particles does not decrease by more than 35% from 25 1 to 3 bar dispersion pressure.
19. The process of claim 1, wherein the rate of removal in step c) is 0.40 to 0.46 batch volumes per hour.
20. The process of claim 1, wherein the crystallizer vessel of step d) is cooled to a temperature of 0oC or less, or -10 oC. 5
21. The process of claim 1, further comprising a step of filtering the isoxazoline compound particles of step d).
22. The process of claim 21, wherein the temperature of the filtering is maintained at a ature of 0oC or less, or at -10 oC.
23. The process of any one of claims 21-22, wherein the ed isoxazoline particles 10 are dried.
24. A process of any one of claims 1-15 and 19-23 substantially as herein bed with reference to any example thereof and with or without reference to the accompanying drawings.
25. A fluralaner particle composition of any one of claims 16-18 substantially as 15 herein described with reference to any example thereof and with or without reference to the anying drawings. Labile solution (L+S) p B c OA c Nucleation Meta-stable c zone ^ D Stable on (L) Temperature 3 o O iO o o hS O H W bJ o l+i O oo o oo o ho "O '/ ft isopropanol (IPA). T 60 R2: 0.9969 a: 4.9586 b: 0.0492 p(b*x) fluralaner in 50 of 40 Temp °C solubility of the 30 Temperature dependence _ _ Rsqr: 0.9983 5.6229 a: 3.2576 b: 0.0552 f=y0+a*exp(b*x) 20 20
NZ765172A 2018-11-06 Process for preparing large size isoxazoline particles NZ765172B2 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US201762582381P 2017-11-07 2017-11-07
US201762608904P 2017-12-21 2017-12-21
PCT/EP2018/080230 WO2019091940A1 (en) 2017-11-07 2018-11-06 Process for preparing large size isoxazoline particles

Publications (2)

Publication Number Publication Date
NZ765172A NZ765172A (en) 2024-05-31
NZ765172B2 true NZ765172B2 (en) 2024-09-03

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