Method for preparing large-sized isoxazoline particles

Abstract

The present application relates to a method for producing large isoxazoline compound particles, which includes initiating crystallization and then maintaining the crystallization temperature in the metastable zone by removing, reheating, and recycling a portion of the solvent, thereby allowing the existing crystals to grow larger while minimizing the formation of newer and smaller crystals.

Description

[0001] Background

[0002] Isoxazoline compounds are known in the art and their use as antiparasitic agents is described, for example, in US Patent Application US 2007 / 0066617 and International Patent Applications WO 2005 / 085216, WO 2007 / 079162, WO 2009 / 002809, WO 2009 / 024541, WO 2009 / 003075, WO 2010 / 070068, and WO 2010 / 079077, the disclosures of which, together with the references cited therein, are hereby incorporated by reference. Such compounds are known to have excellent activity against ectoparasites, i.e., parasitic insects and mites such as fleas and ticks, and endoparasites such as nematodes.

[0003] An example of an isoxazoline compound is a carbamoylbenzamide phenyl isoxazoline (CBPI) compound. A specific example of a CBPI compound is 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-methyl-N-[(2,2,2-trifluoroethylcarbamoyl)-methyl]-benzamide (CAS RN [864731-61-3]) – USAN fluralaner.

[0004]

[0005] The CBPI compound fluralaner is disclosed in Patent Application WO 2005 / 085216.

[0006] Bravecto® is a chewable tablet containing fluralaner that is approved for the treatment and prevention of flea infestations and the treatment and control of tick infestations in dogs (see NADA 141-426, May 15, 2014).

[0007] Crystallization is a commonly used technique for purifying chemical and pharmaceutical substances. It is a separation technique in which solids are separated from a solution. When a solid substance (solute) is mixed with a liquid solvent and stirred, the solute dissolves in the solvent to form a solution. As more and more solute is added to the solvent, a point is reached beyond which no more solute can be dissolved in the solvent. This point is called the saturation point, and the solution is called a saturated solution. For most substances, the amount of solute that can be dissolved in a solvent varies with temperature. As the temperature of the solvent increases, the amount of solute that can be dissolved increases. When a heated saturated solution is cooled, some of the dissolved solute comes out of the solution and begins to form crystals of the solute. The size of the crystals formed during this process depends on the cooling rate. If the solution is cooled rapidly, it forms a large number of tiny crystals. Large crystals are formed at slow cooling rates (see “Crystallization: Separation of Substances”, October 31, 2017, https: / / byjus.com / chemistry / crystallization / , accessed on December 19, 2017).

[0008] A theoretical explanation of the temperature dependence of crystal formation is provided below and elucidated in Figure 1 as follows:

[0009] “Suppose we start from the undersaturated point A in the figure. Any crystals added to the solution in this region will dissolve. If we now cool to a point between A and B, we enter the metastable region, where existing crystals will grow but no new crystals will form. By further cooling, we obtain an unstable solution at point B, where spontaneous formation of new crystals, i.e., nucleation, occurs. This significantly reduces the concentration and reaches point C. By further cooling, the crystals formed between B and C grow and consume any supersaturation that we have built up by cooling, so we remain in the metastable region until we reach the crystallization end point at point D”.

[0010] Source: “Practica in Process Engineering II Crystallization” Spring 2014https: / / www.ethz.ch / content / dam / ethz / special-interest / mavt / process-engineering / separation-processes-laboratory-dam / documents / practica%20in%20process%20engineering%202 / crystallization.pdf, accessed on December 19, 2017.

[0011] A method for controlling the particle size of isoxazoline compound crystals is not disclosed in any of these references. Summary of the Invention

[0013] A method for preparing isoxazoline compound particles

[0014] wherein the isoxazoline compound is a compound of formula (I) or a salt or solvate thereof

[0015] (Formula I)

[0016] wherein

[0017] R 1 = halogen, CF3, OCF3 or CN;

[0018] n = an integer from 0 to 3 inclusive;

[0019] m = 1 or 2;

[0020] R 2 = C1-C3 haloalkyl;

[0021] T = a ring structure: 5- or 6-membered, or bicyclic, optionally substituted by one or more groups Y;

[0022] Y = methyl, halomethyl, halogen, CN, NO2, NH2-C=S, or two adjacent groups Y together form a chain;

[0023] Q = X-NR 3 R 4 、NR 5 -NR 6 -X-R 3 、X-R 3 or a 5-membered N-heteroaryl ring, optionally substituted by one or more groups;

[0024] X = CH2, CH(CH3), CH(CN), CO, CS;

[0025] R 3= hydrogen, methyl, haloethyl, halopropyl, halobutyl, methoxymethyl, methoxyethyl, halomethoxymethyl, ethoxymethyl, haloethoxymethyl, propoxymethyl, ethylaminocarbonylmethyl, ethylaminocarbonylethyl, dimethoxyethyl, propynylaminocarbonylmethyl, N-phenyl-N-methyl-amino, haloethylaminocarbonylmethyl, haloethylaminocarbonylethyl, tetrahydrofuranyl, methylaminocarbonylmethyl, (N,N-dimethylamino)-carbonylmethyl, propylaminocarbonylmethyl, cyclopropylaminocarbonylmethyl, propenylaminocarbonylmethyl, haloethylaminocarbonylcyclopropyl, alkylthioalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, cycloalkyl,

[0026]

[0027]

[0028]

[0029]

[0030]

[0031] wherein

[0032] Z A = hydrogen, halogen, cyano or halomethyl (CF3);

[0033] R 4 = hydrogen, ethyl, methoxymethyl, halomethoxymethyl, ethoxymethyl, haloethoxymethyl, propoxymethyl, methylcarbonyl, ethylcarbonyl, propylcarbonyl, cyclopropylcarbonyl, methoxycarbonyl, methoxymethylcarbonyl, aminocarbonyl, ethylaminocarbonylmethyl, ethylaminocarbonylethyl, dimethoxyethyl, propynylaminocarbonylmethyl, haloethylaminocarbonylmethyl, cyanomethylaminocarbonylmethyl or haloethylaminocarbonylethyl;

[0034] R 5 = H, alkyl or haloalkyl;

[0035] R 6 = H, alkyl or haloalkyl;

[0036] or wherein R 3 and R 4 together form a substituent selected from:

[0037]

[0038] and

[0039] ,

[0040] The method comprises

[0041] a) dissolving an isoxazoline compound in a solvent having a temperature-dependent solubility of the isoxazoline compound in a crystallizer vessel to produce a batch of an isoxazoline compound solution;

[0042] b) initiating crystallization as follows

[0043] i) cooling the crystallizer vessel to supersaturation or

[0044] ii) vibrating the crystallizer vessel or

[0045] iii) adding seeds of the isoxazoline compound to the crystallizer vessel or

[0046] iv) a combination of one or more of the above;

[0047] c) removing a portion of the batch, heating the removed portion to completely dissolve the isoxazoline compound particles in the solvent and returning the dissolved isoxazoline compound solution to the crystallizer vessel; wherein the return rate is equal to the removal rate and is approximately 0.25 to 0.75 batch volumes per hour; and wherein the batch volume is the volume of the isoxazoline compound solution produced in step a); and

[0048] d) cooling the crystallizer vessel to achieve isoxazoline compound particles of a desired size;

[0049] wherein the desired particle size is a particle having a volume-weighted particle size distribution (d50) of 75 to 120 µm as measured by a light scattering instrument and an average particle thickness of greater than 10 µm, preferably greater than 20 µm as measured by scanning electron microscopy.

[0050] An isoxazoline compound particle composition comprising particles having a thickness of greater than 10 µm, preferably greater than 20 µm as measured by scanning electron microscopy (SEM) and a mechanical resilience as measured by pressure titration using Sympatec HELOS, wherein the particle size distribution (d50) of the particles does not decrease by more than 40% from 1 bar to 3 bar of dispersion pressure.

[0051] Description of the Drawings

[0052] Figure 1 - Temperature dependence of crystal formation.

[0053] Figure 2 – Temperature dependence of the solubility of fluralaner in isopropanol (IPA).

[0054] Figure 3- Schematic diagram of the crystallizer vessel and other components of the system.

[0055] Figure 4 - (3A) Particle size distribution of fluralaner crystals made by methods other than the method of the present invention; and (3B) SEM image of the same crystals.

[0056] Figure 5 - Pressure titration of fluralaner crystals made by methods other than the method of the present invention. Sympatec pressure titration: As the pressure increases from 1 bar to 3 bar, the particle size (d50) decreases from 50 µm to 25 µm. Material made by non-optimized recycling method. In this case, it can be seen from the pressure titration experiment that the crystals are thin and not mechanically robust, where between 1 bar and 3 bar of dispersion pressure, x50 decreases from 110 µm at 1 bar to 80 µm at 2 bar, and then to 60 µm at 3 bar, or a 46% reduction in size from 1 bar to 3 bar.

[0057] Figure 6 - Particle size distribution and pressure titration of fluralaner crystals made by the method of the present invention. Sympatec pressure titration: As the pressure increases from 1 bar to 3 bar, the particle size (d50) decreases from 100 µm to 73 µm.

[0058] Figure 7 - Particle size distribution and pressure titration of fluralaner crystals made by the method of the present invention.

[0059] Figure 8 - SEM image of fluralaner crystals made by methods other than the method of the present invention.

[0060] Figure 9 - SEM image of fluralaner crystals made by the method of the present invention.

[0061] Figure 10 - Particle size distribution of the material made in Example 3. The resulting material has an x50 of 108 and a reduction in x50 of approximately 24% in the pressure titration from 1 bar to 3 bar.

[0062] Figure 11 - SEM of the material made in Example 3.

[0063] Figure 12 - Schematic diagram of the pilot-scale equipment used in Example 4.

[0064] Figure 13 - Particle size distribution of the material made in Example 4. The resulting material has a d50 of 103 µm, a d10 of 47.3 µm, and a d90 of 158.8 µm. The particle size measurement of this sample was carried out wet using a Microtrac static light scattering system.

[0065] Figure 14 - SEM of the material made from Example 4.

[0066] Figure 15 - Particle size distribution of the material made from Example 5. The resulting material has an average d50 of 99 µm and a reduction in d50 of approximately 20% in a pressure titration from 1 bar to 3 bar.

[0067] Figure 16 - SEM of the material made from Example 5.

[0068] Details

[0069] An improved method for producing large isoxazoline compound particles, which includes initiating crystallization and then maintaining the crystallization temperature in the metastable zone by removing, reheating, and recycling a portion of the solvent, thereby allowing the existing crystals to grow larger while minimizing the formation of newer and smaller crystals.

[0070] Crystallization is initiated by nucleation, which occurs spontaneously or is induced by vibration or seed particles. The nucleated crystals are small crystals formed when the temperature of the saturated solution is decreased. If nucleation starts too quickly, too many small crystals will grow.

[0071] In the case of isoxazoline compounds, especially fluralaner, the seed length is typically less than 10 µm.

[0072] The crystallization process begins by adding nucleated material (seeds) to a solution of the dissolved isoxazoline compound to achieve the surface properties of the starting crystals suitable for growth. When crystallization is initiated, a slurry of isoxazoline compound particles in the solvent is formed. This initial slurry is maintained at a relatively high temperature (52 - 54 °C) to promote a reasonable growth rate and avoid further nucleation. At lower temperatures, the growth rate is significantly slower and the risk of nucleation is higher. A portion of this batch of isoxazoline compound particle slurry is removed, heated to dissolve any crystals that have formed, and returned to the crystallizer to provide continuous supersaturation to drive crystal growth. This recycle rate cannot be too low because under these growth conditions, thin flakes that are prone to breakage are preferentially formed. The recycle rate cannot be too high because nucleation or aggregation can occur under these conditions. Once the starting slurry has grown to a sufficient extent, the slurry is cooled at a rate that avoids nucleation to the temperature to achieve the desired crystal size.

[0073] The dissolved isoxazoline compound solution is returned to the crystallizer vessel at a rate of approximately 0.25 to 0.75 batch volumes per hour to achieve continuous crystal growth of isoxazoline compound particles.

[0074] After sufficient particle size growth is achieved by repeatedly removing the slurry from the crystallizer and returning the dissolved isoxazoline to the crystallizer, the crystallizer is cooled to about 0 °C, preferably about -10 °C, after 10 - 48 hours, preferably 12 - 20 hours, to further relieve supersaturation and achieve growth to the desired size.

[0075] It has been found that injectable compositions comprising particles of an isoxazoline compound having a specified particle size made by the process of the present invention exhibit desirable bioavailability and duration of efficacy, while causing minimal irritation at the injection site. Such compositions also provide desirable safety characteristics for warm-blooded and avian animal recipients. In addition, it has been found that a single administration of such a composition generally provides potent activity against one or more parasites (e.g., ectoparasites such as fleas, ticks or mites), while also tending to provide a rapid onset of activity, a long duration of activity and / or desirable safety characteristics.

[0076] Definitions

[0077] Scanning electron microscopy (SEM) is an analytical instrument that uses a high-energy focused electron beam to generate various signals on the surface of a solid specimen. These signals reveal information about the sample, including external morphology (texture), chemical composition and crystal structure, as well as the orientation of the materials that make up the sample.

[0078] A solvent having a temperature-dependent solubility for a solute means that the solubility of the solute in the solvent varies with temperature. Generally, this means that the solubility increases with increasing temperature.

[0079] The temperature sensitivity of the solubility of fluralaner in isopropanol (IPA) is shown in Figure 1 where the x-axis shows the temperature and the y-axis shows the solubility of fluralaner in mg / mL.

[0080] The metastable zone of the solubility temperature curve is the region where existing crystals will grow but no new crystals will form.

[0081] A crystallizer vessel is a vessel in which crystallization takes place.

[0082] Saturation is the state of a solution having the maximum equilibrium amount of dissolved substance at a given temperature.

[0083] Supersaturation is when the solution contains more solute than a saturated solution at equilibrium.

[0084] A slurry is a dilute suspension.

[0085] A batch is solvent + solute.

[0086] The batch volume is the volume of the batch.

[0087] As used herein, the reported particle size data is volume-weighted particle size as measured by conventional particle techniques known to those skilled in the art, such as static light scattering (also known as laser diffraction), image analysis, or sieving. More discussion of particle size measurement is provided below.

[0088] Mechanical resilience is the resistance of a crystal or particle to breaking into smaller crystals or particles when exposed to pressure or stress from other sources. Mechanical resilience is measured by pressure titration using a Sympatec HELOS. This instrument can simultaneously measure the particle size distribution. In this experiment, pressure is applied to the crystals to disperse or separate them from each other. The change in the d50 particle size distribution measurement is monitored as the pressure on the crystals is increased from 1 bar to 3 bar. Preferably, the isoxazoline compound particles of the present invention do not reduce their d50 particle size distribution measurement by more than 30 - 40% as the dispersion pressure is increased from 1 bar to 3 bar.

[0089] In one embodiment of the isoxazoline used in the present invention, T is selected from

[0090]

[0091]

[0092] wherein in T-1, T-3, and T-4, the group Y = hydrogen, halogen, methyl, halomethyl, ethyl, or haloethyl.

[0093] In one embodiment of the isoxazoline used in the present invention, Q is selected from

[0094]

[0095] wherein R 3 、R 4 、X, and Z A are as defined above, and

[0096]

[0097]

[0098] In one embodiment, the isoxazoline used in the present invention is as shown in Table 1.

[0099]

[0100]

[0101]

[0102] In one embodiment, the isoxazoline used in the present invention is as shown in Table 2.

[0103]

[0104]

[0105] In one embodiment, the isoxazoline for use in the present invention is the following compound:

[0106] (Formula 2)

[0107] wherein R 1a , R 1b , R 1c are, independently of one another: hydrogen, Cl or CF3.

[0108] Preferably, R 1a and R 1c are Cl or CF3, and R 1b is hydrogen,

[0109] T is

[0110]

[0111] wherein Y is methyl, bromo, Cl, F, CN or C(S)NH2; n = 1 or 2; and Q is as described above.

[0112] In one embodiment of the isoxazoline as defined herein, R 3 is H, and R 4 is: -CH2-C(O)-NH-CH2-CF3, -CH2-C(O)-NH-CH2-CH3, -CH2-CH2-CF3 or -CH2-CF3.

[0113] The isoxazoline for use in the present invention also includes its pharmaceutically acceptable salts, esters and / or N-oxides. In addition, reference to an isoxazoline compound also refers to any polymorph or stereoisomer thereof.

[0114] Regarding stereospecific forms, the pharmaceutical compositions according to the present invention may use a racemic mixture of the isoxazolines for use in the present invention, which contains equal amounts of the enantiomers of such isoxazoline compounds as described above. Alternatively, the pharmaceutical composition may use an isoxazoline compound containing a stereoisomer enriched in one enantiomer of the isoxazoline as defined herein compared to the racemic mixture. The pharmaceutical composition may also use an essentially pure stereoisomer of such an isoxazoline compound. Such enriched or purified stereoisomeric preparations of the isoxazolines for use in the present invention can be prepared by methods known in the art. Examples are chemical methods using catalytic asymmetric synthesis, or the separation of diastereomeric salts (see, for example, WO2009 / 063910 and JP 2011 / 051977, respectively).

[0115] In one embodiment of the pharmaceutical composition according to the present invention, the isoxazoline is one or more selected from fluralaner, afoxolaner, lotilaner or sarolaner.

[0116] In one embodiment, the compound of formula (I) is 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-methyl- N -[(2,2,2-trifluoroethylcarbamoyl)-methyl]-benzamide (CAS RN 864731-61-3 - USAN fluralaner).

[0117] In one embodiment, fluralaner is S-fluralaner.

[0118] In another embodiment, the compound of formula (I) is 4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-N-[2-oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl]-1-naphthamide (CAS RN 1093861-60-9, USAN - afoxolaner) as disclosed in WO2007 / 079162.

[0119] In one embodiment of the pharmaceutical composition according to the present invention, the isoxazoline is lotilaner (CAS RN: 1369852-71-0; 3-methyl-N-[2-oxo-2-(2,2,2-trifluoroethylamino)ethyl]-5-[(5S)-5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4H-1,2-oxazol-3-yl]thiophene-2-carboxamide).

[0120] In one embodiment of the pharmaceutical composition according to the present invention, the isoxazoline is sarolaner (CAS RN: 1398609-39-6; 1-(5'-((5 S )-5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3'-H-spiro(azetidine-3,1'-(2)benzofuran)-1-yl)-2-(methylsulfonyl)ethanone).

[0121] In another embodiment, the compound of formula (I) is (Z)-4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-N-[(methoxyimino)methyl]-2-methylbenzamide (CAS RN 928789-76-8).

[0122] In another embodiment, the compound of formula (I) is 4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methyl-N-(thietan-3-yl)benzamide (CAS RN 1164267-94-0) as disclosed in WO2009 / 0080250.

[0123] In one embodiment, the compound according to the invention is 5-[5-(3,5-dichlorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-3-methyl-N-[2-oxo-2-[(2,2,2-trifluoroethyl)amino]ethyl]-2-thiophenecarboxamide (CAS RN: 1231754-09-8) as disclosed in WO 2010 / 070068.

[0124] One embodiment of the invention is a method for preparing particles of an isoxazoline compound, wherein the isoxazoline compound is a compound of formula (I), the method comprising

[0125] a) combining the isoxazoline compound with a solvent having a temperature-dependent solubility of the isoxazoline compound in a crystallizer vessel;

[0126] b) heating the crystallizer vessel until the isoxazoline compound is dissolved in the solvent;

[0127] c) cooling the crystallizer vessel to 48 - 55 °C to form a batch of supersaturated isoxazoline compound in the solvent;

[0128] i) adding seeds of the isoxazoline compound to the crystallizer vessel to initiate crystallization and particle growth;

[0129] ii) forming a slurry of isoxazoline compound particles and the solvent in the crystallizer vessel;

[0130] d) maintaining the temperature of the crystallizer vessel at 48 - 55 °C;

[0131] e) removing a portion of the batch and heating the removed portion to completely dissolve the isoxazoline compound particles in the solvent; wherein the removal rate is at a rate of about 0.25 to 0.75 batch volumes per hour; and wherein the batch volume is the volume of the supersaturated isoxazoline compound solution produced in step c);

[0132] f) returning the dissolved isoxazoline compound solution to the crystallizer vessel; wherein the return rate is equal to the removal rate of step e); and

[0133] g) cooling the crystallizer vessel to achieve isoxazoline compound particles of the desired size;

[0134] The required particle size is a particle having a volume-weighted particle size distribution (d50) of 75 to 120 µm as measured by a light scattering instrument and an average particle thickness greater than 10 µm, preferably greater than 20 µm.

[0135] In one embodiment, the isoxazoline compound is fluralaner.

[0136] In one embodiment, the solvent is methanol or acetone. In yet another embodiment, the solvent is acetate or acetonitrile. In one embodiment, the solvent is selected from dimethylacetamide (DMA), N-methylpyrrolidone (NMP), dimethyl sulfoxide (DMSO), N,N-diethyl-m-toluamide (DEET), 2-pyrrolidone, acetone, g-caprolactone, tetraethylene glycol, methyl ethyl ketone, diethylene glycol monoethyl ether (Transcutol®), ethyl lactate, isosorbide dimethyl ether, ethyl acetate, caprylic / capric polyethylene glycol glyceride (Labrasol®), dipropylene glycol monomethyl ether (Dowanol™ DPM), glycerol formal, benzyl alcohol, methanol, polyethylene glycol 200, propylene carbonate, 1-methoxy-2-propyl acetate (Dowanol™ PMA), isopropylidene glycerol (solketal), ethanol, triacetin, isopropyl alcohol, propylene glycol, medium-chain triglycerides (Miglyol® 812), ethyl oleate, toluene, ethyl acetate, or a mixture thereof.

[0137] In one embodiment, the solvent is isopropyl alcohol.

[0138] In one embodiment, the solvent is a mixture of toluene and ethyl acetate.

[0139] In one embodiment, the crystallizer in step b is heated to a temperature higher than 60 °C, preferably about 65 °C.

[0140] In one embodiment, in step c), the crystallizer vessel is cooled to achieve supersaturation, preferably to a temperature of about 48 - 55 °C, more preferably to a temperature of about 52 - 54 °C.

[0141] In one embodiment, the withdrawn portion is heated to a temperature higher than 60 °C, preferably about 65 °C.

[0142] In one embodiment, the withdrawn portion is heated by means of a heat exchanger or in a second vessel.

[0143] In one embodiment, the withdrawal rate in step e) is 0.40 to 0.46 batch volumes per hour.

[0144] In one embodiment, the extraction rate is maintained for about 4 to 24 hours, preferably about 6 hours.

[0145] In one embodiment, the crystallizer vessel of step g) is cooled to a temperature of about 0 °C or lower, preferably about -10 °C.

[0146] A further embodiment of any of the above methods further comprises the step of filtering the isoxazoline compound particles of step g).

[0147] In one embodiment, the temperature of the filtration is maintained at a temperature of 0 °C or lower, preferably at -10 °C.

[0148] In one embodiment, the filtered isoxazoline particles are dried.

[0149] Embodiments of the present invention are isoxazoline compound particles made by any of the methods disclosed herein.

[0150] One embodiment of the present invention is an isoxazoline compound particle composition comprising particles having a thickness of greater than 10 µm, preferably greater than 20 µm as measured by scanning electron microscopy (SEM) and a mechanical resilience as measured by pressure titration using Sympatec HELOS, wherein the particle size distribution (d50) of the particles does not decrease by more than 40% from 1 bar to 3 bar of dispersion pressure.

[0151] In one embodiment, the particle size distribution (d50) of the particles does not decrease by more than 35% from 1 bar to 3 bar of dispersion pressure.

[0152] In one embodiment, the particle size distribution (d50) of the particles does not decrease by more than 30% from 1 bar to 3 bar of dispersion pressure.

[0153] In one embodiment, the isoxazoline compound particle composition comprises particles having a thickness of greater than 10 µm but less than 100 µm, preferably greater than 20 µm but less than 90 µm, preferably greater than 30 µm but less than 80 µm as measured by scanning electron microscopy (SEM).

[0154] In one embodiment, the isoxazoline compound particle composition comprises particles having a thickness of greater than 10 µm, preferably greater than 20 µm.

[0155] In one embodiment, the isoxazoline compound has a particle size distribution of D50, as measured by a static light scattering instrument, of from about 25 microns to about 250 microns, a particle size of from about 11 microns to about 250 microns, a particle size of from about 50 microns to about 150 microns, a particle size of from about 75 microns to about 125 microns, a particle size of from about 75 microns to about 150 microns, a particle size of from about 90 microns to about 110 microns, or a particle size of from about 30 microns to about 100 microns.

[0156] The particle size distribution describes the relative amounts of particles present according to size. D10 is the particle size distribution representing the size below which 10% of the particles are smaller. D50 is the particle size measurement distribution representing the size below which 50% of the particles are smaller. D90 is the particle size measurement distribution representing the size below which 90% of the particles are smaller.

[0157] In a specific embodiment, the D10 of the particle size is about 10 µm, about 20 µm, about 30 µm, about 40 µm, about 50 µm, about 60 µm, or about 80 µm.

[0158] In a specific embodiment, the D50 of the particle size is about 50 µm, about 75 µm, about 80 µm, about 90 µm, about 100 µm, about 110 µm, about 120 µm, about 130 µm, about 140 µm, or about 150 µm.

[0159] In a specific embodiment, the D90 of the particle size is about 100 µm, about 130 µm, about 150 µm, about 175 µm, about 200 µm, or about 250 µm.

[0160] In a specific embodiment, the D10 of the particle size is about 20 to 35 µm, the D50 of the particle size is about 90 to 105 µm, and the D90 of the particle size is about 155 to 175 µm.

[0161] In a specific embodiment, the D10 of the particle size is about 25 to 30 µm, the D50 of the particle size is about 95 to 100 µm, and the D90 of the particle size is about 160 to 170 µm.

[0162] In a specific embodiment, the D10 of the particle size is about 10 to 20 µm, the D50 of the particle size is about 85 to 110 µm, and the D90 of the particle size is about 170 to 185 µm.

[0163] In a specific embodiment, the D10 of the particle size is about 10 to 15 µm, the D50 of the particle size is about 95 to 105 µm, and the D90 of the particle size is about 175 to 180 µm.

[0164] In a particular embodiment, the D10 of the particle size is about 10 to 25 µm, the D50 of the particle size is about 40 to 60 µm and the D90 of the particle size is about 95 to 100 µm.

[0165] In a particular embodiment, the D10 of the particle size is about 15 to 20 µm, the D50 of the particle size is about 45 to 55 µm and the D90 of the particle size is about 90 to 95 µm.

[0166] In a particular embodiment, the D10 of the particle size is about 30 to 50 µm and the D50 of the particle size is about 70 to 130 µm.

[0167] In a particular embodiment, the D10 of the particle size is about 35 to 45 µm and the D50 of the particle size is about 90 to 110 µm.

[0168] In a particular embodiment, the D10 of the particle size is about 40 µm and the D50 of the particle size is about 100 µm.

[0169] The volume-weighted particle size can be measured by sieving, microscopy or laser diffraction (Malvern or Sympatec). The volume-weighted particle size measurement can be carried out with a Malvern Mastersizer 2000 with a Hydro 2000G measuring element or with a Horiba LA-910 laser scattering particle size distribution analyzer. The volume-weighted particle size can be measured by a Sympatec Helos instrument.

[0170] In one embodiment, the isoxazoline compound is fluralaner. Examples

[0171] Example 1 – Method for Forming Large-Grained Fluralaner

[0172] Fluralaner was added to IPA at a concentration of 100 mg / mL, and 60 g was added to 600 mL of isopropanol. This composition was heated to 65 °C for 1 hour and aged for 1 hour to ensure complete dissolution. The solution was cooled to 50 °C over 20 minutes and seeded with 0.6 g of crystalline fluralaner. The batch was further cooled to 20 °C over 2 hours to establish the starting particles. The batch was heated to 54 °C, at which point a stream of the batch was taken out and heated to an elevated temperature until completely dissolved (>65 °C). The withdrawal rate and return rate of the crystallizer were set to about 4.4 - 4.8 mL / min. The recycle loop continued for 6 hours, at which point the x50 particle size was about 40 µm. The batch was aged at 54 °C for 6 hours to further relieve supersaturation, then cooled to 45 °C over 6 hours and further cooled to 0 °C over 16 hours. For a schematic diagram of the process equipment, see Figure 3The resulting slurry was filtered and dried to produce fluralaner particles. The dried fluralaner particles were measured to determine particle size and mechanical resilience.

[0173] Example 2 – Determination of Particle Size and Mechanical Resilience of Fluralaner Particles

[0174] The volume-weighted particle size of fluralaner crystals was measured by laser diffraction (Sympatec Helos) to determine the particle size distribution. Mechanical resilience was also determined during a pressure titration experiment. Figure 4 shows the particle size distribution of fluralaner crystals made by a method other than the method of the present invention. In this case, this material was the product of a previous commercial method using a seedless distillation crystallization method from an ethyl acetate, toluene solvent system. It is notable the lower particle size and generally broader size distribution of the particles.

[0175] In Figure 5 showing the results of the pressure titration experiment, the fragile nature of the particles not representative of the method of the present invention was confirmed. In this experiment, the particle size distribution was monitored as the particles were exposed to increasing pressures from 1 bar to 3 bar. Figure 5 It is shown that as the pressure increased, the median particle size (d50) decreased from 110 μm to 60 μm, a loss of approximately 45%. In addition, the particle size distribution curve broadened and shifted towards smaller particle sizes. This is evidence that these particles break under increased pressure and indicates that the particles are very thin.

[0176] In contrast, Figure 10 shows the particle size distribution of fluralaner crystals made by the method of the present invention. These particles have a d50 larger than that of the particles of Figure 5 . In addition, in the pressure titration test, for the particles made by the method of the present invention, the decrease in d50 was only about 25% of the original value. This indicates an increase in the mechanical resilience of these particles. It is also notable the fact that at elevated pressures the distribution does not broaden in the same manner as the particles from the unoptimized method shown in Figure 5 .

[0177] Figure 7 shows the particle size distribution and pressure titration of another batch of fluralaner particles made by the method of the present invention. In this case, the original d50 of approximately 103 μm decreased to approximately 67 μm, a loss of approximately 35%.

[0178] Figure 8 is a scanning electron micrograph of fluralaner particles not made by the method of the present invention. It is notable that these crystals are rather thin.

[0179] Figure 9 is a scanning electron micrograph of fluralaner particles made by the method of the present invention. Different from Figure 8The particles shown in [figure] have a large size (about 100 μm) and a thickness (about 10 - 20 μm).

[0180] Example 3: – Method for Forming Large-Grained Fluralaner on a 6 L Scale

[0181] Fluralaner was added to isopropyl alcohol (IPA) at a concentration of 100 mg / mL. 600 g was added to 6 L of isopropyl alcohol. This composition was heated to 65 °C for 1 hour and aged for 1 hour to ensure complete dissolution. The solution was cooled to 50 °C over 20 minutes and seeded with 6 g of crystalline fluralaner seeds, in this case unground seeds with a d50 of approximately 10 μm. The batch was further cooled to 20 °C over 2 hours to establish the starting particles. The batch was heated to 54 °C, at which point 1.2 L of the batch was removed and heated to an elevated temperature until all solids were completely dissolved (>65 °C). Then the recycle loop was started, and the withdrawal rate and return rate of the crystallizer were set to approximately 44 - 48 mL / min. The recycle loop continued for 3 hours, at which point the d50 particle size was approximately 45 µm. The batch was aged at 54 °C for 6 hours to further relieve supersaturation, then cooled to 45 °C over 6 hours and further cooled to 0 °C over 16 hours. The resulting slurry was filtered and dried to produce fluralaner particles. The dried fluralaner particles were measured to determine the particle size and report the mechanical resilience of the particles, and are shown in Figure 10 in. SEM images of the resulting particles are shown in Figure 11 .

[0182] Example 4: – Method for Forming Large-Grained Fluralaner on a Pilot Scale

[0183] Fluralaner was added to IPA at a concentration of 100 mg / mL. 60 kg was added to 600 L of isopropyl alcohol. This composition was heated to 65 °C for 1 hour and aged for 1 hour to ensure complete dissolution. The solution was cooled to 50 °C over 20 minutes and seeded with 600 g of crystalline fluralaner seeds, still using unground seeds with a d50 of approximately 10 μm. The batch was further cooled to 20 °C over 2 hours to establish the starting particles. The batch was heated to 54 °C, at which point 120 L of the batch was removed and heated to an elevated temperature until completely dissolved (>65 °C). The withdrawal rate and return rate of the crystallizer were set to approximately 4.4 - 4.8 L / min. The recycle loop continued for 2.75 hours, at which point the d50 particle size was approximately 40 µm. The batch was aged at 54 °C for 6 hours to further relieve supersaturation, then cooled to 45 °C over 6 hours and further cooled to 0 °C over 16 hours. For a schematic diagram of the process equipment, see Figure 12。The resulting slurry is filtered and dried to produce fluralaner particles. Stirring is restricted during filtration and drying. The material is delumped at low speed in a conical mill. The dried fluralaner particles are measured to determine particle size and mechanical resilience. The particle size distribution and mechanical resilience are shown in Figure 13 。The SEM image of the resulting particles is shown in Figure 14 。

[0184] Example 5: – Method for Forming Large-Grained Fluralaner from an Alternative Solvent System

[0185] Fluralaner is added at a concentration of 100 mg / mL in toluene:ethyl acetate at 5:3 (by volume). 60 g is added to 600 mL of solvent. This composition is heated to 65 °C over 1 hour and aged for 1 hour to ensure complete dissolution. The solution is cooled to 50 °C over 20 minutes and seeded with 0.6 g of crystalline fluralaner seeds, still using unground seeds with a d50 of approximately 10 μm. The batch is further cooled to 20 °C over 2 hours to establish the initial particles. The batch is heated to 54 °C, at which point 120 mL of the batch is removed and heated to an elevated temperature until complete dissolution (>65 °C). The withdrawal rate and return rate of the crystallizer are set to approximately 4.3 mL / min. The recycle loop continues for 2.2 hours, at which point the x50 particle size is approximately 50 μm. The batch is aged at 54 °C for 5 hours to further relieve supersaturation, then cooled to 45 °C over 6 hours and further cooled to 0 °C over 16 hours. The dried fluralaner particles are measured to determine particle size and mechanical resilience. The particle size distribution and mechanical resilience as measured by pressure titration on a Sympatec static light scattering system are shown in Figure 15 。The SEM image of the resulting particles is shown in Figure 16 。These results show that using the recycle method, the target particle size and mechanical resilience can be achieved. It should be noted that, as Figure 16 observed, the solvent may affect the morphology, where the crystal surface is slightly altered compared to the surface of the crystals grown from isopropanol.

Claims

1. A method for preparing fluralaner particles, the method comprising a) dissolving fluralaner in a solvent selected from isopropanol and a mixture of toluene and ethyl acetate in a crystallizer vessel to produce a batch of fluralaner solution; b) initiating crystallization as follows i) cooling the crystallizer vessel to supersaturation or ii) vibrating the crystallizer vessel or iii) adding seeds of fluralaner to the crystallizer vessel or iv) a combination of one or more of the above; c) taking out a portion of the batch, heating the taken-out portion to completely dissolve the fluralaner particles in the solvent and returning the dissolved fluralaner solution to the crystallizer vessel; wherein the return rate is equal to the take-out rate and is 0.25 to 0.75 batch volumes per hour; and wherein the batch volume is the volume of the fluralaner solution produced in step a); and d) cooling the crystallizer vessel to achieve fluralaner particles of the desired size; wherein the desired particle size is a particle having a volume-weighted particle size distribution (d50) measured by a static light scattering instrument of 50 to 150 μm and an average particle thickness measured by scanning electron microscopy (SEM) greater than 10 μm.

2. A method for preparing fluralaner particles, the method comprising a) combining fluralaner with a solvent selected from isopropanol and a mixture of toluene and ethyl acetate in a crystallizer vessel; b) heating the crystallizer vessel until fluralaner is dissolved in the solvent; c) cooling the crystallizer vessel to 48 - 55 °C to form a batch of supersaturated fluralaner in the solvent; i) adding seeds of fluralaner to the crystallizer vessel to initiate crystallization and particle growth; ii) forming a slurry of fluralaner particles and the solvent in the crystallizer vessel; d) maintaining the temperature of the crystallizer vessel at 48 - 55 °C; e) taking out a portion of the batch and heating the taken-out portion to completely dissolve the fluralaner particles in the solvent; wherein the take-out rate 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 fluralaner solution produced in step c); f) returning the dissolved fluralaner solution to the crystallizer vessel; wherein the return rate is equal to the take-out rate of step e); and g) cooling the crystallizer vessel to achieve fluralaner particles of the desired size; wherein the desired particle size is a particle having a volume-weighted particle size distribution (d50) measured by a static light scattering instrument of 50 to 150 μm and an average particle thickness measured by scanning electron microscopy (SEM) greater than 10 μm.

3. The method according to any one of claims 1 - 2, wherein the solvent is isopropanol.

4. The method according to claim 2, wherein the crystallizer in step b) is heated to a temperature higher than 60 °C.

5. The method according to claim 2, wherein the crystallizer in step b) is heated to a temperature of 65 °C.

6. The method according to any one of claims 1 - 2, wherein the taken-out portion is heated to a temperature higher than 60 °C.

7. The method according to any one of claims 1 - 2, wherein the taken-out portion is heated to a temperature of 65 °C.

8. The method according to any one of claims 1 - 2, wherein the taken-out portion is heated by means of a heat exchanger or in a second vessel.

9. The method of claim 2, wherein the withdrawal rate in step e) is 0.40 to 0.46 batch volumes per hour.

10. The method of any one of claims 1 - 2, wherein the withdrawal rate is maintained for 4 to 24 hours.

11. The method of any one of claims 1 - 2, wherein the withdrawal rate is maintained for 6 hours.

12. The method of claim 2, wherein the crystallizer vessel in step g) is cooled to a temperature of 0 °C or lower.

13. The method of claim 2, wherein the crystallizer vessel in step g) is cooled to a temperature of -10 °C.

14. The method of any one of claims 1 - 2, wherein the crystallizer vessel is cooled over 10 - 48 hours.

15. The method of any one of claims 1 - 2, wherein the crystallizer vessel is cooled over 12 - 20 hours.

16. The method of claim 2, which further comprises the step of filtering the fluralaner particles of step g).

17. The method of claim 16, wherein the temperature of the filtration is maintained at 0 °C or lower.

18. The method of claim 16, wherein the temperature of the filtration is maintained at -10 °C.

19. The method of any one of claims 16 - 18, wherein the filtered fluralaner particles are dried.

20. Fluralaner particles produced by the method of any one of claims 1 - 19, wherein when the mechanical resilience measured by pressure titration increases from 1 bar to 3 bar of dispersion pressure, the volume - weighted particle size distribution (d50) of the particles measured by static light scattering instrument does not decrease by more than 40%.

21. A fluralaner particle composition, which comprises particles having a volume - weighted particle size distribution (d50) measured by static light scattering instrument of 50 to 150 μm and a thickness greater than 10 μm measured by scanning electron microscopy (SEM), wherein when the mechanical resilience measured by pressure titration increases from 1 bar to 3 bar of dispersion pressure, the volume - weighted particle size distribution (d50) of the particles measured by static light scattering instrument does not decrease by more than 40%.

22. The fluralaner particle composition of claim 21, wherein the particle size distribution (d50) of the particles does not decrease by more than 35% from 1 bar to 3 bar of dispersion pressure.

23. The method of claim 1, wherein the withdrawal rate in step c) is 0.40 to 0.46 batch volumes per hour.

24. The method of claim 1, wherein the crystallizer vessel in step d) is cooled to a temperature of 0 °C or lower.

25. The method of claim 1, wherein the crystallizer vessel in step d) is cooled to a temperature of -10 °C.

26. The method of claim 1, which further comprises the step of filtering the fluralaner particles of step d).

27. The method of claim 26, wherein the temperature of the filtration is maintained at 0 °C or lower.

28. The method of claim 26, wherein the temperature of the filtration is maintained at -10 °C.

29. The method of any one of claims 26 - 28, wherein the filtered fluralaner particles are dried.

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