Method for reducing the particle size of ivermectin

Abstract

The present invention provides a method for reducing the particle size of ivermectin, comprising the steps of incorporating ivermectin particles in a wet or liquid medium and subjecting the medium containing the particles to mixing in a high shear mixer.

Description

Detailed Description of the Invention

[0001] [Field of the Invention]

[0001] The present invention relates to a new method designed to control the particle size and related substance content of ivermectin. In one aspect, the method involves micronization of ivermectin in a wet or liquid medium to reduce the particle size to a level suitable for downstream formulation. In a preferred aspect, the method also includes purification of ivermectin in the solvent mixture used to micronize the product. Purification of ivermectin occurs by purging of related substances during micronization. Another important feature of the method is that it includes the use of a suitable antioxidant that acts as a radical scavenger to prevent the degradation of ivermectin by air oxidation during micronization. The antioxidant also prevents air oxidation of ivermectin during storage.

[0002] [Background of the invention]

[0002] Ivermectin, the compound of molecular structure (I), is an anti-helminthically active medicinal substance prescribed for the treatment of head lice, scabies, river blindness, strongyloidiasis and lymphatic filariasis, among other diseases promoted by parasites. [ka]

[0003]

[0003] Ivermectin is composed of 80% or more of component B1a and 20% or less of component B1b. Compound I was first disclosed in US Patent No. 4,199,569, which describes a method for its preparation, which comprises hydrogenating compound II, abamectin, composed of 80% or more of avermectin B1a and 20% or less of avermectin B1b, in the presence of the catalyst tris(triphenylphosphine)rhodium(I) chloride, which is Wilkinson's catalyst. [ka]

[0004] This method describes two successive recrystallizations to isolate ivermectin after hydrogenation. The first recrystallization is carried out in a mixture of ethanol, formamide and water (4:10:2) in which ivermectin is dissolved at 40-50°C, followed by crystallization by slow cooling under stirring overnight. The second recrystallization is carried out by dissolving the product obtained from the first crystallization in a mixture of ethanol and water (4:4) at 35-40°C, followed by slow cooling under stirring overnight. Under the conditions described by the inventors, ivermectin is obtained from abamectin in a yield of 83% by weight. The authors claim ivermectin in a mixture containing about 80% component B1a and 20% component B1b.

[0005] In a publication describing the analytical profile of ivermectin (Analytical Profiles of Drug Substances, vol. 17, 1988, pp. 155-184), the authors described the stability characteristics of the product in solution and in the solid state. According to the authors, ivermectin contains many functional groups, and ivermectin is unstable in acidic and basic solutions. The degradation rate of the product increases both with increasing acidity and with increasing basicity. In acidic solutions, ivermectin undergoes hydrolysis reactions of the two sugar rings, resulting in monosaccharide and aglycone by-products. In basic solutions, ivermectin undergoes isomerization, resulting in 2-epi-ivermectin and Δ 2 -ivermectin by-products. It is noted that the optimum pH for ivermectin stability in solution is 6.3. The main mode of degradation of ivermectin under neutral conditions is oxidation at the 8a position to produce by-products, namely 8a-oxoivermectin and 8a-hydroperoxideivermectin. Ivermectin is also photolabile and the products resulting from its photodegradation are C8-C9 and C 10 ~C 11It is a geometric isomer of olefins. The authors also report that pure ivermectin is a stable molecule in the crystalline state in the absence of extraneous reactants and impurities. Nevertheless, air oxidation of ivermectin in the solid state is a known phenomenon, as recognized by the fact that the impurity 8a-oxoivermectin is listed in the ivermectin related substances test in both the European and US Pharmacopoeias.

[0006]

[0006] US Patent No. 6,072,052 claims a method for preparing ivermectin by selective hydrogenation of abamectin using rhodium salts and rhodium-phosphine complexes with hydrazine. The inventors describe a method in which the ivermectin obtained from hydrogenation is purified by removal of the catalyst by extraction with a lipophilic solvent in which the catalyst dissolves well but ivermectin does not dissolve well. According to the inventors, ivermectin precipitates from the mixture when a lipophilic solvent such as an aliphatic hydrocarbon is added to the mixture to dissolve the catalyst. The inventors mention obtaining crude ivermectin containing 1.3% avermectin, 94.8% ivermectin and 25% tetrahydroavermectin by HPLC.

[0007]

[0007] U.S. Patent No. 6,265,571 describes a method for purifying ivermectin by reversed-phase flash column chromatography, the chromatography column being C 18The method is claimed to include a silica gel column, and the eluent includes a mixture of lower alkyl alcohol and water with acetonitrile. The inventors report obtaining ivermectin with 95.15% component B1a and 2.22% component B1b by HPLC. The inventors claim the method has a purity level of purified ivermectin including at least about 98%. The inventors report that the purity of ivermectin is calculated by adding the area % of component B1a to the area % of component B1b, and subtracting the residual content of water and volatile substances. The implementation of column chromatography in the pharmaceutical industry shows several disadvantages related to the need for large pumps operating at high pressure, large consumption of solvents resulting in large amounts of liquid waste, and long processing times.

[0008]

[0008] WO 2019 / 180417 claims amorphous ivermectin obtained by spray drying a solution of ivermectin prepared by dissolving ivermectin in an organic solvent or a mixture of organic solvents or a mixture of organic solvents and water. The inventors mention ethanol, methyl ethyl ketone, acetone or 1-butanol as solvents that can be used to prepare a solution of ivermectin. The inventors claim amorphous ivermectin with a particle size distribution of 0.1 μm to 20 μm. No data are disclosed on the purity of ivermectin obtained by the claimed method.

[0009] Ivermectin has been used to treat a variety of diseases caused by ectoparasites and endoparasites in humans and other animals. Ivermectin is available commercially in the following pharmaceutical forms: oral tablet (Stromectol®), oral suspension (combined formulation, e.g., from Wedgewood Pharmacy), chewable tablet (Tri-Heart Plus®), topical lotion (Skilice®) and cream (Rosiver® and Soolantra®). Many other pharmaceutical forms have been developed, including subcutaneous formulations (Sharun K, Shyamkumar TS, Aneesha VA, Dhama K, Pawde AM, Pal A (2019), Current therapeutic applications and pharmacokinetic modulations of ivermectin, Veterinary World, 12(8): 1204-1211). Ivermectin is a compound with low solubility and high permeability in water and is classified as a BCS class II drug. Due to the low water solubility of ivermectin and the low stability of aqueous formulations, there are great challenges in the manufacture of formulations. In the manufacture of pharmaceutical formulations, several physicochemical characteristics from the active pharmaceutical substance are required to ensure stable bioavailability. Prior art has reported the modification of pharmacokinetic properties of ivermectin by changing the formulation type (Albert Lo, PK., Fink, DW, Williams, JB et al., Pharmacokinetic studies of ivermectin: Effects of formulation. Vet Res Commun 9, pp. 251-268 (1985)). In addition, a requirement of some types of formulations is that the active pharmaceutical substance exhibits a reduced particle size to ensure uniform distribution of the active substance throughout the pharmaceutical form.

[0010]

[0010] Conventionally, the method of reducing the particle size of solid ivermectin particles has typically been carried out as a dry process using jet milling. We have now recognized that there is an unmet need in the prior art for a method that can reduce the particle size of ivermectin while simultaneously increasing its purity, which provides benefits to the formulation process. The method of the present invention can reduce the particle size of ivermectin in a wet medium through a high shear mixer technique using a solvent mixture, which allows for the purging of impurities and produces a purer ivermectin. Another related aspect of the method is that it includes the use of an antioxidant to prevent air oxidation of ivermectin during processing and even storage. The high shear mixer process generates strong shear forces and high temperatures, which can promote degradation of the product when subjected to these conditions. Therefore, such a process was thought to be completely unsuitable for the use of ivermectin. Surprisingly, the inventors have now found that the method of the present invention does not promote the degradation of ivermectin, a sensitive compound susceptible to several side reactions.

[0011] [Summary of the invention]

[0011] According to the present invention, there is provided a method for reducing the particle size of ivermectin, comprising the steps of incorporating ivermectin particles in a wet or liquid medium and subjecting the medium containing the particles to mixing in a high shear mixer.

[0012]

[0012] High shear mixing as a technique is well understood in the art. Any suitable high shear mixer device may be used in the present invention, including batch or in-line high shear mixers, or ultra-high shear mixers. In contrast to low shear mixing, high shear mixing can be properly understood for the purposes of the present invention as a mixing process that has the ability to reduce the average size of the solid particles of the API material. Generally, low shear mixing does not reduce the average particle size of the API.

[0013]

[0013] Thus, in one preferred embodiment, the present invention discloses a method for reducing the particle size of ivermectin in an organic solvent and / or a mixture of an organic solvent and water, preferably in a wet or liquid medium further comprising formamide.

[0014]

[0014] The present invention discloses a method for purifying ivermectin while reducing the particle size, thus reducing the total content of related substances in ivermectin. Given the sensitive nature of ivermectin, this is a particular and surprising advantage of the method. The organic solvent can be, for example, an alcohol, an ester, a ketone, an ether, an amide, a hydrocarbon or a halogenated hydrocarbon. In a preferred embodiment, the organic solvent is an alcohol, and in a more preferred embodiment, the organic solvent is ethanol. [Brief description of the drawings]

[0015] [Figure 1] 1 is an HPLC chromatogram of Example 1. [Diagram 2] 1 is a particle size distribution histogram of Example 1. [Diagram 3] HPLC chromatogram of Example 2. [Figure 4] 1 is a particle size distribution histogram of Example 2. [Diagram 5] 1 is an HPLC chromatogram of Example 3. [Figure 6] 1 is a particle size distribution histogram of Example 3. [Figure 7] HPLC chromatogram of Example 4. [Figure 8] 1 is a particle size distribution histogram of Example 4. [Figure 9] HPLC chromatogram of Example 5. [Figure 10] 1 is a particle size distribution histogram of Example 5. [Figure 11] HPLC chromatogram of Example 6. [Figure 12] 1 is a particle size distribution histogram of Example 6. [Figure 13]HPLC chromatogram of Example 7. [Figure 14] 1 is a particle size distribution histogram of Example 7. [Figure 15] 1 is a typical HPLC chromatogram of the starting material. [Figure 16] 1 is a typical particle size distribution histogram of the starting material.

[0016] [Detailed Description of the Invention] In a preferred embodiment, the particle-containing medium comprises a suspension of ivermectin. Thus, typically, solid particles of ivermectin are suspended in a liquid medium. A liquid medium as used herein means a medium that is in a liquid state at room temperature (e.g., 20-25°C). The liquid medium suitably comprises an organic solvent or a mixture of an organic solvent and water. The initial particle size of the ivermectin particles may vary, but typically will be in the range of 200-300 microns or more in diameter, as typically produced by standard manufacturing methods. V (90) order.

[0017] The organic solvent may be any suitable solvent, but preferably comprises or consists of an alcohol, an ester, a ketone, an ether, an amide, a hydrocarbon or a halogenated hydrocarbon. One or more of these solvents may be used, for example as a mixture.

[0018]

[0017] When the organic solvent is an alcohol, preferably it is an aliphatic alcohol, for example a C2-C8 aliphatic alcohol. Particularly preferred is ethanol or isopropanol.

[0019]

[0018] When the organic solvent is an ester, a compound of general formula RCOOR', preferably this is an ester in which R and R' are alkyl groups, for example C1-C3 alkyl groups, preferably ethyl acetate or isopropyl acetate.

[0020]

[0019] When the organic solvent is a ketone, a compound of general formula RCOR', preferably this is a ketone in which R and R' are alkyl groups, for example C1-C3 alkyl groups, preferably acetone or methyl ethyl ketone.

[0021]

[0020] When the organic solvent is an ether, a compound of general formula ROR', it is preferably an ether in which R and R' are alkyl groups, for example C1-C3 alkyl groups, preferably diethyl ether or diisopropyl ether. Optionally, the ether is a cyclic ether of general formula RO, for example a C6 cyclic ether, preferably tetrahydrofuran, or a cyclic ether of general formula RO2, for example a C4 cyclic ether, preferably dioxane.

[0022] When the organic solvent is an amide, a compound of general formula RR'NCOR'', preferably this is an amide in which R and R' are alkyl groups, for example C1 alkyl groups, and R'' is hydrogen or a C1 alkyl group, preferably dimethylformamide or dimethylacetamide.

[0023]

[0022] When the organic solvent is a hydrocarbon, preferably it is an aliphatic or aromatic hydrocarbon, for example a C6-C7 aliphatic hydrocarbon, preferably hexane or heptane, or a C7 aromatic hydrocarbon, preferably toluene.

[0024]

[0023] When the organic solvent is a halogenated hydrocarbon, preferably it is an aliphatic halogenated hydrocarbon, such as a C1 halogenated aliphatic hydrocarbon, preferably dichloromethane.

[0025]

[0024] The liquid medium comprises an organic solvent, or a mixture of organic solvents, or a mixture of an organic solvent and water, preferably further comprising formamide. The organic solvent is a solvent in which ivermectin is soluble or freely soluble. To increase the yield of the process, a mixture of an organic solvent and a solvent in which ivermectin is insoluble, such as a mixture of alcohol and water, can be used to carry out the high shear mixer process. Table 1 summarizes the solubility data of ivermectin disclosed in the prior art (Analytical Profiles of Drug Substances, vol. 17, 1988, pp. 155-184). [Table 1]

[0026] The proportion of liquid medium for carrying out the high shear mixer process can be, for example, from 2 vol and 30 vol, preferably from 4 vol to 8 vol, based on the weight of ivermectin. For mixtures of soluble or easily soluble organic solvents and insoluble solvents, the proportion (by volume) of soluble solvent to insoluble solvent can be, for example, 10 to 0.01, or 0.01 to 10, preferably 8 to 1.

[0027]

[0026] The ratio of formamide to ivermectin relative to the weight of ivermectin may be, for example, 0.1 vol to 2 vols, preferably 0.2 vol to 0.4 vol.

[0028]

[0027] The ratio of the antioxidant to ivermectin based on the weight of ivermectin may be, for example, 0.00001 to 0.001, preferably 0.0001 to 0.0003.

[0029]

[0028] Thus, the liquid medium typically comprises or consists of an organic solvent and / or a mixture of an organic solvent and water. In a preferred embodiment, the process involves micronization of ivermectin particles in a mixture of an aliphatic alcohol, for example a C2-C8 aliphatic alcohol, and water by high shear mixing. For example, a mixture of an aliphatic alcohol, for example a C2-C4 aliphatic alcohol, and water can be used. Particularly preferred is a mixture of ethanol and water.

[0030] In a preferred embodiment of the present invention, an antioxidant may be added to the solvent or solvent mixture (ie, the liquid medium) to prevent air oxidation of the ivermectin during recirculation in the high shear mixer.

[0031]

[0030] Thus, in one embodiment, the liquid medium containing the ivermectin particles also contains an antioxidant. In one example, the antioxidant includes a paraben derivative, a phenol derivative, or a thiol derivative.

[0032] Suitably, the antioxidant may comprise or consist of an alkylparaben, such as methyl or ethylparaben.

[0033] Alternatively or in addition, the antioxidant may comprise or consist of an alkylated phenol derivative, preferably an alkylated hydroxyanisole. Preferred examples include butylated hydroxyanisole (BHA), butylated hydroxytoluene or tocopherol. Alternatively or in addition, the antioxidant may comprise or consist of a thiol derivative, such as cysteine.

[0034] In a further aspect, a method according to the invention is provided, wherein the liquid medium containing particles of ivermectin further comprises a stabilizer to minimize desolvation of ivermectin, which is primarily designed to prevent loss of solvation solvent from the ivermectin particles via dissolution in the liquid medium, but may also contribute to the purification or purging process resulting in a reduction in total impurity levels.

[0035] In one example, the stabilizer comprises an aliphatic monocarboxylic acid amide. Preferably, the stabilizer comprises or consists of formamide. Lower aliphatic alcohols such as ethanol may also function as stabilizers, or in addition to formamide (or the like).

[0036] Quite surprisingly, it has been found that the process of the present invention reduces the particle size of ivermectin particles without adversely affecting the stability of ivermectin. In fact, far from resulting in degradation, it has been found that the process leads to a reduction in the total impurity levels (e.g., degradation products or side reaction products) while still maintaining a good yield of ivermectin.

[0037] In one embodiment, the present invention provides a method for the preparation of ivermectin particles having a D V (90) is significantly reduced, for example to less than 100 microns, or less than 80 microns, or preferably less than 60 microns. V Particles with (90) can be obtained depending on the length and intensity of high shear mixing.

[0038]

[0037] Thus, the duration of the mixing step can be any suitable time, so long as it provides the necessary reduction in particle size. This can vary depending on the final pharmaceutical formulation in which ivermectin is designed to be incorporated. The ivermectin particles provided by the present invention are particularly suitable for incorporation into oral pharmaceutical formulations. The method can be used to obtain, if desired, a D reduction down to about 30 microns. V 90. A mixing time of 1 to 4 hours is typically required. A preferred mixing time is from about 2 or 2.5 hours to about 3 or 3.5 hours.

[0039]

[0038] We have found that the method can simultaneously reduce both the particle size of ivermectin and the total level of impurities present within the particles, such as degradation or decomposition products of ivermectin. In one aspect, the present invention provides a method in which the reduction in total impurities of the resulting ivermectin particles, as measured by HPLC (% area), is 10% or more compared to the initial ivermectin particles. Alternatively expressed, the present invention provides a method in which the total impurities of the resulting ivermectin particles, as measured by HPLC (% area), is 3.0% or less, optionally 2.8% or less, or 2.7% or less.

[0040]

[0039] In one particularly preferred embodiment, the liquid medium containing the ivermectin particles comprises water; ethanol or isopropanol (or a mixture of both) as an organic solvent; methylparaben or ethylparaben (or a mixture of both) as an antioxidant, and an aliphatic monocarboxylic acid amide, such as formamide, as a stabilizer.

[0041] As mentioned above, any suitable high shear mixer can be used to carry out the high shear mixing step. Preferably, the high shear mixer can be operated over a wide range of revolutions per minute (RPM). In one embodiment of the present invention, in the high shear mixing step, the suspension of ivermectin is recirculated at a range of revolutions per minute of the high shear mixer from 500 RPM to 9000 RPM.

[0042]

[0041] Thus, in a preferred embodiment, the suspension of ivermectin is recirculated at a high shear mixer revolutions per minute range of 1000 RPM to 2000 RPM. We have found that this range tends to provide a gradual and controlled reduction in particle size over time, which can be suitably monitored by suitable sampling of the liquid medium (at various time intervals), as will be appreciated by those skilled in the art.

[0043] In a preferred mode, the high shear mixer process is run at moderate revolutions per minute, preferably around 2000 RPM.

[0044]

[0043] The high shear mixing step, or indeed the entire process, may be carried out at room temperature or lower. In a preferred mode of operation, the high shear mixing step may be carried out at a temperature between 0°C and 5°C.

[0045]

[0044] Thus, in one embodiment, there is provided a process according to the present invention, wherein in the high shear mixing step, the liquid medium containing the ivermectin particles is recirculated at a temperature between 0° C. and 25° C. In a further preferred embodiment, the suspension of ivermectin may be recirculated at a temperature between 0° C. and 5° C.

[0046] In a further aspect of the invention, the step of incorporating the ivermectin particles into the wet or liquid medium may be carried out at room temperature or lower. In a preferred mode of operation, this step may be carried out at a temperature between 0° C. and 25° C., or more preferably, at a temperature between 0° C. and 5° C. This step may, for example, involve the incorporation or addition of ivermectin into a liquid medium, the liquid medium comprising water (if present), an organic solvent component, an antioxidant component (if present), and a stabilizer component (if present).

[0047] In a further aspect of the invention, the method comprises a step of isolating the obtained ivermectin particles (after the high shear mixing step) from the liquid medium. This may for example comprise a step of filtration and one or more washing steps. The isolation step, or any part thereof, such as the filtration and washing steps, may be carried out at room temperature or at a lower temperature. In a preferred mode of operation, the isolation step, or any part thereof, may be carried out at a temperature between 0°C and 25°C, or more preferably, at a temperature between 0°C and 5°C.

[0048] In a further aspect of the invention, the methods described herein may further comprise a step of washing the recovered ivermectin particles with an antioxidant after high shear mixing. We have found that this helps protect the product from oxidation after processing, e.g. during storage. Such a washing step can be used to incorporate some of the antioxidant into the final product. This washing step can be part of the isolation step described above.

[0049] For this washing step, the antioxidant may be, for example, an alkyl paraben, such as methyl or ethyl paraben, or an alkylated phenol derivative, such as, for example, an alkylated phenol hydroxyanisole, such as butylated hydroxyanisole; butylated hydroxytoluene; or tocopherol. The antioxidant used in this washing step may be the same or different from the antioxidant (if present) used in the liquid medium containing the ivermectin particles that have been subjected to high shear mixing.

[0050]

[0049] In one embodiment, the step of washing with an antioxidant may be carried out at a temperature between 0°C and 25°C, preferably between 0°C and 5°C.

[0051]

[0050] As a result of the novel process of the present invention provided herein, and in particular the effect of this process on impurity levels, the present invention therefore also provides novel ivermectin particles that can be obtained or have been obtained by the process of the present invention described herein.

[0052]

[0051] In a further aspect, there is further provided the use of high shear mixing to reduce the particle size of ivermectin in a suspension of ivermectin particles in a liquid medium.

[0053]

[0052] The liquid medium may comprise an organic solvent or a mixture of an organic solvent and water. The organic solvent may be any suitable solvent, but preferably comprises or consists of an alcohol, an ester, a ketone, an ether, an amide, a hydrocarbon or a halogenated hydrocarbon. One or more of these solvents may be used, for example as a mixture. When the organic solvent is an alcohol, preferably it is an aliphatic alcohol, for example a C2-C8 aliphatic alcohol. Particularly preferred is ethanol or isopropanol.

[0054]

[0053] Thus, the liquid medium typically comprises or consists of an organic solvent and / or a mixture of an organic solvent and water. In a preferred embodiment, the process involves micronization of ivermectin particles in a mixture of an aliphatic alcohol, for example a C2-C8 aliphatic alcohol, and water by high shear mixing. For example, a mixture of an aliphatic alcohol, for example a C2-C4 aliphatic alcohol, and water can be used. Particularly preferred is a mixture of ethanol or isopropanol and water.

[0055]

[0054] In a preferred embodiment, there is provided the use of high shear mixing to reduce the particle size of ivermectin in a suspension of ivermectin particles in a liquid medium, the liquid medium comprising water; an organic solvent comprising ethanol or isopropanol; and a stabilizer comprising formamide.

[0056]

[0055] It will be understood by those skilled in the art that the ivermectin produced by the methods of the present invention can be incorporated into pharmaceutical formulations, along with suitable pharma- ceutical acceptable excipients as necessary, to provide a medicament for treating a patient in need thereof.

[0057]

[0056] Therefore, the invention described herein includes a method for reducing particle size and simultaneously purifying ivermectin. The method preferably includes loading ivermectin into a solvent mixture containing an antioxidant, recirculating the resulting suspension in a high shear mixer until the target particle size is achieved, stopping the recirculation and isolating the product by filtration and drying. The use of organic solvents described herein can reduce the particle size of ivermectin, but at the same time, purify ivermectin and therefore reduce the total content of impurities.

[0058]

[0057] Ivermectin is a mixture of two main components, component B1a and component B1b, which also contains some related substances. The related substances can be expressed as the total content of impurities. The method described herein can reduce the total content of impurities in ivermectin. This effect is made possible by the use of organic solvents in the solvent mixture used to micronize ivermectin.

[0059]

[0058] Under the conditions described in this invention, ivermectin can be subjected to high shear forces without degradation. The high shear mixing process provides stressful conditions that promote the degradation of compounds subjected to such processes. The stressful conditions include recirculating the compound and solvent mixture at very high speeds through a mechanical system that generates unaligned forces, forcing strong collisions between the particles and the mechanical parts of the high shear mixer and between the particles themselves. These collisions break the product particles, thus reducing their particle size. A secondary effect of the mechanical collisions is a significant increase in temperature during the high shear mixer process. Surprisingly, ivermectin, an active pharmaceutical substance that is highly sensitive to hydrolytic, oxidative and temperature side reactions, can be subjected to the high shear mixer process of this invention without causing product degradation. In fact, ivermectin is purified in good yields under the high shear process conditions described in this invention.

[0060] The following examples are presented to aid in the understanding of the invention, but are not intended, and should not be construed as in any way limiting its scope.

[0061] [Example] Example 1: D of 301 μm V Ivermectin (25 g) having (90) and a total impurity content of 2.92% (HPLC area %) was added to a mixture of ethanol (100 ml), water (12.5 ml), formamide (10 ml) and methylparaben (0.0075 g) pre-cooled to 0-5°C. The suspension was recirculated through a high shear mixer at 2000 RPM for approximately 3 hours while maintaining the mixture at a temperature of 0-5°C. The product was filtered and washed with a mixture of ethanol (2.5 ml) and water (22.5 ml) pre-cooled to 0-5°C, followed by a mixture of water (25 ml) and methylparaben (0.0075 g) pre-cooled to 0-5°C. The wet product was dried at 60°C and purified by HPLC using a 56 μm D V (90) and 21.75 g of ivermectin was obtained with a total impurities content of 2.61% by HPLC (area %).

[0062] Example 2: D of 301 μm V Ivermectin (25 g) having (90) and a total impurity content of 2.92% (HPLC area %) was added to a mixture of ethanol (120 ml), water (15 ml), formamide (6 ml) and BHA (0.0075 g) pre-cooled to 0-5°C. The suspension was recirculated through a high shear mixer at 2000 RPM for approximately 3 hours while maintaining the mixture at a temperature of 0-5°C. The product was filtered and washed with a mixture of ethanol (3 ml) and water (27 ml) pre-cooled to 0-5°C, followed by a mixture of water (30 ml) and BHA (0.0075 g) pre-cooled to 0-5°C. The wet product was dried at 60°C and purified using a 53 μm D V (90) and 26.1 g of ivermectin was obtained with a total impurities content of 2.63% by HPLC (area %).

[0063] Example 3: D of 301 μmV Ivermectin (50 g) having (90) and a total impurity content of 2.21% (HPLC area %) was added to a mixture of ethanol (100 ml), water (50 ml), formamide (10 ml) and methylparaben (0.0075 g) pre-cooled to 0-5°C. The suspension was recirculated through a high shear mixer at 2000 RPM for approximately 3 hours while maintaining the mixture at a temperature of 0-5°C. The product was filtered and washed with a mixture of ethanol (5 ml) and water (55 ml) pre-cooled to 0-5°C, followed by a mixture of water (50 ml) and methylparaben (0.0075 g) pre-cooled to 0-5°C. The wet product was dried at 60°C and purified using a 57 μm D V (90) and 45.5 g of ivermectin was obtained with a total impurities content of 2.06% by HPLC (area %).

[0064] Example 4: D of 295 μm V Ivermectin (30 g) having (90) and a total impurity content of 3.33% (HPLC area %) was added to a mixture of water (150 ml), isopropanol (75 ml), formamide (6 ml) and methylparaben (0.0075 g) pre-cooled to 0-5°C. The suspension was recirculated through a high shear mixer at 2000 RPM for approximately 3 hours while maintaining the mixture at a temperature of 0-5°C. The product was filtered and washed with a mixture of ethanol (3 ml) and water (27 ml) pre-cooled to 0-5°C, followed by a mixture of water (30 ml) and methylparaben (0.0075 g) pre-cooled to 0-5°C. The wet product was dried at 60°C and purified using a 56 μm D V (90) and 29.4 g of ivermectin was obtained with a total impurities content of 3.03% by HPLC (area %).

[0065] Example 5: D of 300 μm VIvermectin (4 g) having (90) and a total impurity content of 3.22% (HPLC area %) was added to a mixture of water (16 ml), ethanol (16 ml) and formamide (1.6 ml) pre-cooled to 0-5°C. The suspension was recirculated through a high shear mixer at 1000 RPM for approximately 2 hours while maintaining the mixture at a temperature of 0-5°C. The product was filtered and the wet product was dried at 60°C to obtain a 42 μm D V (90) and 3.66 g of ivermectin was obtained with a total impurities content of 2.76% by HPLC (area %).

[0066] Example 6: D of 300 μm V Ivermectin (2 g) having (90) and a total impurity content of 3.22% (HPLC area %) was added to a mixture of water (26 ml), ethanol (30 ml) and formamide (3 ml) pre-cooled to 0-5°C. The suspension was recirculated through a high shear mixer at 1000 RPM for approximately 2 hours while maintaining the mixture at a temperature of 0-5°C. The product was filtered and the wet product was dried at 60°C to obtain a 36 μm D V (90) and 1.77 g of ivermectin was obtained with a total impurities content of 2.87% by HPLC (area %).

[0067] Example 7: D of 300 μm V Ivermectin (2 g) having (90) and a total impurity content of 3.22% (HPLC area %) was added to a mixture of water (1 ml), ethanol (30 ml) and formamide (3 ml) pre-cooled to 0-5°C. The suspension was recirculated through a high shear mixer at 1000 RPM for approximately 2 hours while maintaining the mixture at a temperature of 0-5°C. The product was filtered and the wet product was dried at 60°C to obtain a 56 μm D V (90) and 0.96 g of ivermectin was obtained with a total impurities content of 2.75% by HPLC (area %).

[0068]

[0067] HPLC chromatograms were obtained on a reversed phase C18 HPLC column, dimensions 250 x 4 mm, pore size 5 µm, at 25°C, detection wavelength 254 nm, mobile phase water / methanol / acetonitrile (15:34:51 v / v / v), in isocratic mode.

[0069]

[0068] Particle size data were obtained using the Sympatec module HELOS (Helium-Neon Laser Optics), a dispersion unit RODOS / M, a powerful product accessory ASPIROS, lenses R5 (4.50 μm - 875 μm) and R4 (1.80 μm - 350 μm), conditions R5, 0.1 bar - 1 bar, 18 mm / s, R4, 3 bar, 18 mm / s.

[0070]

[0069] Reference symbols in the figures include the following: Sv Volume-specific surface area - the total surface area of ​​a material per bulk volume.

[0071] Sm mass-specific surface area - the total surface area of ​​a material per unit mass.

Claims

1. A method for preparing ivermectin particles having a reduced particle size, the method comprising the steps of incorporating ivermectin particles into a liquid medium comprising a mixture of an organic solvent and water, and subjecting the medium containing the particles to mixing in a high-shear mixer.

2. The method according to claim 1, wherein the ivermectin particles are suspended in the liquid medium.

3. The method according to claim 1, wherein the organic solvent is alcohol, ester, ketone, ether, amide, hydrocarbon or halogenated hydrocarbon.

4. The organic solvent is an aliphatic alcohol, and optionally the aliphatic alcohol is ２ ~C ８ The method according to claim 1 or 3, wherein the alcohol is an aliphatic alcohol.

5. wherein the aliphatic alcohol is C ２ to C ４ The method according to claim 4, comprising an aliphatic alcohol, and optionally, the aliphatic alcohol is ethanol or isopropanol.

6. The method according to claim 1, wherein the medium containing the particles further comprises an antioxidant.

7. The method according to claim 6, wherein the antioxidant is a parabens derivative, a phenol derivative or a thiol derivative.

8. The method according to claim 7, wherein the antioxidant is alkylparaben, optionally methylparaben.

9. The method according to claim 7, wherein the antioxidant is an alkylated phenol derivative, optionally an alkylated phenol hydroxyanisole such as butylhydroxyanisole; butylhydroxytoluene; or tocopherol.

10. The method according to claim 1, wherein the medium containing the particles further comprises a stabilizer for minimizing the desolvation of ivermectin.

11. The method according to claim 10, wherein the stabilizer comprises an aliphatic monocarboxylic acid amide.

12. The method according to claim 11, wherein the stabilizer comprises formamide.

13. D of the mixed ivermectin particles Ｖ The method according to claim 1, wherein (90) is less than 60 microns.

14. The method according to claim 1, wherein the reduction of the total impurities of the obtained ivermectin particles measured by HPLC (% area) is 10% or more compared to the initial ivermectin particles.

15. The method according to claim 1, wherein the total impurities of the obtained ivermectin particles measured by HPLC (% area) are 3.0% or less, optionally 2.8% or less, or 2.7% or less.

16. The method according to claim 1, wherein the medium containing the particles comprises water; ethanol or isopropanol as an organic solvent; methylparaben as an antioxidant; and formamide as a stabilizer.

17. The method according to claim 1, wherein in the step of mixing, the suspension of ivermectin is recycled in the range of the rotational speed per minute of the high-shear mixer of 500 RPM to 9000 RPM.

18. The method according to claim 17, wherein the suspension of ivermectin is recycled at a rotational speed per minute of the high-shear mixer in the range of 1000 RPM to 2000 RPM.

19. The method according to claim 1, wherein in the step of mixing, the medium containing the ivermectin particles is recycled at a temperature of 0°C to 25°C.

20. The method according to claim 19, wherein the suspension of ivermectin is recycled at a temperature of 0°C to 5°C.

21. The method according to claim 1, further comprising the step of washing the recovered ivermectin particles with an antioxidant after the mixing.

22. The method according to claim 21, wherein the antioxidant is alkyl paraben, optionally methyl paraben; or alkylated phenol derivative, optionally alkylated phenol hydroxyanisole, for example, butyl hydroxyanisole.

23. The method according to claim 21 or 22, wherein the washing step is carried out at a temperature of 0°C to 25°C, optionally at a temperature of 0°C to 5°C.

24. Ivermectin particles obtainable or obtained by the method according to claim 1.

25. Use of high-shear mixing for reducing the particle size of ivermectin in a suspension of ivermectin particles in a liquid medium.

26. The use according to claim 25, wherein the liquid medium comprises water; an organic solvent containing ethanol or isopropanol; and a stabilizer containing formamide.

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