A crystallization process for ivermectin short rods
By using a mixed solvent of acetone and water and a crystallizing agent to control the crystallization process, high-purity, high-yield short rod-shaped ivermectin was prepared, solving the problems of long processing time, high cost, and uneven particle size in existing processes, thus improving the production efficiency and quality of ivermectin formulations.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- HEBEI UNIV OF SCI & TECH
- Filing Date
- 2023-08-25
- Publication Date
- 2026-05-29
Smart Images
Figure CN117362362B_ABST
Abstract
Description
Technical Field
[0001] This invention relates to the field of fine chemical production technology, and in particular to a crystallization process for short rod-shaped ivermectin. Background Technology
[0002] Ivermectin is a macrolide antibiotic insecticide, a derivative of avermectin. It is a semi-synthetic broad-spectrum antiparasitic drug, with its main components being more than 80% ivermectin B1a and less than 20% B1b. Ivermectin exhibits extremely high insecticidal efficacy at very low doses with few side effects, and has been widely used in veterinary clinical practice. Ivermectin does not exhibit cross-resistance with other antiparasitic drugs and can also be used to treat infections caused by common human parasites. Furthermore, it possesses antiviral activity, and its potential role as an anti-COVID-19 drug is attracting considerable attention. Therefore, ivermectin has a very broad market prospect and future development prospects.
[0003] Particle size of active pharmaceutical ingredients (APIs) is a key material property in formulation development. It affects not only the powder properties of the API (such as flowability), the uniformity of formulation content, and the chemical stability of both the API and the formulation, but also the dissolution performance of the formulation, which in turn affects the release and absorption of the drug in the human body, ultimately impacting the bioavailability and efficacy of the drug. In the formulation manufacturing process, good flowability of the formulation materials is required. Many factors influence the flowability of materials, but the most critical are particle size and surface morphology.
[0004] Currently, the main process for separating and purifying ivermectin for industrial applications involves cooling recrystallization, which suffers from problems such as long processing time and low yield. Furthermore, some processes require repeated recrystallization with formamide, consuming large amounts of solvent and resulting in high crystallization costs. In addition, the ivermectin prepared by current processes mainly exhibits a single, long rod-like crystal structure with small and uneven particle size, making it inconvenient for subsequent processing. Therefore, developing a simple, low-cost, high-purity, and high-yield ivermectin is of great importance. Summary of the Invention
[0005] To address the problems of complex operation, high production cost, and small and uneven crystal size in existing cooling crystallization processes for preparing ivermectin, this invention provides a crystallization process for short rod-shaped ivermectin.
[0006] To solve the above-mentioned technical problems, the technical solution provided by the present invention is as follows:
[0007] A crystallization process for short rod-shaped ivermectin includes the following steps:
[0008] Step 1: Dissolve crude ivermectin in a crystallization solvent to obtain an ivermectin solution;
[0009] Step 2: Heat the ivermectin solution to 50℃~55℃, add the crystallizing agent, mix evenly, and then cool it down to 35℃~40℃ at a rate of 0.1℃ / min~0.3℃ / min. Add ivermectin seed crystals, continue to cool down to 5℃~15℃, keep warm to grow crystals, filter, and dry to obtain the ivermectin product.
[0010] The crystallization solvent is a mixture of acetone and water; the crystallization agent is at least one of magnesium sulfate, sodium sulfate, or Tween 80.
[0011] Compared to existing technologies, the crystallization process for short rod-shaped ivermectin provided by this invention uses a mixed solvent of acetone and water as the crystallization solvent, adds specific crystallization mordant and seed crystals, and regulates the crystal growth process by controlling the timing of the addition of the mordant and seed crystals, as well as controlling the crystallization process conditions, such as temperature control, cooling rate, and crystal growth temperature. This process yields short rod-shaped ivermectin crystals with uniform particle size distribution, complete crystal structure, and no aggregation. The ivermectin crystallization process provided by this invention can produce ivermectin products with high purity and yield in a single crystallization step. The product has complete crystal structure, moderate particle size, and the crystal slurry is easy to filter, wash, and dry, effectively improving the efficiency of the crystallization process. Furthermore, the product has good flowability, facilitating subsequent formulation applications. Using the ivermectin product obtained through this process as a raw material for formulations can greatly improve the production efficiency and product quality of ivermectin formulations, demonstrating high practical application value.
[0012] Ivermectin has a large molecular weight, and in actual production, formamide is usually added to avoid gelation during crystallization. However, formamide is difficult to remove after addition, resulting in low purity of the prepared ivermectin. This invention abandons the traditional crystallization process that requires the addition of formamide, using acetone and water as crystallization solvents, effectively avoiding formamide residue. Furthermore, by controlling the timing of adding the crystallizing agent and seed crystals, as well as parameters such as cooling temperature, crystal growth temperature, and time during the crystallization process, short rod-shaped ivermectin products with uniform particle size distribution and complete crystal structure are prepared. At the same time, the amount of solvent used is significantly reduced, avoiding the problem of repeated crystallization, effectively improving the efficiency of the crystallization process, and achieving significant progress.
[0013] Preferably, the crystallization solvent is a mixture of acetone and water in a volume ratio of 2:1 to 4:1.
[0014] More preferably, the crystallization solvent is a mixture of acetone and water in a volume ratio of 3:1.
[0015] The preferred crystallization solvent can reduce impurity inclusions in the crystals and improve the purity of the product while ensuring product yield, and it is also beneficial to the separation of the crystallized product. At the same time, the preferred crystallization solvent, together with the crystallizing agent and seed crystal, can effectively control the growth process of ivermectin crystals, obtain short rod-shaped ivermectin, and help to make the prepared ivermectin crystals concentrated and more uniformly distributed in terms of particle size.
[0016] When the ratio of acetone to water is less than 2:1, ivermectin solution is prone to oil precipitation during crystallization, making the system a viscous gel-like substance that is difficult to separate; when the ratio is greater than 3:1, the crystallization yield decreases significantly.
[0017] Preferably, the ivermectin solution has a mass concentration of 8% to 12%.
[0018] If the concentration of ivermectin solution is too low, the product yield will be reduced; if the concentration is too high, although the product yield can be improved, it is not easy to control the supersaturation of the system within a range that is conducive to good crystal growth, and impurities are also easily trapped in the ivermectin crystals, which is not conducive to improving the purity of the product. If the concentration of ivermectin is too high, it will also lead to an excessively fast crystallization rate, with fine microcrystals adhering to the crystal surface, resulting in uneven product particle size, agglomeration, and incomplete crystal structure.
[0019] Preferably, the temperature at which the crystallizing agent is added is 55°C.
[0020] For example, a crystallizer is added under stirring conditions of 250 r / min to 350 r / min. After the crystallizer dissolves, stirring continues for 25 min to 35 min, followed by cooling. Preferably, the stirring rate is 300 r / min.
[0021] Optimal addition temperature and stirring speed can prevent crystal deposition and agglomeration, and also avoid explosive nucleation leading to the formation of fine crystals and excessive crystal fragmentation. Under these optimized conditions, ivermectin crystals can be ensured to grow uniformly and without breakage, thereby improving the crystal integrity and particle size uniformity of the product.
[0022] Preferably, the amount of the mordant added is 1% to 3% of the crude weight of ivermectin.
[0023] The optimal crystal mordant and its dosage can effectively control the supersaturation of the system, preventing further growth of crystals after fine crystals have already formed. This effectively regulates the crystal nucleation and growth rate of ivermectin, resulting in good crystal growth and a relatively concentrated particle size distribution.
[0024] Preferably, the average particle size of the ivermectin seed crystals is 250 μm to 350 μm.
[0025] Preferably, the amount of ivermectin seed crystals added is 1% to 3% of the crude ivermectin mass.
[0026] The optimal seed crystal size and amount, combined with the seed crystal addition temperature, can avoid explosive nucleation and help consume the supersaturation of the system, inhibiting the generation of new nuclei. This is beneficial for preparing short rod-shaped ivermectin crystals with uniform particle size distribution. At the same time, it also helps to improve the purity of ivermectin products.
[0027] Preferably, the heat preservation and crystal growth time is 1 hour to 3 hours.
[0028] More preferably, the temperature for heat preservation and crystal growth is 5°C, and the time for heat preservation and crystal growth is 2 hours.
[0029] More preferably, in step two, the temperature is reduced to 5°C at a rate of 0.1°C / min.
[0030] By controlling a specific cooling process, the crystallization system can be kept at a suitable supersaturation level, which controls the nucleation and growth of crystals, avoids explosive nucleation, reduces the inclusion of impurities in the crystals, and also helps to inhibit the formation of new nuclei and improve the particle size uniformity of ivermectin products.
[0031] The crystallization process of ivermectin provided by this invention achieves effective control over the particle size and crystal habit of ivermectin product during crystallization by selecting a specific crystallization solvent, adding a crystallizing agent and seed crystal at a specific stage, and controlling the cooling rate and crystal growth time. This results in short rod-shaped ivermectin product with uniform particle size, a purity of over 97%, a yield of over 95%, and good product flowability, which is convenient for subsequent formulation applications. In addition, the amount of crystallization solvent added is small, and multiple crystallization cycles are not required, which effectively reduces the cost of the crystallization process and has extremely high practical application value. Attached Figure Description
[0032] Figure 1 This is a microscope image of the crude ivermectin from Example 1;
[0033] Figure 2 Microscopic photograph of the ivermectin product prepared in Example 1;
[0034] Figure 3 The particle size distribution diagram is shown for the ivermectin product prepared in Example 1.
[0035] Figure 4 The image shows the X-ray diffraction (XRD) pattern of the ivermectin product prepared in Example 1.
[0036] Figure 5 Microscopic photograph of the ivermectin product prepared for Comparative Example 1;
[0037] Figure 6 Microscopic photograph of the ivermectin product prepared for Comparative Example 2;
[0038] Figure 7 Microscopic photograph of the ivermectin product prepared for Comparative Example 3;
[0039] Figure 8 Microscopic photograph of the ivermectin product prepared for Comparative Example 4. Detailed Implementation
[0040] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to embodiments. It should be understood that the specific embodiments described herein are merely illustrative and not intended to limit the invention.
[0041] Example 1
[0042] A crystallization process for ivermectin:
[0043] Step 1: Measure 45 mL of acetone and 15 mL of deionized water, mix them evenly, add them to a jacketed crystallizer, then add 6.168 g of crude ivermectin, heat to 53 °C, stir at 300 r / min, and after the solution becomes clear, obtain ivermectin solution.
[0044] Step 2: Add 0.1268g of magnesium sulfate to the ivermectin solution, stir at 300r / min until clear, continue stirring for 30min, then cool to 38℃ at a rate of 0.2℃ / min, add 0.124g of ivermectin seed crystals with a particle size of 300μm, continue cooling to 5℃, keep warm to grow crystals for 2h, filter, and dry in a vacuum oven at 45℃ to obtain the ivermectin product.
[0045] The ivermectin product prepared in this embodiment was analyzed by an Agilent 1220 high-performance liquid chromatograph, and the results showed that its purity was 99.3% and the product yield was 97.96%.
[0046] Microscopic photographs of crude ivermectin and the prepared ivermectin product in this embodiment are shown below. Figures 1-2 As shown in the figure, the ivermectin product prepared in this embodiment is a short rod-shaped crystal with a small aspect ratio, complete crystal habit, clean crystal surface and no aggregation.
[0047] The particle size of the ivermectin product prepared in this embodiment was measured using a Master size 3000 Malvern particle size analyzer. Figure 3 As shown in the figure, the particle size distribution of ivermectin products exhibits a unimodal distribution, with the main particle size being 443 μm.
[0048] The XRD pattern of the ivermectin product prepared in this embodiment is as follows: Figure 4 As shown in the figure, the XRD peak positions of the ivermectin product and the crude ivermectin are basically the same, indicating that the same substance was prepared.
[0049] Example 2
[0050] A crystallization process for ivermectin:
[0051] Step 1: Measure 40 mL of acetone and 20 mL of deionized water, mix them evenly, add them to a jacketed crystallizer, then add 4.587 g of crude ivermectin, heat to 50 °C, stir at 250 r / min, and after the solution becomes clear, obtain ivermectin solution.
[0052] Step 2: Add 0.137g of sodium sulfate to the ivermectin solution, stir at 250r / min until clear, continue stirring for 35min, then cool to 35℃ at a rate of 0.3℃ / min, add 0.136g of ivermectin seed crystals with a particle size of 250μm, continue cooling to 10℃, keep warm to grow crystals for 1h, filter, and dry in a vacuum oven at 45℃ to obtain the ivermectin product.
[0053] The ivermectin product prepared in this embodiment was analyzed by an Agilent 1220 high-performance liquid chromatograph, and the results showed that its purity was 97.1% and the product yield was 95.2%.
[0054] The particle size of the ivermectin product prepared in this embodiment was determined by a Master size 3000 Malvern particle size analyzer. The particle size distribution of the ivermectin product showed a single peak, with the main particle size being 339 μm.
[0055] Example 3
[0056] A crystallization process for ivermectin:
[0057] Step 1: Measure 48 mL of acetone and 12 mL of deionized water, mix them evenly, add them to a jacketed crystallizer, then add 6.754 g of crude ivermectin, heat to 55 °C, stir at 350 r / min, and after the solution becomes clear, obtain ivermectin solution.
[0058] Step 2: Add 0.085g Tween 80 to the ivermectin solution, stir at 350r / min until clear, continue stirring for 25min, then cool to 40℃ at a rate of 0.1℃ / min, add 0.094g of ivermectin seed crystals with a particle size of 350μm, continue cooling to 15℃, keep warm for crystal growth for 3h, filter, and dry in a vacuum oven at 45℃ to obtain the ivermectin product.
[0059] The ivermectin product prepared in this embodiment was analyzed by an Agilent 1220 high-performance liquid chromatograph, and the results showed that its purity was 98.5% and the product yield was 96.27%.
[0060] The particle size of the ivermectin product prepared in this embodiment was measured by a Master size 3000 Malvern particle size analyzer. The particle size distribution of the ivermectin product showed a single peak, with the main particle size being 302 μm.
[0061] Comparative Example 1
[0062] This comparative example provides a crystallization process for ivermectin:
[0063] Step 1: Measure 64 mL of anhydrous ethanol and add it to the jacketed crystallizer. Then add 6.168 g of crude ivermectin, heat to 53 °C, and stir at 300 r / min. After the solution becomes clear, you will get an ivermectin solution.
[0064] Step 2: Add 0.1268g of magnesium sulfate to the ivermectin solution, stir at 300r / min until clear, continue stirring for 30min, then cool to 38℃ at a rate of 0.2℃ / min, add 0.124g of ivermectin seed crystals with a particle size of 300μm, continue cooling to 5℃, keep warm to grow crystals for 2h, filter, and dry in a vacuum oven at 45℃ to obtain the ivermectin product.
[0065] The ivermectin product prepared in this comparative example was analyzed by an Agilent 1220 high-performance liquid chromatograph, and the results showed that its purity was 94.2% and the product yield was 63.6%.
[0066] Microscopic images of the ivermectin product prepared in this comparative example are shown below. Figure 5 As shown in the figure, the ivermectin product prepared by the above method has an uneven particle size distribution and a large aspect ratio.
[0067] The particle size of the ivermectin product prepared in this comparative example was determined by a Master size 3000 Malvern particle size analyzer. The particle size distribution of the ivermectin product showed a unimodal distribution with a main particle size of 231 μm.
[0068] Comparative Example 2
[0069] This comparative example provides a crystallization process for ivermectin:
[0070] Step 1: Measure 45 mL of acetone and 15 mL of deionized water, mix them evenly, add them to a jacketed crystallizer, then add 6.168 g of crude ivermectin, heat to 53 °C, stir at 300 r / min, and after the solution becomes clear, obtain ivermectin solution.
[0071] Step 2: Cool the ivermectin solution to 38℃ at a rate of 0.2℃ / min, add 0.124g of ivermectin seed crystals with a particle size of 300μm, continue cooling to 5℃, keep warm for 2 hours to grow crystals, filter, and dry in a vacuum oven at 45℃ to obtain the ivermectin product.
[0072] The ivermectin product prepared in this comparative example was analyzed by an Agilent 1220 high-performance liquid chromatograph, and the results showed that its purity was 96.7% and the product yield was 83.9%.
[0073] Microscopic images of the ivermectin product prepared in this comparative example are shown below. Figure 6 As shown in the figure, the ivermectin product prepared by the above method has an uneven particle size distribution and a large aspect ratio.
[0074] The particle size of the ivermectin product prepared in this comparative example was determined by a Master size 3000 Malvern particle size analyzer. The particle size distribution of the ivermectin product showed a unimodal distribution with a main particle size of 257 μm.
[0075] Comparative Example 3
[0076] This comparative example provides a crystallization process for ivermectin:
[0077] Step 1: Measure 65 mL of anhydrous ethanol and add it to a jacketed crystallizer. Then add 14.819 g of crude ivermectin, heat to 70 °C, and stir at 300 r / min. After the solution becomes clear, pump in the solvent (30 mL of purified water + 1.5 mL of formamide), cool to 64 °C, add 0.303 g of ivermectin seed crystals with a particle size of 100 μm, and then cool to 15 °C at a rate of 0.3 °C / min. Filter and dry in a vacuum oven at 45 °C to obtain the ivermectin product.
[0078] The ivermectin product prepared in this comparative example was analyzed by an Agilent 1220 high-performance liquid chromatograph, and the results showed that its purity was 92.0% and the product yield was 78.8%.
[0079] Microscopic images of the ivermectin product prepared in this comparative example are shown below. Figure 7 As shown in the figure, the ivermectin product prepared by the above method is aggregated and has an uneven particle size distribution.
[0080] The particle size of the ivermectin product prepared in this comparative example was determined by a Master size 3000 Malvern particle size analyzer. The particle size distribution of the ivermectin product showed a unimodal distribution with a main particle size of 258 μm.
[0081] Comparative Example 4
[0082] A crystallization process for ivermectin:
[0083] Step 1: Measure 45 mL of acetone and 15 mL of deionized water, mix them evenly, add them to a jacketed crystallizer, then add 6.168 g of crude ivermectin, heat to 53 °C, stir at 300 r / min, and after the solution becomes clear, obtain ivermectin solution.
[0084] Step 2: Add 0.1268g of ammonium chloride to the ivermectin solution, stir at 300r / min until clear, continue stirring for 30min, then cool to 38℃ at a rate of 0.2℃ / min, add 0.124g of ivermectin seed crystals with a particle size of 300μm, continue cooling to 5℃, keep warm for 2h to grow crystals, filter, and dry in a vacuum oven at 45℃ to obtain the ivermectin product.
[0085] The ivermectin product prepared in this comparative example was analyzed by an Agilent 1220 high-performance liquid chromatograph, and the results showed that its purity was 94.1% and the product yield was 94.2%.
[0086] Microscopic images of the ivermectin product prepared in this comparative example are shown below. Figure 8 As shown in the figure, the particle size distribution of the ivermectin product prepared by the above method is not uniform.
[0087] The particle size of the ivermectin product prepared in this comparative example was measured by a Master size 3000 Malvern particle size analyzer. The particle size distribution of the ivermectin product showed a bimodal distribution, with the main particle size being 139 μm.
[0088] Comparative Example 5
[0089] A crystallization process for ivermectin:
[0090] Step 1: Measure 45 mL of acetonitrile and 15 mL of deionized water, mix them evenly, add them to a jacketed crystallizer, then add 6.168 g of crude ivermectin, heat to 53 °C, stir at 300 r / min, and after the solution becomes clear, obtain ivermectin solution.
[0091] Step 2: Add 0.1268g of magnesium sulfate to the ivermectin solution, stir at 300r / min until clear, continue stirring for 30min, then cool to 38℃ at a rate of 0.2℃ / min, add 0.124g of ivermectin seed crystals with a particle size of 300μm, continue cooling to 5℃, keep warm for 2h to grow crystals, observe that the product forms a gel and sticks to the wall severely, cannot be completely collected, and the yield is very low.
[0092] Comparative Example 6
[0093] A crystallization process for ivermectin:
[0094] Step 1: Measure 45 mL of isopropanol and 15 mL of deionized water, mix them evenly, add them to a jacketed crystallizer, then add 6.168 g of crude ivermectin, heat to 53 °C, stir at 300 r / min, and after the solution becomes clear, obtain ivermectin solution.
[0095] Step 2: Add 0.1268g of magnesium sulfate to the ivermectin solution, stir at 300r / min until clear, continue stirring for 30min, then cool to 38℃ at a rate of 0.2℃ / min, add 0.124g of ivermectin seed crystals with a particle size of 300μm, continue cooling to 5℃, and keep warm for 2h to grow crystals. During the crystallization process, severe oil precipitation and severe gelation occurred, making stirring impossible, and the experiment failed.
[0096] Comparative Example 7
[0097] A crystallization process for ivermectin:
[0098] Step 1: Measure 45 mL of n-propanol and 15 mL of deionized water, mix them evenly, add them to a jacketed crystallizer, then add 6.168 g of crude ivermectin, heat to 53 °C, stir at 300 r / min, and after the solution becomes clear, obtain ivermectin solution.
[0099] Step 2: Add 0.1268g of magnesium sulfate to the ivermectin solution, stir at 300r / min until clear, continue stirring for 30min, then cool to 38℃ at a rate of 0.2℃ / min, add 0.124g of ivermectin seed crystals with a particle size of 300μm, continue cooling to 5℃, keep warm for 2h to grow crystals, observe that no crystals precipitate, the experiment fails.
[0100] Comparative Example 8
[0101] A crystallization process for ivermectin:
[0102] Step 1: Measure 45 mL of methanol and 15 mL of deionized water, mix them evenly, add them to a jacketed crystallizer, then add 6.168 g of crude ivermectin, heat to 53 °C, stir at 300 r / min, and after the solution becomes clear, obtain ivermectin solution.
[0103] Step 2: Add 0.1268g of magnesium sulfate to the ivermectin solution, stir at 300r / min until clear, continue stirring for 30min, then cool to 38℃ at a rate of 0.2℃ / min, add 0.124g of ivermectin seed crystals with a particle size of 300μm, continue cooling to 5℃, keep warm for 2h to grow crystals, and observe that the product is fine and severely aggregated.
[0104] By comparing the examples and comparative examples, it can be concluded that the yield of ivermectin product is increased by more than 30% compared with Comparative Example 1, which uses ethanol as a crystallization solvent; and the yield of ivermectin product of the present invention is increased by more than 14% compared with Comparative Example 2, which does not use a crystallizing agent. The aspect ratio of the ivermectin product prepared in the examples of the present invention is 1.0 to 1.3, while the aspect ratio of the ivermectin product prepared in the comparative examples is approximately 2.1 to 4.8.
[0105] Liquidity test
[0106] The ivermectin products prepared in Example 1 and Comparative Examples 1-2 were tested for their angle of repose according to the method provided in the "Guidelines for Determination of Powder Flowability" issued by the National Pharmacopoeia Commission. The results are shown in Table 1.
[0107] Table 1
[0108] Cone diameter / cm Cone radius / cm Cone height / cm tanα Angle of repose α / ° raw materials 5.77 2.89 4.12 1.43 55.03 Example 1 7.53 3.77 1.80 0.48 25.64 Comparative Example 1 5.84 2.92 3.34 1.14 48.74 Comparative Example 2 4.92 2.46 2.90 1.18 49.72 Comparative Example 3 7.30 3.65 3.11 0.85 40.36 Comparative Example 4 4.94 2.47 2.10 0.93 42.92
[0109] The above results demonstrate that the short rod-shaped ivermectin product prepared in the embodiments of the present invention has a smaller angle of repose and better flowability, which can effectively avoid the problem of clumping during transportation and storage, and also has better drug-likeness and additivity.
[0110] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions or improvements made within the spirit and principles of the present invention should be included within the protection scope of the present invention.
Claims
1. A crystallization process for short rod-shaped ivermectin, characterized in that, Includes the following steps: Step 1: Dissolve crude ivermectin in a crystallization solvent to obtain an ivermectin solution; Step 2: Heat the ivermectin solution to 50℃~55℃, add the crystallizing agent, mix evenly, and then cool it down to 35℃~40℃ at a rate of 0.1℃ / min~0.3℃ / min. Add ivermectin seed crystals, continue to cool down to 5℃~15℃, keep warm to grow crystals, filter, and dry to obtain the ivermectin product. The crystallization solvent is a mixture of acetone and water in a volume ratio of 2:1 to 4:1; the crystallization catalyst is at least one of magnesium sulfate, sodium sulfate, or Tween 80; and the mass concentration of the ivermectin solution is 8% to 12%.
2. The crystallization process of short rod-shaped ivermectin as described in claim 1, characterized in that, The crystallization solvent is a mixture of acetone and water in a volume ratio of 3:
1.
3. The crystallization process of short rod-shaped ivermectin as described in claim 1, characterized in that, The amount of the crystallizing agent added is 1% to 3% of the crude weight of ivermectin.
4. The crystallization process of short rod-shaped ivermectin as described in claim 1, characterized in that, The average particle size of the ivermectin seed crystals is 250 μm to 350 μm.
5. The crystallization process of short rod-shaped ivermectin as described in claim 4, characterized in that, The amount of ivermectin seed crystals added is 1% to 3% of the crude ivermectin mass.
6. The crystallization process of short rod-shaped ivermectin as described in claim 1, characterized in that, The heat preservation and crystal growth time is 1 hour to 3 hours.
7. The crystallization process of short rod-shaped ivermectin as described in claim 6, characterized in that, The temperature for heat preservation and crystal growth is 5℃, and the heat preservation and crystal growth time is 2 hours.
8. The crystallization process of short rod-shaped ivermectin as described in claim 1, characterized in that, Add the crystallizer under stirring conditions of 250 r / min to 350 r / min. After the crystallizer dissolves, continue stirring for 25 min to 35 min, and then cool down.