Preparation method of compound anticoccidial preparation containing diclazuril

Abstract

The invention relates to the technical field of veterinary pharmaceutical preparations, and discloses a preparation method of a diclazuril-containing compound anticoccidial preparation, which comprises the following steps: mixing and heating diclazuril, amprolium hydrochloride and a hydrogen bond donor to form a uniform liquid eutectic system; adding anhydrous organic acid into the system, and uniformly dispersing to obtain a drug loading system; and finally, adsorbing the drug carrying system on an inert carrier, and drying and granulating to obtain the preparation. According to the invention, insoluble diclazuril is subjected to amorphous dispersion at a molecular level by using a eutectic technology, and anhydrous organic acid is introduced as a structural disintegration component for water response. When the preparation encounters water, the components are preferentially hydrated to destroy the hydrogen bond network of the eutectic system, resulting in disintegration of the system. The preparation prepared by the method solves the technical problems of slow dissolution of diclazuril and asynchronous release of the diclazuril and the amprolium hydrochloride, realizes synchronous and rapid release of the two active components, and the obtained amorphous system has high physical stability and good flowability of the final product.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of veterinary pharmaceutical preparations, in particular to a preparation method of a compound anticoccidial preparation containing diclazuril. BACKGROUND

[0002] Coccidiosis is a common parasitic disease caused by Eimeria, which is harmful to poultry and livestock breeding industry. Diclazuril and amprolium hydrochloride are widely used anticoccidial drugs in clinic, and their combination has the effects of synergistic effect and delaying drug resistance, and is a commonly used compound combination for preventing and treating coccidiosis.

[0003] However, the physicochemical properties of the two active ingredients are quite different. Amprolium hydrochloride is a water-soluble drug, while diclazuril is almost insoluble in water, which belongs to a poorly soluble drug. This difference leads to the difficulty in synchronizing the release behavior of the two drugs in conventional compound solid preparations. When the preparation disintegrates in the animal digestive tract, amprolium hydrochloride dissolves rapidly, while the dissolution of diclazuril is significantly delayed due to its stable crystal structure and slow dissolution rate. This non-synchronous release behavior makes the two drugs unable to reach the target site at the same time, affecting the synergistic effect.

[0004] To improve the dissolution of poorly soluble drugs, the prior art often adopts the method of preparing them into amorphous state, such as preparing them into solid dispersions. Amorphous drugs usually have higher apparent solubility and faster dissolution rate due to the absence of lattice energy constraints. However, amorphous state is a metastable state in thermodynamics, and has the tendency to spontaneously transform into a more stable crystalline state. This physical instability is particularly prominent under high temperature and humidity storage conditions. Once recrystallization occurs, the dissolution advantage of the preparation will be lost, thereby affecting the quality uniformity and efficacy of the product. Therefore, it is a technical problem to be solved in the field to develop a preparation method that can solve the dissolution problem of diclazuril and ensure the synchronous release of the two drugs, and has high physical stability. SUMMARY

[0005] The technical problem solved by the present application is that the compound preparation containing diclazuril in the prior art has the problems of slow dissolution rate of the poorly soluble drug diclazuril and non-synchronous release behavior with the water-soluble drug amprolium hydrochloride. At the same time, conventional amorphization techniques such as solid dispersions can improve the dissolution of diclazuril, but the physical stability is insufficient and recrystallization easily occurs under humid conditions, affecting the quality of the product.

[0006] To solve the above problems, the present application provides the following technical solutions: In a first aspect, the present application provides a preparation method of a compound anticoccidial preparation containing diclazuril, which adopts the following technical solutions: A preparation method of a compound anticoccidial preparation containing diclazuril, comprising the following steps: (a) mixing diclazuril, meclizine hydrochloride and a hydrogen bond donor; (b) heating the mixture obtained in step (a) to form a homogeneous liquid eutectic system; (c) adding anhydrous organic acid to the liquid eutectic system and uniformly dispersing to obtain a drug-loaded system; (d) adsorbing the drug-loaded system on an inert carrier to obtain the preparation.

[0007] By adopting the technical scheme, the application changes the physical state of the drug and controls the release behavior by constructing a eutectic system and introducing a water-responsive structure disintegration component in the system. The working principle is as follows: First, in the preparation process, the interaction between the two solid crystal active ingredients, diclazuril and meclizine hydrochloride, and the hydrogen bond donor molecules is caused by heating, the original crystal lattice structure of each component is destroyed, and a new stable hydrogen bond network is formed. This makes the mixture change into a thermodynamically stable, homogeneous liquid single phase, i.e. a eutectic system, at a temperature much lower than the melting point of each component.

[0008] In the system, the poorly soluble diclazuril is dispersed at the molecular level, and its dissolution process is no longer limited by the lattice energy, which is the basis for subsequent rapid release.

[0009] Secondly, the anhydrous organic acid introduced into the stable eutectic system acts as a water-responsive structure disintegration component, and its mechanism of action includes two stages: 1. In the anhydrous environment of the preparation, the anhydrous organic acid is dispersed in the eutectic system as a stable component, and does not interfere with the hydrogen bond network and physical stability of the system.

[0010] 2. When the preparation enters the aqueous environment, due to the strong hydrophilicity and hydration ability of the anhydrous organic acid molecules, they will combine with water molecules before the components of the eutectic system. This competitive hydration will destroy the original hydrogen bond network that maintains the stability of the eutectic system.

[0011] Finally, the destruction of the original hydrogen bond network leads to the disintegration of the supramolecular structure of the entire eutectic system, allowing the molecularly dispersed diclazuril and meclizine hydrochloride to be released simultaneously. The released high-energy amorphous diclazuril can form a temporary supersaturated microenvironment on the surface of the carrier, thereby increasing its apparent dissolution rate and extent. Therefore, the preparation method solves the problems of low dissolution of diclazuril and non-synchronous release of diclazuril and meclizine hydrochloride by synchronous disintegration of the system. At the same time, the eutectic system formed itself shows good physical stability, which can effectively inhibit the recrystallization of diclazuril during storage.

[0012] Preferably, before step (a), a step of drying the ammonium chloride and / or the anhydrous organic acid is further included.

[0013] By using the above technical solution, the residual moisture in the raw material is removed in advance, which can prevent the moisture from interfering with the construction of the hydrogen bond network in the process of forming the eutectic system, while ensuring the efficiency of the anhydrous organic acid in the final preparation and the storage stability of the product.

[0014] Preferably, the temperature of the heating in step (b) is 45-70℃, and the time is 1.5-4 hours.

[0015] By using the above technical solution, the process parameter range can ensure the complete formation of the eutectic system, while avoiding the possible drug degradation caused by excessive temperature or excessive time.

[0016] Preferably, the average particle size D50 of the diclazuril in step (a) is 1.6-4.5μm.

[0017] By using the above technical solution, the use of micronized diclazuril raw material can increase its specific surface area, improve its uniformity in the mixture, and accelerate the formation rate of the eutectic system.

[0018] Preferably, the hydrogen bond donor is propylene glycol or glycerol. The anhydrous organic acid is anhydrous citric acid or anhydrous malic acid. The inert carrier is high-dispersible silicon dioxide or microcrystalline cellulose.

[0019] Preferably, the specific implementation of step (d) is: the drug-loaded system is sprayed on the inert carrier by a fluidized bed granulator; or the drug-loaded system is added dropwise into the inert carrier by a high-shear mixing granulator for adsorption granulation. After step (d), a step of drying and granulating the inert carrier adsorbed with the drug-loaded system is further included.

[0020] By using the above technical solution, the liquid drug-loaded system can be uniformly loaded on the inert carrier, and a solid preparation with uniform content and good flowability can be prepared, and the moisture content and particle size of the final product can meet the quality standards.

[0021] Preferably, the weight parts of each component of the preparation are: diclazuril 100-250 parts; ammonium chloride 100-180 parts; hydrogen bond donor 15-50 parts; anhydrous organic acid 5-40 parts; inert carrier 585-695 parts.

[0022] In summary, the present application includes at least one of the following beneficial technical effects: 1.The present application solves the problem of inconsistent release rate of each component in complex preparation caused by the difference in physicochemical properties by constructing a eutectic system, dispersing the poorly soluble diclazuril at the molecular level, and introducing a water-responsive disintegration mechanism. When the preparation enters an aqueous environment, the entire system structure collapses synchronously, thereby achieving synchronous and rapid release of the two active ingredients.

[0023] 2.The preparation prepared by the present application has high physical stability. In the eutectic system, the diclazuril molecules are fixed in the stable amorphous matrix through hydrogen bonding, effectively inhibiting the recrystallization tendency during storage and transportation. Compared with conventional amorphization techniques such as solid dispersion, the physical stability of the preparation of the present application is better.

[0024] 3.The preparation process of the present application improves the physical properties of the final product. By adsorbing the formed liquid drug-loaded system on an inert carrier, the method is essentially a granulation process. Compared with direct physical dry mixing of each component, the obtained powder or granules have a smaller angle of repose, showing excellent flowability, which is beneficial to subsequent automated dispensing and practical application. BRIEF DESCRIPTION OF DRAWINGS

[0025] Figure 1 Differential scanning calorimetry spectra of the eutectic system prepared for Example 1 of the present application, pure diclazuril, pure amprolium hydrochloride, and the product of Comparative Example 1. DETAILED DESCRIPTION

[0026] Now, various exemplary embodiments of the present application will be described in detail, which should not be considered as limiting the present application, but should be understood as a more detailed description of certain aspects, characteristics and embodiments of the present application.

[0027] Preparation Example 1: The present preparation example provides a method for obtaining smaller average particle size diclazuril micropowder, comprising the following steps: Take veterinary-grade diclazuril raw material and place it in an airflow pulverizer. Set the feeding pressure to 0.9 MPa and the pulverizing pressure to 1.1 MPa for pulverization. Collect the obtained powder and detect its average particle size (D50) of 1.6 μm and D90 of 4.2 μm by a laser particle size analyzer. The obtained product is sealed for use.

[0028] Preparation Example 2: The present preparation example provides a method for obtaining larger average particle size diclazuril micropowder, comprising the following steps: Take the veterinary drug grade diclazuril raw material, place it in an air jet mill, set the feed pressure to 0.6 MPa, and the crushing pressure to 0.7 MPa for crushing. Collect the obtained powder and detect it by a laser particle size analyzer, and measure the average particle size (D50) to be 4.5 μm and D90 to be 9.8 μm. The obtained product is sealed for standby use.

[0029] Preparation Example 3: The present preparation example provides a method for drying treatment of moisture-sensitive raw materials required in subsequent steps, comprising the following steps: Take the prescription amount of amprolium hydrochloride and anhydrous citric acid respectively, lay them flat on a clean tray, and place them in a vacuum drying oven. Under the condition of 60℃ and vacuum degree of-0.09 MPa, continuously dry for 6 hours. After drying, cool to room temperature and take out. By Karl Fischer method, the moisture content of amprolium hydrochloride is 0.38%, and the moisture content of anhydrous citric acid is 0.07%, which meets the requirements of subsequent processes. The obtained product is sealed and stored in a desiccator for standby use.

[0030] Example 1: The present example provides a preparation method of a compound anticoccidial preparation containing diclazuril, comprising the following steps: (1) Take 150 g of the diclazuril micro-powder obtained in Preparation Example 1, 120 g of amprolium hydrochloride dried by Preparation Example 3, 15 g of propylene glycol, 20 g of anhydrous citric acid dried by Preparation Example 3, and 695 g of high-dispersibility silicon dioxide dried.

[0031] (2) Put the diclazuril micro-powder and amprolium hydrochloride into a reaction kettle with jacket heating, and add propylene glycol dropwise under stirring (50 rpm) until well mixed.

[0032] (3) Start jacket heating, and increase the temperature to 55℃ at a rate of 2℃ / min. Keep the temperature constant and stir for 2 hours until the material in the kettle forms a uniform and clear viscous liquid to obtain a eutectic system.

[0033] (4) Stop heating and pass cooling water to reduce the temperature of the system to 35℃. Slowly add anhydrous citric acid microcrystalline powder under stirring, and continue stirring for 30 minutes to make it uniformly dispersed.

[0034] (5) Deliver the above drug-loaded system to a fluidized bed granulator through a peristaltic pump, and uniformly spray it on the pre-fluidized high-dispersibility silicon dioxide carrier in a top-spray manner. Set the inlet air temperature to 60℃ and the material temperature to 40℃ until all the liquid is sprayed.

[0035] (6) Continue drying in the fluidized bed for 20 minutes to make the total moisture content of the material less than 3.0%. Granulate the obtained product with a 40-mesh sieve to obtain a powder with good flowability, and seal and package.

[0036] Example 2: The present example provides a preparation method of a compound anticoccidial preparation containing diclazuril, comprising the following steps: (1) Take 100 g of the diclazuril micro-powder obtained in Preparation Example 2, 180 g of the dried hydrochloric acid ammonium propyl, 20 g of propylene glycol, 30 g of dried anhydrous citric acid, and 670 g of dried high-dispersible silicon dioxide.

[0037] (2) Put the diclazuril micro-powder and the hydrochloric acid ammonium propyl into a reaction kettle, and add the propylene glycol under stirring (40 rpm) to mix uniformly.

[0038] (3) Start heating and raise the temperature to 45°C, and keep constant temperature stirring at this lower temperature for 4 hours until the material forms a uniform eutectic system.

[0039] (4) Lower the system temperature to 30°C, add the anhydrous citric acid microcrystalline powder, and continue stirring for 45 minutes to disperse uniformly.

[0040] (5) Pass the drug-loaded system through a high-shear mixing granulator, and slowly drop into the high-dispersible silicon dioxide carrier under high-speed stirring to perform adsorption and granulation.

[0041] (6) Transfer the obtained soft material to a vacuum drying oven, and dry at 50°C for 3 hours to make the total water content less than 3.0%. Granulate the obtained product with a 20-mesh sieve to obtain granules, and seal and package.

[0042] Example 3: The present example provides a preparation method of a compound anticoccidial preparation containing diclazuril, comprising the following steps: (1) Take 200 g of the diclazuril micro-powder obtained in Preparation Example 1, 150 g of the dried hydrochloric acid ammonium propyl, 25 g of glycerol, 40 g of dried anhydrous malic acid, and 585 g of dried microcrystalline cellulose.

[0043] (2) Put the diclazuril micro-powder and the hydrochloric acid ammonium propyl into a reaction kettle, and add the glycerol under stirring (60 rpm) to mix uniformly.

[0044] (3) Start heating and raise the temperature to 70°C, and keep constant temperature stirring at this higher temperature for 1.5 hours until the material forms a uniform eutectic system.

[0045] (4) Lower the system temperature to 40°C, add the anhydrous malic acid microcrystalline powder, and continue stirring for 25 minutes to disperse uniformly.

[0046] (5) Adopt a method similar to that in Example 1 to spray the drug-loaded system on the microcrystalline cellulose carrier by a fluidized bed. Set the inlet air temperature to 70°C and the material temperature to 45°C.

[0047] (6) After the spraying is completed, continue drying for 30 minutes to make the total moisture content less than 3.0%. The obtained product is sized with a 40-mesh screen to obtain a powder with good flowability, which is sealed and packaged.

[0048] Example 4: The present example provides a preparation method of a compound anticoccidial preparation containing diclazuril, comprising the following steps: (1) Take 250 g of the diclazuril micro-powder obtained in Preparation Example 1, 100 g of the dried amprolium hydrochloride, 50 g of propylene glycol, 5 g of dried anhydrous citric acid, and 595 g of dried high-dispersibility silicon dioxide.

[0049] (2) Put the diclazuril micro-powder and the amprolium hydrochloride into a reaction kettle, and add the propylene glycol under stirring (50 rpm) to mix uniformly.

[0050] (3) Start heating and raise the temperature to 60°C, and keep the temperature constant under stirring for 2.5 hours until the material forms a uniform eutectic system.

[0051] (4) Lower the temperature of the system to 35°C, add the anhydrous citric acid microcrystalline powder, and continue stirring for 30 minutes to make it disperse uniformly.

[0052] (5) Use a method similar to that in Example 2 to perform carrier adsorption and granulation through a high-shear mixer-granulator.

[0053] (6) Vacuum-dry the obtained product at 60°C for 2.5 hours to make the total moisture content less than 3.0%. Size the obtained product with a 40-mesh screen to obtain granules, which are sealed and packaged.

[0054] Comparative Example 1: Compared with Example 1, the difference is that all the prescription amounts of the components (diclazuril, amprolium hydrochloride, propylene glycol, anhydrous citric acid, and high-dispersibility silicon dioxide) are directly placed in a three-dimensional mixer for physical dry mixing without the step of heating to form a eutectic system, and the rest is the same.

[0055] Comparative Example 2: Compared with Example 1, the difference is that first, 150 g of diclazuril and 150 g of polyvinylpyrrolidone K30 are prepared into a solid dispersion through solvent evaporation, and then the solid dispersion and other prescription components (amprolium hydrochloride, anhydrous citric acid, and high-dispersibility silicon dioxide) are physically dry mixed without the step of heating to form a eutectic system, and the rest is the same.

[0056] Comparative Example 3: The difference compared with Example 1 is that the formulation does not contain anhydrous citric acid, and the step of adding and dispersing the intelligent release module into the eutectic system is omitted in the preparation, and the rest is the same.

[0057] Comparative Example 4: The difference compared with Example 1 is that the amount of propylene glycol in the formulation is increased to 200 g, and no anhydrous citric acid is contained. In the preparation, the two active ingredients are directly heated and stirred in propylene glycol at 55°C to dissolve the active ingredients in propylene glycol as much as possible to form a supersaturated solution or a partially dissolved suspension, and then immediately adsorbed with a corresponding reduced amount of high-dispersibility silicon dioxide, and the rest is the same.

[0058] Test Example 1: The experimental steps are as follows: (1) The pure diclazuril, pure amprolium hydrochloride, the final product of Comparative Example 1, and the eutectic system liquid before carrier adsorption in the preparation process of Example 1 were weighed respectively, the sample mass was controlled at 3-8 mg, and they were placed in sealed aluminum crucibles.

[0059] (2) The sample crucible and an empty reference crucible were placed in the sample chamber of the differential scanning calorimeter.

[0060] (3) Under a nitrogen atmosphere (flow rate 50 mL / min), the thermal analysis program was started, and the sample was heated from 25°C to 250°C at a heating rate of 10°C / min, and the heat flow signal was recorded as a function of temperature.

[0061] (4) The collected DSC curves were analyzed to determine the presence of crystalline melting peaks or glass transitions.

[0062] The experimental results are shown in Table 1 and Figure 1 .

[0063] Table 1 Differential scanning calorimetry (DSC) test results of various samples:

[0064] The DSC test results show that the diclazuril and amprolium hydrochloride raw materials have sharp melting endothermic peaks at 243.7°C and 249.2°C, respectively, confirming that their initial state is crystalline. The physical mixture of Comparative Example 1 retains two independent melting peaks at similar temperature points (242.9°C and 248.8°C), indicating that simple physical mixing does not change the crystal structure of each active ingredient, and they still coexist in the form of independent crystals.

[0065] The eutectic system prepared in Example 1 shows fundamental difference in thermal behavior. In the DSC curve of this system, the characteristic melting peaks of both raw materials completely disappear, and a single glass transition appears in the low temperature region of 18.5-23.1 °C.

[0066] The disappearance of the crystalline melting peaks is direct evidence of the destruction of the long-range order structure of the raw material crystal lattice, and the appearance of a single glass transition temperature proves that diclazuril and amprolium hydrochloride have formed a homogeneous, amorphous single phase at the molecular level. This series of thermal analysis characteristics collectively confirms that, through the method of the present application, the two active ingredients initially in solid crystal form have been converted into a thermodynamically stable eutectic system through intermolecular interactions (such as hydrogen bond reorganization). This phase transition from a multi-phase crystal mixture to a single-phase amorphous system is the basis for achieving molecular-level dispersion of the poorly soluble drug diclazuril, and constitutes the fundamental mechanism by which the subsequent formulation performance is improved.

[0067] Test Example 2: The experimental procedure is as follows: (1) Prepare two groups of solvents: Group A is anhydrous ethanol, and Group B is a 95% (v / v) ethanol aqueous solution.

[0068] (2) Take 1 g of the eutectic system prepared in Example 1 and add it to 20 mL of Group A solvent; take another 1 g of this sample and add it to 20 mL of Group B solvent.

[0069] (3) Take 1 g of the eutectic system prepared in Comparative Example 3 and add it to 20 mL of Group A solvent; take another 1 g of this sample and add it to 20 mL of Group B solvent.

[0070] (4) Stir the above four samples at 25 °C with a magnetic stirrer at a speed of 300 rpm for 10 minutes.

[0071] (5) After stirring, let stand for 1 minute, and observe and record the clarity of each system and whether solid material has precipitated.

[0072] The experimental results are shown in Table 2.

[0073] Table 2: Stability investigation results of each system in different solvents:

[0074] According to the data in Table 2, the eutectic systems of Example 1 and Comparative Example 3 are both clear and stable in anhydrous ethanol, indicating that the structures of both systems are stable in a non-aqueous environment.

[0075] When the solvent environment was changed to a 95% ethanol solution containing water, the two systems showed significant differences. The system of Comparative Example 3 (without citric acid) only showed slight turbidity, indicating that its hydrogen bond network structure had a certain resistance to the invasion of a small amount of water molecules, and the system structure was basically maintained. In contrast, the system of Example 1 (containing anhydrous citric acid) rapidly produced a large amount of precipitate after contacting the aqueous solvent.

[0076] The internal mechanism of this phenomenon is that the intervention of water molecules and the hydration of citric acid form a competitive destruction of the original hydrogen bond network. In the system of Example 1, the anhydrous citric acid as the intelligent release module has a strong hydrophilicity, and the multiple carboxyl and hydroxyl functional groups on its molecule will preferentially combine with water molecules. This strong hydration, together with the direct participation of water molecules, breaks the original hydrogen bond balance that maintains the molecular dispersion of diclazuril and amprolium hydrochloride. Once the supramolecular structure of the eutectic system disintegrates, the poorly soluble drug diclazuril in a dissolved state rapidly precipitates due to the sharp change in the polarity of the solvent environment, and macroscopically forms a precipitate.

[0077] Therefore, the test results confirm the design mechanism of the intelligent release module in the present application: the anhydrous organic acid exists as a stable dispersion component in the anhydrous preparation environment, and then transforms into a highly efficient hydrogen bond competitor when entering the aqueous environment (simulating the animal digestive tract), triggering the disintegration of the eutectic system structure, thereby achieving rapid release of the active ingredient.

[0078] Test Example 3: The experimental steps are as follows: (1) Flowability test The repose angle of each sample was determined by the fixed funnel method. The sample powder or granules were passed through a standard size funnel and allowed to naturally accumulate into a conical body on a horizontal plate. The height (h) and base radius (r) of the conical body were measured, and the repose angle (θ) was calculated by the formula tan(θ) = h / r. Each sample was measured three times, and the average value was taken.

[0079] (2) Accelerated stability test The final product samples of Examples 1-4 and Comparative Examples 1-4 were taken in an appropriate amount and placed in a weighing bottle, which was then placed in a constant temperature and humidity chamber at 40°C / 75% RH. After 30 days, the samples were taken out and immediately subjected to powder X-ray diffraction (PXRD) testing. The PXRD test conditions were: Cu Kα radiation source, tube voltage 40 kV, tube current 40 mA, scanning range 2θ 5°-40°, scanning rate 2° / min.

[0080] The experimental results are shown in Table 3.

[0081] Table 3: Physical properties and accelerated stability test results of each preparation:

[0082] According to the data in Table 3, the angle of repose of the formulations of Examples 1-4 are all less than 32°, while the physical mixtures of Comparative Examples 1 and 2 have an angle of repose greater than 45°. This result shows that the process of adsorptive granulation by liquid eutectic system can obtain a final product with significantly better flowability than the traditional physical dry mixing.

[0083] The PXRD results of the physical stability investigation show that, after being stored at 40°C, 75% RH for 30 days, the samples of Examples 1-4 and Comparative Example 3 all do not have crystal diffraction peaks, maintaining their amorphous state. This confirms that the intermolecular interaction in the eutectic system forms a stable amorphous matrix, which effectively inhibits the rearrangement and crystallization of the molecules under high temperature and humidity conditions. In contrast, the samples of Comparative Examples 2 and 4 have the characteristic diffraction peaks of diclazuril under the same conditions, indicating that the amorphous material prepared by solid dispersion or adsorption of cosolvents has insufficient physical stability and will undergo a transition to the crystal form in a humid heat environment.

[0084] Test Example 4: The experimental procedure is as follows: (1) The second method of the Chinese Pharmacopoeia for dissolution determination (paddle method) was used, with 900 mL of dissolution medium, the temperature was set at 37 ± 0.5°C, and the rotation speed was 75 rpm.

[0085] (2) The formulation samples of Examples 1, Comparative Example 1 and Comparative Example 3, equivalent to 100 mg of the labeled amount of diclazuril, were placed into the dissolution cups.

[0086] (3) First, the dissolution was carried out in pH 1.2 artificial gastric juice (containing 0.5% Tween-80). After sampling at 120 minutes, pre-prepared phosphate buffer was immediately added to each dissolution cup to adjust the pH value of the medium to 6.8 (simulated artificial intestinal fluid), and the dissolution test was continued.

[0087] (4) At the time points of 5, 15, 30, 60, 120, 180, 240 minutes, 5 mL of solution was taken from the dissolution cup and immediately supplemented with an equal volume of fresh dissolution medium.

[0088] (5) After filtering all samples through a 0.45 μm microporous filter, the concentrations of diclazuril and amprolium hydrochloride in the filtrate were determined simultaneously by high performance liquid chromatography (HPLC), and the cumulative release percentage was calculated.

[0089] The experimental results are shown in Table 4.

[0090] Table 4: In vitro cumulative release of diclazuril (DIC) and amprolium hydrochloride (AMP) in different formulations (%):

[0091] According to the data in Table 4, in Comparative Example 1 (physical mixture), the ammonium chloride is released rapidly, while the diclazuril has a cumulative release of less than 15% at 4 hours. The difference in release behavior is due to the different physicochemical properties of the two components, as the crystal structure of diclazuril limits its dissolution.

[0092] In the formulation of Example 1, the release behavior of diclazuril and ammonium chloride shows synchronicity, and the cumulative release of diclazuril is more than 90% within 60 minutes. The realization of this release characteristic is based on two aspects: the construction of the eutectic system disperses diclazuril in an amorphous state at the molecular level, eliminating the lattice energy barrier in the dissolution process; when the formulation enters the aqueous medium, the anhydrous citric acid in the system hydrates, destroying the hydrogen bond network that maintains the eutectic system, leading to the collapse of the system structure. The collapse of the system causes the two active ingredients to be released simultaneously, and the supersaturation of diclazuril on the surface of the carrier increases its apparent dissolution rate.

[0093] The results of Comparative Example 3 (without organic acid) provide evidence for the above mechanism, as the dissolution of diclazuril in this formulation is faster than in Comparative Example 1, but the final release is only about 70%. This indicates that, in the absence of citric acid-triggered collapse, the release of the eutectic system is not complete, and may be limited by the dissolution or diffusion process.

[0094] In summary, the test data of the examples and comparative examples verify the technical solution of the present application from different aspects.

[0095] The stability results of differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD) together confirm that the present application constructs a physically stable, homogeneous amorphous system with molecular-level dispersion of diclazuril and ammonium chloride through eutectic interaction. The release behavior of this system is regulated by the built-in organic acid module. In vitro stability and dissolution tests show that this module triggers the structural disintegration of the eutectic system by preferential hydration in an aqueous environment, thereby achieving the simultaneous and rapid release of the two active ingredients.

[0096] This integrated formulation strategy not only solves the dissolution rate problem of the poorly soluble drug diclazuril, but also overcomes the technical difficulty of inconsistent release rates of components in conventional compound formulations through a fundamental phase transformation. At the same time, the results of the angle of repose test of the final product also show that the formulation prepared by the process of the present application has good flowability, which is beneficial to subsequent production and use.

[0097] Although embodiments of the present application have been shown and described, it is to be understood that various modifications, substitutions, replacements and changes can be made to these embodiments without departing from the principles and spirit of the present application, and the scope of the present application is defined by the appended claims and their equivalents.

Claims

1. A method for preparing a compound anticoccidial preparation containing diclazuril, characterized in that, Includes the following steps: (a) Mix diclazuril, amprolium hydrochloride, and a hydrogen bond donor; (b) Heating the mixture obtained in step (a) to form a homogeneous liquid eutectic system; (c) Add anhydrous organic acid to the liquid eutectic system and disperse it evenly to obtain a drug-loaded system; (d) The drug delivery system is adsorbed onto an inert carrier to obtain the formulation.

2. The method for preparing a compound anticoccidial preparation containing diclazuril according to claim 1, characterized in that, Prior to step (a), the process further includes a drying step of the aminopropionate hydrochloride and / or the anhydrous organic acid.

3. The method for preparing a compound anticoccidial preparation containing diclazuril according to claim 1, characterized in that, The heating temperature in step (b) is 45–70°C, and the heating time is 1.5–4 hours.

4. The method for preparing a compound anticoccidial preparation containing diclazuril according to claim 1, characterized in that, The average particle size D50 of diclazuril described in step (a) is 1.6–4.5 μm.

5. The method for preparing a compound anticoccidial preparation containing diclazuril according to claim 1, characterized in that, The hydrogen bond donor is propylene glycol or glycerol.

6. The method for preparing a compound anticoccidial preparation containing diclazuril according to claim 1, characterized in that, The anhydrous organic acid is anhydrous citric acid or anhydrous malic acid.

7. The method for preparing a compound anticoccidial preparation containing diclazuril according to claim 1, characterized in that, The inert carrier is highly dispersed silica or microcrystalline cellulose.

8. The method for preparing a compound anticoccidial preparation containing diclazuril according to claim 1, characterized in that, The specific implementation method of step (d) is as follows: The drug-loaded system is sprayed onto the inert carrier using a fluidized bed granulator; or the drug-loaded system is dripped onto the inert carrier for adsorption granulation using a high-shear mixing granulator.

9. The method for preparing a compound anticoccidial preparation containing diclazuril according to claim 1, characterized in that, Following step (d), the process also includes drying and granulating the inert carrier on which the drug-loaded system is adsorbed.

10. The method for preparing a compound anticoccidial preparation containing diclazuril according to claim 1, characterized in that, The weight parts of each component of the formulation are as follows: Diclazuril 100-250 parts; 100-180 parts of amprolium hydrochloride; 15-50 parts of hydrogen bond donor; 5-40 parts of anhydrous organic acids; 585–695 copies of inert carrier.

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