Highly water-soluble florfenicol powder and a method for preparing the same

Abstract

The application discloses a high-water-solubility florfenicol powder and a preparation method thereof, and belongs to the technical field of veterinary drug preparations. The powder is prepared from florfenicol, a water-soluble polymer carrier, tetraethyl orthosilicate or a mixture of the tetraethyl orthosilicate and methyl triethoxysilane and a C2-C6 organic polyacid containing polyhydroxy and polycarboxyl groups as raw materials through in-situ sol-gel spray drying one-step method. In the preparation, the controllable hydrolysis and condensation of organosilane and the in-situ esterification cross-linking of the organic polyacid are used to synergistically assemble and build an organic-inorganic hybrid network skeleton, and the amorphous florfenicol is anchored in the network skeleton. The product has both instant and moisture-proof properties. The method is simple in process, and the raw and auxiliary materials are safe and easy to obtain, so the method is suitable for industrial production and solves the problem that traditional solid dispersions are easy to absorb moisture and form lumps.

Description

Technical Field

[0001] This invention relates to veterinary chemical drug formulation technology, specifically to a highly water-soluble florfenicol powder and its preparation method. Background Technology

[0002] Florfenicol is a monofluorinated derivative of thiamphenicol. As a new generation of broad-spectrum antibiotics for animals, it exhibits high sensitivity against Gram-negative bacteria such as Actinobacillus pleuropneumoniae, Haemophilus parasuis, Escherichia coli, and Riemerella anatipestifer, as well as some Gram-positive bacteria, and holds an irreplaceable clinical position in intensive farming.

[0003] Florfenicol's equilibrium solubility in water at 25°C is only about 1.3 mg / mL, falling into the category of "virtually insoluble." In modern aquaculture, florfenicol is mainly administered via drinking water, typically requiring a final concentration of 20–100 mg / L. Directly adding the raw drug to the drinking water system will cause it to settle rapidly, clog the water line, and result in inaccurate dosage, severely limiting its clinical application.

[0004] There are currently four main solubilization strategies for florfenicol, but all of them have drawbacks: (1) Co-solvent and surfactant system: It can completely dissolve the drug, but the storage and transportation costs of liquid formulations are high, the chemical stability is poor, the organic solvent is irritating, and precipitation is easy to occur when diluted at the breeding site. (2) Cyclodextrin inclusion technology: It uses cyclodextrin cavity to include the drug, which increases the solubility by 5 to 20 times, but the inclusion balance is greatly affected by temperature and humidity, the drug loading is low (<15%), and the drug is easy to escape during humid heat storage, resulting in cyclodextrin crystallization, powder agglomeration, and decreased dissolution. (3) Micronization and nanocrystal technology: It reduces the drug to the nanoscale to improve solubility, but the surface energy is extremely high, and Ostwald ripening and agglomeration are easy to occur during drying and storage. A large amount of stabilizer and freeze-drying protectant are required, and the process is complicated. (4) Solid dispersion technology: Hydrophilic polymers are used as carriers to make drugs in an amorphous form, with apparent solubility of more than 20 mg / mL. However, it has thermodynamic defects: the amorphous form is in a metastable state with high free energy and spontaneously transforms into a crystalline state. Environmental moisture is a key triggering factor: water acts as a plasticizer, and adsorption of 1% to 3% can cause the glass transition temperature (Tg) to drop sharply from more than 150°C to below room temperature. The system becomes rubbery, drug molecules migrate to the particle surface, rearrange and nucleate under the action of adsorbed water, grow into whiskers, and form strong "crystal bridges" between particles, resulting in powder agglomeration, loss of fluidity and fast solubility, and difficulty in redispersing.

[0005] To address the above problems, conventional solutions fall into three main categories: adding anti-caking agents (such as micronized silica gel), but this cannot prevent crystal bridge-type agglomeration; coating with hydrophobic materials, but this will slow down dissolution; or placing desiccants, but these only reduce humidity and increase costs. Summary of the Invention

[0006] The present invention aims to solve the problem of physical stability failure induced by environmental moisture during storage of existing amorphous solid dispersion florfenicol powder, and provides a highly water-soluble florfenicol powder and its preparation method, which maintains excellent instant solubility while achieving long-term storage without absorbing moisture, clumping, or crystallizing.

[0007] To achieve the above objectives, this application adopts the following technical solution: In a first aspect, the present invention provides a highly water-soluble florfenicol powder, which is prepared by a one-step in-situ sol-gel spray drying method from the following components in parts by weight: Florfenicol (active ingredient); The water-soluble polymeric carrier is selected from one or more of polyvinylpyrrolidone (PVP), copovidone (VA64), polyethylene glycol (PEG4000-6000), and hydroxypropyl methylcellulose (HPMC E3 / E5), with PVP K30 being preferred. Organosilanes are tetraethyl orthosilicate (TEOS) or a mixture thereof with methyltriethoxysilane (MTES); Organic polyacids are small C2-C6 organic acids containing at least one hydroxyl group and at least two carboxyl groups, preferably citric acid or tartaric acid, and particularly preferably citric acid monohydrate.

[0008] In a preferred embodiment, the weight ratio of florfenicol, water-soluble polymeric carrier, organosilane (based on the equivalent of SiO2 generated by complete hydrolysis and condensation) to organic polyacid is 1:(1.5-4):(0.1-0.8):(0.2-0.8), more preferably 1:(2-3):(0.2-0.5):(0.3-0.6).

[0009] The highly water-soluble florfenicol powder has the following characteristics: (a) When stored open for 30 days at 40°C and 75% relative humidity, the moisture absorption weight gain rate does not exceed 3.0%, and the powder remains in a loose and flowing state that can be judged by the naked eye, without any hard lumps that can be seen when lightly pressed with a spatula; (b) Take the equivalent of 0.25g of florfenicol powder and put it into 50mL of deionized water at 25℃. Shake gently and the powder will be completely dispersed within 30 seconds to form a homogeneous liquid phase. After filtering the liquid phase through a 0.45μm microporous membrane, the concentration of florfenicol in the filtrate shall not be less than 20mg / mL.

[0010] Secondly, the present invention provides a method for preparing the highly water-soluble florfenicol powder, comprising the following steps: Step (1): Preparation of silica sol precursor solution Organosilanes, alcohol solvents, acid catalysts, and water are mixed and stirred for 0.5 to 2 hours at pH 3.5–4.5 and temperature 15–40°C to produce oligomeric siloxane sols rich in active silanol groups (Si-OH), denoted as solution A.

[0011] Furthermore, the alcohol solvent is preferably anhydrous ethanol or isopropanol, with ethanol being particularly preferred. The volume ratio of the organosilane to the alcohol solvent is preferably 1:(5-15). The amount of water added satisfies a molar ratio of water to organosilane of (1-4):1. The acid catalyst is preferably hydrochloric acid, and the amount used is sufficient to adjust the pH of the system to 3.5-4.5.

[0012] Step (2): Preparation of drug-carrier-polydentate ligand solution In another container, the water-soluble polymeric carrier, florfenicol, and organic polyacid are dissolved in an alcohol solvent and stirred at 30–55°C (preferably 40–50°C) until all solids are completely dissolved, resulting in a clear solution, denoted as solution B.

[0013] Furthermore, ethanol is preferred as the alcohol solvent, and its amount is 3 to 8 times the total weight of the carrier and the drug.

[0014] Step (3): Preparation of pre-assembly solution Under continuous stirring at 20–50°C (preferably 35–45°C), slowly add solution A obtained in step (1) to solution B obtained in step (2) over a period of approximately 15–30 minutes. After the addition is complete, continue stirring for 20–90 minutes (preferably 30–60 minutes) to obtain the pre-assembled solution.

[0015] Step (4): Spray drying and in-situ co-assembly Immediately spray dry the pre-assembled liquid obtained in step (3). Process parameters: inlet air temperature 160-200℃ (preferably 170-190℃), outlet air temperature 70-95℃ (preferably 80-90℃).

[0016] During this process, the droplets undergo drying in a very short time (usually <1 second) in the hot gas flow. At this instant, the solvent evaporates and concentrates, and florfenicol is "frozen" in the matrix in an amorphous form; at the same time, the following two independent in-situ chemical cross-linking reactions occur: (i) silanol condensation to form a Si-O-Si inorganic network; (ii) the carboxyl groups of organic polybasic acids undergo esterification or amidation reactions with specific functional groups in the framework of water-soluble polymer carriers to form an organic cross-linking network. The two types of cross-linking reactions occur independently and synchronously within milliseconds, forming an interpenetrating double cross-linked hybrid network structure.

[0017] Step (5): Post-processing Collect the powder and granulate it through a 60-100 mesh stainless steel sieve as needed to obtain the finished product.

[0018] This invention abandons the conventional approach of "preparing the dispersion first, then adding external protection," instead employing a method where an organosilane precursor and an organic polybasic acid are simultaneously introduced during the same transient process of spray drying to prepare the solid dispersion. Two independent chemical cross-linking reactions are utilized: (a) the hydrolysis and condensation of silane to form a Si-O-Si inorganic network; and (b) esterification or amidation cross-linking between the carboxyl groups of the organic polybasic acid and specific functional groups of the polymeric carrier framework—constructing a bi-crosslinked hybrid network where the organic and inorganic phases interpenetrate. This network possesses both rigid framework support and chemical anchoring functions, fundamentally blocking moisture-induced failure chains.

[0019] When added to drinking water, the hydrophilic components in the network react rapidly with water, causing the particles to disintegrate and release the drug; while in solid storage, the rigidity and chemical anchoring provided by the network work together to keep the powder dry and loose for a long time, combining rapid solubility and moisture resistance.

[0020] Compared with the prior art, the present invention has the following beneficial effects: 1. The highly water-soluble florfenicol powder of this invention possesses both rapid dissolution and moisture-proof properties: When added to drinking water at 25°C, the product disperses completely within 30 seconds. After filtration through a 0.45μm filter membrane, the florfenicol concentration reaches 20–30 mg / mL, with no drug crystal precipitation within 4 hours. Furthermore, when stored openly for 30 days under accelerated conditions at 40°C and 75% relative humidity, the product's moisture absorption weight gain does not exceed 3.0%, and the powder remains dry and loose, without any noticeable clumping.

[0021] 2. The preparation process of the highly water-soluble florfenicol powder of the present invention is simple, has a wide process parameter window, and good reproducibility.

[0022] 3. The highly water-soluble florfenicol powder of the present invention is green and safe, with readily available raw and auxiliary materials and controllable cost. Attached Figure Description

[0023] Figure 1 This is a schematic flowchart of the method for preparing highly water-soluble florfenicol powder according to the present invention. Detailed Implementation

[0024] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to the accompanying drawings and specific embodiments. It should be noted that the following embodiments are only for explaining the invention and not for limiting it. All other embodiments obtained by those skilled in the art based on the embodiments of this invention without creative effort are within the scope of protection of this invention.

[0025] The present invention will be further described below with reference to specific embodiments, but the scope of protection of the present invention is not limited thereto.

[0026] Example 1 A highly water-soluble florfenicol powder is prepared using the following steps (e.g.) Figure 1 ): Step 1: Preparation of silica sol precursor solution (solution A) In a 500 mL jacketed glass reactor, add 250 g of anhydrous ethanol and 25 g of TEOS, and stir at 20 °C for 5 minutes to mix thoroughly. Separately, premix 12 g of deionized water with 1.2 g of 0.1 mol / L hydrochloric acid, and slowly add this mixture dropwise to the ethanol solution while stirring, completing the addition over approximately 15 minutes. Finely adjust the pH of the system to 4.0 ± 0.2 using 0.1 mol / L hydrochloric acid (monitored with precise pH test paper). Continue stirring at a constant temperature of 28 °C for 75 minutes to obtain oligomeric silica sol, denoted as solution A.

[0027] Step 2: Preparation of drug-carrier-multidentate ligand solution (Solution B) In a 1L flask, add 400g of anhydrous ethanol, 60g of PVP K30, 30g of florfenicol, and 12g of citric acid monohydrate in sequence. Heat in a water bath to 50°C and stir magnetically until all solids are completely dissolved (about 25 minutes), yielding a clear solution, denoted as solution B.

[0028] Step 3: Preparation of pre-assembly solution Cool solution A to 40°C. While mechanically stirring at 150 rpm, slowly add solution A dropwise to solution B using a constant pressure dropping funnel, completing the addition in approximately 25 minutes. After the addition is complete, maintain the temperature at 40°C and continue stirring for 45 minutes to obtain a clear and transparent pre-assembled solution.

[0029] Step 4: Spray drying Immediately process the pre-assembled solution on a laboratory spray dryer. Parameter settings: inlet air temperature 180℃, outlet air temperature automatically stabilized at 84–87℃; peristaltic pump feed rate 20% (approximately 12 mL / min); atomizing compressed air flow rate approximately 40 L / min. Collect the white to slightly yellow fluffy powder from the cyclone separator and collection bottle. 82.4 g of product obtained.

[0030] Step 5: Granulation The powder was passed through an 80-mesh stainless steel sieve, with a yield of approximately 94% (based on total solids input). The resulting powder was designated FP-1.

[0031] Example 2 The formula for solution B was adjusted to: 350g anhydrous ethanol, 50g PVP K30, 40g florfenicol, and 15g citric acid monohydrate. All other operations and parameters were the same as in Example 1. The product was labeled FP-2.

[0032] Example 3 In step one, a mixture of 18g TEOS and 7g MTES was used to replace pure TEOS (the total silane content remained at 25g). The amount of water added was adjusted accordingly to 14g, and 1.4g of 0.1mol / L hydrochloric acid was added. The pH was adjusted to 4.5, and the reaction was carried out at 32°C for 90 minutes. The rest of the process was the same as in Example 1. The product was labeled FP-3.

[0033] Example 4 In step two, 14g of tartaric acid with an equimolar amount of carboxyl groups was used to replace citric acid monohydrate, and the rest was the same as in Example 1. The product was labeled FP-4.

[0034] Comparative Example 1 Refer to Example 1, but completely omit citric acid monohydrate in solution B. All other steps and parameters are identical. The resulting powder is labeled CP-1.

[0035] Comparative Example 2 An equivalent amount of TEOS from Example 1 was prepared into a sol under the same hydrolysis conditions and freeze-dried to obtain silica gel powder. This silica gel powder was then mixed with PVP K30 (60g), florfenicol (30g), citric acid monohydrate (12g), and anhydrous ethanol (400g) to form a physical suspension, which was then spray-dried using the same parameters as in Example 1. The resulting powder was labeled CP-2.

[0036] Comparative Example 3 PVP K30 (60g) and florfenicol (30g) were dissolved in anhydrous ethanol (400g) and spray-dried. Parameters were the same as in Example 1. The resulting powder was labeled CP-3.

[0037] Performance testing Test method: (1) Instant solubility and filtration concentration: Accurately weigh the equivalent of 0.25 g of each group of florfenicol powder and put it into a 100 mL stoppered graduated cylinder containing 50 mL of 25 °C deionized water. Shake the cylinder up and down (about once per second) and record the time (seconds) required for the powder to be completely dispersed and form a homogeneous liquid phase. After standing for 2 hours, take the supernatant and filter it through a 0.45 μm hydrophilic microporous membrane. The concentration of florfenicol in the filtrate was determined by high performance liquid chromatography, and the filtration concentration (mg / mL) was calculated.

[0038] (2) Moisture resistance: Accurately weigh about 2g of powder and spread it evenly in a weighing bottle that has been pre-weighed. Place the bottle open in a constant temperature and humidity desiccator at a temperature of 40℃ and a relative humidity of 75% (maintained by a saturated sodium chloride solution). Take the bottle out and weigh it on the 7th, 14th and 30th days, and calculate the percentage of moisture absorption weight gain (%).

[0039] (3) Anti-caking property: Visually observe the state of the powder after the above accelerated test. Press the powder surface lightly with a spatula. If it remains loose and flowing, it is recorded as "non-caking"; if soft clumps that can be easily broken apart appear, it is recorded as "slight caking"; if hard clumps that need to be crushed are formed, it is recorded as "severe caking".

[0040] (4) Glass transition temperature (Tg) determination: differential scanning calorimetry (DSC), nitrogen atmosphere, heating rate 10℃ / min.

[0041] (5) Chemical stability: The chemical stability was evaluated as the percentage of florfenicol content (HPLC method) after 30 days of accelerated testing relative to the initial content. The content was determined according to the method for florfenicol content determination in the Chinese Veterinary Pharmacopoeia.

[0042] The test results are summarized in Table 1: Table 1 Performance Test Results As shown in Table 1, the products of this invention (FP-1 to FP-4) have high Tg values ​​and simultaneously meet the dual requirements of rapid dissolution (≤35 seconds), high filtration concentration (≥19.8 mg / mL), and excellent storage stability (30-day moisture absorption weight gain ≤2.2%, no clumping, content ≥98.5%). Comparing with Comparative Example 1, it can be seen that Comparative Example CP-1, lacking organic polyacids, exhibits a sharp deterioration in its anti-moisture and anti-caking properties (30-day moisture absorption weight gain 8.5%, severe clumping), with the filtration concentration decreasing to 15.2 mg / mL and the rapid dissolution time nearly doubling. Comparing with Comparative Example 2, it can be seen that Comparative Example CP-2, after physical mixing and spray drying, performs significantly better than CP-1 and CP-3, but is significantly inferior to FP-1 of this invention in terms of moisture absorption, anti-caking, and dissolution. Comparing with Comparative Example 3, it can be seen that the pure organic solid dispersion CP-3, although exhibiting the best initial rapid dissolution (25 seconds), suffers from the most severe moisture absorption and clumping (14.2%), with a significant decrease in content.

[0043] Although this application has been described in detail with reference to the foregoing embodiments, those skilled in the art can still modify the technical solutions described in the foregoing embodiments or make equivalent substitutions for some of the technical features. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of this application should be included within the protection scope of this application.

Claims

1. A highly water-soluble florfenicol powder, characterized in that, The mixture is prepared by a one-step in-situ sol-gel spray drying method from a raw material composition consisting of florfenicol, a water-soluble polymeric carrier, an organosilane, and a C2-C6 organic polybasic acid containing at least one hydroxyl group and at least two carboxyl groups; wherein the weight ratio of florfenicol, the water-soluble polymeric carrier, the organosilane, and the organic polybasic acid, based on SiO2 equivalents, is 1:(1.5-4):(0.1-0.8):(0.2-0.8).

2. The highly water-soluble florfenicol powder according to claim 1, characterized in that, The water-soluble polymeric carrier is selected from one or more of polyvinylpyrrolidone, copolyvinyl ketone, polyethylene glycol, and hydroxypropyl methylcellulose.

3. The highly water-soluble florfenicol powder according to claim 1 or 2, characterized in that, The organic polyacid is citric acid or tartaric acid; the organosilane is tetraethyl orthosilicate or a mixture thereof with methyltriethoxysilane.

4. The highly water-soluble florfenicol powder according to claim 3, characterized in that, The weight ratio is 1:(2-3):(0.2-0.5):(0.3-0.6).

5. A method for preparing highly water-soluble florfenicol powder as described in any one of claims 1-4, characterized in that, Includes the following steps: (1) Mix organosilane, alcohol solvent, acid catalyst and water, adjust pH to 3.5-4.5, stir reaction to obtain oligomeric siloxane sol containing active silanol groups; (2) Dissolve the water-soluble polymeric carrier, florfenicol, and organic polyacid in an alcohol solvent and stir to dissolve to obtain a drug-carrier solution; (3) Add the sol obtained in step (1) to the solution obtained in step (2) while stirring, and continue stirring to obtain the pre-assembled solution; (4) Spray dry the pre-assembled liquid and collect the powder to obtain the final product.

6. The preparation method according to claim 5, characterized in that, In step (1), the stirring reaction temperature is 15-40℃ and the time is 0.5-2 hours; the alcohol solvent is ethanol or isopropanol, and the volume ratio of organosilane to alcohol solvent is 1:(5-15); the acid catalyst is hydrochloric acid, and the amount of water added is 1-4 times the molar amount of organosilane.

7. The preparation method according to claim 5, characterized in that, In step (2), the alcohol solvent is ethanol, and the stirring and dissolving temperature is 30-55°C.

8. The preparation method according to claim 5, characterized in that, In step (3), the stirring temperature is 20-50℃ and the stirring time is 20-90 minutes.

9. The preparation method according to claim 5, characterized in that, In step (4), the inlet air temperature of the spray dryer is 160-200℃ and the outlet air temperature is 70-95℃.

10. The preparation method according to any one of claims 5-9, characterized in that, It also includes a granulation process of passing the collected powder through a 60-100 mesh sieve.

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