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Sulphadimidine Injection 100ml (Sodium Sulfonamide Injection 100ml) is a widely used sulfonamide antibiotic in veterinary clinical practice. The drug is a colorless or slightly yellow clear liquid that is prone to deterioration when exposed to light, so it needs to be stored away from light. Its packaging specifications are diverse, including 100ml, 250ml, 500ml, and 1000ml, to meet different treatment needs. In the field of veterinary medicine, sulfamethoxazole sodium injection is widely used for the treatment of infections in livestock such as cattle, sheep, pigs, and poultry. For example, in dairy sheep farms, the drug can be directly discharged into nearby rivers by flushing wastewater, but attention should be paid to the potential pollution it may cause to the environment. In addition, in livestock and poultry farming, this drug is also commonly used to prevent and treat diseases caused by sensitive bacteria.
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Sulphadimidine COA
Sulphadimidine Injection 100ml (sulfamethazine sodium injection) is a broad-spectrum antibiotic, belonging to the sulfonamide antibiotics, specially designed for livestock and poultry breeding industry to treat infectious diseases caused by sensitive bacteria. Its manufacturing background stems from the global demand for efficient and safe antibiotics in the livestock and poultry industry, especially in developing countries where disease prevention and control is a key link in ensuring livestock output. This product exerts antibacterial effects by inhibiting bacterial folate metabolism, and has significant therapeutic effects on Gram positive bacteria, some Gram negative bacteria, and protozoa (such as coccidiosis). It is suitable for gastrointestinal infections, respiratory infections, and urinary and reproductive system infections in livestock such as pigs, cows, sheep, and horses.
Product core positioning and synthesis background
Sulfamethoxazine (SM2) is the core active ingredient (API) of sulfonamide antibiotics, with the chemical name N - (4,6-dimethyl-2-pyrimidinyl) sulfonamide, molecular formula C ₁₂ H ₁₄ N ₄ O ₂ S, and molecular weight 278.33. The design of its synthesis path needs to meet the following core requirements:
Antibacterial mechanism adaptability: By inhibiting bacterial dihydrofolate synthase and blocking folate metabolism chain, it is necessary to ensure that the molecular structure is highly similar to para aminobenzoic acid (PABA) to achieve competitive inhibition.
Pharmacokinetic optimization: Molecular polarity needs to be controlled to achieve rapid gastrointestinal absorption (bioavailability ≥ 85%) and wide tissue distribution (cerebrospinal fluid concentration reaching 30% -80% of blood drug concentration).
Feasibility of industrialization: It is necessary to choose a route with readily available raw materials, simple steps, and stable yield to reduce production costs (target cost ≤ 150 yuan/kg).
Analysis of mainstream synthesis routes
Globally, the industrial synthesis of Sulphadimidine Injection 100ml mainly adopts the following three technological routes, and their technical and economic comparisons are shown in the table below:
| Route type | Raw material combination | Key steps | Overall yield | Raw material cost | Maturity of industrialization |
| Pyrimidine ring condensation method | 4-Acetylaminobenzenesulfonyl chloride+2-amino-4,6-dimethylpyrimidine | Sulfonylation → Condensation → Hydrolysis | 68%-72% | 120-140 | High |
| Acetylacetone cyclization method | Sulfonamide+Acetylacetone | Ring synthesis → oxidation → neutralization | 75%-78% | 95-110 | Upper middle |
| Chloropyrimidine displacement method | Sodium sulfonamide+2-chloro-4,6-dimethylpyrimidine | Nucleophilic substitution → refinement | 62%-65% | 150-180 | Chinese |
1.Pyrimidine ring condensation method (classic route)
Raw material preparation
4-Acetylaminobenzenesulfonyl chloride (ASC): Prepared from p-nitrobenzenesulfonyl chloride by reduction (Fe/HCl) and acetylation (Ac ₂ O), with a purity of ≥ 99.5%.
2-Amino-4,6-dimethylpyrimidine: synthesized by condensation of acetylacetone and guanidine (catalyzed by NaOH, refluxed at 120 ℃ for 6 hours) with a yield of 82% -85%.
Core reaction
Sulfonylation stage: ASC and 2-amino-4,6-dimethylpyrimidine are condensed in pyridine solvent (reaction at 80 ℃ for 8h) to generate N-sulfonyl intermediate with a yield of 92% -94%.
C₈H₈N₂O₃SCl + C₆H₁₀N₄ → C₁₄H₁₆N₆O₃S + HCl
Hydrolysis stage: The intermediate is hydrolyzed in NaOH solution (2M) (refluxed at 100 ℃ for 2 hours) to remove the acetyl protecting group and generate crude SM2 with a yield of 98% -99%.
Refining process
Crystallization control: Dissolve the crude product in hot water (60 ℃), add activated carbon (1% w/w) for decolorization, slowly cool to 10 ℃ for crystallization, filter and recrystallize with ethanol water mixed solvent (3:1), dry to obtain API (HPLC purity ≥ 99.0%).
Quality control: Residual pyridine (≤ 0.1%), heavy metals (≤ 10ppm), and related substances (individual impurities ≤ 0.5%) need to be tested.
Technical advantages: Easy to obtain raw materials, clear steps, suitable for large-scale production.
Technical challenge: It is necessary to strictly control the hydrolysis pH value (8.5-9.0), otherwise it may lead to pyrimidine ring opening.
2.Acetylacetone cyclization method (innovative route)
Raw material pretreatment
Sulfonamide: It is synthesized by the condensation of sulfonamide and nitroguanide, and the particle size distribution (D50=50-70 μ m) needs to be controlled to improve the reaction rate.
Acetylacetone: It needs to be dehydrated to a moisture content of ≤ 0.05%, otherwise it will affect the selectivity of cyclization.
Core reaction
Ring stage: Sulfonamide, acetylacetone, and sodium bisulfite (1:1.2:0.1 molar ratio) are heated and refluxed in NaOH solution (1M) at 100 ℃ for 12 hours to generate ring intermediates with yields ranging from 78% to 82%.
C₇H₉N₃O₂S + C₅H₈O₂ → C₁₂H₁₄N₄O₂S + H₂O + CO₂
Oxidation stage: The intermediate is oxidized with H ₂ O ₂ (30%) at room temperature for 2 hours, converting the thiol group to a sulfonyl group with a yield of 95% -97%.
Post processing optimization
Neutralization crystallization: Neutralize the oxidizing solution with hydrochloric acid to pH 5.5-6.0, add seed crystals to induce crystallization, filter and dry to obtain API.
Process innovation: Adopting a continuous flow reactor instead of a kettle reaction, shortening the cyclization time to 4 hours and increasing the yield to 85%.
Technical advantages: fewer steps, lower raw material costs, suitable for flexible production.
Technical challenge: During the cyclization stage, by-products such as sulfamethoxazole are easily generated, and the catalyst system needs to be optimized.
3.Chloropyrimidine displacement method (supplementary route)
Synthesis of key intermediates
2-Chloro-4,6-dimethylpyrimidine: Prepared by chlorination of 2,4,6-trimethylpyrimidine with chlorine gas (80 ℃, 2h), the selectivity of the chlorination site needs to be controlled (target product ≥ 90%).
Nucleophilic substitution reaction
Sodium sulfonamide reacts with 2-chloro-4,6-dimethylpyrimidine in DMF solvent (120 ℃, 6h) to produce SM2 with a yield of 65% -70%.
C₆H₈N₂O₂SNa + C₆H₇ClN₂ → C₁₂H₁₄N₄O₂S + NaCl
Technical limitations: The cost of chloropyrimidine raw materials is high, and the reaction requires anhydrous conditions, making industrialization difficult.
Key process parameter control
Optimization of reaction conditions
Temperature control
Sulfonylation reaction: 75-85 ℃ (the reaction rate increases by 1.2 times for every 5 ℃ increase, but exceeding 90 ℃ can easily lead to the decomposition of sulfonyl chloride).
Ring reaction: 95-105 ℃ (precise control is required to avoid side reactions).
PH adjustment
Hydrolysis stage: pH=8.5-9.0 (monitored in real-time using a pH meter, with a deviation of ± 0.2 requiring the addition of alkaline solution).
Neutralization stage: pH=5.5-6.0 (acid solution needs to be slowly added dropwise to prevent local over acidification).
Catalyst selection
Sulfonylation reaction: Pyridine (dosage 1.5eq) can enhance the reaction selectivity to 92%.
Ring reaction: Sodium bisulfite (0.1eq) can inhibit oxidative side reactions.
Impurity control strategy
Impurities in starting materials
ASC needs to control residual p-nitrobenzenesulfonyl chloride (≤ 0.5%), otherwise nitro impurities are easily generated.
Sulfonamide residues (≤ 0.3%) need to be tested for sulfonamide, otherwise it may lead to excessive levels of related substances in the final product.
Process impurities
Sulfonylation byproduct: Reduce the formation of disulfonyl impurities by controlling the reaction time (≤ 8h).
Cyclic by-products: The content of sulfamethoxazole is reduced by using a stepwise feeding method (adding acetylacetone in three parts).
Degradation impurities
The forced degradation test showed that SM2 is prone to generating sulfonic acid impurities at high temperatures (105 ℃), and the drying temperature should be controlled to be ≤ 80 ℃
Construction of Quality Control System
Raw material inspection standards
| Inspection Item | Method | limit |
| Purity | HPLC (area normalization method) | ≥99.5% |
| Moisture | Karl Fischer method | ≤0.5% |
| Residual solvent | GC (headspace method) | Ethanol ≤ 0.5% |
| Heavy metal | Atomic absorption spectroscopy | ≤10ppm |
Intermediate control
Sulfonylation intermediates
Melting point: 198-202 ℃ (differential scanning calorimetry, DSC).
Content: HPLC determination ≥ 98.0%.
Cyclic intermediates
Infrared spectroscopy (IR): characteristic peaks should appear at 1650cm ⁻¹ (C=O stretching vibration) and 1580cm ⁻¹ (C=N stretching vibration).
Moisture content: determined by Karl Fischer method ≤ 1.0%.
Finished product release standards
| Inspection Item | Method | limit |
| Content | HPLC (External Standard Method) | 98.5%-101.0% |
| Related substances | HPLC (self comparison method) | Single impurity ≤ 0.5% |
| Residual solvent | GC (headspace method) | Acetone ≤ 0.3% |
| Dissolution | Paddle method (50rpm, 30min) | ≥85% |
| Microbial Limit | Membrane filtration method | Total aerobic bacteria count ≤ 100CFU/g |
Industry Trends and Future Directions
Technological upgrade
Continuous manufacturing: Using microchannel reactors to achieve continuous sulfonation hydrolysis, shortening the production cycle to 8 hours (traditional kettle type requires 16 hours).
Enzyme catalysis technology: Developing sulfotransferase catalyzed synthesis of SM2, reducing the use of chemical reagents by 30%.
Green Chemistry
Solvent recovery: Recover pyridine solvent (boiling point 115 ℃) with a recycling rate of ≥ 90%.
Atomic economy: Optimize the cyclization route to reduce the E factor (environmental factor) from 8.2 to 5.6.
Customized services
Polycrystalline control: Adjust the crystal form (Form I/Form II) through crystallization solvent (ethanol/water ratio) to meet different formulation requirements.
Customization of impurity spectra: Control specific impurities (such as sulfamethoxazole ≤ 0.2%) according to customer requirements.
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