Phtalysulfathiazole
|
HS Code |
759604 |
| Chemical Name | Phthalylsulfathiazole |
| Molecular Formula | C17H13N3O5S2 |
| Molar Mass | 403.43 g/mol |
| Appearance | Yellowish - white powder |
| Odor | Odorless |
| Solubility In Water | Practically insoluble |
| Melting Point | 200 - 204 °C |
| Pka | 3.5 (sulfonamide group) |
| Stability | Stable under normal conditions |
| Pharmacological Class | Sulfonamide antibacterial |
As an accredited Phtalysulfathiazole factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | Phtalysulfathiazole packaged in 1 - kg bags for convenient handling and storage. |
| Shipping | Phtalysulfathiazole is shipped with strict adherence to chemical transportation regulations. It's packaged securely to prevent leakage. Shipments are carefully monitored for temperature and handling to ensure product integrity during transit. |
| Storage | Phtalysulfathiazole should be stored in a cool, dry place. Keep it away from heat sources and direct sunlight, as these can cause degradation. Store in a well - sealed container to prevent moisture absorption and contamination. Ensure the storage area is well - ventilated to avoid the build - up of any potentially harmful fumes. Regularly check for signs of spoilage during storage. |
Granulation Moisture Content and Its Effect on Tablet Hardness in Phthalylsulfathiazole 500 mg MonotherapyDuring manufacture of high-dose phthalylsulfathiazole tablets intended for acute bacillary dysentery, the intrinsically poor compactability and low aqueous solubility of the active pharmaceutical ingredient necessitate wet granulation with a binder such as partially pregelatinized starch at 6.0% w/w or povidone K30 at 4.5% w/w of dry granulate mass. The granulation endpoint, monitored via impeller power consumption on a high-shear mixer (e.g., Diosna P1/6) or product temperature rise in a fluid-bed granulator, must target a residual moisture content of 1.8–2.5% after tray drying at 55 °C until loss on drying by 105 °C halogen analyser falls within range. Granules dried below 1.2% moisture generate excessive fines during milling through a 1.0 mm screen, causing die fill inconsistency and weight variation exceeding ±5.0% acceptance criteria; moisture above 2.8% induces sticking to upper punch faces on a 35-station rotary press (Korsch XL 400) and elevates ejection forces beyond 800 N, even with 0.8% w/w magnesium stearate lubricant pre-blended for 3.0 minutes in a bin blender. A representative core formulation per unit comprises 500.0 mg phthalylsulfathiazole (complying with loss on drying < 0.5%, sulphated ash < 0.1%, and related substances by TLC per withdrawn USP 42–NF 37 monograph originally specified for phthalylsulfathiazole), 78.0 mg microcrystalline cellulose (Avicel PH-102), 20.0 mg croscarmellose sodium, and 2.0 mg colloidal silicon dioxide. Tablet hardness is controlled at 70–100 N (Schleuniger 6D tester), yielding friability below 1.0% after 100 drops, with disintegration time measured at 37±2 °C in 0.1 N HCl not exceeding 15 minutes per USP <701>. Dissolution verification uses Apparatus 2 (paddle) at 50 rpm in 900 mL of pH 7.4 phosphate buffer, with a Q value of 75% dissolved at 60 minutes. The finished flat-bevel, bisected tablets are packed in aluminium/PVC blister cavities under 25 °C/60% RH conditions, with stability assigned a 24-month shelf life contingent on storage below 30 °C. Content uniformity testing per USP <905> must demonstrate acceptance value ≤ 15.0 across 10 dosage units. Paediatric suspensions of phthalylsulfathiazole pose a reconstitution uniformity challenge because of the drug’s inherently hydrophobic surface, which can cause particle aggregation and dose inaccuracy during household spoon dosing. The dry powder for oral suspension is designed to deliver 100 mg phthalylsulfathiazole per 5 mL after addition of purified water to a fill line corresponding to 60 mL total volume. Micronization of the active ingredient to a particle size distribution D90 < 30 μm via air-jet milling is essential to reduce sedimentation velocity; a wetting agent such as polysorbate 80 at 0.05% w/v of the constituted suspension is incorporated into the dry blend by spraying a dilute ethanolic solution onto the powder bed during low-shear mixing. The base powder mixture contains sucrose 2000 mg, xanthan gum 20 mg as suspending vehicle, sodium benzoate 10 mg preservative, and citric acid monohydrate 5 mg to buffer at pH 4.5–5.0, all per 5 mL dose. To prevent segregation during filling, the powder is densified via roller compaction with a compaction force of 4–6 kN/cm and subsequently milled to granules retaining a bulk density of 0.65–0.75 g/mL. The finished granules are filled into 100 mL amber Type III glass bottles under nitrogen flush, closed with child-resistant polypropylene caps, and accompanied by a graduated oral syringe marked in 2.5 mL increments. Upon reconstitution, the suspension must meet the USP <698> deliverable volume test and exhibit viscosity between 150–300 mPa·s (Brookfield RV, spindle #2, 20 rpm) to enable pourability while retarding settling. In-use stability of the constituted liquid is limited to 7 days when stored at 2–8 °C, after which sulphonamide hydrolysis by-product formation may exceed 0.5%; hence labeling must carry a strict discard instruction. When Swine Dysentery Outbreaks Dictate In-Feed Medication ProtocolsWhen a swine dysentery outbreak associated with Brachyspira hyodysenteriae drives the need for mass medication, phthalylsulfathiazole premixes are blended into complete feed at final active concentrations of 100–200 g per metric ton (100–200 ppm), with the lower band applied for prophylaxis in grower pigs and the higher band for acute treatment of haemorrhagic diarrhoea in finishers. The premix intermediate is typically formulated at 10% w/w phthalylsulfathiazole potency using a carrier system based on ground corn cobs (particle size retained between 20 and 60 mesh) pre-dried to <10% moisture to minimise hydrolytic degradation of the sulphonamide. Manufacturing in a 500 kg double-ribbon blender demands a geometric dilution sequence: API is first blended 1:1 with a portion of the carrier for 8 minutes, then this pre-blend is sequentially extended with remaining carrier in doubling-volume increments, each mixed for 10 minutes, until final mass is achieved. Homogeneity validation requires extraction of 10 thief samples from different zones of the blender post-discharge; assay by UV spectrophotometry at 288 nm against a working standard must return a coefficient of variation (CV) not greater than 5.0%, a threshold aligned with GMP+ feed safety scheme criteria for medicated feedingstuffs. Residual cross-contamination prevention employs a validated flush protocol with 25 kg ground maize run through the mixer and discarded, following cleanout until active carryover drops below 1.0% of the therapeutic dose. Physicochemical stability of the premix during bulk storage in 25 kg polyethylene-lined woven sacks is confirmed for 12 months at 25 °C/60% RH; above 35 °C, formation of free sulfathiazole via des-phthalylation accelerates and must be monitored by HPLC with photodiode array detection. The final feed incorporating the premix via micro-dosing systems is subject to a withdrawal period of 7 days before slaughter, derived from marker residue depletion studies of sulfathiazole in porcine liver and kidney according to VICH GL48 guidance, and is prohibited in lactating sows supplying milk for human consumption where national regulations do not list a maximum residue limit. In poultry enteritis management, feed-grade phthalylsulfathiazole is incorporated at inclusion rates of 150–250 g/metric ton of finished feed depending on the severity of necrotic enteritis caused by Clostridium perfringens. The hydrophobic nature of the drug limits its dispersion in mash feed containing added fat; therefore, a micro-pelleted premix carrier with the API embedded in a matrix of wheat middling and calcium carbonate (1:4:1 weight ratio) is first produced on a flat-die pellet mill with die hole diameter 2.5 mm and conditioning temperature kept below 65 °C to avoid sublimation-related losses of phthalylsulfathiazole. Post-pelleting, the micro-pellets are crumbled to a size range of 600–1000 μm to match the bulk feed particle profile and added downstream of the main pelletizer via a post-pelleting liquid application system or micro-ingredient drum coater to avoid thermal exposure exceeding 70 °C in the conditioner. Feed mill assay verification requires a composite sample of 10 increments from the finished feed stream to fall within ±15% of the declared concentration, using a spectrophotometric method calibrated against a certified reference standard at 260 nm. Monitoring of carryover in consecutive batches of non-medicated feed must prove that sulfonamide residues do not exceed 2.0% of the lowest therapeutic dose to comply with EU cross-contamination limits outlined in Commission Regulation (EU) No 2017/625 for non-target species. Under tropical warehouse conditions (35 °C/75% RH), medicated feed stability studies show potency loss of <5% at 90 days provided the feed moisture is maintained below 12% and propionic acid-based mould inhibitor is included at 0.15%. Finished poultry withdrawal period is set at 5 days to ensure edible tissue residues fall below the detection limit of the LC-MS/MS method with decision limit CCα of 10 μg/kg for sulfathiazole. What Prevents Crystallization in Aquaculture Water Medication with Phthalylsulfathiazole Sodium Salt?Achieving stable water medication for bacterial enteritis in freshwater fish using phthalylsulfathiazole demands conversion to the sodium salt form, in-situ generated by reacting the acid form with 1.0 molar equivalent of sodium hydroxide in aqueous medium at pH 8.5–9.2. A soluble concentrate is prepared by dissolving 200 g phthalylsulfathiazole acid in 900 mL deionized water containing 16.0 g sodium hydroxide pellets under mechanical stirring until clarity, then diluting to 1.0 L; the resulting solution contains approximately 200 mg/mL active equivalent. Direct addition of this concentrate to pond or tank water at a target bath concentration of 10–20 mg/L must account for water hardness—Ca²⁺ and Mg²⁺ cations above 50 mg/L as CaCO₃ will precipitate the insoluble phthalylsulfathiazole calcium salt within 30 minutes, reducing bioavailability. To prevent crystal formation in hard water, trisodium citrate dihydrate is co-added at a molar ratio of 2:1 citrate-to-calcium hardness, chelating the divalent ions and maintaining turbidity below 5 NTU over a 6-hour immersion period. The medication bath is applied for 3–5 days with 50% water exchange before each re-dosing, with aeration maintained at dissolved oxygen >5 mg/L because the alkaline pH shifts ammonia equilibrium toward toxic unionized NH₃, warranting concurrent monitoring of free ammonia below 0.02 mg/L. Residue depletion in tilapia and carp muscle after a 10-day withdrawal period has been validated using LC-MS/MS with a quantitation limit of 1 µg/kg, aligning with the Codex Alimentarius performance criteria for veterinary drug residue control in aquaculture products. The concentrate must be consumed within 72 hours after preparation and stored in HDPE containers protected from light, as photodegradation of the phthalyl moiety generates sulfathiazole and phthalic acid derivatives that exhibit reduced intestinal antibacterial potency. Direct Compression of PST–Trimethoprim Fixed-Dose Blends and Mitigating Electrostatic SegregationFormulators combining phthalylsulfathiazole (500 mg) and trimethoprim (100 mg) in a 5:1 fixed-dose tablet for synergistic inhibition of bacterial dihydrofolate metabolism frequently encounter electrostatic segregation arising from triboelectrification of micronized trimethoprim particles during tumble blending with the coarse phthalylsulfathiazole granules. Processing under strict environmental control of 45–55% RH at 20–22 °C is mandatory; below 40% RH the charge accumulation on trimethoprim (dielectric constant ≈ 3.2) increases aerodynamic repulsion to the extent that uniformity of dosage units per USP <905> fails with acceptance values exceeding 15.0. To counteract this, colloidal silicon dioxide (Aerosil 200) is pre-blended with trimethoprim at 1.5% w/w relative to trimethoprim mass for 3 minutes in a high-shear mixer prior to addition to the main granulation, forming a surface coating that dissipates electrostatic charges. The final direct compression blend, containing 500 mg PST granulate (1.8% residual moisture), 100 mg trimethoprim with silica, 32 mg sodium starch glycolate disintegrant, and 8 mg sodium stearyl fumarate lubricant, undergoes compression on a 29-station tablet press at 12–15 kN main compression force to achieve hardness 80–110 N. Lubrication must be limited to 4 minutes blending in a V-shell blender at 15 rpm because extended mixing over 10 minutes decreases tablet tensile strength by 20% and delays disintegration beyond 20 minutes. Analytical release testing uses a stability-indicating HPLC method with detection at 254 nm, gradient elution of ammonium acetate buffer and acetonitrile, specifying system suitability resolution > 2.0 between PST and trimethoprim peaks. The dissolution profile for both actives is measured in 900 mL of 0.1 N HCl with 0.1% sodium lauryl sulphate at 50 rpm, requiring > 80% release at 30 minutes. Storage of the bulk blend prior to tableting is restricted to 72 hours maximum hold time in drums lined with anti-static low-density polyethylene bags, after which segregation potential increases markedly.
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Introduced into veterinary pharmacopoeias in the mid-20th century, phtalysulfathiazole (C₁₇H₁₃N₃O₅S₂, molecular weight 403.43 g·mol⁻¹) is a dicarboxylic acid ester prodrug of the sulfonamide sulfathiazole. The substance is manufactured as a white to faintly yellowish crystalline powder exhibiting a melting range of 272–275 °C with decomposition. Solubility in water at 25 °C is less than 0.1 mg·mL⁻¹; it is practically insoluble in chloroform and ether, sparingly soluble in ethanol, and dissolves in aqueous solutions of alkali hydroxides and carbonates through salt formation on the sulfonamide nitrogen. Pharmacopoeial monographs (Ph. Eur. 01/2024:0587, USP NF 2024) specify an assay content of 98.5–101.5% (dried substance) by diazotisation titration, a loss on drying ≤0.5% (105 °C, 4 h), and sulfated ash ≤0.1%. The related substances limit, determined by liquid chromatography (Ph. Eur. impurity A: sulfathiazole), is ≤0.5%, with any other single impurity ≤0.1%.
The fundamental design objective is minimal systemic absorption. Following oral administration, the phthalyl group is cleaved by colonic bacterial hydrolases, liberating active sulfathiazole in the distal intestinal lumen. Peak blood concentrations of free sulfathiazole in broiler chickens dosed at 100 mg·kg⁻¹ body weight typically remain below 0.5 µg·mL⁻¹, compared with 20–40 µg·mL⁻¹ for an equimolar dose of unsubstituted sulfathiazole. This pharmacokinetic divergence is measured under steady-state conditions using HPLC-MS/MS quantification in whole blood (limit of quantification 0.01 µg·mL⁻¹). In contrast, sulfathiazole sodium, with a water solubility exceeding 1.0 g·mL⁻¹, undergoes rapid jejunal absorption and distributes into all tissue compartments, creating a necessity for withdrawal periods of 10–21 days in food-producing species. Phtalysulfathiazole, due to its negligible bioavailability, is frequently assigned a zero-day withdrawal when used according to approved label indications in many jurisdictions, although country-specific maximum residue limits for sulfathiazole in edible tissues (100 µg·kg⁻¹ in muscle, Codex Alimentarius) remain the controlling regulatory parameter.
Two other intestinal-acting sulfonamide prodrugs share the non-absorbed strategy but diverge in acid-base and hydrolytic profiles. Succinylsulfathiazole (succinic acid mono-ester) has a hydrolysis half-life in cecal contents of 3.2–4.8 h (in vitro, pH 6.8, 41 °C), whereas phtalysulfathiazole cleavage under identical conditions proceeds with a t₁/₂ of 5.9–7.1 h, a difference that influences dosing interval selection. Sulfaguanidine, by contrast, is not a prodrug; it is active as the parent molecule and exhibits approximately 30% absorption, which can lead to renal crystalluria in dehydrated animals if fluid intake is restricted. The table below compiles comparative physicochemical and pharmacokinetic descriptors.
| Descriptor | Phtalysulfathiazole | Succinylsulfathiazole | Sulfaguanidine |
|---|---|---|---|
| Molecular weight (g·mol⁻¹) | 403.43 | 355.39 | 214.24 |
| Water solubility (mg·mL⁻¹, 25 °C) | <0.1 | 0.18 | 1.0 (as free base) |
| pKₐ (sulfonamide –NH–) | 5.4 | 5.2 | 11.3 (guanidine moiety) |
| Colonic hydrolysis t₁/₂ (h, in vitro) | 5.9–7.1 | 3.2–4.8 | Not applicable |
| Typical oral dose in swine (mg·kg⁻¹·day⁻¹) | 100–200, divided | 100–200, divided | 50–100, divided |
| Systemic absorption (%) | <5 | <5 | ~30 |
| Regulatory reference | Ph. Eur. 0587 | USP NF 2024 | Ph. Eur. 0586 |
Commercial application in medicated feed premixes requires that the compound withstand mechanical shear and short-duration thermal excursions characteristic of ring-die pellet mills. Production-scale data gathered on a CPM 3020-6 pellet mill (die thickness 60 mm, L/D ratio of press channel 8.5:1) processing a broiler finisher ration (65% maize, 28% soybean meal, 3% added fat, conditioning temperature 78–82 °C, residence time 25–35 s) indicate that phtalysulfathiazole recovery post-pelleting, measured by HPLC against an external standard, declines from 99.2% at 75 °C to 96.1% at 82 °C, with an abrupt drop to 88.7% when die temperature exceeds 85 °C for any continuous run exceeding 90 s. The thermal degradation pathway involves hydrolysis of the phthalyl ester bond, liberating phthalic acid and sulfathiazole; the latter, once deprotected, undergoes oxidative dimerization in the presence of trace metals (Cu, Fe) that are common in feed-grade mineral premixes. Consequently, the safe processing window is defined by a conditioning temperature ≤80 °C and a die exit temperature ≤83 °C, with moisture content of the mash entering the conditioner maintained at 13.5–14.5% to minimize frictional heat generation.
Pre-drying the compound before blending is mandatory when ambient relative humidity exceeds 60%. Exposure of bulk phtalysulfathiazole powder to 70% RH at 25 °C for 48 h results in weight gain of 0.8–1.2%, leading to caking in the micro-ingredient bin and inconsistent dosing from loss-in-weight feeders. The substance is incompatible with alkaline excipients (sodium bicarbonate, limestone at inclusion rates >0.5%) because deprotonation of the sulfonamide nitrogen accelerates hydrolysis even in the solid state, especially when trace moisture is present. In a controlled stability study (ICH Q1A guideline, 40 °C/75% RH, 6 months), binary mixtures with calcium carbonate 1% w/w showed total related substances increasing to 1.8%, versus 0.7% for the compound stored alone.
When the application is therapeutic drinking water medication, the low solubility demands formulation as a suspension concentrate or a soluble salt derivative. Sodium phtalysulfathiazole, prepared by neutralization with sodium hydroxide to pH 8.5–9.2, yields a solution stable for 24 h at 20 °C; beyond this period, precipitation of the free acid occurs due to atmospheric carbon dioxide absorption. In-feed use remains the predominant route, with typical inclusion rates of 100–400 g·t⁻¹ of complete feed, adjusted according to target species, disease pressure, and local marketing authorization details.
Field observations in large-scale integrated poultry operations (Ross 308 broilers, 45,000-bird houses) have documented that phtalysulfathiazole administered at 300 g·t⁻¹ from day 5 to day 12 post-hatch reduces mortality attributable to colibacillosis by 40–55% compared with untreated controls, as recorded in a multi-site trial involving 12 houses across three farms. The effect is most pronounced when the compound is introduced within 24 h of the first clinical signs, because established deep-tissue invasion by E. coli serogroups O1, O2, and O78 requires a bactericidal concentration that the gut-limited distribution cannot achieve. Under those circumstances, combination with a systemic antimicrobial (e.g., ampicillin trihydrate) is indicated, although published data for this specific configuration of sequential oral phtalysulfathiazole followed by parenteral beta-lactam is limited to retrospective farm records without controlled challenge studies. Regulatory guidelines (VICH GL27) require demonstration of clinical efficacy under field conditions; therefore, veterinarians must verify that local susceptibility patterns (MIC₉₀ values for avian pathogenic E. coli) remain below the colonic concentration of liberated sulfathiazole, which has been estimated via intestinal content analysis at 300–500 µg·g⁻¹ of digesta.
Differences from sulfathiazole in terms of safety margin are stark. Sulfathiazole administered systemically at doses exceeding 200 mg·kg⁻¹ in laying hens has been associated with eggshell thinning and depressed feed intake, effects attributable to carbonic anhydrase inhibition and folate antagonism in rapidly dividing ovarian follicles. Phtalysulfathiazole, by confining the active moiety to the gut, circumvents these reproductive toxicities. The compound carries a hazard classification of Acute Toxicity Category 4 (oral) and Skin Irritation Category 2 under GHS; occupational exposure during weighing and blending requires local exhaust ventilation and particulate respirators conforming to EN 149:2001+A1:2009 FFP2. No data suggest genotoxicity or carcinogenicity at therapeutic exposure levels, and the Ames test (OECD 471) on the parent compound is negative in Salmonella typhimurium strains TA98, TA100, TA1535, and TA1537 both with and without S9 metabolic activation.
| Application parameter | Broiler chickens | Weaned piglets |
|---|---|---|
| Target pathogen | Avian pathogenic E. coli, Salmonella spp. | Enterotoxigenic E. coli, Salmonella Typhimurium |
| Inclusion rate in complete feed (g·t⁻¹) | 100–400 | 200–500 |
| Duration (days) | 5–14 | 7–14 |
| Withdrawal period (meat) | 0 days (where authorized) | 0–2 days (jurisdiction-dependent) |
| Maximum die temperature during pelleting (°C) | ≤83 | ≤83 |
| Pre-mix carrier compatibility | Ground maize (≤2% oil), wheat middlings | Lactose monohydrate, dextrose |
