| HS Code | 735398 |
| Chemical Name | 4-amino-N-pyrimidin-2-ylbenzenesulfonamide |
| Molecular Formula | C10H10N4O2S |
| Molecular Weight | 250.28 g/mol |
| Cas Number | 68-35-9 |
| Description | White to slightly yellowish crystalline powder |
| Solubility | Very slightly soluble in water; soluble in dilute mineral acids and alkali hydroxides |
| Melting Point | 252-256 °C |
| Assay | 98.0% to 102.0% on dried basis |
| Storage | Store in tightly closed container, protected from light, at controlled room temperature |
| Therapeutic Category | Antibacterial / Sulfonamide |
| Indication | Used in treatment of toxoplasmosis, urinary tract infections, and as adjunct in malaria |
| Dosage Forms | Tablet, Capsule, Granule, Injection |
| Route Of Administration | Oral and Injectable |
As an accredited Sulphadiazine Pharma Grade API for Tablet / Capsule / Granule / Injection, Oral & Injectable factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | Packaged in tamper-evident, double-lined sealed drums, 25 kg net per drum, ensuring purity and stability for pharmaceutical formulation. |
| Container Loading (20′ FCL) | 20′ FCL: Sulphadiazine Pharma Grade API packed in sealed drums on pallets, safely secured for oral/injectable pharmaceutical use. |
| Shipping | Shipments of Sulphadiazine Pharma Grade API are handled in sealed, moisture-proof, food-grade containers with tamper-evident seals. Transport complies with GDP and IATA/IMDG regulations, maintaining controlled temperatures and full documentation. DG-trained logistics staff ensure safe, traceable, secure delivery for oral and injectable pharmaceutical use. |
| Storage | Store Sulphadiazine Pharma Grade API in tightly closed, light-resistant containers in a cool, dry, well-ventilated area, protected from moisture and direct sunlight. Maintain controlled room temperature (15–30°C). Avoid excessive heat and incompatible substances. Keep container intact when not in use. Follow good handling practices and use appropriate personal protection to preserve quality and safety. |
| Shelf Life | Shelf life is 24 months from manufacture, when stored in tightly closed containers, protected from light and moisture. |
In direct compression layouts on rotary tablet presses, sulphadiazine base presents a narrow processing window due to its low bulk density and high elastic recovery. Tablets labelled at 500 mg sulphadiazine per unit are commonly produced with an API content of 60–75% w/w; the remaining excipient phase contains microcrystalline cellulose at 20–30% w/w, crospovidone or sodium starch glycolate at 5–10% w/w, and magnesium stearate at 0.5–1.0% w/w, but published data for optimized direct-compression formulations specific to sulphadiazine is limited. Release testing must meet the USP Sulfadiazine Tablets monograph, USP <905> Uniformity of Dosage Units, USP <711> Dissolution, USP <701> Disintegration, and ICH Q3D Elemental Impurities. On production-scale rotary presses, forced feeders and pre-compression stations are used because the API segregates from denser excipients during hopper feeding; capping and lamination appear when main compression force exceeds approximately 25 kN, particularly when residual moisture falls below 1.0% or when blending time after magnesium stearate addition exceeds 10 min. The tablet core is compressed to a hardness of 80–120 N and film-coated with hydroxypropyl methylcellulose-based systems to mask the bitter aftertaste of sulphadiazine. The terminal dosage form is an immediate-release film-coated tablet intended for oral administration.
Hard capsule filling of sulphadiazine on tamping-pin machines requires a plug density within 0.65–0.85 g/cm³ for size 00 capsules at 500 mg fill weight; below this range, plug ejection from the tamping pins is incomplete, and above it, capsule bodies split during closure. The formulation typically combines milled sulphadiazine at 85–95% w/w with fumed silica at 0.5–1.0% w/w and magnesium stearate at 0.25–0.5% w/w, passed through a 500 μm screen before filling. Compliance testing includes USP <905> Uniformity of Dosage Units, USP <711> Dissolution, and USP <701> Disintegration for capsules, with assay limits per the USP Sulfadiazine Capsules monograph where it exists; published monograph-specific capsule dissolution acceptance criteria for sulphadiazine are limited and should be confirmed against the current compendial text. On Bosch GKF dosing disk machines, tamping pin penetration depth is adjusted to compensate for batch-to-batch variation in API particle size distribution; over-tamping generates hard plugs that delay disintegration beyond 15 min in 0.1 N hydrochloric acid, while under-tamping produces weight variability exceeding 3.0% RSD. The terminal product type is hard gelatin or hydroxypropyl methylcellulose capsule dosage form used in antibacterial treatment regimens.
When low bulk density and poor compression scalability make direct compression unworkable, wet granulation routes are selected for sachet granules intended for oral suspension. The granulation charge contains sulphadiazine at 40–60% w/w, povidone K30 or pregelatinized starch at 3–5% w/w as binder, crospovidone or sodium starch glycolate at 5–10% w/w as disintegrant, and microcrystalline cellulose as filler. High-shear granulator processing with an impeller speed of 200–300 rpm and wet massing time of 2–5 min produces the granule batch; over-granulation in vessels larger than 600 L increases the fraction retained on a 1.0 mm sieve, which correlates with slow reconstitution and sedimentation in the final oral suspension. Drying in a fluid bed at inlet air temperature 60–70°C until moisture is below 2.0% is standard. Compliance testing should include the Ph Eur Granules monograph, USP <786> Particle Size Distribution by Analytical Sieving, USP <616> Bulk Density and Tapped Density, USP <1174> Powder Flow, and ICH Q3C Residual Solvents. The terminal product type is oral granules in single-dose sachets for reconstitution with water, with a labelled sulphadiazine content per sachet commonly 500 mg.
Intravenous-grade sulphadiazine solutions are prepared from the base by controlled neutralization with sodium hydroxide in Water for Injection; the sodium salt is formed at a molar ratio of NaOH to sulphadiazine base between 1.00 and 1.05, targeting a pH of 9.0–10.5. Concentrations equivalent to 50 mg/mL sulphadiazine base are typical for injection. The free base solubility in water at 25°C is below 0.1 mg/mL, making in situ salt formation mandatory for injectable strengths. The solution is filtered through a 0.45 μm prefilter and a 0.22 μm membrane filter, then filled aseptically into Type I glass vials. Compliance standards include USP <71> Sterility Tests, USP <85> Bacterial Endotoxins, USP <788> Particulate Matter in Injections, USP <790> Visible Particulates, and 21 CFR 211.113 microbiological contamination control. Terminal sterilization is generally avoided for this alkaline solution when thermal degradation of sulphadiazine is observed; aseptic filtration is the preferred route. The pH must be maintained above 8.0 during dilution for administration because lower pH values precipitate free sulphadiazine base. Carbon dioxide absorption from the environment can depress pH during manufacturing; nitrogen sparging of the bulk solution before filling minimizes this drift. Production-scale pumps, tubing, and filling needles must be passivated to avoid metal ion contamination; published data for specific adsorption or stability of sulphadiazine sodium on large-scale aseptic lines is limited. The terminal product type is an injectable solution for intravenous infusion after dilution with compatible diluents.
| Process parameter | Control range / requirement | Reference designation |
|---|---|---|
| Sodium hydroxide to sulphadiazine base molar ratio | 1.00–1.05 | USP Sulfadiazine Sodium monograph |
| Final solution pH | 9.0–10.5 | USP <791> pH |
| Particulate matter ≥10 μm and ≥25 μm | USP <788> Light Obscuration Test limits | USP <788> |
| Bacterial endotoxins | Monograph-defined limit; verify current compendial text | USP <85> |
Combination therapy for toxoplasmosis introduces a low-dose, light-sensitive partner, pyrimethamine, alongside a higher-dose sulphadiazine component. A fixed-dose tablet with 500 mg sulphadiazine and 25 mg pyrimethamine requires separate processing of pyrimethamine because a direct blend at 25 mg per unit is highly susceptible to segregation and content uniformity failure. Pyrimethamine is prepared by direct compression or by moisture-controlled granulation, while sulphadiazine is granulated separately and the two components are combined in a final blend. The sulphadiazine component typically occupies 60–70% w/w of the final core weight. Compliance testing includes USP <905> Uniformity of Dosage Units for both actives, USP <711> Dissolution with separate quantification for both drugs, ICH Q3B Degradation Products, and ICH Q3D Elemental Impurities. The basic micro-environment of sulphadiazine can raise local pH in the dissolution medium and interfere with pyrimethamine release when the dissolution medium pH remains below 4.5; published data for this specific fixed-dose combination at commercial scale is limited. The terminal product type is a fixed-dose tablet for toxoplasmosis treatment.
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Sulphadiazine (CAS 68-35-9; 4-amino-N-(pyrimidin-2-yl)benzenesulfonamide; molecular formula C10H10N4O2S; relative molecular mass 250.28 g/mol) is supplied as a pharmaceutical-grade active pharmaceutical ingredient for oral and injectable finished-dose manufacture. The substance is a white to faintly yellowish crystalline powder with weak-acid behaviour and pH-dependent aqueous solubility. Manufacturer-specific oral and injectable grades are differentiated by bioburden, bacterial endotoxin, residual solvent, elemental impurity, and particle-size controls; no harmonised model nomenclature exists across compendial registries. The API is released according to the current Ph. Eur. Sulfadiazine monograph 0294 and the USP Sulfadiazine monograph for tablets, capsules, granules, oral preparations, and aqueous or pH-adjusted injectable preparations. Sulphadiazine inhibits dihydropteroate synthase, and its clinical use includes treatment of toxoplasmosis when combined with pyrimethamine.
For tablet and capsule operations, the oral-grade material is controlled by compendial purity, related substance, and physicochemical parameters. The assay on dried basis is typically controlled between 99.0% and 101.0%, with individual unspecified impurities held at or below 0.10% and total related substances at or below 0.5%. Loss on drying is controlled at or below 0.5%, and sulfated ash at or below 0.1%. These limits are aligned to the Ph. Eur. Sulfadiazine monograph 0294 and the USP Sulfadiazine monograph, with residual solvents assessed under ICH Q3C and elemental impurities under ICH Q3D.
| Parameter | Specification / Typical Release Limit | Test Method Designation |
|---|---|---|
| Appearance | White to faintly yellowish crystalline powder | Visual examination; compendial description |
| Identification | Infrared absorption spectrum concordant with reference; chromatographic retention time concordant | Ph. Eur. 2.2.24; Ph. Eur. 2.2.27; USP Sulfadiazine monograph |
| Assay, dried basis | 99.0–101.0% | HPLC; Ph. Eur. 2.2.29 |
| Related substances | Specified impurity ≤ 0.10%; total ≤ 0.5% | HPLC; Ph. Eur. 2.2.29 |
| Loss on drying | ≤ 0.5% | Ph. Eur. 2.2.32; USP General Chapter 731 |
| Sulfated ash | ≤ 0.1% | Ph. Eur. 2.4.14 |
| Particle-size distribution | As agreed with finished-dose manufacturer; no universal compendial limit | Laser diffraction; Ph. Eur. 2.9.31; ISO 13320 |
| Bulk and tapped density | Report result; internal range per product type | Ph. Eur. 2.9.34 |
| Residual solvents | ICH Q3C limits | USP General Chapter 467; Ph. Eur. 5.4 |
| Elemental impurities | ICH Q3D limits | USP General Chapters 232 and 233; Ph. Eur. 2.4.20 |
| Bacterial endotoxins, injectable grade | Validated limit based on finished-product maximum dose | Ph. Eur. 2.6.14; USP General Chapter 85 |
The API has low aqueous solubility at neutral pH; therefore, dissolution profiling of finished tablets is performed using USP General Chapter 711 or Ph. Eur. 2.9.3, with media selection justified by the dosage form. For immediate-release tablets, content uniformity is assessed by Ph. Eur. 2.9.40 or USP General Chapter 905. Incoming inspection under 21 CFR Part 211.84 includes identity testing by infrared and chromatographic methods before use. Sampling of injectable-grade sulphadiazine is performed in an ISO 14644-1 classified area with controlled microbial load, and vendor qualification includes periodic independent verification of residual solvent and elemental impurity data against ICH Q3C and Q3D.
Injectable-grade sulphadiazine is not directly soluble at neutral pH. Injectable formulations are aqueous solutions of the sodium salt or are prepared by pH adjustment with sodium hydroxide under nitrogen. Release of the injectable-grade API includes bacterial endotoxin testing according to Ph. Eur. 2.6.14 or USP General Chapter 85, bioburden control according to Ph. Eur. 2.6.12 or USP General Chapter 61, and particulate matter controls carried through to the finished injectable preparation according to Ph. Eur. 2.9.19 and USP General Chapter 788. Sterility is not an API property; terminal sterilisation or aseptic filtration is validated at finished-product scale according to Ph. Eur. 2.6.1 and USP General Chapter 71.
Sulphadiazine contains a pyrimidin-2-yl substituent, whereas sulfamethoxazole contains a 5-methylisoxazol-3-yl substituent and sulfamerazine contains a 4-methylpyrimidin-2-yl substituent. These structural differences affect dissolution, pKa behaviour, protein binding, renal elimination, and the choice of combination therapy. Sulphadiazine is a short-acting sulfonamide and is frequently used with pyrimethamine; sulfamethoxazole is an intermediate-acting sulfonamide used commonly with trimethoprim as co-trimoxazole; sulfamerazine is used in some triple sulfonamide combinations.
| Characteristic | Sulphadiazine | Sulfamethoxazole | Sulfamerazine |
|---|---|---|---|
| Heterocyclic substituent | pyrimidin-2-yl | 5-methylisoxazol-3-yl | 4-methylpyrimidin-2-yl |
| Aqueous solubility at neutral pH | practically insoluble; sodium salt used for injection | low; solubility increased in alkaline media | low |
| Dosing pattern | short-acting; more frequent administration than sulfamethoxazole | intermediate-acting; 12 h dosing common | short-to-intermediate; often in triple sulfonamide combinations |
| Primary combination therapy | pyrimethamine for toxoplasmosis | trimethoprim as co-trimoxazole | combined with other sulfonamides in selected regions |
| Finished-dose processing implications | dry or wet granulation preferred; injectable requires pH shift | poor flow requires granulation; direct compression possible only with modified excipients | similar granulation and flow control required |
The APIs are not directly interchangeable in a fixed-dose combination or formulation without new bioavailability and dissolution acceptance criteria. A finished product developed for sulfamethoxazole/trimethoprim cannot be rebranded as sulphadiazine/trimethoprim solely by API replacement. Sulphadiazine may require tighter control of the micronised particle-size fraction because dissolution from granulated matrices is sensitive to specific surface area and agglomeration behaviour. Differences in crystallization, residual solvent profile, and light sensitivity also require separate stability protocols.
Sulphadiazine powder should be stored in airtight, light-resistant containers; light exposure can produce yellow or brown discoloration. In aqueous alkaline injections, carbon dioxide absorption lowers pH and can precipitate the free acid from sodium sulphadiazine solutions. Manufacturing vessels with nitrogen overlay, sealed transfer lines, and limited headspace oxygen reduce this risk. Strong oxidising agents, acidic buffers, and certain metal cations may accelerate degradation or form incompatible admixtures; compatibility with stoppers, filters, and tubing is validated under finished-product stability conditions.
Compounded sodium sulphadiazine injections are commonly stored under defined refrigerated or ambient temperature conditions, but published kinetic data for terminal sterilisation of sulphadiazine sodium under all pH and oxygen conditions are limited. Each holder must perform product-specific degradation studies under simulated worst-case conditions, including pH shift, colour formation, and assay recovery. The operational boundary is defined by precipitation pH and degradation rate, not by visual clarity alone. Prolonged exposure above 25 °C is generally avoided unless product-specific stability data support otherwise.
Sulphadiazine powder often exhibits low bulk density, poor flow, and high interparticulate cohesion; direct compression is seldom feasible. Dry granulation by slugging or roller compaction improves flow and reduces segregation, while wet granulation in high-shear mixers or fluid-bed systems is common for low-dose tablets. The wet mass is passed through a screen mesh of approximately 1.0 mm to 1.6 mm, then dried to a target loss on drying below 2.0%. Dried granules are sized before blending with disintegrant and lubricant; magnesium stearate at 0.5–1.0% w/w is typical, but over-lubrication reduces tablet tensile strength.
For capsules, controlled granule particle-size distribution improves filling consistency; powder segregation is monitored by bulk and tapped density measurements according to Ph. Eur. 2.9.34. Tablet compression force is set to balance friability and disintegration; compendial friability testing follows Ph. Eur. 2.9.7 or USP General Chapter 1216. Dissolution failures during scale-up often originate from changes in granule porosity, drying endpoint, or API particle size rather than from raw material purity. Production-scale equipment behaviour is therefore monitored through impeller torque, inlet air dew point, and exhaust air temperature during wet granulation. Published design-space data for sulphadiazine high-shear granulation are limited; scale-up studies therefore retain a high experimental burden.
For injectable manufacturing, the sodium salt is dissolved in water for injection, pH-adjusted under nitrogen, and filtered through a validated sterilising-grade membrane before filling. The injectable-grade boundary is defined by bioburden, endotoxin, particulate matter, and residual solvent controls rather than by appearance alone. When oral and injectable grades are supplied from the same site, the injectable grade must be reserved for parenteral applications; oral-grade material is not released for injection under the same certificate of analysis. Batch-to-batch shifts in micronised particle fraction, bulk density, or residual solvent profile should be trended because these variables influence granule strength, content uniformity, and final dissolution rate.
