| HS Code | 624994 |
| Chemical Name | Tiamulin |
| Cas Number | 55297-95-5 |
| Molecular Formula | C28H47NO4S |
| Molecular Weight | 493.75 g/mol |
| Description | White to off-white crystalline powder with a bitter taste |
| Solubility | Soluble in organic solvents; slightly soluble in water |
| Melting Point | 140-146°C |
| Storage Conditions | Store in tightly closed container in cool, dry place; protect from light and moisture |
| Shelf Life | 3 years when properly stored |
| Dosage Forms | Tablets, Injections, Capsules, Powders, Granules, Premix, Solutions |
| Veterinary Use | Antibiotic effective against Gram-positive bacteria and mycoplasma infections |
As an accredited Tiamulin Premix Veterinary Grade API for Tablets / Injections / Capsules / Powders / Granules / Premix / Solutions factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | Tiamulin Premix veterinary-grade API is packaged in 25 kg drums with double polyethylene liners, ensuring stability for tablets, injections, and other formulations. |
| Container Loading (20′ FCL) | A 20-foot FCL of Tiamulin Premix veterinary grade API, packed in sealed drums or cartons on pallets, ready for safe shipment. |
| Shipping | Ship in sealed, moisture-proof containers, protected from light and extreme temperatures. Store in a cool, dry, ventilated area. Ensure compliance with veterinary pharmaceutical transport regulations, including proper documentation, labeling, and handling precautions to avoid dust inhalation or environmental contamination. Deliver promptly to maintain product integrity. |
| Storage | Store in a cool, dry, well-ventilated area at controlled room temperature, away from direct sunlight, moisture, and heat sources. Keep the container tightly sealed to prevent contamination and degradation. Protect from strong oxidizing agents. Use appropriate personal protective equipment when handling. Follow manufacturer’s expiration date and regulatory storage guidelines for all dosage forms. |
| Shelf Life | Shelf life is typically 2–3 years when stored in the original, tightly sealed container under recommended cool, dry conditions. |
In commercial swine feed manufacturing, tiamulin hydrogen fumarate premix is handled as a Type A medicated article under 21 CFR 558.600 and diluted through pre-blending and finished-feed mixing into Type C medicated feeds. The molecule belongs to the pleuromutilin class and inhibits the 50S ribosomal subunit at the peptidyl transferase centre, which accounts for its activity against Mycoplasma spp., Brachyspira hyodysenteriae, and Lawsonia intracellularis. The feed premix segment is not a single indication: low-inclusion control programs for swine dysentery and porcine proliferative enteropathy operate separately from treatment-level batches. Under published FDA label conditions, control of swine dysentery and Lawsonia-associated ileitis commonly uses 35 g/t tiamulin hydrogen fumarate in complete feed, while treatment of clinical swine dysentery may use 200 g/t for 14 days. Regional labels differ, and the withdrawal period is species-specific and must be verified against the receiving market. The API is first dispersed onto a carrier such as ground corn cob, rice hulls, or lactose monohydrate to form a homogeneous premix. The carrier is not a passive filler: its particle-size distribution, bulk density, and moisture content determine whether the finished premix segregates during silo discharge or conveyer transfer. The Type A premix is metered through a micro-dosing system into a horizontal ribbon mixer or paddle mixer. Mixing is not considered complete when the visible blend is uniform; the target coefficient of variation across ten sampling points is kept below 5.0% for the active component. This is confirmed by HPLC assay of complete feed sampled at the mixer midpoint and discharge ends. In a multi-species feed mill, the equipment train must be sequenced so that tiamulin-containing feed does not follow monensin, narasin, or salinomycin batches without a validated flush. Tiamulin and ionophores are mutually incompatible; co-exposure can produce severe ionophore toxicosis. The first feed produced after a tiamulin run is assayed to demonstrate that tiamulin carryover is below the site-specific limit of quantitation. The same segregation controls apply to finished-feed bins, trucks, and bagging lines. Medicated feed production must be managed within the current good manufacturing practice framework of 21 CFR 225.1, including master production records, equipment cleanout documentation, and batch-to-batch line clearance.
The conversion of tiamulin hydrogen fumarate into drinking-water solutions and soluble powders is driven by poultry respiratory disease associated with Mycoplasma gallisepticum and Mycoplasma synoviae. In broiler flocks, tiamulin is administered through the drinking-water system at a final concentration of 250 mg/L for 3 to 5 days in many label jurisdictions; stock solutions are prepared at higher concentration and proportioned into the water line by a metering pump or venturi proportioner. A 1:128 proportioner setting is common for stock solutions, but the final ratio depends on stock concentration, water consumption, and the drinker-line volume. Because solubility and chemical stability of tiamulin hydrogen fumarate are pH-dependent, the stock solution is normally acidified with a pharmaceutically acceptable organic acid. Acidification keeps the salt in solution, suppresses alkaline degradation, and reduces precipitation in distribution lines. Published stability data for the exact pH window vary; the formulation pH must therefore be confirmed by forced degradation studies rather than transferred from another product. The finished medicated water is a clear solution; any increase in turbidity above the baseline value at the farthest drinker indicates precipitation or incompatibility with the water source and requires rechecking of total hardness, alkalinity, and line hygiene. For water-soluble powder presentations, the API is dry-blended with an acidic carrier such as citric acid plus lactose monohydrate, then dissolved in the stock tank before proportional delivery. Powder blend uniformity is tested according to a validated HPLC method, and the powder must dissolve within a defined period without foaming or caking. Stock solutions held for more than 24 hours require preservative efficacy testing under Ph. Eur. 5.1.3; multi-day stock tanks must be protected from light and microbial ingress. The same water system must not contain residual monensin, salinomycin, or narasin from previous poultry batches. Residual ionophore in proportioners, drinker lines, or header tanks is incompatible with tiamulin and must be flushed before introduction. Analytical verification of the final medicated water concentration is performed by HPLC; dye tracers may identify plumbing dead legs but do not substitute for chemical assay. Batch records must include the stock concentration, proportioner setting, final water pH, and the assay result at the farthest drinker.
Tiamulin hydrogen fumarate injectable solutions are used in porcine respiratory disease control in regulated markets. The manufacturing route differs fundamentally from feed and water formulations because the final product must be sterile, non-pyrogenic, and stable in contact with glass and elastomer closures. A typical processing batch comprises Water for Injections, tiamulin hydrogen fumarate calculated as tiamulin base, a tonicity-adjusting agent, and a pH-adjustment system. The salt correction factor between tiamulin hydrogen fumarate and tiamulin base must appear in the master formula; the label claim is expressed as tiamulin base, and the salt weight is derived from the molecular mass ratio. The solution is compounded in closed stainless-steel vessels under nitrogen overlay because atmospheric oxygen can promote oxidative degradation. The bulk solution is filtered through a 0.22 µm sterilising-grade membrane. If terminal sterilisation at 121°C for 15 minutes is not supported by stability data, aseptic filtration is used, and the entire filling line must comply with Ph. Eur. 5.1.1 and USP <71> sterility criteria. Filter integrity is tested before and after filtration by the bubble point or diffuse-flow method specified by the filter manufacturer. The vials are filled under laminar flow, and particulate matter is controlled according to Ph. Eur. 2.9.19 or USP <788>. Multi-dose vials may include benzyl alcohol as a preservative; single-dose vials omit preservatives. The finished injectable is stored below 25°C in light-protective containers, and freeze-thaw cycling is avoided because it can destabilise the solution and compromise container closure integrity. Forced degradation under ICH Q1B and pH stability screening are required because the API is sensitive to alkaline conditions and prolonged heat. The injectable route demands the tightest microbial and endotoxin control of all tiamulin conversion routes: the Water for Injections system, depyrogenation tunnel, and aseptic filling line are all part of the release dossier. Published data for specific commercial tiamulin injectable formulations are limited; each development batch must therefore establish its own sterilisation, stability, and extractables profile rather than relying on class-level assumptions.
Dry granulation and encapsulation of tiamulin hydrogen fumarate for oral solid dosage forms begins with de-agglomeration of the API through a cone mill fitted with a 0.5 mm screen. The drug substance is then pre-blended with a diluent such as lactose monohydrate or mannitol in a geometric dilution sequence. The bitter taste and moderate electrostatic charging of the API mean that direct compression is only feasible when the formulation contains microcrystalline cellulose and a glidant; wet granulation with a povidone binder is preferred for tablets intended to survive film coating. Granules are dried in a fluid-bed dryer until loss on drying is within the range established by the stability protocol. The dried granulate is passed through a 1.0 mm oscillating granulator, lubricated with magnesium stearate, and compressed on a rotary tablet press with a target content uniformity acceptance value of not more than 15.0 under USP <905> or Ph. Eur. 2.9.5. Capsule filling of the same granulate is performed on a dosator or tamping-pin machine; the fill weight is adjusted based on the tapped density of the granulate. All operations are performed in controlled relative humidity because tiamulin hydrogen fumarate can retain moisture and cause sticking to tablet punches. The API is not micronized without a dust-containment system; cross-contamination control under 21 CFR 211 requires dedicated or validated cleaning procedures and airborne exposure limits. The oral solid route is used where regulatory authorisation exists or under extemporaneous compounding for individual animals; it is not universally licensed in all jurisdictions. Formulation development must include excipient compatibility screening, forced degradation, and dissolution method validation, because no universal pharmacopoeial dissolution monograph exists for tiamulin tablets in every region.
| Conversion route | Reference standard | Critical quality attribute | Typical acceptance value |
|---|---|---|---|
| Medicated feed premix dilution | 21 CFR 558.600; 21 CFR 225.1 | Mixer coefficient of variation | <5.0% |
| Drinking-water stock solution | Ph. Eur. 5.1.3 | Preservative efficacy for multi-day stock | Criterion A |
| Injectable solution | Ph. Eur. 5.1.1; USP <71> | Sterility | No growth |
| Tablets and capsules | USP <905>; Ph. Eur. 2.9.5 | Content uniformity acceptance value | ≤15.0 |
| Oral granules | Ph. Eur. 2.2.32 | Loss on drying | Validated range |
The most critical process conflict in tiamulin feed production is the transition from ionophore-containing rations to tiamulin-containing rations. Monensin, salinomycin, and narasin are toxicologically incompatible with tiamulin hydrogen fumarate; simultaneous exposure in swine or poultry can cause severe ionophore toxicosis. The risk is not limited to direct mixing: residual ionophore in elevator legs, drag conveyors, pellet mill dies, coolers, and bulk load-out bins can transfer into the next batch. A robust sequencing procedure starts with a flush of ground corn or a similar non-medicated feed through the full manufacturing line after an ionophore batch. The flush volume is not fixed; it must be derived from equipment-specific carryover validation. Samples are collected from the first tiamulin batch after the flush at the mixer discharge and at the final packaging point. If the assay for tiamulin or the previous ionophore fails acceptance, the bin is held and the flush is repeated. The cleanout protocol includes physical removal of caked material from the pellet mill conditioner and cooler trays, because steam conditioning can create residues that are not removed by dry flushing alone. The use of dedicated bins and dedicated lines is the only fully reliable method where regulatory controls demand zero carryover. Written sequence controls must be part of the site’s 21 CFR 225.1 medicated feed CGMP program. Analytical methods for tiamulin in feed are typically HPLC-based; the limit of quantitation is established during method validation and must be low enough to detect carryover at the defined rejection threshold. For sites where the same line is used for ionophore and tiamulin feeds, the master production schedule places tiamulin first or uses a physical barrier; production orders that do not respect this sequence are treated as critical deviations. The segregation extends to bagging lines, truck compartments, and customer delivery records. In poultry operations, the same logic applies to water-delivery systems, where ionophore residues in share tanks or header lines are a known source of incompatibility.
Direct compression of tiamulin hydrogen fumarate is constrained by the flow properties and compactibility of the API. Tiamulin hydrogen fumarate is not recommended as a sole direct-compression ingredient; it requires a directly compressible excipient system consisting of microcrystalline cellulose and lactose or dicalcium phosphate. The dry blend is prepared by geometric pre-blending of the API with a 1:10 portion of microcrystalline cellulose that has been passed through a 0.5 mm sieve. The pre-blend is then added to the main excipient mass in a bin blender, where a target blend uniformity of not more than 5.0% relative standard deviation across sampling points is verified before lubrication. Magnesium stearate is added at a low concentration to avoid excessive lubrication, which can reduce tablet hardness. The compression force is adjusted on a rotary press to produce tablets with a hardness sufficient to survive film coating; the exact target depends on tablet geometry. Film coating with an HPMC-based system is used for taste masking and for protection against moisture. Process gains are limited by the API’s hygroscopicity and electrostatic charge; if the relative humidity in the compression suite exceeds 60%, pre-conditioning of the blend and punch lubrication are required. Dissolution testing is performed in 0.1 M HCl using USP Apparatus 2 at 50 rpm; where no regional monograph exists, the method is validated in-house. Content uniformity and assay are performed on the finished tablets according to Ph. Eur. 2.9.5 or USP <905>. Release criteria include related substances by HPLC, loss on drying, and microbial limits under Ph. Eur. 5.1.4 or USP <61>/<62>. Cross-contamination after a tablet run is controlled by cleaning validation with swab limits expressed in µg/cm²; tiamulin residues are quantified by HPLC with a validated limit of quantitation appropriate to the permitted daily exposure. The direct-compression route is suitable only for low-dose tablets with a substantial excipient mass; it is not a universal substitute for wet granulation when the API content exceeds the practical dilution capacity of the directly compressible system.
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Tiamulin premix veterinary grade API, supplied as tiamulin hydrogen fumarate (CAS 55297-96-2), is a semisynthetic pleuromutilin antibiotic of diterpene origin. The substance is a white to off-white crystalline powder with molecular formula C28H47NO4S·C4H4O4 and molar mass 609.8 g/mol. The active substance is intended for downstream manufacture of veterinary medicinal products in tablet, injectable solution, capsule, oral powder, granule, feed premix, and drinking-water solution forms for swine and poultry. Compared with unformulated tiamulin base, the hydrogen fumarate salt provides aqueous solubility appropriate for liquid dosage forms and retains dry-state stability for solid oral and feed premix processing. The API is distinguished from macrolide and tetracycline antimicrobials by its binding site on the 50S ribosomal subunit and by its spectrum against Brachyspira hyodysenteriae, Lawsonia intracellularis, Mycoplasma hyopneumoniae, Mycoplasma gallisepticum, and Mycoplasma synoviae.
Identity is confirmed by infrared absorption spectrophotometry and by high-performance liquid chromatographic retention against a chemical reference substance. Assay on the dried substance is performed by reversed-phase HPLC on octadecylsilyl silica gel with ultraviolet detection at 205 nm; the release target is 98.0% to 102.0%. Related substances are controlled by area normalisation using the same HPLC system, with individual and total impurity limits defined in the current European Pharmacopoeia monograph and in the national registration dossier. Oral and parenteral grades differ mainly in the bacterial endotoxin limit and in microbial quality. A representative specification is summarised below; exact limits are product-registration dependent.
| Parameter | Typical release target | Method designation |
|---|---|---|
| Appearance | White to off-white crystalline powder | Visual inspection |
| Identification | Infrared spectrum concordant with reference standard; HPLC retention time concordant | Ph. Eur. 2.2.24, Ph. Eur. 2.2.29 |
| Assay on dried substance | 98.0% to 102.0% | Ph. Eur. 2.2.29 |
| Loss on drying | ≤ 0.5% after 2 h at 105 °C | Ph. Eur. 2.2.32 |
| Sulfated ash | ≤ 0.1% | Ph. Eur. 2.4.14 |
| Elemental impurities | Complies with ICH Q3D for oral and parenteral routes | Ph. Eur. 2.4.20 |
| Residual solvents | Complies with Ph. Eur. 5.4 | Ph. Eur. 2.4.24 |
| Particle size, premix grade | D90 ≤ 100 µm; D50 20–60 µm | Ph. Eur. 2.9.31 |
| Bulk density | 0.30–0.55 g/mL | Ph. Eur. 2.9.34 |
| Bacterial endotoxins, parenteral grade | ≤ 0.50 EU/mg | Ph. Eur. 2.6.14 |
For oral solids, the particle-size target supports content uniformity in low-dose tablets and capsules. A D90 ≤ 100 µm reduces segregation in final blends and permits acceptance under USP <905>. Parenteral-grade material does not require a fine particle-size specification for dissolution because the API is dissolved before sterile filtration; the release-critical parameter is the bacterial endotoxin limit of ≤ 0.50 EU/mg and compliance with Ph. Eur. 2.6.14.
Analytical method validation for stability-indicating HPLC uses forced degradation under acidic, alkaline, oxidative, thermal, and photolytic conditions. The method is validated for specificity, linearity, precision, accuracy, and robustness under ICH Q2(R1). Degradation products are resolved from the tiamulin peak with resolution not less than 2.0. A representative system suitability profile uses a 250 mm × 4.6 mm octadecylsilyl column with 5 µm particle size, column temperature 30 °C, and mobile phase consisting of acetonitrile and phosphate buffer at pH 6.0. Ultraviolet detection at 205 nm is used because tiamulin has a weak chromophore. System suitability requires relative standard deviation not more than 1.0% for six replicate injections. Residual solvents are controlled by headspace gas chromatography under Ph. Eur. 2.4.24; class I solvents are absent, class II solvents are below monograph limits, and class III solvents are not more than 0.5% w/w. Water content by Karl Fischer titration is ≤ 0.5% when tested under Ph. Eur. 2.5.12.
Following size reduction through a comminuting mill fitted with a 0.8 mm screen, tiamulin hydrogen fumarate is incorporated into feed premixes by geometric dilution. A horizontal ribbon blender operated at 70–80% usable volume and mixed for 12 min at 25 rpm is a representative production parameter set. Content uniformity is measured at 10 sampling points by HPLC with ultraviolet detection at 205 nm; the process capability target is a relative standard deviation not exceeding 5.0% according to Ph. Eur. 2.9.40 and USP <905>. Final premixes are filled into multi-wall paper bags with an inner polyethylene liner and stored below 25 °C and 60% relative humidity.
During wet granulation for tablets and capsules, an aqueous binder solution is sprayed at product temperature below 35 °C. Dryer inlet air is maintained at 50–60 °C, but product temperature above 40 °C triggers a hold step because the hydrogen fumarate salt is heat-sensitive in the presence of moisture. Dried granules are sieved through a 1.0 mm screen before compression. For direct compression, 0.5–1.0% colloidal silicon dioxide and 1.0–2.0% magnesium stearate are typical excipient ranges; lubricant concentration above 2.0% may retard dissolution in low-dose formulations and must be validated by dissolution testing per Ph. Eur. 2.9.3 or USP <711>. Dissolution testing of tablets is performed in 900 mL of 0.1 M hydrochloric acid at 37 °C with paddle speed 50 rpm. The acceptance criterion is registration-specific and is not set by the API monograph; a validated dissolution method must distinguish changes in granulation, lubrication, and compression force. Capsules are filled with a powder blend that meets the same content uniformity and dissolution requirements as tablets.
For drinking-water powders, the formulation is reconstituted in potable water at 20–25 °C within 5 min under gentle agitation. The final solution pH is maintained between 6.0 and 7.0; high carbonate hardness may precipitate the active substance, so citric acid or another chelating buffer is included in the formula. The solution should be protected from light and used within the in-use stability period defined by the finished product registration.
Tiamulin hydrogen fumarate dissolves in water for injection after pH adjustment. A citrate-phosphate buffer system is used to hold the solution at pH 6.0–7.0 at 25 °C. The solution is protected from light and purged with nitrogen to keep dissolved oxygen below 2.0 mg/L, because oxidative degradation can increase related substances. Terminal sterilization at 121 °C for 15 min is applied only after the registered formulation has been shown to remain within assay and impurity limits after the heat cycle; otherwise, aseptic filtration through a 0.22 µm polyvinylidene difluoride filter is used. The pH must not exceed 7.5 during compounding or storage, because alkaline hydrolysis accelerates degradation. Sterility of the finished product is confirmed by Ph. Eur. 2.6.1; bacterial endotoxin testing is performed by Ph. Eur. 2.6.14.
Tiamulin binds to the 23S rRNA of the 50S ribosomal subunit at the peptidyl transferase center and blocks polypeptide chain elongation. Macrolides bind to a different region of the same subunit; tetracyclines bind to the 30S subunit. Tiamulin can remain active against some strains that carry erm methylase-mediated macrolide resistance because the binding site is different, but cross-resistance with valnemulin and other pleuromutilins must be assumed when 23S rRNA or ribosomal protein L3 mutations are present. Susceptibility testing is performed by broth microdilution according to CLSI VET01 and interpreted with CLSI VET08 or the applicable national breakpoints. In swine, the relevant target pathogens are Brachyspira hyodysenteriae, Lawsonia intracellularis, Mycoplasma hyopneumoniae, Actinobacillus pleuropneumoniae, and Pasteurella multocida; in poultry, Mycoplasma gallisepticum and Mycoplasma synoviae are the primary label indications. Published MIC distributions vary by region; national resistance monitoring programs should be consulted before using historical breakpoints.
Compared with tylosin tartrate, tiamulin shows a different ribosomal binding site and a spectrum that includes Brachyspira and Lawsonia. Compared with chlortetracycline or oxytetracycline, tiamulin does not bind the 30S subunit and is not classified as a tetracycline. Compared with the free base, the hydrogen fumarate salt has higher aqueous solubility and is therefore preferred for injectable and oral liquid formulations; the free base is more lipophilic and is not normally used in aqueous systems.
Feed mills that run tiamulin and ionophore coccidiostats on the same line must sequence production and validate a flush procedure. Because low-level carryover of tiamulin into monensin, salinomycin, or narasin feed can produce clinical toxicity in target animals, flush material is assayed by liquid chromatography-tandem mass spectrometry until tiamulin is below the method limit of detection of 0.1 mg/kg in the finished feed. The limit of detection is method-dependent and must be established during validation per ICH Q2(R1).
Tiamulin inhibits the metabolism of ionophore coccidiostats in target species. Co-administration with monensin, salinomycin, or narasin is contraindicated because reduced ionophore clearance can lead to skeletal muscle damage and mortality. This incompatibility is stated in registered summaries of product characteristics and in the U.S. Code of Federal Regulations for tiamulin medicated feed under 21 CFR 558.618. Withdrawal periods and target-species restrictions are jurisdiction-specific and must be taken from the finished product registration; no API-level withdrawal period applies.
The API is not intended for human use. Occupational handling requires a N95 or equivalent particulate respirator, nitrile gloves, and local exhaust ventilation; no harmonized regulatory occupational exposure limit is published for tiamulin hydrogen fumarate, so an internal control band should be assigned from the toxicological data in the registration dossier. Bulk material should be protected from light and moisture, stored at 15–25 °C, and not exposed to relative humidity above 60% for more than 8 h during dispensing. Stability studies for the API and finished products are conducted according to VICH GL3; accelerated conditions of 40 °C/75% RH for 6 months and long-term conditions of 25 °C/60% RH for 24 months are representative, but results are product-specific and must be generated for each dosage form.
