| HS Code | 753615 |
| Product Name | Colistin Sulfate Premix Veterinary Grade API |
| Api Name | Colistin Sulfate |
| Grade | Veterinary Grade |
| Dosage Forms | Tablets, Injections, Capsules, Powders, Granules, Premix, Solutions |
| Appearance | White or almost white powder |
| Solubility | Freely soluble in water; practically insoluble in acetone and ether |
| Ph Of 1 Aqueous Solution | 4.0 to 6.0 |
| Function | Antibiotic active against gram-negative bacteria |
| Storage | Store in tightly sealed containers, protected from moisture, heat, and light |
| Shelf Life | 24 months when stored under recommended conditions |
As an accredited Colistin Sulfate 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 | Packaged in 25 kg net, sealed polyethylene bags inside aluminum foil pouches, ensuring stability and safety for veterinary pharmaceutical use. |
| Container Loading (20′ FCL) | One 20-foot FCL loaded with Colistin Sulfate Premix veterinary-grade API in sealed drums, palletized and secured for safe transport. |
| Shipping | Colistin Sulfate Premix (Veterinary Grade API) is shipped in sealed, moisture-proof containers to maintain stability and potency. Transport under ambient conditions, away from heat and sunlight. Ensure compliance with veterinary drug regulations; handle with care to avoid dust exposure. Proper labeling and documentation accompany all shipments. |
| 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 when not in use. Protect from excessive humidity and contamination. Ensure proper labeling and segregation from food, feed, and other chemicals. Follow veterinary pharmacopoeia guidelines for stability. |
| Shelf Life | Shelf life: 24 months when stored in sealed original container below 25°C, protected from moisture and light. |
Colistin sulfate water-soluble powder for post-weaning diarrhoea (PWD) in swine is formulated around enterotoxigenic Escherichia coli (ETEC) breakpoints and daily drinking-water intake variability. The API is released against Ph. Eur. monograph 0320, which sets a minimum potency of 19,000 IU/mg on the dried basis and limits individual related peptides by HPLC. Compliance for food-producing species in the European Union is controlled under Regulation (EU) 2019/6 and the colistin entry in Commission Regulation (EU) No 37/2010, where tissue-specific residue markers and withdrawal periods are defined for liver, kidney, muscle and fat; final water-soluble powder shipped to EU feedlots or veterinary distributors must therefore be released with residue depletion data aligned to Commission Regulation (EU) No 37/2010. In a representative 10% w/w water-soluble powder, colistin sulfate is first screened through a 100-mesh stainless steel sieve to control D90 at or below 75 µm, then geometrically diluted with anhydrous glucose and citric acid in a double-cone blender operated at 15 rpm for 30 minutes; final moisture is held below 3% w/w, and sachet filling is performed below 30% relative humidity to limit hygroscopic caking. The farm-level formulation addition ratio is calculated from bodyweight and observed water intake: for a 20 kg piglet drinking approximately 2 L/day, a 10% w/w powder is metered to deliver 100,000 IU/kg bodyweight/day, equivalent to approximately 1.0 g of 10% powder per 20 kg piglet per day, and the stock solution must be consumed within 24 hours. Downstream production of the finished powder includes V-blender or ribbon-blender mixing, loss-on-drying verification, and packaging in aluminium foil laminated sachets of 100 g, 500 g and 1 kg; the terminal product types are 10% w/w and 20% w/w oral water-soluble powders for drinking-water administration. In barn-level dilution, a positive-displacement diaphragm metering pump is used to inject stock solution into the header tank at a ratio between 0.2% and 2.0%, and agitation in polypropylene tanks is maintained at 100 rpm to prevent sedimentation. Water hardness above 250 ppm CaCO₃ and free chlorine above 1 ppm can reduce recovered potency, so line flushing before and after medication is required.
In broiler and layer production, water medication with colistin sulfate is directed at avian colibacillosis caused by Escherichia coli, with a target daily dose of 75,000–100,000 IU/kg bodyweight for 3–5 days; this route is selected for flock-level outbreak management when feed refusal or water uptake patterns remain stable. The regulatory boundary is Commission Regulation (EU) No 37/2010, under which egg and tissue residue depletion must be demonstrated in the target class, and Regulation (EU) 2019/6 governs the veterinary medicinal product authorisation. A typical addition ratio for a 10% w/w soluble powder is 1 g per 10 L of drinking water, producing approximately 190,000 IU/L; when a 1 kg broiler consumes 0.4 L/day, the delivered dose is approximately 76,000 IU/kg bodyweight/day. For liquid concentrate manufacture, colistin sulfate is dissolved in purified water at 25°C, adjusted to pH 4.5–5.5 with citric acid/sodium citrate buffer, and processed in a high-shear mixer at 1,500 rpm before filtration through a 10 µm polypropylene filter; the liquid is filled into opaque HDPE jerry cans. Powder production uses a spray-dried lactose monohydrate carrier and sodium citrate to control reconstitution time, with final powder moisture maintained below 3% w/w. Farm delivery relies on in-line proportioners set to a 1% stock solution, with water meter verification twice daily; the terminal finished products are 10% w/w and 20% w/w water-soluble powders, plus 2,000,000 IU/mL oral liquid concentrates for tank dilution.
Medicated feed premix manufacture containing colistin sulfate is performed in feed mills that operate under Regulation (EC) No 183/2005, Regulation (EU) 2019/4 and Codex CAC/RCP 54-2004. The active substance is supplied as a 10% w/w or 20% w/w premix on a calcium carbonate or rice hull carrier. The addition ratio in finished feed is species-specific: for weaned pigs, a 10% w/w premix is incorporated at 2.0–4.0 kg per tonne complete feed, equivalent to 200–400 g colistin sulfate per tonne; for broilers, inclusion is 1.0–2.0 kg per tonne, equivalent to 100–200 g active substance per tonne. These rates are derived from the target dose of 100,000 IU/kg bodyweight/day in pigs and 75,000–100,000 IU/kg bodyweight/day in poultry, adjusted by measured feed intake. The production sequence uses a micro-dosing system with load-cell verification, and the colistin premix is first diluted 1:10 with ground corn or wheat middlings before introduction into a 1,000 kg horizontal paddle mixer. Mixer uniformity is tested by taking 10 samples per batch and requires a coefficient of variation not exceeding 10% under ISO 6497. Pelleting is limited to conditioner temperatures of 70–75°C for 30 seconds; longer dwell times above 85°C may reduce assayable potency. Carry-over control uses a post-batch flush of 50 kg ground corn, and cleaning validation is confirmed by HPLC assay of the first non-medicated batch. Terminal product types are 10% and 20% medicated premixes, complete medicated mash feed, and pelleted medicated feed.
| Species | 10% premix inclusion per tonne finished feed | Active colistin sulfate per tonne | Mixer uniformity limit | Target dosage basis |
|---|---|---|---|---|
| Weaned pigs | 2.0–4.0 kg | 200–400 g | CV ≤ 10% | 100,000 IU/kg b.w./day |
| Broilers | 1.0–2.0 kg | 100–200 g | CV ≤ 10% | 75,000–100,000 IU/kg b.w./day |
For pre-ruminant calves and lambs, colistin sulfate oral solution is manufactured as a 2,000,000 IU/mL liquid dosage form intended for individual animal administration when milk replacer intake is measurable and water medication is impractical. Compliance is anchored to Commission Regulation (EU) No 37/2010 for bovine and ovine residue depletion, Regulation (EU) 2019/6 for product authorisation, and the general Ph. Eur. monograph for oral liquids. The dose is calculated at 50,000 IU/kg bodyweight twice daily; for a 50 kg calf, one dose equals 2,500,000 IU, corresponding to 1.25 mL of 2,000,000 IU/mL solution. Production uses a stainless steel mixing vessel with a propeller impeller at 250 rpm, dissolution at 25°C, pH adjustment to 4.5–5.5, and addition of potassium sorbate at 0.1% w/v as preservative. The solution is filtered through a 10 µm polypropylene filter and filled into amber HDPE bottles under nitrogen purge to limit oxidative degradation. Terminal product types are 100 mL, 250 mL and 1 L oral solutions and drench presentations. At farm level, the dose is mixed into milk replacer immediately before feeding; diluted solution must be used within 24 hours, and pH below 3.0 or exposure to direct sunlight reduces measurable potency.
Solid oral dosage forms containing colistin sulfate are produced where individual animal dosing is required, such as veal calf units, piglet hospital pens, or companion animal gastrointestinal protocols. The relevant standards are the Ph. Eur. general monograph on tablets, Ph. Eur. 2.9.1 for disintegration, Ph. Eur. 2.9.3 for dissolution, USP <905> for uniformity of dosage units, and ICH Q7 for API and finished product GMP. A representative direct compression tablet formulation contains colistin sulfate 20% w/w, microcrystalline cellulose 76.5% w/w, croscarmellose sodium 3% w/w, and magnesium stearate 0.5% w/w; for a 500 mg tablet core, colistin sulfate content is 100 mg, equivalent to approximately 1,900,000 IU. Because colistin sulfate exhibits poor flow and high hygroscopicity, wet granulation is preferred: a high-shear granulator is used with 5% w/w PVP K30 binder solution, followed by fluid-bed drying at inlet air 60°C and product temperature 38°C to a final granule moisture below 2% w/w. Compression on a rotary tablet press is maintained between 8 kN and 12 kN, with tablet hardness controlled at 60–80 N and friability below 1%. Capsule filling uses a tamp-pin capsule machine at 60% relative humidity, with 50 mg colistin sulfate per size 1 HPMC capsule and lactose monohydrate as filler. Terminal product types are 100 mg tablets and 50 mg capsules; process validation is required for each strength because dissolution failure and capping have been observed at lubricant levels above 0.5% w/w.
Granule manufacturing for colistin sulfate follows a fluid-bed top-spray layering process applied to sugar spheres, producing a free-flowing oral granule for feed top-dressing in piglets and small ruminants. The compliance framework includes the Ph. Eur. general monograph for granules, USP <1174> for powder flow, and Commission Regulation (EU) No 37/2010 for food-producing species residue requirements. A 5% w/w colistin sulfate granule is prepared by spraying a binder solution of hydroxypropyl methylcellulose E5 at 3% w/w onto 0.5–0.6 mm sugar spheres in a fluid-bed granulator with inlet air temperature 60°C and product temperature 38°C; the dried granules are sieved to 0.8–1.4 mm. The addition ratio is calculated from bodyweight: for a 20 kg piglet, 2.1 g of 5% granules delivers approximately 105 mg colistin sulfate, equivalent to approximately 100,000 IU/kg bodyweight/day. Granule friability must remain below 1% during sachet filling, and residual fines below 150 µm are limited to 5% w/w to prevent segregation. Terminal product types are 5% w/w and 10% w/w oral granules packed in single-dose sachets for feed top-dressing. Published industrial data on granule-specific thermal stability are limited; process validation therefore relies on assay, dissolution and moisture rather than extrapolated thermal degradation models.
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Colistin sulfate premix veterinary grade API is a fermentation-derived polypeptide antibiotic complex supplied as a white to off-white, hygroscopic powder. The material consists primarily of polymyxin E1 and E2 sulfate salts, with the sulfate complex identified by CAS registry number 1264-72-8. Compendial identity is established against Ph. Eur. monograph 0320, and the active substance is manufactured under ICH Q7 good manufacturing practice as an active pharmaceutical ingredient. The powder is standardised to a minimum potency of 19000 IU/mg on the dried basis, with the exact batch value reported on the certificate of analysis. Because the sulfate salt is freely soluble in water, it can be transferred into oral solutions and wet granulation fluids, while the dry powder is suitable for blending into medicated premixes, feed powders, granules, and final solid dosage forms.
No universal model designation applies to a veterinary API. Manufacturer-assigned grade codes usually distinguish the material by particle-size cut, bulk density, residual solvent class under VICH GL18, and endotoxin load. The term “premix grade” indicates that the powder is intended for dilution into a carrier or finished feed at a licensed feed mill or pharmaceutical manufacturer, not for direct administration without mixing. The main formulation routes covered by this grade are tablets, capsules, powders, granules, medicated premixes, drinking-water solutions, and injectable solutions only when the batch is explicitly released against a sterile, injectable-grade specification. In the European Union, the API must be accompanied by the relevant GMP and written confirmation documentation required under the applicable national rules for imported active substances.
The compendial monograph defines identity, potency, related substances, water content, sulfated ash, sulfate ion, and pH. A 1% aqueous solution is specified at pH 4.0 to 6.0; the assay and impurity profile are determined by HPLC using the Ph. Eur. 0320 method for colistin sulfate. However, the chemical monograph does not by itself establish a route-specific endotoxin limit. A premix-grade batch may carry a higher bacterial endotoxin limit or may not be tested for sterility, while an injectable-grade batch requires bacterial endotoxin testing by Ph. Eur. 2.6.14 and additional particulate and sterility controls. The same chemical monograph can therefore support both oral premix feedstock and injectable feedstock, but the release profile differs according to the intended route.
| Release parameter | Premix / oral grade control | Injectable-grade additional control |
|---|---|---|
| Appearance | White to off-white hygroscopic powder, Ph. Eur. 0320 | Same, with visual inspection after reconstitution |
| Potency | Not less than 19000 IU/mg on dried basis | Same or tighter in-house range |
| Bacterial endotoxins | May be uncontrolled or vendor-specified for oral use | Validated limit below the parenteral monograph limit |
| Water content | Compendial limit; dry-blend grades may be controlled at NMT 3.5% | NMT 3.5%, with lower target for dry blending |
| Particle size | Fit-to-use specification, e.g., D90 below 150 µm for feed blending | Defined D50 by laser diffraction or spray-dried grade |
| Related substances | Ph. Eur. total and specified impurities | Same, with additional residual solvent documentation per VICH GL18 |
Pharmacopoeial water content is determined by method 2.5.12; loss on drying uses 2.2.32. Residual solvents are assessed under VICH GL18 with gas chromatography. For highly diluted medicated premixes, the carrier type and overage are established during process validation because colistin sulfate can segregate when the mean particle-size difference between the API and carrier exceeds approximately 100 µm. The batch is not released for feed use if the final blend potency falls outside 90.0% to 110.0% of the declared label claim.
Production-scale blending of colistin sulfate into a medicated premix is performed in tumble blenders, ribbon blenders, or double-cone blenders with pharmaceutical-grade stainless-steel contact parts. Because a 10% w/w premix contains a high active fraction relative to the final feed level, a geometric dilution sequence is used: the API is first blended with an equal mass of carrier, then the pre-blend is passed through a 0.5 mm sieve and added to the remaining carrier. Blending time is established by homogeneity studies; initial validation samples are commonly drawn at 5, 10, and 15 min to establish the minimum mixing time. Acceptance criteria for blend uniformity are based on a relative standard deviation of not more than 5.0% in the active assay for the sampling points, but this value is derived from process validation and may be tightened by the marketing-authorisation holder. Powder flow is measured by Ph. Eur. 2.9.36 for flow through an orifice and Ph. Eur. 2.9.34 for bulk and tapped density.
For final feed premixes, a carrier such as rice hulls, lactose monohydrate, or corncob meal is selected on the basis of particle size, water uptake, and electrostatic charge. Electrostatic segregation can occur under low-humidity processing conditions, particularly when the API is milled to a fine particle size. Operators may use stainless-steel equipment grounding and controlled relative humidity between 40% and 60% to reduce dusting and electrostatic losses; published data for this specific configuration are limited, so process validation must generate site-specific limits. The final blend is sampled at multiple locations and assayed by the validated HPLC method; the coefficient of variation of the active assay across the blender is a batch record parameter.
Because the active strength is expressed in International Units, the formula weight of colistin sulfate is not used directly for dose calculation. A batch formulated to deliver 1 000 000 IU per gram of premix requires 52.63 g of API per kilogram if the benchmark potency is 19000 IU/mg. If the certificate of analysis records a higher potency, the weighed quantity is adjusted proportionally: mass equals target activity divided by batch potency. This calculation is performed by the pharmacist or feed-mill operator under a controlled worksheet; errors in this conversion are a common cause of batch failure when fixed-volume feeders are used.
Fixed-volume auger feeders used in feed mills are calibrated against the actual premix batch because bulk density changes with moisture and particle size. A volumetric feeder set by volume will deliver a different mass if the bulk density differs from the calibration lot; therefore, gravimetric or loss-in-weight feeders are preferred when the inclusion rate is below 1 kg/tonne. The premix is added after the main feed has cooled to below 40°C in the mixer line to avoid local thermal stress on the polypeptide.
For tablets and capsules, direct compression is not normally used because the active fraction is high in some dose units and the API requires taste masking. Wet granulation is preferred when the sulfate salt is dissolved in purified water or starch paste. If the formulation contains calcium carbonate, dibasic calcium phosphate, or magnesium oxide, the granulation pH can rise above 6.0; the resulting local pH shift can accelerate degradation in the presence of moisture. Published data for the specific degradation rate in dry granulations containing alkaline earth oxides are limited; formulators therefore map the pH of the granulation fluid before scale-up. The granule is dried to a loss-on-drying target below 3.0% to preserve flow and reduce hydrolysis during storage. Final tablets are coated because colistin sulfate is bitter and hygroscopic; a tablet breaking force of 60 N to 100 N may be used for polymer-coated tablets, but this is formulation-specific and not a compendial requirement.
Colistin sulfate contains the sulfated base and is used mainly for oral and topical administration. Colistimethate sodium is a methanesulfonated derivative that is less potent by weight and is used parenterally; the methanesulfonate groups must hydrolyse to release active colistin. The two derivatives are not interchangeable on a unit-for-unit basis in a formula. Polymyxin B sulfate is a separate fermentation complex with a different polypeptide ratio and a different pharmacopoeial identity; combining polymyxin B sulfate with colistin sulfate does not produce an interchangeable gram-negative spectrum and may alter the specific toxicity profile. In feed premixes, colistin sulfate is selected because it remains largely in the gastrointestinal tract after oral administration, limiting systemic absorption and supporting its use as an enteric antibiotic. That property is not relevant to an injectable dosage form, where systemic availability is required and the starting material must meet injectable-grade endotoxin, sterility, and particulate requirements.
Aqueous solutions of colistin sulfate are prepared with purified water and are maintained within the compendial pH range 4.0 to 6.0. Prolonged storage of solution above 25°C is not recommended because the cyclic peptide ring can undergo hydrolysis. If an oral solution is prepared at farm level, the dosing stock should be used within 24 h unless a preservative and stability study supports a longer in-use period. The powder should be stored in tightly closed, low-moisture-permeability containers below 25°C and protected from light. Open handling at relative humidity above 60% should be minimized because the material is hygroscopic and may clump. Strong oxidizing agents, concentrated acids, and concentrated alkali are incompatible. No laboratory-supported incompatibility with common oral feed excipients such as lactose monohydrate, maize starch, or microcrystalline cellulose is reported, but the formulator must verify pH, water activity, and oxidation potential for each formulation.
| Test method | Standard designation | Application boundary |
|---|---|---|
| Potency by HPLC | Ph. Eur. 0320 | Dried basis; batch release |
| Water content | Ph. Eur. 2.5.12 | Dry premix blending |
| Loss on drying | Ph. Eur. 2.2.32 | Stability and storage |
| pH of aqueous solution | Ph. Eur. 2.2.3 | 1% aqueous solution |
| Bacterial endotoxins | Ph. Eur. 2.6.14 | Parenteral grade only |
| Microbial enumeration | Ph. Eur. 2.6.12 / 2.6.13 | Oral premix release |
| Residual solvents | VICH GL18 / Ph. Eur. 5.4 | ICH Q3C classes |
Ph. Eur. 2.6.12 applies to non-sterile oral dosage forms and feed premixes; a total aerobic microbial count and total combined yeasts and moulds count are recorded. Absence of Escherichia coli and Salmonella is tested by Ph. Eur. 2.6.13 or relevant feed hygiene methods, because colistin sulfate is an antibacterial but does not sterilize the excipient blend. The API itself is not a sterilizing agent and cannot be used to mask microbial contamination of the carrier or equipment.
For injectable solutions, the starting material is dissolved in water for injection, pH-adjusted with dilute hydrochloric acid or sodium hydroxide, and filtered through a sterile 0.22 µm membrane. The solution is filled into depyrogenated vials and terminally sterilised or aseptically processed depending on the marketing authorisation. The premix-grade material cannot enter this line unless it is first re-processed and released as injectable grade; simple addition of a premix powder to water for injection does not make an injectable product.
Capsule filling with colistin sulfate may be performed on a low-speed tamping machine or a dosator-type capsule filler, but the powder is often granulated to improve flow and to reduce dusting during filling. The filled capsules are tested for uniformity of mass by Ph. Eur. 2.9.5. In medicated feed powders, the final mixture is milled or sieved through 1.0 mm to break soft agglomerates before packing.
In the EU, colistin for veterinary use is subject to the restrictions of Regulation (EU) 2019/6 and the associated rules on antimicrobial use. In many national formularies, colistin sulfate premix is a prescription-only medicated premix for enteric infection in pigs, poultry, and calves; use as a growth promoter is prohibited in the EU. Users must confirm that the target species and dosing regimen are authorised in the destination country.
Replacement of colistin methanesulfonate with colistin sulfate in an injectable formula requires a new formulation development study. The sulfate salt is not a direct substitute for the methanesulfonate in parenteral products because the reconstitution pH, tonicity, injection-site tolerability, and toxicological profile differ. A premix-grade colistin sulfate is not sterile and is not pyrogen-free; the batch must be rendered suitable by dissolution, depyrogenation, and sterile filtration only if the injectable-grade specification is met and the process is validated. Without such validation, the premix material must not be used for injection. This limitation is the principal operational boundary for veterinary licenced products: the same API name can appear on a premix certificate of analysis and an injectable certificate of analysis, but route-specific testing, endotoxin control, and manufacturing controls are not equivalent.
