| HS Code | 941122 |
| Chemical Name | Polymyxin E (Colistin) Sulfate |
| Cas Number | 1264-72-8 |
| Molecular Formula | C52H98N16O13 |
| Molecular Weight | 1155.45 g/mol |
| Appearance | White to almost white crystalline powder |
| Solubility | Freely soluble in water; slightly soluble in ethanol; practically insoluble in acetone and ether |
| Assay Content | 95.0% to 102.0% on dried basis |
| Ph Range | 4.0 to 6.5 for 1% aqueous solution |
| Storage Condition | Preserve in airtight containers, protected from light and moisture, store below 25°C |
As an accredited Polymycin E (Colistin) 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 | Supplied in sealed double-layer polyethylene bags with tamper-evident closure, 25 kg net weight, packed in fiber drums for safe transport. |
| Container Loading (20′ FCL) | Polymycin E (Colistin) veterinary API is packed in sealed drums, palletized, and securely loaded into a 20′ FCL container. |
| Shipping | Polymycin E (Colistin) Veterinary Grade API is shipped in sealed, moisture-proof drums or double-lined bags to maintain stability. Store in a cool, dry place away from direct sunlight. Proper labeling, documentation, and temperature-controlled transport prevent contamination and ensure regulatory compliance throughout delivery. |
| Storage | Store Polymycin E (Colistin) Veterinary Grade API in a tightly sealed, original container, protected from light, moisture, and heat. Keep in a cool, dry, well-ventilated area at controlled room temperature (20–25°C). Avoid exposure to strong oxidizing agents. Ensure proper labeling and segregation to prevent cross-contamination. |
| Shelf Life | Shelf Life: 24 months from manufacture date when stored in a cool, dry place, protected from light and moisture. |
Porcine post-weaning enteritis caused by F4- or F18-positive enterotoxigenic E. coli remains the highest-volume downstream application for colistin sulfate in food-animal production. The API is pre-micronized to a D90 of 150 μm before dry dispersion onto a lactose monohydrate or wheat middlings carrier; the intermediate premix is released at 10% w/w colistin sulfate, which at a pharmacopoeial potency of 19,000 IU/mg corresponds to 1,900,000 IU/g. Where tighter assay tolerance is required, a second intermediate is produced at 5% w/w through geometric dilution rather than direct weighing. Batch release is anchored to Ph. Eur. 0321 for API assay, Ph. Eur. 2.2.32 for loss on drying with a limit of ≤5.0%, and Ph. Eur. 2.9.38 for particle-size distribution. Medicated feed homogeneity after dilution is governed by Regulation (EU) 2019/4, while prescription-only administration falls under Regulation (EU) 2019/6. Processing in a horizontal ribbon blender at 50–70% gross fill is preferred; high-shear bowl choppers are avoided because localized heat input above 55°C raises the risk of polymyxin degradation. When granule presentation is required, a 5% povidone K30 binder solution is sprayed at 30–40°C product temperature, followed by fluid-bed drying with inlet air not exceeding 70°C and outlet air monitored to keep product temperature below 55°C. Batch-to-batch segregation is observed when the carrier-to-API particle-size ratio exceeds 4:1; pneumatic transfer of dry premix without line densification widens assay variability beyond ±5%. Terminal products are 5% and 10% premix powders, 100 g and 1 kg sachets, and bulk 25 kg liner bags for feed-mill dilution systems.
Avian colibacillosis medication through drinking water demands rapid reconstitution and absence of insoluble residues that obstruct nipple drinkers. Water-soluble powder formulations carry colistin sulfate at 50% w/w, with anhydrous lactose, sodium citrate/citric acid buffer, and q.s. to 100%; the powder is milled to a D90 of 200 μm and blended in a low-shear cone blender. In a 1% w/v reconstituted solution, pH is maintained between 4.5 and 6.5; alkaline pH above 7.5 is a known hydrolysis risk for polymyxins and therefore constitutes a release-rejection criterion. API assay follows Ph. Eur. 0321; pH is measured per Ph. Eur. 2.2.3. Sachet filling at ≤40% relative humidity and 20–25°C is standard because colistin sulfate is hygroscopic; loss on drying by Ph. Eur. 2.2.32 is held at ≤2.0%. Water-soluble powder dissolution is checked in a 1 L vessel at 15–20°C with gentle agitation; complete wetting should occur within 3 minutes, and any undissolved residue greater than 0.5% of fill weight is treated as a process deviation. Regulatory distribution in the EU is controlled by Regulation (EU) 2019/6; colistin remains on the WHO CIA list, requiring prescription-only use and batch-level documentation. Finished product types are 100 g and 1 kg water-soluble powder sachets, plus 1 L and 5 L oral solution concentrates for proportioner systems.
For neonatal calf enteritis caused by E. coli K99/F5, oral solid dosage forms reduce in-feed cross-contamination and allow individual administration. Tablet cores are direct-compressed with colistin sulfate loading between 5% and 25% w/w; microcrystalline cellulose, lactose monohydrate, crospovidone at 2–4% w/w, and magnesium stearate at 0.25–0.5% w/w are typical excipients, though published formulation data for this specific configuration is limited compared with swine and poultry premixes. Direct compression is performed at 20–25°C and ≤40% relative humidity; product temperature above 50°C during any drying step is avoided. Tablet hardness is targeted at 40–80 N per Ph. Eur. 2.9.8; disintegration in water at 37°C is required to be ≤15 minutes per Ph. Eur. 2.9.1. Content uniformity is evaluated by Ph. Eur. 2.9.40 with an acceptance value ≤15; dissolution profiling per Ph. Eur. 2.9.3 is applied with product-specific acceptance limits because a harmonised veterinary dissolution specification is not established. Capsule filling uses hard gelatin capsules and automatic tamping-type fillers; powder fill weight control is verified at ±5% for capsules below 300 mg. Terminal finished products include 25 mg and 50 mg colistin sulfate tablets, capsules, and oral powder sachets for milk-replacer administration. API release remains under Ph. Eur. 0321; manufacturing follows 21 CFR Part 211 when imported into the United States or Regulation (EU) 2019/6 for EU-bound batches.
Injectable Polymyxin E cannot be based on sulfate salt; the methanesulfonate derivative is required because it is the form cleared for parenteral administration and undergoes hydrolysis to the active base in vivo. Lyophilised vials are compounded as aqueous solutions of colistimethate sodium equivalent to 2 million IU colistin per vial, sterile-filtered through a 0.22 μm polyethersulfone membrane, and freeze-dried under aseptic conditions. Reconstitution with 10 mL water for injection yields 200,000 IU/mL; the formulator sets the colistimethate sodium charge on a IU/mL basis after reconstitution. Formulation addition ratio is controlled by anhydrous colistimethate sodium assay per Ph. Eur. 0320; sodium content is a release parameter because excessive sodium contributes to hypernatraemia in neonatal animals. Sterility is verified by Ph. Eur. 2.6.1; bacterial endotoxin testing follows Ph. Eur. 2.6.14 with a limit established in the marketing authorisation. Aseptic filling is conducted in an ISO 14644-1 class 5 cleanroom under EU GMP Annex 1; lyophilisation typically proceeds from −40°C to +25°C shelf temperature at chamber pressure 10–30 Pa, with primary drying endpoint determined by product temperature and Pirani/capacitance manometer divergence. Terminal finished product types are 2 million IU powder for injection vials, 1 million IU vials for smaller species, and ready-to-use injectable solution where local stability permits, though published data for ready-to-use veterinary injectable colistin is limited.
| Dosage form | API monograph | Critical method designation | Downstream regulatory anchor |
|---|---|---|---|
| Dry premix/granule | Ph. Eur. 0321 | Ph. Eur. 2.2.32, Ph. Eur. 2.9.38, NIR blend uniformity | Regulation (EU) 2019/4, Regulation (EU) 2019/6 |
| Water-soluble powder/solution | Ph. Eur. 0321 | Ph. Eur. 2.2.3, Ph. Eur. 2.2.32, wetting time | Regulation (EU) 2019/6, WHO CIA |
| Tablets/capsules | Ph. Eur. 0321 | Ph. Eur. 2.9.1, Ph. Eur. 2.9.3, Ph. Eur. 2.9.8, Ph. Eur. 2.9.40 | 21 CFR Part 211 or Regulation (EU) 2019/6 |
| Powder for injection | Ph. Eur. 0320 | Ph. Eur. 2.6.1, Ph. Eur. 2.6.14 | EU GMP Annex 1, ISO 14644-1 |
Lambs and goat kids with coliform scours are dosed via oral solution containing colistin sulfate rather than colistimethate sodium, because the sulfate salt has appropriate stability in aqueous oral vehicles when pH is controlled. The formulation addition ratio is 10% w/v colistin sulfate, corresponding to approximately 1,900,000 IU/mL at a potency of 19,000 IU/mg; purified water, citric acid/sodium citrate buffer, and preservative are q.s. to final volume. Dissolution is performed at 20–25°C with a recirculating mixer; the solution is clarified through a 5 μm cartridge filter before filling into HDPE bottles with tamper-evident closures. pH is held between 4.5 and 6.0 per Ph. Eur. 2.2.3; assay follows Ph. Eur. 0321, and microbial quality is controlled by Ph. Eur. 2.6.12 for non-sterile products. Production experience shows that high-speed rotary filling lines generate foam when fill rate exceeds 120 bottles per minute, requiring deaeration or reduced line speed; foam residues can create cap-sealing defects and underweight fills. Terminal finished products are 100 mL, 250 mL, and 1 L oral drench solutions, with an optional 5% w/v low-concentration variant for automatic drench guns.
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Polymycin E (colistin) veterinary grade API is supplied as the sulfate salt of a fermentation-derived cyclic polypeptide antibiotic. The product designation covers oral and feed-based intermediates for tablets, capsules, powders, granules, premix, and solutions; the injectable route is addressed through the separately qualified methanesulfonate derivative, not through the sulfate salt. The active principal consists of a decapeptide ring with an N-terminal fatty acyl chain, dominated by colistin A (polymyxin E1) and colistin B (polymyxin E2). The sulfate is freely soluble in water and slightly soluble in ethanol, which establishes its utility in drinking-water medication, soluble powders, and aqueous granulation. The antibiotic binds the lipid A region of Gram-negative lipopolysaccharide and displaces magnesium and calcium from the outer membrane, producing permeability defects in susceptible Enterobacterales. It is not active against Gram-positive bacteria or anaerobic bacteria. The molecule differs from polymyxin B sulfate by the presence of D-Leu at position 6, whereas polymyxin B contains D-Phe; this single substitution changes reversed-phase HPLC retention and requires a separate identity method. The API is released as a white to almost white powder with microbiological potency determined by the cylinder-plate assay of Ph. Eur. 2.7.2 at not less than 19000 IU/mg on the dried basis.
Batch-to-batch variation in the relative proportions of colistin A and colistin B arises from fermentation conditions. Finished API lots are blended to reduce biological variance, and the component profile is monitored by liquid chromatography. Microbiological potency remains the compendial release criterion because the polymyxins are weakly chromophoric and multicomponent; HPLC area-percent is not a direct substitute for potency. The product is available in standard powder and micronized powder grades. The micronized grade is controlled by laser diffraction according to ISO 13320-1, while the standard grade is controlled by sieve analysis; particle-size limits are manufacturer-specific and are stated on the certificate of analysis.
Release specifications follow the current Ph. Eur. 0320 colistin sulfate monograph together with veterinary-specific controls for residual solvents, elemental impurities, and microbial enumeration. The certificate of analysis reports batch-specific values for water content, sulfated ash, related components, and potency. Residual solvent testing follows VICH GL18 and Ph. Eur. 5.4; because colistin sulfate is fermentation-derived, the solvent profile is normally limited to ethanol or acetone if crystallization aids are used. Elemental impurities are assessed under the risk-based approach of Ph. Eur. 5.20. Microbial limits follow Ph. Eur. 5.1.4 for non-sterile veterinary pharmaceutical substances, with acceptance criteria assigned by intended route and regional filing.
| Attribute | Test method / condition | Acceptance criterion |
|---|---|---|
| Potency | Ph. Eur. 2.7.2 cylinder-plate | ≥19000 IU/mg dried basis |
| Loss on drying | Ph. Eur. 2.2.32 | ≤3.5% |
| pH of a 20 g/L solution | Ph. Eur. 2.2.3 | 4.0–6.0 |
| Sulfated ash | Ph. Eur. 2.4.14 | ≤0.5% |
| Solubility | Compendial descriptive test | Freely soluble in water; slightly soluble in ethanol; practically insoluble in acetone |
Related components are determined by reversed-phase liquid chromatography with ultraviolet detection near 210 nm using a C18 column and an acidic mobile phase. The mobile-phase pH is held below 3.0 and the column temperature is controlled at 30 °C to sharpen peak shape. The sum of colistin A and colistin B peak areas is reported for batch consistency, but the microbiological assay remains the primary potency method. Where regional compendial limits differ, the tighter of the Ph. Eur. 0320 or current USP colistin sulfate monograph is applied.
Tablet and capsule manufacture with colistin sulfate requires control of blend moisture, particle-size distribution, and lubricant contact time. The API is hygroscopic; at relative humidity above 60%, water uptake reduces flow through a rotary tablet press and can cause picking or sticking. Pre-drying at 50 °C to a loss-on-drying value below 3.5% is applied before direct compression. Blending in a V-blender or bin blender with an intensifier bar is used because the material is fine and cohesive. Magnesium stearate is added at 0.5–1.0% w/w and blended for less than 5 min to avoid excessive shear; over-lubrication reduces tablet tensile strength and increases disintegration time. For capsule filling, dosator-type machines require higher fill consistency than tamping-pin machines when low-inclusion blends are used. If the colistin sulfate content exceeds 20% w/w, a pre-roller-compaction step may be required to improve flow and reduce segregation.
Wet granulation can be performed with aqueous binder systems, but the granulation end-point is controlled by loss-on-drying and the drying step is maintained below 60 °C to avoid peptide degradation. Fluid-bed dryers with inlet air at 50–60 °C are preferred over tray drying because the API can form hard aggregates during static drying. Calcium carbonate and other strongly alkaline excipients are evaluated for pH shift because colistin sulfate is most stable at pH 4.0–6.0; extended contact with strongly alkaline granulating fluids can hydrolyze the peptide ring. Because colistin is cationic, compatibility with anionic polysaccharides or high concentrations of anionic surfactants is checked by precipitation testing.
Long-term stability data are generated according to VICH GL3 at 25 °C/60% RH with accelerated storage at 40 °C/75% RH. The API is packaged in sealed aluminum-foil or aluminum-polyethylene laminate pouches with desiccant because moisture gain above 3.5% loss-on-drying can initiate hydrolysis and reduce microbiological potency. Multi-dose premix bags use resealable closures with desiccant; bulk containers are kept closed under nitrogen or dry air. In drinking-water systems, colistin sulfate solutions are most stable in the pH range 4.0–6.0; buffered systems with organic acidifiers are preferred over chlorinated hard water. Sunlight exposure promotes degradation, and opaque or amber dosing tanks are used for solutions stored longer than 24 h. Published data for longer solution-holding periods are formulation-dependent and must be verified by stability-indicating HPLC in the intended farm water quality.
The injectable presentation is not interchangeable with the sulfate. Colistimethate sodium is prepared by derivatization of colistin sulfate with formaldehyde and sodium bisulfite, reducing the number of free amino groups and lowering acute parenteral toxicity. The conversion of colistimethate sodium to active colistin after administration is slow, pH-dependent, and incomplete. The sulfate salt retains direct antibacterial activity and is therefore used orally or topically, where systemic absorption is minimal and local exposure in the intestinal lumen is desired. If a parenteral dosage form is required, the formulation specification identifies colistimethate sodium and its counterion ratio, not colistin sulfate. Dosed quantities cannot be expressed as direct IU equivalence because the conversion to active base is time-dependent and body-temperature dependent. Finished product release for injectable grades includes bacterial endotoxin testing by Ph. Eur. 2.6.14 and sterility testing by Ph. Eur. 2.6.1; these tests are not usually applied to oral premix powders.
Colistin sulfate is selected over polymyxin B sulfate where enteric Gram-negative infections are the target and where feed or water medication is authorized. The two antibiotics share the same lipopolysaccharide-binding mechanism and exhibit cross-resistance to a substantial degree, but they are not identical. Regulatory residue methods using LC-MS/MS distinguish colistin A and B from polymyxin B1 and B2 because of the position-6 substitution and different fatty acyl chain distributions. Colistin sulfate is used in oral group treatment because it is poorly absorbed from the gastrointestinal tract; polymyxin B sulfate is more frequently reserved for human parenteral or topical use. Colistin is classified as a highest-priority critically important antimicrobial for human medicine by the World Health Organization, and some jurisdictions restrict prophylactic or growth-promotion use. Formulators must verify current market authorization and maximum residue limits before use.
| Attribute | Colistin sulfate | Colistimethate sodium | Polymyxin B sulfate |
|---|---|---|---|
| Active form | Directly active cation | Prodrug requiring hydrolysis | Directly active cation |
| Position 6 residue | D-Leu | D-Leu after hydrolysis | D-Phe |
| Primary route | Oral/feed/water | Parenteral | Parenteral/topical |
| Water solubility | Freely soluble | Very soluble | Freely soluble |
| Systemic toxicity | Low oral absorption | Nephrotoxic/neurotoxic after parenteral use | Nephrotoxic/neurotoxic after parenteral use |
| Release potency frame | ≥19000 IU/mg dried basis as sulfate | Lower intrinsic activity per mg until conversion | Compendial potency as sulfate |
The substitution of colistin sulfate for polymyxin B sulfate in a premix line also changes dry-blend behavior. Colistin sulfate tends to be finer and more hygroscopic than some polymyxin B sulfate lots, so transfer lines should be inspected for electrostatic accumulation and wall fouling. In aqueous dilution systems, colistin sulfate solutions are more sensitive to alkaline pH than polymyxin B sulfate solutions; the same pH control range of 4.0–6.0 is applied, but the acidifier demand may differ because the buffer capacity of the two salts is not identical.
The micronized grade is produced by air-jet milling and is controlled by laser diffraction according to ISO 13320-1. A common release range is d90 ≤ 50 µm and d50 ≤ 20 µm, but these limits are manufacturer-specific and are confirmed on the certificate of analysis. In low-inclusion premixes containing 0.1–1.0% w/w colistin sulfate, fine particles improve distribution but increase dusting and electrostatic adhesion to stainless-steel mixer walls. Ribbon blenders with paddle speed below 25 rpm or double-cone blenders operated at 50–70% fill volume reduce segregation. If the premix is stored above 60% RH, micronized particles can form agglomerates that fail sieve analysis; in those cases, the carrier is dried to below 1.0% moisture before mixing. Dust extraction during blending is minimized because the fine fraction contains active colistin and excessive extraction can reduce blend potency below the target assay.
For granules and extruded pellets, the standard powder grade is preferred because the coarse particle size reduces dusting and improves flow into the granulator. The micronized grade is reserved for suspension concentrates, soluble powders, and low-dose direct compression where particle-size homogeneity is more important than dust control. In both grades, in-process controls include sieve analysis, loss-on-drying, and composite assay of blend samples taken from defined positions in the mixer. Failure modes observed on production-scale lines include over-lubricated blends with extended disintegration, moisture-induced picking on rotary tablet tooling, and segregation in transported premix containers; these are controlled by pre-drying, mixer fill discipline, and in-container sampling studies.
