| HS Code | 216893 |
| Chemical Name | (4S,4aR,5S,5aR,6S,12aS)-4-(Dimethylamino)-3,5,6,10,12,12a-hexahydroxy-6-methyl-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide |
| Molecular Formula | C22H24N2O9 |
| Molecular Weight | 460.43 g/mol |
| Cas Number | 79-57-2 |
| Appearance | Yellow to pale yellow crystalline powder |
| Solubility | Sparingly soluble in water; soluble in dilute acids and alkaline solutions; slightly soluble in ethanol |
| Melting Point | Approximately 183°C with decomposition |
| Assay | 98.0% to 102.0% on dried basis |
| Particle Size | D50 typically 20 to 60 micrometers for formulation use |
| Storage Conditions | Store in airtight containers, protected from light, in a cool, dry place |
As an accredited Oxytetracycline Base 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 | Oxytetracycline Base Pharma Grade API is packed in 25 kg drums with double polythene liners for oral and injectable formulations. |
| Container Loading (20′ FCL) | 20′ FCL loading of Oxytetracycline Base Pharma API: dry, clean container, secure palletized drums, protected from moisture and contamination. |
| Shipping | Oxytetracycline Base Pharma Grade API ships in sealed, moisture-proof drums or fiber containers, protected from light and heat. Shipments follow IATA/IMDG and local pharmaceutical regulations, with cold-chain options if required. Include SDS, COA, and export documentation. Ensure secure, traceable delivery for oral and injectable manufacturing use. |
| Storage | Store Oxytetracycline Base Pharma Grade API in a cool, dry, well-ventilated area at controlled room temperature, ideally below 25°C. Keep in tightly closed, light-resistant, original containers. Protect from moisture, excessive heat, and direct sunlight. Avoid contact with oxidizing agents. Use within manufacturer’s stated shelf life to maintain potency and suitability for oral and injectable formulations. |
| Shelf Life | Shelf life: 3 years when stored in a cool, dry place, protected from light, in tightly sealed original packaging. |
Oxytetracycline base enters tablet manufacturing with a bulk density commonly in the range of 0.30–0.45 g/mL and a needle-like crystal habit that lowers hopper flow and increases segregation risk during direct compression. A representative 250 mg strength film-coated tablet uses a core weight of 700.0 mg, placing active content at 35.7% w/w. The formulation avoids dicalcium phosphate dihydrate and calcium sulfate because tetracycline chelation with divalent cations can reduce oral bioavailability; the development formula contains lactose monohydrate at 40.0% w/w, microcrystalline cellulose at 20.0% w/w, crospovidone at 2.0% w/w, and magnesium stearate at 1.0% w/w. Production runs follow wet granulation rather than direct compression: the API is sieved through 600 µm mesh, dry-blended in a 300 L high-shear granulator at 120 rpm impeller speed, then granulated with purified water added at 2.0–2.5 kg/min until impeller power draw reaches 8–10 kW. Wet mass is dried in a fluid-bed dryer with inlet air at 50 °C to a loss-on-drying endpoint of 1.5–2.0% w/w; residual moisture above 2.5% w/w during compression increases punch-face sticking on rotary presses, while moisture below 1.0% w/w raises friability and edge capping. Granules are lubricated for 5 min and compressed on a 27-station rotary tablet press at 12–16 kN compression force and 45,000 tablets/h; target hardness is 80–120 N and friability is kept below 1.0% per USP <1216>. Dissolution is tested under USP <711> using Apparatus 2 at 50 rpm in 900 mL of 0.1 N hydrochloric acid at 37 ± 0.5 °C. Content uniformity follows USP <905>, elemental impurity release is conducted per ICH Q3D, and in-process controls are maintained under 21 CFR 211.110. The resulting film-coated immediate-release tablet is released for oral antibacterial therapy.
Inside hard gelatin capsule filling suites, the limiting variable is not dissolution but powder flow into the dosator bowl, because oxytetracycline base with a D90 above 200 µm can force equipment operators to reduce dosator speed below 60 capsules/min. A representative 250 mg strength capsule uses a 500.0 mg fill weight with API at 50.0% w/w; pregelatinized starch at 43.0% w/w and lactose monohydrate at 5.0% w/w are dry-blended with colloidal silicon dioxide at 0.5% w/w and sodium stearyl fumarate at 1.5% w/w as lubricant. Magnesium stearate is limited to 0.5% w/w or excluded when fill remains in the hopper longer than 30 min, because its hydrophobic film on API crystals can delay capsule shell disintegration. Compliance is defined by the USP Oxytetracycline Capsules monograph, USP <905> content uniformity, USP <711> dissolution in 0.1 N hydrochloric acid, ICH Q3D elemental impurity verification, and release testing under 21 CFR 211.165 with assay, related substances, water content by USP <921> Karl Fischer, and microbial limits per USP <61> and USP <62>. The downstream production process runs on an intermittent-motion dosator encapsulation machine at 35–42% RH and 18–22 °C; humidity below 30% RH increases electrostatic adhesion to the hopper surface, while humidity above 55% RH softens gelatin shells and increases deformation during closure. Blend uniformity is verified after 15 min of bin blending at 12 rpm, capsule lock length is monitored at 1.8–2.2 mm, and in-process weight checks reject capsules outside ±3.0% of target fill. Final capsule product is released as a 250 mg hard gelatin capsule for oral administration.
This failure mode appears when sachet filling is validated by average fill weight alone, because a suspension vehicle containing xanthan gum at 0.2% w/w can resuspend poorly distributed granules after shaking and mask segregation that occurred during vertical form-fill-seal packaging. The terminal unit is a single-dose sachet of granules for oral suspension, reconstituted with water to deliver 250 mg oxytetracycline base per 5 mL. Dry granule fill weight is set at 6.0 g, giving API content of 4.17% w/w; the remaining mass includes sucrose at 80.0% w/w, mannitol at 10.0% w/w, povidone K30 at 2.5% w/w, xanthan gum at 0.4% w/w, and sodium benzoate at 0.1% w/w. Published data for this exact suspending vehicle formulation is limited, so viscosity specifications are established during scale-up rather than transferred from compendial text. Production in a fluid-bed top-spray granulator requires inlet air at 45–50 °C, spray rate 60–80 g/min, and atomizing air pressure 1.5–2.0 bar; granules are dried to moisture 1.0–1.8% w/w and sieved through 1.0 mm and 250 µm screens to remove both lumps and fines. Bulk density is maintained at 0.55–0.65 g/mL, with tapped density not more than 1.25× bulk density, to prevent density-driven stratification during hopper discharge. Sachet filling on a vertical form-fill-seal line operates at 30 cycles/min with auger dosing; qualification is by individual weight variation because static charge on dried sugar granules can shift delivered mass by up to 3.0% when ambient humidity falls below 30% RH. Compliance standards include USP <905> uniformity of dosage units by weight variation, USP <711> dissolution after reconstitution in 900 mL of 0.1 N hydrochloric acid, USP <921> for water content, non-sterile oral microbial limits per USP <61> and USP <62>, and 21 CFR 211.110 in-process control requirements. At release, the product is a single-dose granulate sachet for reconstitutable oral suspension.
Sterile injectable suspensions of oxytetracycline base are manufactured under conditions where terminal moist-heat sterilisation at 121 °C for 15 min is generally unsuitable because the thermal cycle accelerates crystal growth and produces a sediment that cannot be redispersed by hand shaking; the process therefore uses aseptic milling and aseptic filling after pre-sterilisation of the vehicle. For a long-acting 200 mg/mL intramuscular suspension, the API is incorporated at 20.0% w/v; a development vehicle includes medium-chain triglycerides or fractionated coconut oil with aluminium monostearate at 2.0% w/v as viscosity modifier, but published data for this specific configuration is limited and the exact excipient ratio is adjusted against sedimentation volume. Compliance is anchored to USP <71> sterility, USP <85> bacterial endotoxin, USP <429> laser diffraction particle size analysis, USP <790> visible particulates, and EU GMP Annex 1 aseptic processing requirements. The API is first passed through a dry jet mill to break needle-like crystals, then wet-milled in a closed rotor-stator mill at 10,000 rpm with a 0.3 mm gap until the suspension reaches D90 <20 µm and D50 <5 µm; milling temperature is held below 25 °C by jacketed cooling because oxytetracycline base degrades more rapidly in heated aqueous-organic mixtures. The milled suspension is filled into depyrogenated Type I glass vials at 8–12 °C under unidirectional airflow, stoppered with silicone-coated bromobutyl closures, and subjected to 100% visual inspection according to USP <790>. In-process controls under 21 CFR 211.110 include particle size distribution, bulk viscosity, and sedimentation volume ratio; a sedimentation volume below 0.90 after 24 h indicates inappropriate flocculation and requires reformulation. Sterility testing per USP <71> uses membrane filtration with 14 days incubation, and bacteriostasis/fungistasis validation is performed before release. The filled aseptic vial is labelled as a sterile injectable suspension for intramuscular use in food-producing animals under veterinary prescription.
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Oxytetracycline base is supplied as a fermentation-derived, amphoteric tetracycline antibiotic API with CAS registry number 79-57-2, molecular weight 460.43 g/mol, and molecular formula C22H24N2O9. The product is standardized as a pharma grade active ingredient for tablet, capsule, granule, oral suspension, and injectable formulation development, with the base form specifically requiring particle engineering, granulation, salt conversion, or non-aqueous suspension technology to compensate for its practically insoluble aqueous solubility. The material is controlled against the European Pharmacopoeia monograph for oxytetracycline dihydrate and the corresponding USP monograph. In comparison with oxytetracycline hydrochloride, tetracycline hydrochloride, and doxycycline hyclate, the base differs in salt composition, aqueous solubility, dissolution strategy, and parenteral handling requirements.
Lot release testing includes HPLC assay by Ph. Eur. 2.2.29 with an acceptance interval of 95.0–102.0% on the dried basis. Specific optical rotation is measured as −203° to −217°, determined at 25 °C in a 1% solution in 0.1 M hydrochloric acid. The pH of a 1% suspension is controlled between 3.5 and 6.0. Water content by Karl Fischer titration is typically 6.0–9.0%, consistent with the dihydrate form. Sulfated ash is limited to ≤0.1%, and heavy metals are controlled to ≤50 ppm. Residual solvents are controlled under Ph. Eur. 5.4 and ICH Q3C, with Class 3 solvents generally held at not more than 0.5% unless otherwise justified. Elemental impurities are controlled under ICH Q3D using product-specific permitted daily exposure values and routine ICP-MS release testing.
| Release attribute | Analytical method / standard reference | Acceptance criterion |
|---|---|---|
| Appearance | Ph. Eur. 2.2.1 / visual examination | Yellow crystalline powder |
| Identification A | Ph. Eur. 2.2.24 infrared absorption | Spectrum matches reference standard |
| Assay on dried basis | Ph. Eur. 2.2.29 liquid chromatography | 95.0–102.0% |
| pH of 1% suspension | Ph. Eur. 2.2.3 | 3.5–6.0 |
| Specific optical rotation | Ph. Eur. 2.2.7 | −203° to −217° on dried basis |
| Water | Ph. Eur. 2.5.12 Karl Fischer | 6.0–9.0% |
| Related substances | Ph. Eur. 2.2.29 | Tetracycline ≤ 1.0%; total impurities ≤ 2.0% |
| Sulfated ash | Ph. Eur. 2.4.14 | ≤ 0.1% |
| Heavy metals | Ph. Eur. 2.4.8 | ≤ 50 ppm |
| Microbial enumeration, non-sterile API | Ph. Eur. 2.6.12 / 2.6.13 | TAMC ≤ 103 CFU/g; TYMC ≤ 102 CFU/g; absence of Escherichia coli and Salmonella |
| Bacterial endotoxins | Ph. Eur. 2.6.14 / USP <85> | Assigned by parenteral dose; commonly controlled to <0.5 EU/mg where required |
The base differs from oxytetracycline hydrochloride primarily in aqueous solubility: the base is classified as practically insoluble in water, whereas the hydrochloride salt is freely soluble. This distinction determines formulation route. For immediate-release tablets and capsules, the base is usually dry-granulated or roller-compacted before compression because direct compression is limited by poor flow and low bulk density. Oxytetracycline hydrochloride can be wet-granulated or dissolved more readily, but it contributes an acidic solution pH and may be more hygroscopic. Doxycycline hyclate is a related tetracycline with greater lipophilicity and a longer serum half-life; its dosing frequency is lower, and its tissue distribution profile differs from oxytetracycline. In oral solid dosage forms, oxytetracycline base requires dissolution-rate control through particle-size reduction, disintegrant selection, and filler compatibility.
The amphoteric behavior of oxytetracycline base is governed by reported pKa values of 3.3, 7.3, and 9.1. At pH values between 3 and 6, the zwitterionic form dominates and aqueous solubility remains low. This pH-solubility relationship makes dissolution testing in 0.1 M hydrochloric acid critical for finished product performance, because the API dissolves more readily under acidic gastric conditions but still requires adequate particle wetting and dispersion.
| Attribute | Oxytetracycline base | Oxytetracycline hydrochloride | Doxycycline hyclate |
|---|---|---|---|
| CAS registry | 79-57-2 | 2058-46-0 | 24390-14-5 |
| Molecular weight | 460.43 g/mol | 496.90 g/mol | 512.94 g/mol |
| Aqueous solubility compendial term | Practically insoluble | Freely soluble | Freely soluble |
| Oral solid dosage route | Tablet, capsule, granule after dry granulation | Tablet, capsule, powder for solution | Tablet, capsule, oral suspension |
| Parenteral feasibility | Requires salt conversion or non-aqueous suspension | Aqueous solution after pH adjustment | Aqueous solution after pH adjustment |
| Pharmacokinetic class | Short-acting | Short-acting | Long-acting |
| Key stability constraint | pH 4–5; hygroscopic dihydrate; light-sensitive | Acidic solution; hygroscopic | pH 4–5; light-sensitive |
Oxytetracycline base as received from fermentation and crystallization is typically cohesive and poorly flowable. For tablet and capsule operations, roller compaction is preferred over direct compression. Production-scale roller compaction of high-dose, poorly flowing APIs commonly operates at roll pressures of 4–6 MPa and screen apertures of 1.0–1.5 mm; published data specific to oxytetracycline base in this configuration is limited, and equipment settings are adjusted against ribbon density and granule particle-size distribution. The resulting granules are blended with microcrystalline cellulose, croscarmellose sodium at 2–4%, and magnesium stearate at 0.5–1.0%. Excess lubricant above 1.0% can prolong disintegration and reduce tablet hardness under compression forces above 12 kN.
Wet granulation is not the primary route for the base unless rapid drying below 45 °C is applied, because exposure to aqueous granulating fluid at pH values outside 4–5 promotes hydrolysis and epimerization. If wet granulation is unavoidable, a non-aqueous granulating liquid such as isopropanol containing 5–10% polyvinylpyrrolidone can be used, with vacuum drying below 45 °C to limit degradation. In capsules, granulated material with a maximum sieve fraction above 1.0 mm is avoided to maintain die-fill consistency on tamping or dosator machines. For dry granule and oral suspension presentations, the API particle-size distribution is typically controlled at D90 below 150 µm to support dispersion and content uniformity; micronization or jet milling may be used for dissolution enhancement, but static charge and agglomeration require controlled humidity below 60% RH.
Finished product dissolution is usually performed with USP Apparatus 2 at 75 rpm in 900 mL of 0.1 M hydrochloric acid; acceptance criteria follow the applicable product monograph. A typical design space for similar high-dose, poorly compressible APIs uses compression forces below 12 kN and granule moisture below 2.5%; published data specific to oxytetracycline base in this configuration is limited.
Because the base is practically insoluble in water, no direct aqueous solution for injection can be prepared from this material without salt formation. Injectable formulations are therefore developed either as sterile non-aqueous suspensions of micronized base or as solutions of the hydrochloride salt after in situ or upstream conversion. For suspension presentations, particle-size control is critical: D90 below 20 µm and D10 above 1 µm support syringability, resuspendability, and avoidance of needle occlusion, while the final suspension is preserved or terminally sterilized only if the degradation profile permits.
For soluble injectable presentations, the hydrochloride salt is commonly used because it is freely soluble in water; the resulting solution pH is acidic, typically below 3, and requires buffering and tonicity adjustment before sterile filtration. Oxytetracycline is heat-labile in aqueous solution, so terminal steam sterilization at 121 °C may produce epimers and anhydro degradation products. Aseptic filtration through a 0.22 µm PVDF or PES membrane is preferred for soluble products, with pre-filtration through a 0.45 µm membrane to reduce membrane loading. For suspension products, dry heat or radiation sterilization of the API may be required if terminal sterilization is not feasible; the selection is defined by the marketing authorization and Ph. Eur. 5.1.1 sterility assurance requirements.
Endotoxin control follows Ph. Eur. 2.6.14 or USP <85>. The limit is calculated from the maximum adult dose; parenteral APIs commonly require an endotoxin limit of 0.5 EU/mg or lower when the maximum single dose exceeds 100 mg, but the final limit is product-specific. If the base is used in an injectable suspension, chelation with divalent and trivalent cations in buffers or stopper leachables must also be controlled, because tetracycline-metal complexes can reduce antimicrobial activity and form particulate matter.
Oxytetracycline base is most stable in the pH range 4–5. At pH values above 6, epimerization and degradation to anhydrotetracycline and related substances accelerate; below 2, acid-catalyzed dehydration becomes significant. The dihydrate form is hygroscopic, and exposure to relative humidity greater than 60% shifts the water content outside specification and promotes hydrolysis. Storage in tight containers with desiccant at controlled room temperature 15–25 °C is therefore standard. Photodegradation is also significant; the API is protected from direct light and packaged in light-resistant containers for bulk transport.
In aqueous suspension or solution, degradation is pH-dependent and temperature-dependent. Refrigerated storage at 2–8 °C reduces degradation, but freeze-thaw cycling can cause crystal growth and particle aggregation in suspension formulations. Prolonged contact with strong oxidizing agents and strong bases is avoided. Tetracyclines form chelates with calcium, magnesium, aluminum, and iron; oral formulations should avoid soluble salts of these metals, and injectable formulations should avoid contact with metal needles, transfer lines, and stoppers that leach metal ions unless compatibility data support the configuration.
The base form is supplied as a single active entity; it is not a simple dilution of the hydrochloride and does not contain sodium or hydrochloride counterions. This distinction is relevant when calculating dosage strength on an anhydrous base basis and when comparing bioequivalence or salt factor to other tetracycline products. For oral granules and suspensions, the base is typically incorporated by dry blending with non-hygroscopic diluents and suspending agents, with reconstitution supported by dispersing agents and acid pH adjustment to 4–5 at the time of administration.
