| HS Code | 719218 |
| Chemical Name | Tetracycline hydrochloride |
| Molecular Formula | C22H24N2O8·HCl |
| Molecular Weight | 480.90 g/mol |
| Cas Number | 64-75-5 |
| Appearance | Yellow crystalline powder |
| Solubility | Freely soluble in water; sparingly soluble in ethanol; practically insoluble in ether |
| Melting Point | 214°C with decomposition |
| Assay | 97.0% to 102.0% on dried basis |
| Ph | 2.0 to 3.0 for a 1% w/v aqueous solution |
| Related Substances | Meets Ph.Eur./USP requirements |
| Storage | Keep in well-closed containers, protected from light and moisture |
| Intended Use | Suitable for oral and injectable pharmaceutical formulations |
As an accredited Tetracyline hydrochloride Pharma Grade API for Tablet / Capsule / Granule / Injection, Oral & Injectable factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | Packaged in sealed double polyethylene bags inside fiber drums, net weight 25 kg per drum, for safe oral and injectable pharmaceutical use. |
| Container Loading (20′ FCL) | 20′ FCL: Tetracycline hydrochloride Pharma Grade API in sealed drums, palletized, moisture-protected, with proper segregation and ventilation for safe transport. |
| Shipping | Tetracycline Hydrochloride Pharma Grade API is shipped in sealed, moisture-proof, light-resistant drums or bags to preserve stability. Transport complies with international pharmaceutical regulations, with full documentation including COA and MSDS. Store in a cool, dry area during transit and delivery to maintain quality for oral and injectable formulations. |
| Storage | Store Tetracycline Hydrochloride Pharma Grade API in a cool, dry, well-ventilated area in tightly closed, light-resistant containers. Protect from moisture, direct sunlight, and excessive heat. Maintain storage temperature between 15–30°C, avoiding humidity. Ensure segregation from incompatible substances and maintain strict cleanliness to preserve stability, potency, and suitability for oral and injectable formulations. |
| Shelf Life | Shelf life is typically 3 years when stored in a cool, dry place, protected from light, in tightly sealed containers. |
Direct compression of pharma-grade tetracycline hydrochloride API into immediate-release tablets is governed by the molecule’s needle-like crystal habit, moisture sensitivity, and pH-dependent hydration and epimerization behaviour. Wet granulation with an aqueous binder is avoided in high-volume tablet manufacture because the drying phase must remain below 45°C to limit 4-epitetracycline formation; even an equilibrium moisture content above 2.0% w/w accelerates degradation during subsequent storage. Production batches are therefore dry-mixed in a V-blender or bin blender equipped with an intensifier bar, and compressed on a rotary tablet press fitted with D-tooling and a precompression station. The lubricant is magnesium stearate at 0.5–1.0% w/w; higher levels delay dissolution because the hydrophobic film on the needle-like particles resists wetting in 0.1 N hydrochloric acid. Dicalcium phosphate dihydrate, magnesium aluminium silicate, and iron oxides are disqualified as excipients because tetracycline forms poorly absorbable chelates with Ca²⁺, Mg²⁺, Al³⁺, and Fe²⁺. Disintegration is controlled according to USP <701> with water at 37 ± 2°C; a target disintegration time below 15 min is used during process qualification, while dissolution is profiled under USP <711> Apparatus II at 75 rpm in 900 mL of 0.1 N hydrochloric acid, with acceptance criteria fixed in the approved product-specific monograph. The compression suite is held at 20–25°C and 35–45% RH. A precompression force of 2–4 kN and main compression force of 8–14 kN are typical screening ranges for a 500 mg core tablet; capping at higher forces is routine when fines generated by the intensifier bar exceed 15% w/w below 75 μm. Film coating uses an aqueous hydroxypropyl methylcellulose system at a pan bed temperature of 38–42°C; organic-coating is reserved for subcoats that block moisture migration. Published production-scale data for long-run tableting of tetracycline HCl at residual moisture above 2.0% is limited, so each campaign is bracketed by high-humidity hold-time studies.
Hard gelatin capsule filling for tetracycline HCl is performed in a dry-granulation workstream because the low bulk density and acicular particle shape of the API create severe die-fill weight variation when direct compression is transferred to a capsule filler. A high-dose 250 mg or 500 mg capsule formulation cannot reliably flow through dosator nozzles unless the blend has been densified by roller compaction at a roll pressure of 20–50 bar and a gap setting of 1.0–2.0 mm, followed by oscillating granulation at 60–80 rpm. The resulting granules are sieved through a 1000 µm screen, fines are limited to 30–40% w/w below 150 µm, and particle size distribution is verified by USP <429> laser diffraction. Empty hard gelatin capsules are conditioned to moisture content 13–16% w/w before filling; if shell moisture falls below 12%, embrittlement and splitting occur on tamping pin machines. The filling suite is therefore controlled at 20–25°C and 35–45% RH, with open-hopper residence time held below 2 h. A tamping pin machine with pin depth set to produce plug density 0.7–0.8 g/mL is preferred over a dosator system because the densified granules have residual fines that segregate under low-frequency vibration. The lubricant level of magnesium stearate is not to exceed 1.0% w/w; replacement with sodium stearyl fumarate at 1.0–1.5% w/w reduces dissolution retardation in hard-water regions but requires compatibility testing because the higher pH microclimate can accelerate epimerization. Content uniformity is checked in accordance with USP <905>, using acceptance value ≤15.0 for 10 units at the beginning, middle, and end of each filling campaign. Disintegration and dissolution are tested on the filled capsule by USP <701> and USP <711>; because capsule shells can delay rupture at low pH, a dissolution medium of 900 mL of 0.1 N HCl with sinker is used. Published data for tetracycline HCl capsule formulations with calcium carbonate antacid excipients is limited, and those combinations are excluded because chelation reduces oral absorption; aluminium lake colourants in the capsule shell are also avoided.
Dry granules for reconstitution into an oral suspension are formulated with an acidulant buffer because tetracycline HCl is most stable as an ionized hydrochloride in an acidic aqueous vehicle and because neutral or alkaline pH accelerates epimerization. The granule is typically built by non-aqueous wet granulation using anhydrous ethanol or isopropyl alcohol as the granulating fluid; water is avoided because it initiates the epimerization reaction during the drying step. Citric acid anhydrous is used as the acidulant and sodium citrate dihydrate as the buffering salt, adjusted to give a reconstituted pH of 2.5–3.5; below 2.0, acid-catalyzed formation of anhydrotetracycline increases, and above 4.0, the equilibrium shifts toward 4-epitetracycline. The suspending system consists of microcrystalline cellulose and carboxymethylcellulose sodium at a combined level of 0.5–1.0% w/w, with xanthan gum at 0.2–0.4% w/w for yield stress and redispersibility. Sucrose or sorbitol is included as the sweetener, and a hydrophobic colloidal silica is added at 0.25% w/w to prevent capillary bridging during storage in high-density polyethylene bottles with aluminium induction seals. The reconstituted suspension is a flocculated system; after shaking, the drug content must be uniformly distributed according to a shake-well label instruction, and viscosity measured by a rotational viscometer is generally targeted between 150 mPa·s and 450 mPa·s at 25°C using a spindle speed of 30 rpm. The fill weight is controlled gravimetrically, and sifter retention on a 710 µm screen is limited to 10% to avoid dose dumping from large granules. Because reconstituted tetracycline HCl suspensions are thermodynamically unstable, the facility must generate real-time and accelerated stability data to fix the discard period; published data for this specific buffered suspension is limited, but the general compendial expectation is that reconstituted aqueous preparations stored at 25°C degrade faster than refrigerated preparations. The label must therefore restrict storage to 2–8°C and require shaking before each dose. The product is tested by USP <791> for pH, USP <905> for content uniformity, and USP <711> for dissolution; dissolution of suspension granules is ordinarily performed with the dry granule filled into a capsule or dispersed directly in 900 mL of 0.1 N HCl with paddle speed 75 rpm.
| Dosage form | Critical attribute | Method / standard | Operational boundary |
|---|---|---|---|
| Immediate-release tablet | Blend loss on drying | USP <731> | ≤2.0% w/w |
| Hard gelatin capsule | Content uniformity | USP <905> | AV ≤15.0 |
| Oral suspension granules | Reconstituted pH | USP <791> | 2.5–3.5 |
| Injectable lyophilized powder | Bacterial endotoxin | USP <85> | Calculated from 5 EU/kg dose |
| Injectable lyophilized powder | Sterility | USP <71> | Membrane filtration |
Injectable tetracycline HCl is manufactured as a sterile lyophilized plug because liquid terminal sterilization degrades the molecule and produces epimerized or oxidized impurities. The bulk solution is prepared with Water for Injection, the API is dissolved under aseptic conditions, and the pH is adjusted with dilute hydrochloric acid or sodium hydroxide to 2.0–3.0, measured by USP <791>. The solution is filtered through a 0.22 µm sterilizing-grade membrane, aseptically filled into depyrogenated vials, and loaded into a lyophilizer. Freeze-dry microscopy is used to set the collapse temperature; published data for tetracycline HCl in the presence of varying amounts of antioxidant and bulking agent is limited, so the cycle must be designed from product-specific freeze-dry microscopy and not from the API’s eutectic point alone. A typical screening cycle freezes the product to −40°C for 2–4 h, anneals at −10°C for 1–2 h, and conducts primary drying at a shelf temperature of −20°C and a chamber pressure of 100 mTorr, with secondary drying at 25°C until residual moisture is below 1.0%. These parameters are not universal; the acceptable operating window can be as narrow as ±5°C for formulations with low glass transition temperature. Antimicrobial preservatives are generally omitted, so reconstitution must be performed immediately before use with Sterile Water for Injection or 5% Dextrose Injection. Lactated Ringer’s, Hartmann’s solution, and other calcium- or magnesium-containing diluents are incompatible because the API chelates divalent cations, forming cloudy solutions and reducing the effective drug concentration. The lyophilized cake is tested for sterility by USP <71>, for bacterial endotoxins by USP <85>, and for particulate matter by USP <788>. The reconstituted solution is inspected visually; any cake meltback, shrinkage, or discoloration from the expected yellow to light yellow indicates product failure. Stability of the unpreserved reconstituted solution is limited, and the administration label must specify the exact hold time derived from validated stability data.
After reconstitution, the tetracycline HCl solution is further diluted for slow intravenous infusion in 5% Dextrose Injection or 0.9% Sodium Chloride Injection; the admixture is prepared in an ISO Class 5 laminar flow hood to maintain sterility and avoid moist air exposure. The target concentration during infusion is generally kept below 2 mg/mL to reduce the risk of thrombophlebitis and to maintain a solution pH above 2.0 after buffering by the diluent; however, the approved concentration is product-specific and must be confirmed by in-use stability data. The final admixture is not autoclaved and must not be mixed with calcium-containing parenteral nutrition, amphotericin B, heparin, or aminophylline unless compatibility data has been generated for the exact concentration, diluent, temperature, and contact time. An in-line 0.22 µm filter is used for final filtration into the patient line; if the solution is held, the manufacturer’s finished-product stability protocol should include chemical assays for 4-epitetracycline, anhydrotetracycline, and total oxidation products by the validated HPLC method. The selection of container closure is controlled by USP <661.1> and USP <661.2>; polyvinyl chloride bags with di(2-ethylhexyl) phthalate are not used for prolonged storage unless the contact time is below the qualified limit. Published data for extended storage of tetracycline HCl admixtures in PVC bags at 25°C is limited; therefore, short hold times and refrigerated storage are used as conservative operational boundaries. The dose is administered slowly, typically over 1–4 h, and the line is flushed with compatible diluent before and after infusion to avoid contact between residual drug and incompatible anions or cations.
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Tetracycline hydrochloride pharma-grade API for tablet, capsule, granule, and injectable manufacturing is a crystalline antibiotic salt with a defined route-specific grade designation. The salt is identified by CAS registry number 64-75-5, molecular formula C22H24N2O8·HCl, and molar mass 480.90 g/mol. The material appears as a yellow crystalline powder and is a broad-spectrum bacteriostatic antibiotic; protein synthesis inhibition occurs through reversible binding to the 30S ribosomal subunit. The product is not a finished dosage form. Oral-grade material is released with residual solvent profiling according to USP <467> or Ph. Eur. 2.4.24, elemental impurity control according to ICH Q3D, and microbiological quality according to Ph. Eur. 5.1.4 or USP <1111>. Injectable-grade material adds bacterial endotoxin testing according to Ph. Eur. 2.6.14 or USP <85> and sub-visible particulate control at the finished-product stage according to USP <788> or Ph. Eur. 2.9.19. Batch manufacture is conducted under a pharmaceutical quality system aligned with ICH Q7 and 21 CFR 210/211.
The release specification for tetracycline hydrochloride is structured around identity, assay, related substances, physicochemical tests, and route-specific safety tests. Representative pharmacopoeial acceptance criteria include pH of a 1% aqueous solution in the range 1.8–2.8, loss on drying not more than 2.0%, specific optical rotation between −240° and −255° on the dried substance, and HPLC assay of 95.0–102.0% on the dried basis. The critical degradation-related impurity 4-epianhydrotetracycline is controlled at ≤0.5%; anhydrotetracycline is commonly controlled at ≤0.5%, with total related substances at ≤2.0%. The assigned methods are Ph. Eur. 2.2.3 or USP <791> for pH, Ph. Eur. 2.2.32 for loss on drying, Ph. Eur. 2.2.7 for optical rotation, and Ph. Eur. 2.2.29 for liquid chromatography. The final acceptance profile depends on the dosage form: tablets and capsules apply the oral monograph, while injectable-grade material requires a bacterial endotoxin limit justified from the maximum intended dose per kilogram of body weight.
| Parameter | Acceptance criterion | Method standard |
|---|---|---|
| Appearance | Yellow crystalline powder | Visual inspection against reference |
| Identification | Infrared spectrum match; chromatographic retention | Ph. Eur. 2.2.24; USP <197> |
| pH of 1% solution | 1.8–2.8 | Ph. Eur. 2.2.3; USP <791> |
| Loss on drying | ≤2.0% | Ph. Eur. 2.2.32 |
| Specific optical rotation | −240° to −255° on dried substance | Ph. Eur. 2.2.7 |
| Assay | 95.0–102.0% on dried basis | HPLC per Ph. Eur. 2.2.29 |
| Related substances | 4-epianhydrotetracycline ≤0.5%; total ≤2.0% | HPLC |
Quality-control laboratories use HPLC with UV detection for assay and related substances. System suitability requires resolution between tetracycline, 4-epianhydrotetracycline, and anhydrotetracycline with a minimum resolution of 2.0. The method is validated for specificity, linearity, precision, and accuracy according to ICH Q2(R1). The tablet and capsule grade is typically supplied in double polyethylene-lined fiber drums, while injection-grade material may be packed in aluminium-foil laminate bags with desiccant. The certificate of analysis is route-specific; an oral-grade lot cannot be used for parenteral manufacture unless it is re-evaluated for bacterial endotoxins, particulate matter, and sterility-assuring attributes. Because the salt form is moisture-sensitive, the container closure system is selected to maintain moisture below the value observed in stability studies; the pharmacopoeial monograph requires storage in an airtight container, protected from light.
During tablet and capsule manufacture, the high aqueous solubility of the hydrochloride salt creates a specific processing condition. If water or an aqueous binder solution is used in high-shear or fluid-bed granulation, the dissolved drug may recrystallize during drying and change particle-size distribution, granule strength, and dissolution rate. Granule growth is controlled by impeller torque or power-consumption endpoints and by binder addition rate, not solely by visual inspection. The wet mass is milled through a screen size appropriate to the formulation, and drying is conducted in a fluid-bed dryer with inlet air temperature controlled as low as practical; temperatures above 60°C are generally avoided for extended periods because degradation accelerates. Direct compression is used only when the API lot has acceptable flow, measured by compendial powder flow methods such as USP <1174>, and acceptable compressibility, measured by tablet tensile strength and friability according to USP <1216>. Batch records for tablet and capsule production also include bulk density, tapped density, and Hausner ratio; a Hausner ratio above 1.35 indicates poor flow and requires reformulation or a glidant such as colloidal silicon dioxide at 0.5–2.0% w/w. Dicalcium phosphate dihydrate, magnesium trisilicate, calcium carbonate, magnesium stearate, and iron-containing colorants are known incompatibilities: divalent and trivalent cations form poorly absorbed chelates with the tetracycline nucleus. If a lubricant is required, magnesium stearate is used at the lowest effective concentration, commonly 0.5–1.5% w/w, because excessive hydrophobic lubricant can delay dissolution. Final blend uniformity is tested according to USP <905> or Ph. Eur. 2.9.40. Dissolution testing for immediate-release tablets and capsules is conducted in 0.1 N HCl or a discriminating medium according to USP <711> or Ph. Eur. 2.9.3; because the salt dissolves rapidly at gastric pH, the method must still separate particle-size or overgranulation changes rather than only detecting total failure.
Granule production for sachets and dry suspensions includes particle-size control by sieve analysis according to USP <786> or Ph. Eur. 2.9.38, and loss-on-drying after fluid-bed drying is held below the monograph limit. The granules are packaged in light-resistant material because tetracycline hydrochloride darkens upon exposure to light; the monograph storage instruction requires an airtight container, protected from light. Film-coated tablets introduce an additional aqueous step: the coating dispersion can wet the core surface and mobilize the drug at the interface. In film coating, the pan exhaust air temperature is typically maintained below 60°C, and the coating system should be free of ferric oxide pigments in direct contact with the API layer or should include a polymer barrier between any iron oxide and the drug. Sugar coating is generally unnecessary and increases the risk of moisture-promoted degradation; if used, the seal coat must be tested for water vapor transmission rate and adhesion. Any addition of sweetened or flavored excipients for pediatric granules must be checked for reactive aldehydes or metal impurities, because the tetracycline nucleus is sensitive to oxidation and metal-catalyzed degradation.
The hydrochloride salt shows faster initial dissolution than the free base in acidic media because the protonated form increases local solubility. In immediate-release tablets and capsules, this can make dissolution less likely to be the sole rate-limiting step, but it does not eliminate dissolution as a critical quality attribute. Chemical stability is narrowest in solution: degradation proceeds via pH- and temperature-dependent epimerization and dehydration to 4-epianhydrotetracycline, anhydrotetracycline, and related derivatives. The pharmacopoeial limit on 4-epianhydrotetracycline is ≤0.5% because this degradation product is considered toxicologically significant. The pH of maximum aqueous stability is acidic; the monograph’s low solution pH therefore serves as both a salt characteristic and a stability indicator. In the solid state, the hydrochloride salt is more stable at controlled room temperature, but it remains sensitive to light and moisture. Preformulation studies should include dynamic vapor sorption and powder X-ray diffraction to detect hydrate formation at relative humidity above 60%. Published data for this specific configuration is limited, but non-barrier packaging under warm humid conditions can produce moisture uptake, darkening, and related substance growth. Antioxidants and chelating agents may be included in the finished dosage form only after compatibility studies, because unnecessary metal chelators can alter dissolution or bioavailability of the drug.
Injectable-grade tetracycline hydrochloride is not simply a sterile powder fill of oral-grade API. The API used for parenteral manufacture must meet a bacterial endotoxin limit justified from the maximum intended dose per kilogram of body weight, tested by Ph. Eur. 2.6.14 or USP <85>. Endotoxin control is achieved through supplier process control and validated cleaning of the sterile manufacturing train rather than by dry-heat depyrogenation of the API, which is unsuitable because the molecule is thermolabile. The reconstituted solution has an acidic pH and can cause venous irritation; injection solutions are therefore diluted into sodium chloride 0.9% or dextrose 5% and administered as a slow infusion where the summary of product characteristics allows. Calcium-containing diluents such as Ringer’s lactate are incompatible because calcium ions chelate the tetracycline nucleus and may form a precipitate. Sub-visible particulate matter in the finished injection is controlled by light obscuration particle count according to USP <788> or Ph. Eur. 2.9.19; the actual limit depends on whether the product is a small-volume or large-volume injection. Filter compatibility and extractables are evaluated with the acidic drug solution, and the filling line is qualified for absence of metal ion contamination from stainless steel, sintered filters, and silicone tubing. Sterile manufacturing is performed by aseptic filtration; terminal heat sterilization is generally avoided because solution degradation accelerates at elevated temperature and can generate 4-epianhydrotetracycline above the monograph limit.
| Property | Tetracycline hydrochloride | Tetracycline base |
|---|---|---|
| CAS registry number | 64-75-5 | 60-54-8 |
| Molar mass | 480.90 g/mol | 444.43 g/mol |
| Aqueous solubility | Freely soluble, approximately 10 mg/mL | Very slightly soluble, below 1 mg/mL |
| Typical use | Tablet, capsule, granule, injection | Topical or extemporaneous formulations where low solubility is acceptable |
| Dose correction factor | Delivers 0.924 mg tetracycline base per 1 mg hydrochloride salt | 1:1 on base basis |
Because the molar mass ratio of base to hydrochloride is 0.924, a 500 mg tetracycline hydrochloride dose delivers approximately 462 mg of tetracycline base. Formulation changes from base to hydrochloride require an assay correction; the label must state whether the strength is expressed as the hydrochloride salt or as the base. The hydrochloride salt is generally selected for solid oral and injectable products because its aqueous solubility allows practical dissolution and parenteral volume. The base is less suitable for wet granulation because of low water solubility and slower dissolution; it may be used in topical or extemporaneous formulations where suspension characteristics are acceptable. The phosphate salt, where used, offers a different dissolution and taste-masking profile, but compendial data for this specific configuration is limited. Selection is based on the manufacturing route, pH, light exposure, metal ion burden, and the stability of the finished dosage form over its assigned shelf life.
