| HS Code | 291002 |
| Product Name | Antazoline Hydrochloride Pharma Grade API for Tablet / Capsule / Granule / Injection, Oral & Injectable |
| Synonyms | Antazoline HCl; 2-(N-Benzylanilinomethyl)-2-imidazoline hydrochloride; 2-[(N-Benzylanilino)methyl]-2-imidazoline hydrochloride; Antistine hydrochloride |
| Cas Number | 2508-72-7 |
| Molecular Formula | C17H19N3·HCl |
| Molecular Weight | 301.81 g/mol |
| Appearance | White or almost white crystalline powder |
| Odor | Odorless or practically odorless |
| Solubility | Freely soluble in water; soluble in ethanol; practically insoluble in ether |
| Melting Point | 237-241°C with decomposition |
| Ph | 4.0-6.0 (2% aqueous solution) |
| Assay | 99.0%-101.0% on dried basis |
| Grade | Pharma Grade / API |
| Pharmacological Class | First-generation antihistamine; H1 receptor antagonist |
| Therapeutic Category | Antihistamine |
| Mechanism Of Action | Competitive antagonist at histamine H1 receptors |
| Route Of Administration | Oral and injectable |
| Dosage Forms | Tablet, capsule, granule, injection |
| Storage Conditions | Store in tight, light-resistant containers at controlled room temperature 15-30°C |
| Packaging | 25 kg fiber drum with double polyethylene bags |
| Shelf Life | 24 months when stored as recommended |
| Standard | BP/EP/USP (as applicable) |
As an accredited Antazoline 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.
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Antazoline hydrochloride immediate-release tablets produced by direct compression require a powder blend engineered around the high aqueous solubility of the salt and the need to avoid wet granulation when a short, robust process is favored. For pharmaceutical-grade formulations targeting 50 mg and 100 mg unit strengths with total core weights of 150 mg to 250 mg, the API mass fraction remains within 20–40% w/w; the remainder comprises microcrystalline cellulose (30–50% w/w), pregelatinized starch (10–20% w/w), crospovidone (4–8% w/w), colloidal silicon dioxide (0.5–1.0% w/w), and magnesium stearate (0.5–1.5% w/w). Compliance during batch release relies on USP <905> for content uniformity, USP <711> for dissolution, ICH Q3D for elemental impurity risk assessment, and 21 CFR Part 211 for finished pharmaceutical GMP. Blending is performed in a bin blender at 15–25 rpm for 10–15 min after a delumping pass through a 0.5–1.0 mm screen; pre-compression force is set at 2–5 kN and main compression at 8–20 kN on a rotary tablet press operating at 20–50 rpm, producing tablet hardness of 60–100 N, friability below 1.0%, and disintegration time under 15 min. Over-lubrication is a known failure mode: when magnesium stearate exceeds 1.5% w/w or total blend time exceeds 15 min, hydrophobic film formation on soluble API particles can retard dissolution and produce content uniformity drift in low-dose blends. Terminal product types are immediate-release tablets of 50 mg and 100 mg for oral antihistamine therapy in allergic rhinitis and urticaria indications; packaging in aluminum-PVC/PVDC blister strips with 40 g/m2 lidding foil provides moisture protection.
For antazoline hydrochloride oral granules intended for unit-dose sachets, wet granulation is selected only when direct compression cannot simultaneously deliver adequate flow, compressibility, and taste masking. The formulation addition ratio is calculated against the finished sachet fill weight: a 50 mg dose in a 1.0 g sachet equals 5.0% w/w API, while a 100 mg dose in a 1.5 g sachet equals 6.7% w/w. The dry phase contains mannitol or lactose (60–80% w/w), pregelatinized starch (10–20% w/w), sodium carboxymethylcellulose (2–5% w/w) as a suspension stabilizer, and aspartame or sodium saccharin at 0.5–1.5% w/w; the granulating binder is a 5–10% w/w aqueous solution of povidone K29/32 sprayed at 2–4 g/min/kg. Processing in a high-shear mixer with impeller tip speed 3–8 m/s and chopper speed 1500–3000 rpm builds granules with mean particle size 0.2–0.8 mm; wet mass is dried in a fluid-bed drier at inlet air temperature 50–70 °C and product temperature 30–40 °C to loss on drying 1.5–2.5%, then calibrated through 0.5–1.4 mm screens. Over-granulation above 2.5% loss on drying at the wet stage or impeller tip speed above 8 m/s produces dense, oversized agglomerates that resist disintegration and shift particle size distribution toward 1.4 mm. Compliance is documented against USP <711> dissolution, USP <905> uniformity of dosage units, ICH Q3C residual solvent limits for aqueous granulation, and ICH Q3D elemental impurities. Terminal product types are oral granules in sealed sachets for reconstitution as suspension or direct administration in pediatric and elderly antihistamine regimens.
Capsule filling operations for low-dose antazoline hydrochloride encounter poor bulk flow and require roller compaction as the densification step before dosator or tamping-pin encapsulation. The API addition ratio for hard capsule products is held between 20–35% w/w for 50 mg and 100 mg unit strengths, with total fill weights of 100–250 mg in size 3 or 4 capsules; the filler phase comprises microcrystalline cellulose (40–60% w/w), lactose monohydrate (10–20% w/w), croscarmellose sodium (3–6% w/w), colloidal silicon dioxide (0.5–1.0% w/w), and sodium stearyl fumarate (0.5–1.0% w/w). Roller compaction is executed at hydraulic pressure 4–10 MPa, roll speed 2–8 rpm, and roll gap 1.0–2.5 mm to generate ribbons with density 0.55–0.70 g/cm3; ribbons are milled at 1000–2000 rpm through a 0.8–1.2 mm screen, and the resulting granules are filled on an intermittent-motion capsule machine operating at 30,000–70,000 capsules/h. Roller compaction pressure above 10 MPa or roll gap below 1.0 mm can produce hard granules with dissolution slowdown; ribbon density above 0.70 g/cm3 is rejected for capsule dissolution control. In-process controls include fill weight variation below ±5%, moisture content below 3.0%, and tamping-pin compression force within 100–300 N depending on capsule size. Compliance markers include USP <711> dissolution testing in 0.1 N HCl or simulated gastric fluid, USP <905> blend uniformity, ICH Q3D elemental impurities, and 21 CFR Part 211 finished pharmaceutical GMP. Terminal product types are immediate-release hard gelatin or hypromellose capsules for oral antihistamine therapy; moisture-sensitive packaging in HDPE bottles with silica gel desiccant or cold-form aluminum blisters limits moisture uptake.
Because antazoline hydrochloride injection is a low-viscosity aqueous solution, sterilizing-grade filtration parameters must account for low pressure drop across the membrane and the need to maintain pre-filtration bioburden at or below 10 CFU/100 mL. Typical parenteral strength is 5 mg/mL antazoline hydrochloride in 0.9% w/v sodium chloride injection, with pH adjusted to 4.5–6.0 using 0.1 N HCl or 0.1 N NaOH; nitrogen sparging for 15–30 min before and after dissolution minimizes oxidative discoloration of the imidazoline moiety. The solution is passed through a two-stage sterilizing filter train: a 0.45 μm prefilter followed by a 0.22 μm sterilizing-grade polyvinylidene fluoride or polyethersulfone filter under differential pressure not exceeding 1.0 bar; filter integrity is verified by forward-flow test to bubble point specifications supplied by the membrane manufacturer. Filled Type I borosilicate glass ampoules or vials are processed either by terminal steam sterilization at 121 °C for 15 min if antazoline hydrochloride thermal degradation data support it, or by aseptic filling in an ISO 14644-1 Class 5 environment with Grade A air supply. Terminal steam sterilization is constrained by thermal degradation: if solution darkens above 121 °C or assay loss exceeds 2.0% in forced degradation, aseptic processing becomes mandatory. Compliance requires USP <71> sterility testing, USP <85> bacterial endotoxins, USP <790> visible particulates, USP <791> pH, and ICH Q3D elemental impurities. Terminal product types are single-dose parenteral preparations of 2 mL and 5 mL containing 10 mg and 25 mg antazoline hydrochloride, respectively, for acute allergic conditions in markets where injectable antihistamine therapy is approved; published data for this specific configuration is limited and should be confirmed with forced-degradation studies.
Before lyophilized antazoline hydrochloride injection can be considered for stability-sensitive markets, collapse temperature mapping and glass transition data must be generated to justify primary drying below the amorphous eutectic failure point. The formulation addition ratio in the bulk solution is determined by filling volume: for a 25 mg dose per 5 mL fill, the API concentration is 5 mg/mL; for a 10 mg dose per 2 mL fill, the same concentration is maintained to simplify scale-up. Bulking agents are selected from mannitol (2–5% w/v) or trehalose (2–5% w/v) to provide a lyophilized cake with reconstitution time below 60 s; citrate or phosphate buffer is added at 5–20 mM to hold pH within 4.5–6.0 when the product is reconstituted with water for injection. The downstream process begins with aseptic filtration through 0.22 μm sterilizing filters, followed by filling into 5 mL Type I glass vials with 13 mm halobutyl stoppers partially seated; lyophilization is performed with ramp freezing at −1 °C/min to −40 °C and annealing at −20 °C for 2–4 h before primary drying at −30 °C and 0.1–0.2 mbar chamber pressure for 24–48 h, then secondary drying at 25–40 °C until moisture content falls below 2.0%. Shelf temperature above 40 °C during secondary drying or collapse temperature misjudgment by ±2 °C can cause cake collapse, longer reconstitution, and visible particulate failures under USP <790>. Compliance markers include USP <71> sterility, USP <85> endotoxin, USP <921> water determination, ICH Q3C residual solvents, and ICH Q3D elemental impurities. Terminal product types are lyophilized powders for injectable reconstitution, supplied in single-dose vials with diluent co-packaged; this format is appropriate only where aqueous antazoline hydrochloride injection has demonstrated insufficient long-term stability, and published data for this specific configuration is limited.
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Antazoline Hydrochloride Pharma Grade API for Tablet / Capsule / Granule / Injection, Oral & Injectable is a white or almost white crystalline powder of 2-[(N-benzylanilino)methyl]-2-imidazoline hydrochloride, CAS 2508-72-7, molecular formula C17H19N3·HCl, and relative molecular mass 301.82 g/mol. The material is supplied under two model designations that distinguish dry-blend solid-oral grades with a laser-diffraction D90 of ≤75 µm from micronized grades with a D90 of ≤15 µm for ophthalmic, nasal, oral liquid, and injectable suspension processing. The hydrochloride salt is freely soluble in water and therefore suitable for aqueous oral and parenteral routes, while the imidazoline-containing structure remains sensitive to strongly alkaline environments. Distributed as a pharmacopeial active pharmaceutical ingredient, the product is intended for incorporation into tablets, capsules, granules, oral solutions, oral suspensions, and injectable preparations after release testing against the relevant pharmacopeial monograph and ICH Q3C/Q3D impurity limits.
Pharmaceutical-grade antazoline hydrochloride is differentiated from technical-grade material by controlled limits for related substances, residual solvents, elemental impurities, and microbial quality. The specification below is applied to each lot intended for finished drug product manufacturing; certificates of analysis include batch-specific results rather than typical values. Assay is determined by HPLC or non-aqueous potentiometric titration after drying, with acceptance criteria of 99.0–101.0% w/w calculated on the dried basis. Related substances are controlled by a stability-indicating HPLC method with a total impurity limit of ≤0.5% w/w and an unspecified impurity limit of ≤0.10% w/w. Residual solvent analysis by headspace gas chromatography follows Ph. Eur. 2.4.24, with Class 1 solvents not detected, Class 2 solvents within ICH Q3C option 1, and Class 3 solvents at ≤0.5% w/w individually. Elemental impurities are tested by ICP-MS per Ph. Eur. 2.2.58 with limits derived from ICH Q3D for oral and parenteral routes; arsenic, cadmium, mercury, and lead are controlled at or below 0.5 ppm unless the parenteral risk assessment requires tighter limits. Microbial enumeration per Ph. Eur. 2.6.12 and 2.6.13 sets TAMC at ≤10² CFU/g and TYMC at ≤10¹ CFU/g, with Escherichia coli absent in 1 g. For injectable applications, bacterial endotoxin release is performed per Ph. Eur. 2.6.14 with a lot-specific limit of ≤0.10 EU/mg or tighter based on the maximum adult daily dose.
| Attribute | Acceptance criterion | Test designation |
|---|---|---|
| Appearance | White or almost white crystalline powder | Visual |
| Identification | IR spectrum matches reference; HPLC retention time matches; chloride test positive | Ph. Eur. 2.2.24, 2.2.29, 2.3.1 |
| Assay (dried basis) | 99.0–101.0% w/w | HPLC or non-aqueous titration |
| Related substances | Total ≤0.5% w/w; unspecified ≤0.10% w/w | Stability-indicating HPLC |
| Residual solvents | Class 1 not detected; Class 2 within ICH Q3C; Class 3 ≤0.5% w/w each | Ph. Eur. 2.4.24 |
| Elemental impurities | As, Cd, Hg, Pb ≤0.5 ppm unless lower | Ph. Eur. 2.2.58 |
| Loss on drying | ≤0.5% w/w | Ph. Eur. 2.2.32 |
| Microbial limits | TAMC ≤10² CFU/g; TYMC ≤10¹ CFU/g; E. coli absent in 1 g | Ph. Eur. 2.6.12, 2.6.13 |
| Bacterial endotoxin | ≤0.10 EU/mg for injectable model | Ph. Eur. 2.6.14 |
In tablet and capsule manufacture, the dry-blend model with D90 ≤75 µm is processed by wet granulation or, less commonly, direct compression after evaluating bulk and tapped density per Ph. Eur. 2.9.34. A Hausner ratio above 1.35 or a Carr index above 25% is an operational boundary for direct compression; beyond these values, segregation and weight variation are controlled by aqueous granulation with polyvinylpyrrolidone or hypromellose as binder. Because antazoline hydrochloride is freely soluble in water, addition of the drug substance to the granulating fluid can lead to binder migration to granule surfaces during drying at inlet air temperatures above 60°C. For this reason, the dry-blend grade is most often dry-mixed with filler, then granulated using a hydroalcoholic binder at 45–55°C product temperature in a top-spray fluid-bed granulator or high-shear mixer. Capsule blends containing the same grade should be sieved through a 0.5 mm screen to disperse agglomerates before lubrication with magnesium stearate at 0.25–1.0% w/w. These are process engineering controls, not acceptance criteria, and are applied after risk assessment on the specific production line.
The micronized model is not interchangeable with the dry-blend model. Laser diffraction per Ph. Eur. 2.9.31 uses a dry dispersion module at 2 bar for the dry-blend grade and a wet dispersion module in 0.1% w/v polysorbate 20 for the micronized grade. The dry-blend model typically shows a span (D90-D10)/D50 of 1.8–2.4, while the micronized model is controlled for D90 ≤15 µm and D50 4–8 µm. Specific surface area by nitrogen adsorption is not routinely required unless the formulation contains a very low dose per unit; when measured, it is reported as BET surface area in m²/g. The micronized model exhibits higher cohesiveness and should not be added to a tumble blender without a pre-blend or forced-addition step. Wet dispersion into purified water or water for injection is the preferred route for ophthalmic and nasal suspensions; high-shear dispersion at 1500–3000 min⁻¹ for 10–15 min reduces aggregate size without excessive foam generation.
| Model designation | Laser-diffraction target | Intended dosage form | Processing constraint |
|---|---|---|---|
| Dry-blend | D90 ≤75 µm; D50 25–40 µm | Tablet, capsule, granule | Wet granulation preferred; direct compression only if Hausner ratio ≤1.25 |
| Micronized | D90 ≤15 µm; D50 4–8 µm | Ophthalmic suspension, nasal suspension, injectable suspension | High-shear dispersion required; avoid dry transfer without containment |
Injectable formulation work with antazoline hydrochloride applies the micronized or dissolved-state route. In aqueous injectable solutions, the drug substance is dissolved in water for injection before pH adjustment; strongly alkaline buffers are incompatible because free-base precipitation occurs when the pH approaches the pKa of the imidazoline nitrogen. Terminal sterilization of the finished solution by moist heat per Ph. Eur. 5.1.1 is generally evaluated at 121°C for 15 min; however, autoclaving can elevate related substances if the formulation pH is above 6.5. Aseptic filtration through 0.22 µm polyethersulfone or PVDF membranes is an alternative for heat-sensitive formulations. For suspension injections, the micronized grade is wet-sterilized or aseptically dispersed after dry heat sterilization at 160°C for 2 h, but thermal degradation at prolonged dry-heat exposure requires lot-specific assay and related-substance verification. Published data for this specific configuration is limited; therefore, terminal sterilization parameters should be justified by formulation-specific validation rather than by analogy.
Antazoline hydrochloride differs from chlorphenamine maleate and diphenhydramine hydrochloride in salt form, molecular weight, melting behaviour, and counterion-related processing risk. Antazoline hydrochloride has a relative molecular mass of 301.82 g/mol and melts with decomposition in the range 237–241°C, whereas diphenhydramine hydrochloride melts at 168–172°C. The hydrochloride counterion avoids the maleate-related plasticization and possible Michael addition reactivity that can occur with chlorphenamine maleate in hot-melt extruded formulations. Compared with diphenhydramine hydrochloride, antazoline hydrochloride contains an additional imidazoline ring that increases polarity and reduces the tendency to form hygroscopic melts during high-shear granulation. These differences are structural and processing-specific; they do not establish therapeutic superiority or inferiority. For oral solid dosage forms, the melting range is relevant because hot-melt extrusion or high-temperature drying above 120°C is generally below the degradation threshold for antazoline hydrochloride, whereas diphenhydramine hydrochloride may soften at lower temperatures. No clinical endpoint comparison is provided in this technical introduction.
The product is incompatible with strongly alkaline materials, carbonate or bicarbonate effervescent systems, and strong oxidizing agents. Contact with sodium hydroxide or potassium carbonate liberates the free base and produces a sticky, poorly compressible residue; this has been observed in wet granulation trials where a carbonate-containing excipient was added before neutralization. In liquid oral preparations, sweeteners and buffering agents should be adjusted to pH 4.0–6.0 to maintain the hydrochloride salt in solution. In tablet and capsule blends, avoid high-moisture excipients such as unmodified starch above 10% w/w if storage relative humidity exceeds 60%; the drug substance is water-soluble and can dissolve in adsorbed moisture, causing local agglomeration and compromised content uniformity. Cleaning of contact surfaces uses purified water followed by 70% ethanol or isopropanol for non-product-contact areas; stainless steel 316L is preferred for product-contact parts because chloride salt solutions can corrode lower-grade stainless steel under prolonged exposure.
Oral liquid formulations containing antazoline hydrochloride are prepared by dissolving the dry-blend or micronized grade in purified water with preservative and buffer. The solution should be protected from light because first-generation imidazoline antihistamines can undergo photodegradation. Storage in amber glass Type III or high-density polyethylene containers is typical; photostability testing per ICH Q1B should be conducted on the finished product. For extemporaneous compounding, the API is not provided sterile unless specifically ordered as an injectable model; any oral suspension prepared from bulk dry powder is not intended for parenteral use.
The release and stability method for antazoline hydrochloride is an HPLC gradient method with UV detection; it is validated as stability-indicating under forced degradation conditions per ICH Q1A. The method separates antazoline from unspecified degradation products generated under oxidative stress, acid hydrolysis, and heat. Alkaline hydrolysis changes the matrix by free-base precipitation; therefore, an acidified diluent is used. Because published data for this specific configuration is limited, forced degradation conditions should be selected using formulation-specific stress studies rather than fixed degradation product identities. The API should be stored in tightly closed containers protected from light and moisture; storage at 15–25°C is appropriate for the unopened original container. The product is manufactured under ICH Q7 and EU GMP Part II, with batch-to-batch control from benzylaniline condensation through imidazoline ring closure, hydrochloric acid salt formation, recrystallization, and micronization. Residual solvents are removed by vacuum drying below 50°C to avoid thermal degradation. Each batch is assigned a retest date, typically 36 months from release when stored in the original unopened container at 15–25°C.
