| HS Code | 476507 |
| Productname | Amantadine HCl Pharma Grade API for Tablet / Capsule / Granule / Injection, Oral & Injectable |
| Chemicalname | 1-Adamantanamine hydrochloride |
| Casnumber | 665-66-7 |
| Molecularformula | C10H17N.HCl |
| Molecularweight | 187.71 g/mol |
| Appearance | White or almost white crystalline powder |
| Assay | 99.0% – 101.0% (dried basis) |
| Grade | Pharmaceutical Grade / API |
| Dosageforms | Tablet / Capsule / Granule / Injection |
| Routeofadministration | Oral & Injectable |
| Solubility | Freely soluble in water and alcohol; practically insoluble in ether |
| Meltingpoint | 360°C (decomposes) |
| Storageconditions | Store in a well-closed container, protected from light, at controlled room temperature |
| Pharmacopoeia | USP / EP / BP / IP |
| Therapeuticcategory | Antiviral; Anti-Parkinsonian; NMDA receptor antagonist |
| Packaging | Fiber drum with double polyethylene bags |
| Shelflife | 36 months |
As an accredited Amantadine hcl 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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Direct compression of amantadine hydrochloride for a 100 mg immediate-release tablet places the greatest stress on blend uniformity because the API is freely water-soluble and densifies rapidly under shear. A representative core formulation is built on 30–40% w/w microcrystalline cellulose, 25–35% w/w anhydrous dibasic calcium phosphate or partially pregelatinized maize starch, 2.0–3.0% w/w croscarmellose sodium, 0.5–1.0% w/w colloidal silicon dioxide, and 0.75–1.25% w/w magnesium stearate. The API is sieved through a 0.8 mm screen at 1200 rpm before charging to an 800 L bin blender; blending is executed at 25 rpm for 20–30 min with a blend uniformity sampling plan aligned to FDA 21 CFR 211.160. Compression is carried out on a 43-station rotary press at 15–22 kN main compression force, maintaining tablet hardness at 7–10 kp and friability below 1.0% by USP <1216>. Disintegration is monitored by USP <701> in 0.1 N hydrochloric acid at 37°C; a 300–340 mg core typically disintegrates in less than 15 min, but product-specific acceptance must be confirmed against the active monograph. Film coating is applied as an aqueous dispersion to a 3–4% weight gain in a perforated side-vented pan with inlet air at 60–65°C, pan speed 4–7 rpm, and atomizing air pressure 1.8–2.2 bar. The finished 100 mg tablet is released against assay, related substances, water content, uniformity of dosage units by USP <905>, dissolution by USP <711>, and microbial limits by USP <61>/<62>. Terminal packaging uses 75 cm³ HDPE bottles with a 1 g silica gel canister or Alu-Alu blisters when accelerated 40°C/75% RH stability data show moisture uptake above 1.5%. The immediate-release presentation is used in influenza A prophylaxis and treatment, with an adult dose of 100 mg twice daily, and as adjunctive therapy in Parkinson’s disease.
When the granulation route is selected to offset dosing-weight segregation in high-speed rotary presses, the formulation is roller-compacted rather than wet-granulated because amantadine hydrochloride dissolves rapidly in aqueous binder and can form hard overgranulated agglomerates. A dry granulation formula for a 100 mg sachet or tablet fill is composed of 45–55% w/w API, 20–25% w/w microcrystalline cellulose, 10–15% w/w mannitol SD 200, 5–8% w/w crospovidone, 0.5–1.0% w/w sodium stearyl fumarate, and 0.5–1.0% w/w colloidal silicon dioxide. The blend is passed through a Gerteis mini-pactor with roller compaction pressure 6–8 kN/cm, roll speed 8–12 rpm, gap 1.5–2.0 mm, and an integrated star-rotor granulator fitted with a 1.0–1.25 mm sieve. Resulting granules are evaluated by USP <1174> powder flow; target compressibility index is below 25% and Hausner ratio below 1.25. Fines below 150 µm are held between 15% and 25% to avoid segregation; oversize material is re-milled once and rechecked. If the granules are filled into stick-pack sachets at 100 mg dose, fill weight is 180–220 mg per sachet, with a long-term moisture barrier of 12 µm PET / 9 µm aluminum foil / 50 µm polyethylene. Reconstitution in 10 mL purified water at 20–25°C should disperse within 30 s under gentle swirling; the resulting suspension has pH 4.5–6.0. Dissolution of the granules is tested by USP <711> Apparatus II at 50 rpm in 500 mL 0.1 N hydrochloric acid, with product-specific acceptance criteria; published data for this specific granular configuration is limited. The finished single-dose granules are used for prescribed amantadine hydrochloride administration in dysphagia patients and for unit-dose repackaging in long-term care settings.
Amantadine HCl can be layered onto sugar spheres in a bottom-spray fluid bed, but the critical process step is the application of a pH-independent barrier film onto drug-layered cores without dissolving the water-soluble API. The starting substrate is generally 25/30 mesh sugar spheres forming 60–70% w/w of the final bead. Amantadine hydrochloride is suspended at 8–10% w/w solids in a binder vehicle of hydroxypropyl methylcellulose 6 cP and purified water, then layered in a Wurster column at inlet temperature 50–55°C, product temperature 38–42°C, spray rate 8–12 g/min, and atomizing air 1.8–2.2 bar until a drug load of 12–18% w/w is achieved. The overcoat consists of an aqueous ethylcellulose or methacrylate copolymer dispersion with triethyl citrate 20% w/w of polymer and talc 40–60% w/w of polymer, applied to 10–18% weight gain. Curing is required at 50–60°C for 2–4 h to complete film coalescence; uncured film leads to burst release in 0.1 N hydrochloric acid. The cured beads are filled into size 1 hypromellose capsules at a target fill weight corresponding to 68.5 mg amantadine base per capsule, equivalent to 85 mg amantadine hydrochloride, or multiples thereof. Dissolution is tested by USP <711> Apparatus I at 100 rpm in 900 mL medium; a two-stage hydrochloric acid-to-phosphate buffer system is typical, but release-rate acceptance criteria are product-specific and publicly available data for the exact formulation is limited. The finished extended-release capsule is indicated for daytime dyskinesia in Parkinson’s disease when administered once daily at bedtime, with a 137 mg base dose frequently reached after two weeks. Stability is assessed under ICH Q1A(R2) at 25°C/60% RH and 40°C/75% RH; assay, dissolved drug, water content, and related substances are tracked at 0, 3, 6, 9, 12, 24, and 36 months.
Parenteral handling of amantadine hydrochloride outside a licensed commercial injection requires strict segregation of aseptic operations and early measurement of pH shift because the salt is freely soluble but its aqueous solution has a high buffer capacity at pH 4.0–6.0. A hospital-pharmacy or contract manufacturing preparation is typically compounded as a 100 mg/500 mL admixture in 0.9% sodium chloride; the solution is adjusted with 1 N hydrochloric acid or 1 N sodium hydroxide to pH 4.5–5.5 and filtered through a 0.22 µm PVDF membrane before aseptic transfer into single-dose infusion bags. Terminal steam sterilization at 121°C for 15 min is acceptable only after forced-degradation data confirm total impurities remain below 1.0% and no leachable is released from the PVC-free bag; otherwise aseptic filtration is the default route. The compounded admixture should be used within the validated beyond-use date, which is commonly 24–48 h at 2–8°C unless chemical and physical stability data support longer storage. Compatibility in polyolefin or EVA bags is required; published data for amantadine hydrochloride in PVC is limited, and the use of PVC bags should be restricted unless extractables data are collected. Release tests include clarity, color, pH by USP <791>, osmolality by USP <785>, particulate matter by USP <788>, sterility by USP <71>, bacterial endotoxin by USP <85>, and assay by HPLC. The parenteral route is reserved for clinical settings where oral administration is impossible or where rapid plasma level control is required under institutional protocols.
| CQA | Target value | Method |
|---|---|---|
| pH | 4.5–5.5 | USP <791> |
| Osmolality | 280–310 mOsm/kg | USP <785> |
| Particulate matter ≥10 µm | ≤25 per container | USP <788> |
| Particulate matter ≥25 µm | ≤3 per container | USP <788> |
| Bacterial endotoxin | NMT 0.5 EU/mg | USP <85> |
| Sterility | No growth after 14 days | USP <71> |
| Assay | 95.0–105.0% label | HPLC |
In sorbitol-based oral solution, the primary technical risk is preservative partitioning into the non-aqueous phase, which reduces aqueous antimicrobial activity. A 50 mg/5 mL oral solution is compounded from amantadine hydrochloride 10 mg/mL, citric acid monohydrate 0.2% w/w, sodium citrate dihydrate 0.3% w/w, sorbitol solution 70% non-crystallizing 30–40% w/w, propylene glycol 5% w/w, methylparaben 0.1% w/w, propylparaben 0.02% w/w, and purified water q.s. The API is dissolved first in 80% of the water at 25±3°C, then the buffer salts are added to pH 4.5–5.5, followed by the parabens pre-dissolved in propylene glycol, and finally sorbitol solution under low-shear stirring to avoid aeration. The finished solution is filtered through a 20 µm nylon strainer and filled into 150 mL amber polyethylene terephthalate bottles with child-resistant polypropylene caps. Preservation effectiveness is challenged using USP <51>; the five-organism panel must meet compendial criteria for oral products. The bottle is equipped with a graduated oral syringe; the dosage is 50 mg/5 mL given once or twice daily according to influenza A prophylaxis or Parkinson’s adjunctive protocols. The solution should be stored at 25°C with excursions allowed to 15–30°C; it should not be diluted with juice because ionic strength and pH changes can precipitate the free base at pH above 6.5.
| Challenge organism | USP <51> requirement for oral preparations | Test points |
|---|---|---|
| Escherichia coli ATCC 8739 | NLT 1 log reduction at 7 days; NLT 3 log reduction at 14 days; no increase at 28 days | 7, 14, 28 days |
| Staphylococcus aureus ATCC 6538 | NLT 1 log reduction at 7 days; NLT 3 log reduction at 14 days; no increase at 28 days | 7, 14, 28 days |
| Pseudomonas aeruginosa ATCC 9027 | NLT 1 log reduction at 7 days; NLT 3 log reduction at 14 days; no increase at 28 days | 7, 14, 28 days |
| Candida albicans ATCC 10231 | No increase from initial count at 7, 14, 28 days | 7, 14, 28 days |
| Aspergillus brasiliensis ATCC 16404 | No increase from initial count at 7, 14, 28 days | 7, 14, 28 days |
A 12-hour hydrophilic matrix tablet containing 100 mg amantadine hydrochloride is typically built on high-viscosity hypromellose 4000 cP or 100,000 cP, with release governed by polymer swelling and erosion rather than by pH-dependent dissolution. The core formulation may include 25–35% w/w hypromellose K4M or K100M, 20–30% w/w microcrystalline cellulose, 10–20% w/w lactose monohydrate, 3–5% w/w sodium alginate or carbomer, 1–2% w/w magnesium stearate, and 0.5–1.0% w/w colloidal silicon dioxide. Direct compression produces a 350–450 mg tablet with hardness 15–20 kp after pre-compression at 5–8 kN and main compression at 18–26 kN on a high-speed rotary press. The matrix tablet is tested by USP <711> Apparatus II at 100 rpm in 900 mL pH 1.2 hydrochloric acid for the first 2 h, then pH 6.8 phosphate buffer; a common release window is NLT 20–40% at 2 h, 40–60% at 4 h, and NLT 70% at 12 h, but exact acceptance limits are product-specific and current public data for amantadine hydrochloride in this matrix composition is limited. The finished tablet is intended as a once-daily adjunct in Parkinson’s disease; it should not be crushed or split because rupture of the matrix causes dose dumping. The tablet must be lagered at 40°C/75% RH for up to 6 months to confirm dissolution stability; photostability is evaluated by ICH Q1B. Terminal packaging in 60 cm³ HDPE bottles with induction-sealed caps is used unless ICH Q1A(R2) data show moisture uptake above 2.0%.
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Amantadine hydrochloride is 1-adamantanamine hydrochloride, CAS 665-66-7, with molecular formula C10H17N·HCl and molecular weight 187.71 g/mol. It is supplied as a pharma-grade active pharmaceutical ingredient in two process grades: an oral solid-dose grade for tablet, capsule, and granule manufacturing, and a low-endotoxin injectable grade for aqueous parenteral compounding. The substance occurs as a white or almost white crystalline powder that is freely soluble in water and soluble in ethanol. A 2% w/v aqueous solution in carbon dioxide-free water has a typical pH of 5.5–6.5, consistent with the protonated primary amine salt. Manufacture is conducted under ICH Q7 and applicable 21 CFR 211 current good manufacturing practice. The API is formulated into oral solids and injectable dosage forms indicated for influenza A virus infection, Parkinsonian syndromes, and drug-induced extrapyramidal reactions. Its pharmacological action includes M2 ion-channel blockade in influenza A and modulation of dopaminergic and glutamatergic transmission in neurological indications. The oral solid-dose grade is controlled for direct compression, roll-compaction dry granulation, and wet granulation; the injectable grade is controlled for bacterial endotoxins, subvisible particulates, and reduced residual solvent levels.
For the oral solid-dose grade, compendial release testing includes assay, identification, chloride content, pH, loss on drying, residue on ignition, related substances, residual solvents, and elemental impurities. The dried-basis assay is controlled between 98.0% and 101.0% relative to C10H17N·HCl; identification relies on infrared absorption spectroscopy and a chloride test under the active substance monograph. Loss on drying is not more than 0.5% by USP <731>; residue on ignition is not more than 0.1% by USP <281>. The pH of a 2% w/v solution is controlled between 5.5 and 6.5 using USP <791> or Ph. Eur. 2.2.3. Elemental impurities are evaluated under ICH Q3D with USP <232>/<233>; residual solvents are controlled under ICH Q3C and USP <467>. Related substances follow the active substance monograph and ICH Q3A reporting, identification, and qualification thresholds. The oral grade does not require bacterial endotoxin testing unless the drug product is used in a sterile route; however, some customers request bioburden and microbial limits based on USP <61>/<62>.
Amantadine hydrochloride produced by common synthetic routes may contain residual solvents such as methanol, isopropanol, and dichloromethane depending on the manufacturing process. The oral solid-dose grade is released only when residual solvent levels comply with ICH Q3C options; ethanol and isopropanol are limited under Class 3, while dichloromethane is controlled under Class 2 with a concentration limit of 600 ppm. In practice, supplier certificates of analysis often report less than 500 ppm total residual solvents, but this is route-dependent. Identity and purity are further confirmed by differential scanning calorimetry; the crystalline form has a melting endotherm above 360 °C with decomposition, consistent with the salt form. This thermal signal is used to distinguish the hydrochloride from the free base and from other amantadine salts during incoming-material qualification.
| Parameter | Oral solid-dose grade | Injectable grade | Test basis |
|---|---|---|---|
| Appearance | White or almost white crystalline powder | White or almost white crystalline powder | USP monograph, Ph. Eur. monograph |
| Assay (dried basis) | 98.0%–101.0% | 98.0%–101.0% | USP/Ph. Eur. titrimetry or HPLC |
| pH (2% w/v solution) | 5.5–6.5 | 5.5–6.5 | USP <791> |
| Loss on drying | ≤0.5% | ≤0.5% | USP <731> |
| Residue on ignition | ≤0.1% | ≤0.1% | USP <281> |
| Bacterial endotoxins | Not applicable for oral route | ≤0.50 EU/mg or dose-calculated per USP <85> | USP <85> |
| Subvisible particulates | Not applicable | Finished parenteral complies with USP <788>/<789> | USP <788>/<789> |
| Residual solvents | ICH Q3C Class 2/3 limits | ICH Q3C Class 2/3 limits | USP <467> |
| Particle-size distribution | Supplier COA; typical oral D90 ≤250 µm, micronized D90 ≤20 µm | Controlled by laser diffraction for dissolution and filtration | Laser diffraction, sieve analysis |
| Elemental impurities | ICH Q3D oral limits | ICH Q3D parenteral limits | USP <232>/<233> |
During direct compression and dry granulation, the particle-size distribution, bulk density, and moisture content of amantadine hydrochloride determine weight uniformity and segregation behavior. On rotary tablet presses, sticking to punch faces is observed when residual granule moisture exceeds 1.0% or when processing ambient relative humidity exceeds 60%. Roller compaction is used to densify the API and reduce fine-particle segregation; ribbon density and granule fines are controlled by roll force and rotor classifier speed. For direct compression, the API is typically pre-sieved through a 500 µm screen and blended in a bin blender at 50–70% fill volume. Bulk density and compressibility index are recorded in the certificate of analysis; lot-to-lot shifts outside the supplier control range are a common cause of weight variation on high-speed capsule fillers. Content uniformity for 100 mg strength tablets is verified by high-performance liquid chromatography against the active substance monograph.
Tablet compression of direct-compression formulations containing amantadine hydrochloride can generate ejection forces that increase when magnesium stearate is over-blended. Blending time for lubricant is therefore limited to 3–5 min after the main blend reaches homogeneity. For roll-compaction dry granulation, the API is compacted at ribbon density from 0.85 g/cm³ to 1.05 g/cm³; ribbons outside this range produce either weak granules with excessive fines or dense granules with reduced compactability. On encapsulation equipment, fill weight is monitored gravimetrically; powder bed height and auger speed are adjusted to maintain a fill-weight relative standard deviation below 2.0%. Process validation batches are used to confirm that tablet hardness, disintegration, and dissolution remain within finished product specifications.
Analytical release for the pharma-grade API commonly uses reversed-phase HPLC with a C18 column, phosphate buffer and acetonitrile mobile phase, and ultraviolet detection at 210 nm. The method is validated for linearity, specificity, accuracy, and precision per ICH Q2(R2). The assay standard is a USP reference substance; the impurity marker list includes process-related compounds and degradation products identified during forced degradation. For injectable grade, a test for particulate matter in the API is performed by dispersing the powder in particle-free water and using light obscuration; acceptance limits are set to ensure that the finished sterile filtered injection can meet USP <788>.
Because the injection route bypasses gastrointestinal barriers, formulation uses the low-endotoxin grade of amantadine hydrochloride. The API is dissolved in Water for Injections at room temperature under low-shear mixing; dissolution is rapid due to high aqueous solubility. Bulk solution pH is controlled between 5.5 and 6.5. Adjustment above 7.0 is not recommended because the free-base form has reduced aqueous solubility and may precipitate during cooling or terminal sterilization. Sterile filtration through a 0.22 µm polyvinylidene fluoride or polyethersulfone membrane is followed by moist-heat terminal sterilization at 121 °C for 15 min where the formulation supports it. Bacterial endotoxin release is controlled by USP <85>; subvisible particulate matter in the finished parenteral is evaluated by USP <788> light obscuration. The injectable grade is specified with low bioburden and reduced particulate content because terminal filtration cannot correct for pyrogen contamination introduced earlier. Container-closure compatibility is verified with Type I glass vials and bromobutyl rubber stoppers; aqueous fills may be blanketed with nitrogen where oxygen sensitivity is demonstrated.
For injectable compounding, the endotoxin limit is calculated as K/M, where K is 5 EU/kg and M is the maximum bolus dose in mg/kg; this calculation frequently yields an API release limit more stringent than 1.0 EU/mg for lower patient-weight populations. Nitrogen sparging of bulk solution can be used to reduce oxygen headspace; dissolved oxygen is controlled below 2.0 mg/L before filling. Filter integrity testing by bubble point or diffusion is performed before and after transfer of the batch. Terminal sterilization cycle at 121 °C for 15 min is validated with biological indicators to a sterility assurance level of 10−6. The pH may drift slightly during autoclaving; therefore, the formulation is buffered and pH is measured after cooling. These controls distinguish the injectable grade from the oral solid-dose grade, which is not manufactured to the same bioburden and particulate specifications.
In high-shear wet granulation operations, the high water solubility of amantadine hydrochloride can produce localized dissolution at binder liquid contact points, leading to sticky mass and non-uniform granule growth. Hydroalcoholic granulating fluids or a low spray rate with controlled chopper speed reduce this effect. Fluid-bed drying is performed with inlet air temperature not exceeding 60 °C; final granule loss-on-drying is maintained below 0.5%. The dried granulate is filled into hard gelatin or hydroxypropyl methylcellulose shells for capsules or compressed into tablets after lubrication. Dissolution testing is performed in 0.1 M hydrochloric acid or purified water per the finished product specification; the high solubility of the salt generally supports rapid release from conventional immediate-release solid oral forms. Sieve analysis by USP <786> is used to control oversized granules and fines; excessive fines below 45 µm can increase segregation risk and should be limited through granulation end-point control.
Compared with rimantadine hydrochloride, amantadine hydrochloride lacks the alpha-methyl substitution on the adamantane cage, resulting in a shorter terminal half-life and a different renal-elimination profile in adults. Both substances act as M2 ion-channel blockers in influenza A, but susceptibility of circulating strains must be interpreted from public-health surveillance because resistance patterns vary geographically and seasonally. Neuraminidase inhibitors such as oseltamivir phosphate and zanamivir act later in the viral replication cycle by blocking release of progeny virions; this mechanistic distinction creates different resistance selection pressure and different formulation constraints. Within salt forms, amantadine hydrochloride is more widely referenced in USP, Ph. Eur., and JP monographs than amantadine sulfate; the sulfate salt requires a different assay correction factor and is not the preferred form for most oral solid-dose registrations. Amantadine free base is not used in conventional tablet or capsule development because of lower aqueous solubility and different handling characteristics. Technical-grade amantadine hydrochloride, used in non-pharmaceutical applications, lacks the controlled impurity profile, residual solvent declaration, and microbial quality required under ICH Q7 and 21 CFR 211.
Amantadine hydrochloride is specific for influenza A virus; it has no direct antiviral activity against influenza B virus, whereas neuraminidase inhibitors generally cover both influenza A and B viruses. This difference influences product positioning and public-health recommendations. For Parkinsonian syndromes, amantadine HCl is distinct from levodopa and dopamine agonists because it acts as a weak NMDA receptor antagonist and may reduce levodopa-induced dyskinesia; this use is not shared by rimantadine HCl, which is not approved for neurological indications. The oral solid-dose and injectable grades described here are not interchangeable with amantadine sulfate oral products without recalculation of the active base content.
In warehouse storage conditions, the pharma-grade API should be kept in tightly closed, light-resistant containers at controlled room temperature. Humidity excursions above 60% RH can increase loss-on-drying and reduce flow; a pre-drying step is recommended when material remains exposed. Incompatibilities include strong oxidizing agents, alkaline media that precipitate amantadine free base, and chlorine-liberating compounds. Stainless steel contact surfaces are acceptable for production equipment. Re-evaluation dates are assigned from stability data generated under ICH Q1A and ICH Q7 quality systems. Lot-to-lot consistency is supported by batch records showing control of crystallographic form, particle-size distribution, residual solvents, and elemental impurities.
If the material has been stored in a humidity chamber or exposed to ambient air above 60% RH for longer than 48 h, loss-on-drying should be re-checked before weighing. Because amantadine hydrochloride is freely water-soluble, it dissolves quickly in gastrointestinal fluid and aqueous media; this property is also relevant for cleaning validation, because water rinsing alone can remove most residues from process equipment. Residue acceptance limits for shared equipment are calculated using permitted daily exposure and the next product characteristics.
