| HS Code | 140123 |
| Product Name | Paracetamol (Acetaminophen) |
| Synonyms | Acetaminophen; N-acetyl-p-aminophenol; APAP; 4-acetamidophenol |
| Cas Registry Number | 103-90-2 |
| Molecular Formula | C8H9NO2 |
| Molecular Weight | 151.16 g/mol |
| Appearance | White or almost white crystalline powder |
| Assay | 99.0%–101.0% (anhydrous basis) |
| Melting Point | 168–172°C |
| Solubility | Sparingly soluble in water; freely soluble in ethanol (96%); soluble in acetone; practically insoluble in chloroform |
| Ph | 5.5–6.5 (1% w/v aqueous suspension) |
| Loss On Drying | ≤0.5% |
| Residue On Ignition | ≤0.1% |
| Heavy Metals | ≤20 ppm |
| Storage Conditions | Store in tightly closed containers, protected from light, at controlled room temperature (20–25°C) |
| Shelf Life | 5 years (typical, when stored properly) |
| Pharmacopoeial Standards | BP, USP, EP, IP, JP |
| Grade | Pharma Grade / API |
| Dosage Forms | Tablet, Caplet, Capsule, Granule, Injection |
| Routes Of Administration | Oral, Injectable |
| Packaging | 25 kg net in fiber drum with two inner polyethylene bags |
| Purity | ≥99.0% |
| Identity | IR, UV, or HPLC |
| Related Substances | Meets pharmacopoeial limits |
| Residual Solvents | Meets ICH Q3C limits |
| Bse Tse Statement | BSE/TSE free |
| Gmo Statement | Non-GMO |
As an accredited Paracetamol (Acetaminophen) Tablet/Caplet 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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On a 45-station rotary tablet press, compression failure modes—not dissolution alone—determine whether a high-dose paracetamol immediate-release tablet can run at commercial speed. Direct compression is viable only when the API is a co-processed grade containing pregelatinized starch, croscarmellose sodium, and a small proportion of povidone K30; otherwise the elastic recovery of pure paracetamol powder causes capping above 12–15 kN main compression force. In a direct compression core, paracetamol is loaded at 70–85 wt% of the tablet core, with microcrystalline cellulose 5–15 wt%, croscarmellose sodium 2–5 wt%, and magnesium stearate 0.5–1.0 wt%. The press is operated with precompression force 4–8 kN and main compression force 12–22 kN; ejection force above 4.5 kN indicates lubricant inhomogeneity and predicts edge chipping and punch filming. For wet granulation, a top-spray fluid-bed granulator with inlet air temperature 55–65°C and product temperature 32–38°C is used with a povidone K30 binder solution at 3–5 wt% solid content; dried granules are milled through a 1.0 mm screen and controlled to loss on drying 1.5–2.5%. The granulation route permits a higher API loading of 80–90 wt% in the core because the granule structure reduces capping sensitivity. In-process sampling follows 21 CFR 211.110, with weight, hardness, thickness, and friability recorded at start-up and every 15–30 min on long runs. Release testing uses USP <711> Apparatus 2 at 50 rpm in 900 mL pH 5.8 phosphate buffer, with Q=80% dissolved at 30 min; content uniformity follows USP <905> with acceptance value AV ≤ 15.0. Residual solvent limits follow USP <467> and ICH Q3C, while elemental impurities are controlled under ICH Q3D. The released tablet cores are film-coated to a 3% weight gain and packaged as 325 mg, 500 mg, or 650 mg immediate-release tablets.
Matrix integrity under high-pH intestinal conditions is the governing constraint for a 650 mg extended-release caplet. The core formula contains 65–75 wt% paracetamol, 15–25 wt% hypromellose K100M or K4M, 5–10 wt% microcrystalline cellulose, and 0.5–1.0 wt% magnesium stearate. Dry blending in a 600 L bin blender at 12 rpm for 15 min precedes direct compression on a 45-station rotary press with caplet tooling; main compression force is held between 15 kN and 25 kN to achieve hardness 120–180 N while maintaining adequate surface smoothness for aqueous film coating. The critical dissolution specification for modified-release paracetamol is run as a two-stage USP <711> test, Apparatus 2 at 100 rpm, using acid phase 0.1 N hydrochloric acid for 2 h followed by pH 6.8 phosphate buffer; acceptance is typically Q=80% at 8 h in the buffer stage. Content uniformity is verified by USP <905> with AV ≤ 15.0, and stability testing is conducted under ICH Q1A conditions. The coating pan applies an aqueous ethylcellulose or methacrylic acid copolymer dispersion to 3–5 wt% weight gain using inlet air temperature 60–70°C, product bed temperature 38–42°C, and spray rate 8–12 g/min/kg tablet load. Formulation limits are process-defining: hypromellose above 25 wt% causes powder flow instability and caplet weight variation, while below 15 wt% the matrix erodes too rapidly and the 8 h release plateau is lost. Crushing or chewing the caplet is contraindicated because it breaches the hydrated matrix and causes dose dumping; this is a use-condition boundary rather than a manufacturing defect within the compendial framework. The finished dosage form is an 8-hour 650 mg extended-release caplet that must not be crushed or chewed.
In hard gelatin capsule filling, a high-dose paracetamol formula forces a trade-off between fill weight and powder flow because paracetamol alone has an angle of repose above 45° and cannot be filled on a dosator machine without weight variation drift. Granulation is therefore the limiting unit operation. In a high-shear granulator with a 600 L bowl, paracetamol and maize starch are dry mixed for 5 min, then water or starch paste is added over 3–6 min at a spray rate of 2–4 kg/min; endpoint is reached at motor power draw 25–35% above the dry load baseline. The wet mass is dried in a fluid-bed dryer to loss on drying 1.5–2.5%, then milled through a 0.8 mm screen. Formula ratio inside the filled hard gelatin capsule is 70–85 wt% paracetamol, 10–20 wt% maize starch, 2–5 wt% talc, and 0.25–1.0 wt% sodium stearyl fumarate. The final granule is filled on an MG2 dosator or Bosch GKF tamping pin machine at 70,000–120,000 capsules/h; acceptable fill weight variation for a 500 mg fill is ±5%, and missing pin or powder bed depth alarms are set at ±7%. Capsule dissolution follows USP <711> Apparatus 1 at 100 rpm in 900 mL water, with Q=80% at 30 min; disintegration is controlled by USP <701> with a limit of 15 min. Gelatin shells must be stored below 30°C and 60% RH to avoid crosslinking; hypromellose capsules are used for export regions requiring vegetarian shells. Terminal presentation is a 325 mg or 500 mg immediate-release hard capsule in PVC/PVDC blister or HDPE bottle.
Granule size distribution is not a release parameter to be ignored; it controls reconstitution time and dose homogeneity in single-dose sachets and oral suspensions. In a paediatric 125 mg/5 mL oral suspension reconstitution system, paracetamol is formulated at 10–25 wt% of the dry granule, with sucrose 40–60 wt%, sorbitol 10–20 wt%, sodium carboxymethylcellulose 1–3 wt%, and citric acid 0.5–1.5 wt%. Granulation is performed in a top-spray fluid-bed granulator with inlet air temperature 50–60°C and spray rate 3–6 g/min/kg; the dried granule is sieved to collect fractions 0.2–0.8 mm, with fines below 0.15 mm limited to ≤15% because they create floating aggregates and slow reconstitution. Moisture specification is ≤1.5% loss on drying, and the sachet laminate is a 12 µm PET / 9 µm aluminium foil / 50 µm LDPE structure with seal temperature 145–160°C and dwell time 0.5–1.0 s on a horizontal form-fill-seal machine. Seal strength is tested by ASTM F88/F88M, and filled sachets are placed on stability at 30°C/65% RH for 24 months. Reconstitution compatibility requires that 85% of labelled paracetamol dissolves within 5 min in water at 25°C using the Ph. Eur. 2.9.3 apparatus. Single-dose mass uniformity is verified by Ph. Eur. 2.9.5, and content uniformity follows USP <905> with AV ≤ 15.0. The powdered presentation is used because paracetamol undergoes hydrolysis in aqueous vehicle over prolonged storage; the dry sachet avoids this degradation route while still permitting rapid reconstitution at the point of administration. The resulting pack is a 125 mg, 250 mg, or 500 mg single-dose sachet for reconstitution into oral solution or suspension.
During aseptic manufacturing, paracetamol injection is exposed to oxidative and pH-dependent degradation that constrain the filtration and filling window. The solution is 1.0 wt/vol% paracetamol in water for injection, with 3.5 wt/vol% mannitol for osmolality, adjusted to pH 5.5 with sodium hydroxide or phosphoric acid. The API must meet a low bacterial endotoxin grade; the product release limit is calculated from Ph. Eur. 2.6.14 using the 5 EU/kg/h threshold and the 1 g maximum adult dose. The compounding vessel is purged with nitrogen to maintain dissolved oxygen below 0.2 mg/L, and the dissolution temperature is held at 55–65°C for not more than 60 min to avoid oxidative discoloration and p-aminophenol-related impurity formation. Sterile filtration is carried out through two 0.22 µm polyethersulfone cartridge filters in series, with a 0.45 µm prefilter; differential pressure across the sterilizing filters is monitored and filters are changed at 1.5 bar. The filtered solution is filled into 100 mL Type I glass vials or blow-fill-seal polyolefin ampoules under EU GMP Annex 1 Grade A conditions, with glass vials depyrogenated at 250°C for ≥30 min and rubber stoppers steam-sterilized. Filter integrity is tested by forward-flow or bubble point before and after filling, and aseptic filling is qualified by media fill according to Annex 1. Terminal steam sterilization cannot be used because paracetamol degrades under alkaline hydrolysis and oxidation; pH drift above 6.0 or oxygen ingress above 0.5 mg/L during hold times increases oxidative impurities. Released presentation is a 1 g/100 mL or 500 mg/50 mL solution for intravenous infusion in Type I glass vials or polyolefin bags.
Taste-masked orodispersible paracetamol is not simply a compression variant; the need for rapid disintegration below 30 s drives a different formulation architecture than immediate-release tablets. The API is coated or granulated with amino methacrylate copolymer or ethylcellulose to mask bitterness, then blended with mannitol, crospovidone 5–10 wt%, and microcrystalline cellulose 5–15 wt%; paracetamol content in the orodispersible tablet is 25–45 wt% of the finished tablet weight, allowing a 250 mg dose in a 600–700 mg tablet with hardness 25–40 N and friability ≤1.0%. Processing uses low compression force 6–12 kN on a rotary press with external lubrication of 0.5–1.5 wt% sodium stearyl fumarate to avoid the disintegration delay caused by hydrophobic magnesium stearate. Taste-masking efficiency is evaluated by in vitro release in pH 6.8 phosphate buffer: not more than 10% dissolved in 1 min and not less than 85% dissolved in 15 min using USP <711> Apparatus 2 at 50 rpm; oral disintegration is tested by USP <701> with discs, limit ≤30 s. The major production failure mode is chipping and edge breakage when hardness exceeds 40 N, which also slows disintegration. Content uniformity follows USP <905> with AV ≤ 15.0. The resulting dosage form is a 125 mg or 250 mg orodispersible tablet that disintegrates in the mouth without water.
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Paracetamol (Acetaminophen) Tablet/Caplet Pharma Grade API for Tablet / Capsule / Granule / Injection, Oral & Injectable is a multi-compendial active pharmaceutical ingredient intended for the manufacture of immediate-release tablets, caplets, hard-shell capsules, oral granules, and injectable solutions. The material is released against the current USP-NF Acetaminophen monograph and Ph. Eur. monograph 0049, with additional supplier-specific release controls for particle-size distribution, bulk density, residual solvents, and—when designated as injectable—bacterial endotoxins and particulate matter. Chemical identity is N-(4-hydroxyphenyl)ethanamide, CAS 103-90-2, with a molecular weight of 151.16 g/mol. The pharmacopoeial assay range is 98.0–101.0% on the dried basis, and the melting range is 168–172°C.
Model designation is supplier-specific; this product is not a co-processed direct-compression system or a finished dosage form. It differs from technical-grade acetaminophen by compliance with ICH Q3C residual solvent limits, USP <467>, and Ph. Eur. 2.4.24; it differs from direct-compression acetaminophen by the absence of functional excipients such as pregelatinized starch or crospovidone. Because the API is a neutral amide rather than a carboxylic acid, its solubility profile differs from weak-acid NSAID crystals; aqueous solubility is approximately 14 mg/mL at 25°C, and the pKa is approximately 9.38.
Acetaminophen crystals exhibit poor plastic deformation and high elastic recovery during compression, which limits direct compression of coarse crystalline API in high-dose formulations. On rotary tablet presses of 16–32 stations, capping and lamination are observed when direct-compression blends exceed approximately 70% API load without a sufficient plasticizing binder. The pharmacopoeia does not define powder flow limits for this API; therefore, USP <1174> powder flow testing and USP <616> bulk/tapped density determinations are used to establish supplier release limits. Lot-to-lot variation in Hausner ratio and Carr index has direct consequences for tablet weight uniformity and capsule fill weight. Published data for a universal direct-compression limit is limited because compaction behaviour depends on crystallite habit, particle-size distribution, and residual moisture.
Where dry granulation is selected, roller compaction with a milling step reduces bulk-volume fluctuation. Where wet granulation is selected, a high-shear mixer or fluid-bed granulator is used; binder addition, water quantity, and granulation end point are controlled by impeller torque or power consumption rather than by fixed water volume. The API should be passed through a screening mill before blending when agglomerates exceed the target sieve fraction. Final blend uniformity is assessed by USP <905> uniformity of dosage units or equivalent process validation criteria. Micronized grades may have D50 values between 10 µm and 30 µm, while standard crystalline grades may be coarser; however, particle size is not a pharmacopoeial monograph attribute and must be controlled by supplier agreement. Laser diffraction by USP <429> is appropriate for routine lot release. Excessive fine particles below 10 µm can cause static and segregation; coarse fractions can increase tablet weight variability.
The injectable-grade API is not simply a finer-milled version of oral powder. It is controlled for bacterial endotoxins, bioburden, and insoluble particulate matter in a manner suitable for parenteral solution preparation. The oral monograph does not impose a bacterial endotoxin limit; an injectable grade typically carries a supplier limit aligned with the intended dosage form, with a common contract release criterion of <0.5 EU/mg where the API is designated for intravenous use. Because no universal pharmacopoeial value exists for API endotoxin, the limit must be derived from the maximum adult dose and the finished-product endotoxin limit under USP <85> or Ph. Eur. 2.6.14.
Injectable solution manufacturing requires dissolution clarity and filterability through a 0.22 µm sterilizing-grade membrane; insoluble particles are controlled in the finished solution by USP <788> or Ph. Eur. 2.9.19. The API itself is not required to meet USP <788> because it is not a final dosage form, but particle-size distribution and foreign-particle counts in the dry powder must be low enough to prevent filter blockage. Aqueous solutions of acetaminophen undergo pH-dependent hydrolysis to p-aminophenol; nitrogen sparging and headspace oxygen exclusion are used during compounding before terminal sterilization. The pH of the aqueous formulation is maintained in the weakly acidic range, where hydrolysis is slowest, and the solution is protected from light during hold times. Terminal sterilization at 121°C for 15 min is a common parenteral cycle; compatibility with API degradation must be confirmed by stability-indicating assays and not assumed from the dry API monograph.
For tablet and caplet manufacture, the API is rarely used as the only compressible component. It is blended with microcrystalline cellulose, pregelatinized starch, crospovidone, and magnesium stearate. Magnesium stearate levels above 1.0% w/w or excessive blending can reduce tablet tensile strength due to hydrophobic lubrication; tablets may show prolonged disintegration. Dissolution testing of the finished dosage form is conducted per USP <711> with acceptance criteria established in the individual monograph. For immediate-release acetaminophen tablets, dissolution is typically run in pH 5.8 phosphate buffer, but the regulatory condition depends on the specific market authorization.
| Attribute | Oral tablet/capsule designation | Injectable designation | Reference method |
|---|---|---|---|
| Assay | 98.0–101.0% dried basis | 98.0–101.0% dried basis | USP-NF Acetaminophen monograph; Ph. Eur. 0049 |
| Melting range | 168–172°C | 168–172°C | USP <741>; Ph. Eur. 2.2.14 |
| Bacterial endotoxins | Not specified unless contractually required | Route-specific; supplier limit often <0.5 EU/mg for intravenous use | USP <85>; Ph. Eur. 2.6.14 |
| Particulate matter | Not a dry API release criterion | Finished solution must meet USP <788> or Ph. Eur. 2.9.19 | USP <788>; Ph. Eur. 2.9.19 |
| Residual solvents | ICH Q3C; USP <467> | ICH Q3C; USP <467>; no Class 1 solvents | Ph. Eur. 2.4.24 |
Because the oral and injectable designations are not interchangeable, routine use of oral-grade material in an injectable process would require additional endotoxin, bioburden, particulate, and residual solvent qualification. Published data for dry powder particulate counts specific to this configuration is limited; supplier specifications must be reviewed against the filtration train and the final fill line.
Residual solvent compliance in the API is governed by ICH Q3C and verified by USP <467> or Ph. Eur. 2.4.24. If the synthesis or recrystallisation route retains a Class 2 solvent such as dichloromethane or methanol, the supplier must demonstrate that drying reduces the residue below the concentration limit. In fluid-bed processing for granulation, the drying step also controls residual water; a target loss on drying of 0.5% or less is often derived from the monograph, but final moisture must be optimized for compression. Acetaminophen itself is stable under normal drying temperatures, but overdrying can shift particle-size distribution by attrition in the fluid-bed, and underdrying can increase tablet capping due to granule friability.
Process validation batches should include worst-case drying times and inlet air temperatures; published data for this specific configuration is limited, so the acceptable operating window must be established with process-capability analysis. Sampling for residual solvent and moisture should occur at the end of drying and after size reduction, because size-reduction equipment can generate localized heat and release residual solvent from particle interiors. If drying is performed in a tray dryer, bed depth and airflow uniformity can create batch-to-batch residual solvent variation; fluid-bed dryers with dew-point-controlled inlet air reduce cycle time but require filter bag integrity checks and periodic temperature mapping.
The principal degradation-related impurity is 4-aminophenol, controlled in the USP-NF and Ph. Eur. monographs by specific limit tests. The pharmacopoeial monograph requires not more than 0.001% of p-aminophenol in the current USP-NF monograph, with total related substances and any unspecified impurity controlled at low thresholds; exact limits should be read from the current monograph because revisions occur. 4-Aminophenol is a hydrolysis product of acetaminophen and a potential impurity of synthesis, so injectable solution processes monitor its formation during storage and terminal sterilization. The API release specification also includes residue on ignition, chloride, sulfate, and heavy metals, but these are not intended to replace product-specific vendor audits.
Related substances are typically determined by high-performance liquid chromatography using an octadecylsilyl column and UV detection at 254 nm; the method must separate p-aminophenol, 4-chloroacetanilide, and other specified impurities. The exact mobile phase and system suitability criteria are given in the current USP-NF monograph. Mass balance should be assessed when any unspecified impurity exceeds the reporting threshold.
In comparison with direct-compression or DC-grade paracetamol, this product does not include binder or flow aid; DC grades may contain pregelatinized starch and microcrystalline cellulose at levels that are not transparent in the API certificate. This API therefore provides formulators with control over excipient ratios and is suitable for wet granulation and roller compaction, but it requires additional processing to achieve acceptable compressibility. The powder is not directly compressible at high drug loads; this is a difference from formulated DC granules, not from the active molecule. Other product types, such as injectable premixes, differ from the API because they contain water, buffers, antioxidants, or mannitol. Compared with weak-acid NSAID crystals, the API does not require enteric protection or pH-modulated dissolution. In contrast to ibuprofen or diclofenac, acetaminophen is not a nonsteroidal anti-inflammatory drug and does not have a carboxylic acid group. This removes the need for enteric coating for gastric protection, but the primary formulation challenge remains mechanical: the API must be granulated or blended with a suitable binder to form robust tablets. The phenolic hydroxyl group can oxidise under strongly alkaline conditions; alkaline granulation media should therefore be avoided unless compatibility data support otherwise, and the final manufacturing route is qualified on that basis.
