| HS Code | 835772 |
| Product Name | Ibuprofen Lysine Pharma Grade API for Tablet / Capsule / Granule / Injection, Oral & Injectable |
| Synonyms | Ibuprofen lysinate; Lysine ibuprofen; Ibuprofen L-lysine salt |
| Cas Number | 57469-77-9 |
| Molecular Formula | C19H32N2O4 |
| Molecular Weight | 352.47 g/mol |
| Chemical Class | Ibuprofen lysine salt |
| Therapeutic Category | Nonsteroidal anti-inflammatory drug (NSAID) |
| Therapeutic Use | Analgesic, antipyretic, anti-inflammatory; injectable form used for closure of patent ductus arteriosus in premature infants |
| Dosage Forms | Tablet, capsule, granule, injection |
| Routes Of Administration | Oral, injectable |
| Appearance | White to off-white crystalline powder |
| Solubility | Freely soluble in water; soluble in ethanol; practically insoluble in acetone |
| Ph | 6.0 to 7.5 (1% w/v aqueous solution) |
| Assay | 98.0% to 102.0% (dried basis) |
| Loss On Drying | ≤0.5% |
| Heavy Metals | ≤20 ppm |
| Residue On Ignition | ≤0.1% |
| Purity | ≥98.0% |
| Grade | Pharmaceutical grade API |
| Storage | Store in a cool, dry, well-ventilated area, protected from light and moisture |
| Shelf Life | 24 months when stored as directed |
| Packaging | 25 kg net in fiber drum with double polyethylene inner bags |
| Regulatory Status | Manufactured under cGMP; suitable for pharmaceutical formulation |
As an accredited Ibuprofen Lysine 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 ibuprofen lysine at a dose equivalent to 200 mg ibuprofen (342 mg of the 1:1 lysine salt) is generally limited to formulations where the API particle size distribution is controlled with a D50 90–140 µm and D90 < 300 µm. On a rotary tablet press fitted with 19.0 × 9.5 mm oval tooling and operated at 35–55 rpm, a typical blend containing 42–48% w/w microcrystalline cellulose PH102, 8–12% w/w croscarmellose sodium, 0.5–1.0% w/w colloidal silicon dioxide, and 0.8–1.2% w/w sodium stearyl fumarate produces compacts with break force in the range of 70–110 N and friability below 0.3%. Compression force is held between 12 kN and 18 kN; above 18 kN, capping probability increases because the salt exhibits elastic recovery above 7% when residual moisture is below 1.2%. In contrast, moisture above 2.5% increases sticking on lower punches and causes weight variation during runs exceeding 120 min. Tablet disintegration in 900 mL phosphate buffer at pH 7.2 and 37 °C under Ph. Eur. 2.9.1 is typically complete within 4–7 min. Dissolution testing in USP Apparatus 2 at 50 rpm using 900 mL phosphate buffer pH 7.2 releases Q ≥ 80% within 15 min for most immediate-release batches. Direct compression becomes less viable above 400 mg ibuprofen equivalent because tablet mass approaches 700–750 mg, powder flow deteriorates in gravity-fed feed frames, and the hygroscopic lysine salt increases punch filming under extended compaction cycles. Lubrication is preferably performed with sodium stearyl fumarate rather than magnesium stearate in direct compression, because the lysine salt can soften under shear and exhibit delayed disintegration when magnesium stearate levels exceed 1.0% w/w.
On an MG2 Futura dosator capsule filler or a Zanasi 40E intermittent-motion machine, powder bed density must be maintained between 0.52 g/cm³ and 0.62 g/cm³ to achieve fill-weight relative standard deviation below 4.0% for size 0 hard capsules. Ibuprofen lysine is hygroscopic, and environmental relative humidity above 40% RH at 25 °C increases water uptake sufficiently to cause powder bridging in the dosator nozzle and non-uniform plug formation. A robust size 0 capsule fill contains 342 mg ibuprofen lysine equivalent to 200 mg ibuprofen, 89 mg lactose monohydrate, 8 mg crospovidone, and 2 mg magnesium stearate. Capsule shells made from HPMC with 4–6% moisture are preferred over gelatin when the packaged product may be stored above 30 °C/65% RH. The ε-amino group of lysine can participate in Maillard-type crosslinking under such conditions, increasing gelatin shell rupture time during dissolution. Dosator filling is recommended over tamping-pin filling because tamping-pin machines generate fines below 75 µm; when fines exceed 25% w/w, flowability falls and weight variation widens. Dissolution testing per Ph. Eur. 2.9.3 in 900 mL phosphate buffer pH 6.8 at 75 rpm yields Q ≥ 75% in 20 min for HPMC shells. Gelatin-shell capsules may exhibit a 3–5 min delay if shell crosslinking has occurred. Powder moisture should be verified by loss on drying at 105 °C to a limit of ≤ 2.0% before encapsulation. Finished capsules are typically packaged in aluminium/PVC blisters with desiccant to limit moisture ingress below 0.5 mg water per capsule per year.
Fluid-bed granulation of ibuprofen lysine for unit-dose sachets is conducted in a Glatt GPCG-120 or equivalent. A 100 kg granulation batch is sprayed with a 10% w/w hydroxypropylcellulose solution in anhydrous ethanol at a binder level of 200 g/kg dry mass, using inlet air temperature 45 °C, product temperature 28–32 °C, and spray rate 1.2–1.8 kg/min. Aqueous binder systems are avoided because ibuprofen lysine dissolves rapidly in water, forming hard agglomerates after drying and shifting particle size irreproducibly. After tray drying at 40 °C for 6 h, residual moisture is held at ≤ 1.5%. Sieve analysis per Ph. Eur. 2.9.12 must show ≤ 15% w/w below 75 µm and ≤ 10% w/w above 355 µm. Excess fines segregate during vertical form-fill-seal filling on a Bosch or Volpak sachet line, while oversized granules reduce dissolution rate because porosity at the granule surface is lower. Each 1.0 g sachet contains 342 mg ibuprofen lysine equivalent to 200 mg ibuprofen plus sucrose or sorbitol filler, citric acid, sodium citrate, xanthan gum, and 0.5% w/w colloidal silicon dioxide. Fill-weight relative standard deviation must remain below 2.0%. Dissolution of the reconstituted suspension at 50 rpm in 900 mL phosphate buffer pH 7.2 meets Q ≥ 80% in 15 min. Granules are reconstituted to 20 mg/mL ibuprofen equivalent. Sachet packaging with desiccant sachets is mandatory above 2.0% residual moisture because caking from lysine salt water uptake has been observed in long-term storage above 30 °C/65% RH.
A single-dose oral solution of ibuprofen lysine equivalent to 20 mg/mL ibuprofen is buffered to pH 5.8–6.5 because the lysine salt hydrolyses sufficiently at lower pH to reduce microbiological stability of preservatives. Benzoic acid preservative activity is poor above pH 5.5, so the formulation uses methyl 4-hydroxybenzoate at 0.18% w/v and propyl 4-hydroxybenzoate at 0.02% w/v to meet the Ph. Eur. 5.1.3 antimicrobial effectiveness criteria. The solution contains 10% w/v sorbitol as a tooth-friendly sweetener, 0.05% w/v citric acid monohydrate as buffer, and 0.3% w/v hydroxyethylcellulose as a viscosity modifier. Aqueous salt formation permits complete dissolution without co-solvents, but the solution should be protected from light using amber glass or opaque polyethylene terephthalate bottles because UV exposure accelerates oxidation of the isobutyl substituent on the propionic acid side chain. Aldehydic flavour compounds such as vanillin are incompatible because the primary amine of lysine forms Schiff bases and progressively yellows the solution. The solution is filled into 100 mL or 200 mL multidose bottles with a dosing syringe graduated in 0.5 mL increments. Delivered-dose uniformity testing per Ph. Eur. 2.9.27 is required due to the multidose container format. Residual oxygen in headspace should be reduced by nitrogen flushing to ≤ 2% oxygen. Physicochemical stability at 25 °C/60% RH is maintained for 24 months when the closure system has a moisture vapour transmission rate below 0.2 mg/day.
Aseptic processing of ibuprofen lysine injection begins with dissolution of the salt in Water for Injection to a concentration equivalent to 5 mg/mL ibuprofen. The solution is tonified to 270–300 mOsm/kg using sodium chloride 9 mg/mL or mannitol 50 mg/mL when neonatal sodium load must be reduced. The pH is adjusted to 7.0–7.4 with 1 M sodium hydroxide or 1 M hydrochloric acid; after adjustment, the solution is not held longer than 4 h prior to filtration because the buffering capacity of lysine can produce pH drift. Terminal moist heat sterilization at 121 °C for 15 min is evaluated for concentrates exceeding 50 mL fill volume, but published data for autoclave stability of ibuprofen lysine at 5 mg/mL is limited. Where terminal sterilization is not validated, filtration through 0.22 µm polyethersulfone filters is used, followed by aseptic fill in an isolator. Subvisible particulate counts per Ph. Eur. 2.9.19 must remain below 25 particles/mL ≥ 10 µm and 3 particles/mL ≥ 25 µm, corresponding to USP Chapter 788 parenteral limits. Bacterial endotoxin limit per Ph. Eur. 2.6.14 is ≤ 0.35 IU/mg ibuprofen. Sterility is tested per Ph. Eur. 2.6.1 with no growth after 14 days. Dilution into 5% w/v glucose infusion bags is acceptable only when the final pH remains above 5.5; below this threshold, free ibuprofen acid may precipitate. Primary stability data for diluted solutions support use within 24 h at 2–8 °C. Point-of-administration inline filtration with 0.22 µm filters is used for neonatal infusions. The infusion is delivered over 15 min; rapid intravenous bolus is not used. The concentrate contains no benzyl alcohol because neonatal benzyl alcohol exposure is associated with metabolic acidosis and respiratory depression.
| Test | Method | Specification | Analytical Technique |
|---|---|---|---|
| Sterility | Ph. Eur. 2.6.1 | No growth after 14 days | Sterility isolator |
| Bacterial endotoxin | Ph. Eur. 2.6.14 | ≤ 0.35 IU/mg ibuprofen | LAL kinetic turbidimetric |
| Subvisible particulate matter | Ph. Eur. 2.9.19 / USP Chapter 788 | ≤ 25 particles/mL ≥ 10 µm; ≤ 3 particles/mL ≥ 25 µm | Light obscuration |
| pH | Ph. Eur. 2.2.3 | 7.0–7.4 | Potentiometric |
| Osmolality | Ph. Eur. 2.2.35 | 270–300 mOsm/kg | Freezing-point depression |
| Related substances | Ph. Eur. 2.2.29 | Unknown impurities ≤ 0.2%; total ≤ 0.5% | HPLC-UV |
Effervescent tablets containing ibuprofen lysine equivalent to 400 mg ibuprofen require water-free granulation and external lubrication to prevent premature carbon dioxide evolution and punch sticking. The excipient base is prepared by melt granulation of anhydrous citric acid and sodium bicarbonate at a molar ratio of 1:2.5, using polyethylene glycol 6000 at 58–62 °C as the melt binder. After cooling and milling, the granulate is blended with 342 mg or 684 mg ibuprofen lysine to achieve 200 mg or 400 mg ibuprofen equivalents, then compressed at low force between 8 kN and 12 kN. Lubrication is applied by an external vibrating brush system delivering 0.2–0.4 g/h magnesium stearate to the die wall region, because internal lubrication would coat the acid and carbonate particles and delay disintegration. The finished tablet disintegrates in 200 mL water at 15–25 °C within 2–3 min under Ph. Eur. 2.9.1, producing a clear solution with no residual particles above 710 µm. Sodium content per 400 mg ibuprofen tablet reaches 250–300 mg, which is a limiting factor in patients with restricted sodium intake. Effervescent tablets must be packed in aluminium strip packs with desiccant; residual moisture in the cavity must be verified below 0.5% to prevent slow acid-base reaction during storage. Dissolution testing is not applicable after full disintegration; instead, solution pH after 3 min is controlled between 4.2 and 5.0.
Orodispersible tablets of ibuprofen lysine equivalent to 20 mg ibuprofen are manufactured by freezing and lyophilising aqueous suspensions directly in blister pockets. The suspension contains 5.0% w/w mannitol, 2.0% w/w glycine, 0.5% w/w xanthan gum, and the lysine salt dissolved in the aqueous phase. Flash freezing to -40 °C is followed by primary drying at a shelf temperature of 20 °C and chamber pressure 80–120 µbar for 18 h. The critical process parameter is the collapse temperature of the lyophilised matrix; product temperature must not exceed -32 °C during primary drying, otherwise the matrix collapses and the porous structure is lost. Residual moisture after drying is controlled at ≤ 2.0%; above 3.0% the unit becomes sticky and adheres to lidding foil. Because ibuprofen lysine ionises rapidly in saliva, taste masking with a weakly acidic cation exchange resin at 1:1 w/w drug-resin ratio reduces bitterness, but adds 2–3 min to aqueous dissolution. The final lyophilised units are tested for uniformity of dosage units per Ph. Eur. 2.9.40 because segregation of the suspension can occur before freezing. Breaking force of these lyophilised tablets is low, typically 0.2–0.5 kg; they are therefore not handled outside the blister pack. Dissolution in the oral cavity occurs within 30 s without water, but this is an in vivo observation and not a compendial release test.
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Ibuprofen Lysine Pharma Grade API for tablet, capsule, granule, and injection dosage forms is a 1:1 molar salt of racemic ibuprofen and L-lysine. The anhydrous substance has the molecular formula C19H32N2O4 and a nominal molecular weight of 352.47 g/mol; the ibuprofen acid moiety accounts for approximately 58.5% by mass. The material is released as a white or almost white crystalline powder under current good manufacturing practice aligned with ICH Q7 and 21 CFR 211, with batch-specific certificates of analysis. Supply differentiation is based on particle-size distribution, residual solvent profile, and bacterial endotoxin control rather than a single universal model number; a typical commercial reference for an injectable-grade crystalline powder is IBU-LYS-PH-02 or equivalent. The salt is specified for oral and injectable processing because the L-lysine counterion confers aqueous solubility that cannot be achieved with ibuprofen free acid without salt formation or cosolvent addition.
Compendial identity is confirmed by infrared absorption against the reference standard and by retention time in liquid chromatography. When a finished product includes a parenteral claim, sterility, endotoxin, and particulate matter are controlled at the drug product level rather than as universal API monograph tests. The API is nevertheless selected and released with extendable parenteral-grade testing where required by the approved dossier.
The salt is produced by reaction of ibuprofen acid with L-lysine in a suitable solvent, followed by crystallization, filtration, drying, and milling. The crystallization solvent and cooling rate influence crystal habit, residual solvent, and particle size; a controlled cooling profile and seeded crystallization are common to avoid acicular growth. Milling is performed under nitrogen or low-humidity air to reduce moisture uptake. Each batch is sampled using a validated sampling plan linked to batch size, and release testing is performed on representative composite samples.
Ibuprofen free acid is classified as practically insoluble in water under Ph. Eur. solubility criteria, with a solubility limit below 0.1 mg/mL at 25°C. The lysine salt is classified as freely soluble, meaning the aqueous solubility is defined by the pharmacopoeial threshold of ≥100 mg/mL at 25°C. The increase in dissolved drug concentration changes the dissolution step from a rate-limiting barrier to a formulation-controlled variable for tablets and capsules. Dissolution testing of immediate-release oral forms is typically performed with USP Apparatus 2 at 50 rpm in 900 mL of buffered medium; the salt form reaches a high dissolved concentration more rapidly than micronized free acid in pH 4.5–6.8 media, but the equilibrium concentration at low gastric pH can still be limited by precipitation of the less soluble acid. Published data for this specific configuration is limited to formulation-specific dissolution profiles, so a formulator must generate comparative intrinsic dissolution data under the target pH and ionic strength.
Dose conversion is not 1:1 between ibuprofen free acid and ibuprofen lysine. A label claim of 200 mg ibuprofen requires approximately 342 mg of anhydrous ibuprofen lysine using the 58.5% active moiety factor. If the batch is a hydrate or carries variable adsorbed water, the required mass is corrected by Karl Fischer titration per USP <921> or Ph. Eur. 2.5.12. This correction is critical in low-dose tablet and liquid-fill capsule manufacture where stoichiometric drift changes label claim and impurity exposure per dose.
For oral granules and sachets, the freely soluble salt may be selected for faster dissolution onset, but the formulation must control local gel formation when contacting water. Dissolution testing is performed with USP Apparatus 2 or 3 depending on the dosage form; the product-specific acceptance criterion is justified by a discriminating method developed during ICH Q2(R2) validation. Analytical range, linearity, and precision follow ICH Q2(R2), and the dissolution method must distinguish between the salt form and the precipitated acid if the medium pH is below the pKa of ibuprofen.
Laser diffraction particle sizing aligned with ISO 13320 is used to control the solid-dosage grade. Representative release criteria for tablet and capsule use include a D90 below 250 µm and a D50 in the 60–140 µm range; injection-grade material may be supplied as a micronized or crystalline cut with tighter upper-size control to facilitate filterability. These ranges are product-specific release criteria rather than universal pharmacopoeial requirements, and published data for this specific configuration is limited. Bulk and tapped density are determined by USP <616> or Ph. Eur. 2.9.34. A compacted bulk density below 0.35 g/mL can produce poor flow from the hopper and requires forced feeding on a rotary tablet press. Content uniformity is evaluated with USP <905>; particle size segregation in low-dose blends becomes more likely when D90 exceeds 250 µm or when the particle shape is acicular.
High-shear wet granulation of ibuprofen lysine reaches the granulation endpoint earlier than ibuprofen free acid because the dissolved salt can act as a binding phase. A 100–300 L high-shear mixer with impeller tip speed of 2–6 m/s is a common scale range for pilot and production batches; water addition is controlled by torque or power consumption rather than fixed volume. Overwetting produces bimodal granule size distributions and hard aggregates that can raise tablet hardness and slow disintegration. Fluid-bed granulation with inlet air dewpoint below -10°C and product temperature of 30–45°C is an alternative when a more porous granule is needed. Direct compression is generally feasible only with densified or co-processed material because standard crystalline powder has insufficient flow and compressibility on high-speed presses.
Tablets containing ibuprofen lysine generally require a compression force in the range of 8–16 kN on a single-station or rotary press with flat-faced or shallow concave punches, but the exact force is dependent on formulation filler and lubricant. Magnesium stearate levels above 0.5% w/w can reduce tensile strength of high-solubility salt formulations; mixing time should be controlled to 3–5 minutes to limit overlubrication. Tablet hardness and disintegration are monitored by USP <701> and USP <1217>.
Capsule and granule operations require residual moisture control. Granules are dried to a target residual water content below 1.0% before tableting or encapsulation to reduce sticking, moisture-mediated degradation, and weight variability. Drying is typically performed in a fluid-bed dryer with end-point determined by loss on drying at 105°C or by Karl Fischer titration. If ambient relative humidity exceeds 60%, pre-drying of the API and humidity-controlled blending suites are required; polyester/polyethylene-lined double bags with desiccant are common for intermediate storage.
The freely soluble lysine salt permits aqueous parenteral formulations without organic cosolvents or pH-shifting agents. Injectable-grade ibuprofen lysine is released with bacterial endotoxin and bioburden limits that are dose-based and defined in the finished product application; a universal API endotoxin limit is not assigned by the pharmacopoeial monograph. Endotoxin is tested by USP <85> or Ph. Eur. 2.6.14. The finished injection is controlled for subvisible particulates by light obscuration particle counting per USP <788>, and the bulk solution is passed through a 0.2 µm sterilizing-grade filter before aseptic filling or terminal sterilization. Container compatibility and extractables/leachables are assessed under USP <1663> and relevant parenteral stability protocols.
Injectable-grade API is not necessarily sterile as supplied; it is bioburden-controlled and intended for subsequent sterile filtration or aseptic processing. Sterility of the finished injection is tested per USP <71> or Ph. Eur. 2.6.1. The dissolved salt produces a solution with a measured pH in the approximate range 6.5–7.5 at therapeutic dilution; the exact value is lot- and water-quality-dependent.
Compounding of injectable solutions requires attention to pH and electrolyte content. Contact with strong mineral acids can precipitate ibuprofen acid. Calcium- or magnesium-containing infusion fluids may present compatibility challenges; visual precipitation, subvisible particle formation, and API assay must be monitored when mixed with other infusions. Terminal sterilization of ready-to-use bags may generate degradation products if exposure time exceeds the validated heat load; container closure integrity testing is therefore part of the drug product control strategy.
Ibuprofen lysine is one of several water-soluble ibuprofen salts. Ibuprofen sodium has a nominal molecular weight of 228.26 g/mol and an ibuprofen moiety mass fraction of approximately 90.4%; this lower molecular weight per active moiety reduces the mass of API required for a given dose but adds sodium. Ibuprofen arginine has a nominal molecular weight of approximately 380.48 g/mol for the 1:1 salt and an active moiety mass fraction near 54.2%. The lysine salt is intermediate in molar mass and active content, while avoiding the sodium load of the sodium salt. Selection among these salts is driven by the target route of administration, national monograph acceptance, patent status, and stability data of the finished product.
| Parameter | Ibuprofen Free Acid | Ibuprofen Lysine | Ibuprofen Sodium |
|---|---|---|---|
| Aqueous solubility class at 25°C | Practically insoluble (0.1 mg/mL) | Freely soluble (≥100 mg/mL) | Freely soluble (≥100 mg/mL) |
| Nominal molecular weight | 206.28 g/mol | 352.47 g/mol | 228.26 g/mol |
| Ibuprofen moiety by mass | 100% | 58.5% | 90.4% |
| Feasible dosage routes | Oral solid; injectable requires pH adjustment or cosolvent | Oral solid, granule, parenteral | Oral solid, parenteral |
| Hygroscopicity | Low | Moderate to high; requires humidity control above RH 60% | Moderate to high |
The API release specification includes identification, assay, related substances, water content, residual solvents, and elemental impurities. A representative specification for pharma-grade material includes assay by HPLC of 98.5%–101.0% on the dried basis, related substances with total impurities ≤0.5% and unspecified individual impurities ≤0.10%, and water content ≤5.0%. These limits are typical but must be verified against the specific monograph or drug master file for the site of manufacture. Residual solvents are controlled under ICH Q3C and USP <467>; class 2 solvents require gas chromatographic quantification with limits based on the administered daily dose. Elemental impurities are controlled under ICH Q3D and tested by USP <232>/<233> or equivalent plasma-based methods; parenteral and oral routes have different permitted concentrations.
| Quality attribute | Reference standard/method | Representative release criterion |
|---|---|---|
| Appearance | Visual / Ph. Eur. 2.2.1 | White or almost white crystalline powder |
| Assay | HPLC, Ph. Eur. 2.2.29 / USP <621> | 98.5–101.0% dried basis |
| Related substances | HPLC, Ph. Eur. 2.2.29 / ICH Q3A | Total ≤0.5%; unspecified ≤0.10% |
| Water content | Karl Fischer, USP <921> / Ph. Eur. 2.5.12 | ≤5.0% |
| Residual solvents | ICH Q3C / USP <467> | Class 2 solvents within daily dose limits |
| Elemental impurities | ICH Q3D / USP <232>, <233> | Parenteral or oral limits per route |
| Bacterial endotoxin (injectable grade) | USP <85> / Ph. Eur. 2.6.14 | Dose-based limit from finished product |
Storage and handling require protection from moisture and low-pH conditions. The API is hygroscopic above 60% RH and is packaged in double polyethylene bags with desiccant inside a sealed HDPE drum. Stability studies for the API are conducted according to ICH Q1A; long-term storage at 25°C/60% RH and accelerated storage at 40°C/75% RH are used to assign retest periods. The salt is incompatible with strong oxidizing agents and concentrated mineral acids; aqueous solutions should not be mixed with acid-containing formulations because ibuprofen acid may precipitate. If the crystallization solvent system changes, residual solvent and crystal habit must be re-qualified under ICH Q3C and particle size release controls. Any blending equipment must be cleaned of oxidizers before use.
