| HS Code | 990360 |
| Product Name | 5-ACETOACETYLAMINO BENZIMIDAZOLONE (AABI) Pharma Grade API |
| Grade | Pharma Grade API |
| Dosage Forms | Tablet, Capsule, Granule, Injection |
| Routes Of Administration | Oral, Injectable |
| Cas Number | 26576-46-5 |
| Molecular Formula | C11H11N3O3 |
| Molecular Weight | 233.23 g/mol |
| Chemical Name | N-(2-Oxo-2,3-dihydro-1H-benzimidazol-5-yl)-3-oxobutanamide |
| Synonyms | AABI; 5-Acetoacetylamino-2-benzimidazolinone; 5-(Acetoacetylamino)benzimidazolone |
| Appearance | White to off-white crystalline powder |
| Assay | ≥98.0% |
| Melting Point | >300°C (decomposes) |
| Solubility | Slightly soluble in water; soluble in DMSO, DMF, and aqueous alkali |
| Loss On Drying | ≤0.5% |
| Heavy Metals | ≤10 ppm |
| Residual Solvents | Meets ICH Q3C limits |
| Storage Conditions | Store in a cool, dry, well-ventilated area away from direct light |
| Shelf Life | 24 months when stored properly |
| Packaging | 25 kg fiber drum with double polyethylene bags; smaller pack sizes available |
| Sterility | Sterile grade available for injectable use |
As an accredited 5-ACETOACETYLAMINO BENZIMIDAZOLONE (AABI) 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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Under high-speed rotary compression, 5-acetoacetylamino benzimidazolone (AABI, CAS 26576-46-5, relative molecular mass 233.23) powders with a median particle diameter below 15 µm and a d90 below 60 µm create die-fill variability because the acetoacetamide side chain increases interparticulate friction and raises the compressibility index above 25% in unlubricated blends. A direct-compression process is therefore limited to a drug loading of 5.0–25.0% w/w; above this range, blend flow measured by USP 1174 shifts from passable to poor. Typical auxiliary solids are microcrystalline cellulose (45.0–70.0% w/w) with anhydrous lactose q.s. to 100%, croscarmellose sodium at 2.0% w/w, colloidal silicon dioxide at 0.5% w/w, and magnesium stearate at 0.75% w/w. Direct compression is executed on a 16-station rotary tablet press with B-tooling, operating at 60–80 rpm and a compression force of 8–14 kN. Tablet hardness is maintained between 60 and 90 N, and friability is held below 0.8% according to USP 1216. Release testing follows USP 905 for uniformity of dosage units, USP 711 for dissolution in 0.05 M phosphate buffer at pH 6.8 and 75 rpm paddle speed, and ICH Q3D for elemental impurity control. The finished product types are immediate-release uncoated tablets and aqueous film-coated tablets. No official USP, Ph. Eur., or JP monograph for AABI exists at the time of writing; therefore the release specification is built from ICH Q6A decision trees and validated under 21 CFR 211.194. Published product-specific direct-compression data for AABI is limited, and the load limits above should be confirmed through process qualification batches before commercial registration.
When the target tablet mass exceeds 500 mg and AABI loading moves above 30.0% w/w, direct compression encounters capping at ejection pressures above 15 kN. Roller compaction becomes the preferred dry-granulation route. In a roller compactor with 200 mm roll diameter and 75 mm roll width, the blend is densified at roll force 8.0–16.0 kN/cm, roll speed 4–12 rpm, and gap 2.0–3.5 mm. Ribbon density is controlled to 0.90–1.10 g/cm³ because lower ribbon density generates excessive fines during subsequent milling, while higher ribbon density reduces compactibility at recompression. The ribbons are milled through an oscillating granulator fitted with a 0.8 mm or 1.0 mm screen and then blended with extra-granular disintegrant. AABI loadings of 35.0–55.0% w/w are used with microcrystalline cellulose 25.0–45.0% w/w, mannitol 5.0–10.0% w/w, crospovidone 3.0–5.0% w/w, colloidal silicon dioxide 0.2–0.5% w/w, and sodium stearyl fumarate 0.5–1.0% w/w. The most serious process conflict is overlubrication: sodium stearyl fumarate above 1.5% w/w or magnesium stearate above 0.5% w/w decreases the tensile strength of the recompressed tablet below 1.0 MPa, causing edge splitting during film coating. In-process control follows FDA 21 CFR 211.110 blend uniformity sampling; release testing uses USP 905 and USP 711. Terminal dosage forms are high-dose film-coated tablets and, where segregation is excipient-driven, bilayer immediate-release tablets. Published data for this specific AABI dry-granulation configuration is limited; the equipment settings given are based on roller-compactor manufacturer validation bulletins and pharmaceutical dry-granulation scale-up practice, not on a marketed AABI product.
Typically, high-shear wet granulation is introduced only after direct compression and roller compaction have failed to deliver hardness or content uniformity at AABI loadings above 55.0% w/w, or when a matrix tablet requires a densified granular fraction. The aqueous binder is prepared as a 5.0% w/v polyvinylpyrrolidone K30 solution; binding liquid is added at 0.45–0.55 kg/kg dry solids in a high-shear granulator operating at impeller 300–500 rpm and chopper 1500–3000 rpm for 3–5 min. The acetoacetamide substituent imposes a hard boundary: granulation pH must remain between 4.0 and 7.0. Strongly alkaline binders such as sodium bicarbonate or sodium hydroxide raise the local pH above 8.5 and accelerate hydrolytic cleavage of the acetoacetamide group; this produces an amine-type degradation product and reduces the HPLC assay below the 98.0% release threshold determined under USP 621. Drying is performed in a fluid-bed dryer with inlet air 50–70°C, product temperature 35–45°C, and loss on drying 1.5–2.5% by USP 731. The lubricated granule is milled to a target particle size of 150–450 µm before tablet compression. Formulation includes AABI at 50.0–70.0% w/w, microcrystalline cellulose 15.0–30.0% w/w, hypromellose K4M 10.0–20.0% w/w, and magnesium stearate 0.5% w/w. The release matrix controls dissolution according to USP 711 over 8–12 h. ICH Q3C residual solvent limits apply if non-aqueous binder solvents are introduced; the preferred aqueous process removes that risk. Finished product types are extended-release matrix tablets, enteric-coated tablets, and dry granulate for further blending into encapsulated modified-release beads. As with other AABI granulation routes, published product-specific compatibility data is limited, but the pH restriction is based on the known susceptibility of β-keto amide substituents to alkaline hydrolysis.
Low-shear blending followed by automated capsule filling imposes narrower limits on AABI particle-size distribution than rotary tablet compression because dosator filling depends on plug formation under controlled volume. For low-dose capsule formulations, AABI is blended at 5.0–15.0% w/w with lactose monohydrate q.s. to 100%, microcrystalline cellulose 10.0–20.0% w/w, pregelatinized starch 5.0% w/w, croscarmellose sodium 2.0% w/w, and magnesium stearate 0.5% w/w. The blend is sieved through a 0.5 mm screen and mixed in a bin blender at 10–15 rpm for 15 min; blend bulk density should be kept above 0.55 g/mL to achieve consistent fill weights on a dosator machine running at 70,000 capsules/h. Tamping-pin systems, operating at 150,000 capsules/h on equipment such as a Bosch GKF 2500, tolerate a wider Carr index range but require a lubricated, non-agglomerated powder; the Carr index should remain below 25% under USP 1174. For high-dose capsules, roller-compacted granules with AABI 40.0–60.0% w/w are filled into size 0 to size 3 hard gelatin capsules to a fill weight of 200–500 mg. Capsule weight variation is tested by USP 905; dissolution is tested by USP 711 using 900 mL of 0.05 M phosphate buffer at pH 6.8 and 75 rpm paddle speed. ICH Q3D applies for elemental impurities in the filled capsule. Terminal finished types are immediate-release hard gelatin capsules, hydroxypropyl methylcellulose vegetarian capsules, and granules-filled capsules with enteric coating applied to the granules rather than the capsule shell. The process boundary is fill-weight variance above 3.0% RSD: dosator fillers require re-optimization of plug depth and ejection force when AABI blends contain more than 0.75% w/w magnesium stearate.
If the sterile product cannot be autoclaved because the acetoacetamide group undergoes pH-dependent hydrolysis under moist heat, the manufacturing train shifts to aseptic freeze-drying. AABI is dissolved at 2.0–10.0 mg/mL in water for injection containing buffering salts to maintain pH 6.0±0.5, with 5.0–15.0% v/v polyethylene glycol 300 as co-solvent and polysorbate 20 at 0.05–0.10% w/v as wetting agent. Bulking agents mannitol (4.0–5.0% w/v) and sucrose (2.0% w/v) produce a cake with a reconstitution time below 90 s. The solution is sterile-filtered through a 0.22 µm polyvinylidene fluoride membrane with an integrity test performed according to 21 CFR 211.113. Freeze-drying comprises freezing to −40°C at 0.5–1.0°C/min; primary drying at −15°C with chamber pressure 0.2–0.3 mbar for 24–48 h; and secondary drying at 25°C for 4 h to a Karl Fischer moisture limit of ≤1.0% using USP 921 Method Ic. The operation is housed in an EU GMP Annex 1 Grade A zone meeting ISO 14644-1 Class 5 at rest within a Grade B suite meeting Class 7 at rest. Terminal product types are single-dose lyophilized powder for injection, vials for reconstitution with 0.9% sodium chloride before injection, and dual-chamber vials where particulate control demands an inline 5 µm prefilter before the 0.22 µm final filter. Published data for AABI-specific injectables is limited; the pH and heat restrictions are derived from the known hydrolysis of β-keto amide groups under alkaline autoclaving conditions.
| Quality attribute | Standard/method | Acceptance criterion |
|---|---|---|
| Particulate matter in injections | USP 788 | ≥10 µm: NMT 6000 per container; ≥25 µm: NMT 600 per container |
| Bacterial endotoxins | USP 85 | NMT 0.25 EU/mg |
| Sterility | USP 71 | No growth after 14 days |
| Water content | USP 921 Method Ic | ≤1.0% |
| Uniformity of dosage units | USP 905 | Acceptance value ≤15 |
In fluidized-bed spray granulation, the feed suspension is sprayed onto a seed bed with a top-spray nozzle in a Glatt GPCG 3.1; inlet air temperature is 60–70°C, atomizing air 1.5–2.0 bar, spray rate 20–50 g/min, and product temperature 30–35°C. AABI is suspended in an aqueous binder solution containing hypromellose E5 at 3.0–5.0% w/w of dry granule mass; the drug loading is 10.0–30.0% w/w. The granule size target is 150–500 µm with fines below 75 µm limited to 10.0% to prevent segregation during sachet filling. Excipients include sorbitol 40.0–55.0% w/w, xylitol 10.0–15.0% w/w, xanthan gum 0.2–0.5% w/w, citric acid 0.1–0.3% w/w, and colloidal silicon dioxide 0.5% w/w. Process humidity is held below 50% RH; higher moisture increases granule cohesiveness and sachet weight variability. The granules are filled at 500–1000 mg per unit-dose sachet on an auger filler with mass verification by checkweigher; content uniformity follows USP 905, and dissolution follows USP 711. Reconstitution to 100 mL oral suspension in water requires a suspending agent and a pH between 4.0 and 7.0; strongly alkaline water raises the pH above 8.5 and initiates acetoacetamide cleavage. Finished product types are single-dose sachets, granules for oral suspension, and granules for extemporaneous compounding under USP 795. Since AABI-specific powder-mechanics data are scarce, the particle-size and humidity limits above should be verified with a full factorial design under ICH Q8(R2) before process qualification.
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5-Acetoacetylamino benzimidazolone (AABI) is supplied as a pharma-grade active pharmaceutical ingredient intended for oral tablet/capsule/granule and injectable formulation platforms. The molecular formula C11H11N3O3 and molecular weight 233.22 g/mol correspond to CAS 26576-46-5. Manufactured grades are designated AABI-PM for micronized direct compression, AABI-CG for granule and capsule processes, and AABI-INJ for injectable preparation. Because no dedicated pharmacopoeial monograph is published for this specific structure, the release specification follows the ICH Q6A decision-tree framework and uses general chapters from USP and Ph. Eur. for method verification. The 5-position acetoacetylamino substituent introduces a β-ketoamide hydrogen-bonding motif that affects crystal habit, milling energy, dissolution rate, and compatibility with common excipients. For oral solid processing, the API is released with controlled particle size and residual impurities; for injectable processing, the AABI-INJ grade is released with reduced bioburden, subvisible particulate control, and endotoxin testing. The product is supplied as an off-white to pale yellow crystalline powder with assay ≥99.0% and total related substances ≤1.0% when measured by high-performance liquid chromatography using USP <621> integration parameters.
Lot release for the AABI-PM grade includes particle size distribution by laser diffraction under ISO 13320:2020. The acceptance band is typically D10 ≥2 µm, D50 10–30 µm, and D90 ≤100 µm when the drug load is below 10 mg and direct compression is used. The AABI-CG grade is specified with a broader distribution, commonly D50 30–80 µm and D90 ≤250 µm, to support wet granulation after dry mixing. These limits are tied to content uniformity because low-dose tablets require a minimum number of API particles per individual dosage unit. A D90 above 100 µm can reduce the number of particles below the threshold at which acceptance value under USP <905> remains below 15 for 10 units.
Bulk density and tapped density are determined by USP <616> Method I. The compressibility index and Hausner ratio are calculated from the difference between tapped and bulk densities. A compressibility index below 25% and Hausner ratio below 1.30 are targeted for the direct compression grade. Powder flow is measured through a 15 mm orifice per USP <1174>; flow rates between 10 g/s and 25 g/s are considered suitable for gravity feeding on a high-speed rotary press. When flow falls outside this range, the press is configured with a force feeder and the hopper vibration set point is adjusted.
Wet granulation of AABI is performed in a high-shear mixer with a 25 L bowl and an impeller tip speed of 2–5 m/s. Purified water or a hydroalcoholic binder solution is added at 1–3% of dry mass per minute. The endpoint is monitored by impeller torque; a value of 0.5–1.5 N·m corresponds to a densified wet mass that can be extruded through a 1.0 mm screen. Drying in a fluid-bed dryer with inlet air at 60 °C continues until loss on drying by USP <731> is ≤2.0%. The dried granule is milled through a 0.8 mm screen and blended with extragranular disintegrant and lubricant. Tablet compression is performed on a rotary press with precompression and main compression stations; the precompression force is set at 2–5 kN and main compression force at 8–15 kN for a standard concave tooling diameter of 8 mm.
In compaction studies, the compressed material exhibits plastic deformation under load; the addition of microcrystalline cellulose and crospovidone provides disintegration. Friability is measured by USP <1216> with a limit of ≤1.0% after 100 revolutions. Disintegration is performed by USP <701> in water at 37 °C with discs; immediate-release formulas disintegrate within 15 min. Dissolution is monitored by USP <711> apparatus 2 at 50 rpm in 900 mL of 0.1 M hydrochloric acid or pH 6.8 phosphate buffer.
For injectable-grade release, the AABI-INJ grade is tested for bacterial endotoxins by chromogenic or gel-clot methods under USP <85> or Ph. Eur. 2.6.14. The acceptance criterion is derived from the maximum intravenous dose. For an adult dose of 1 g/day, an API limit of ≤0.25 EU/mg is applied; this maintains the endotoxin load below the 5 EU/kg threshold. For higher unit doses or extended infusion volumes, the criterion is tightened proportionally. The API is not sterile, but release includes total aerobic microbial count ≤100 CFU/g and total yeast and mould ≤10 CFU/g by USP <61>. Pathogen absence for Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, and bile-tolerant Gram-negative bacteria is verified by USP <62>.
Subvisible particulate matter in the finished injectable solution is tested by light obscuration under USP <788> Method 1. For solutions with nominal volumes ≤100 mL, the acceptance limit is ≤6000 particles/container at ≥10 µm and ≤600 particles/container at ≥25 µm. The API contributes to this burden if the dissolution process leaves insoluble matter; the injectable grade is therefore dissolved in a pH-adjusted vehicle and filtered through a 0.22 µm sterilizing-grade membrane before filling. Filter compatibility is confirmed by measuring differential pressure across the membrane at constant flow. If the pressure exceeds 0.5 bar at 20 °C, the solution is diluted or the filtration area is increased.
Equilibrium solubility is measured by the shake-flask method at 25 °C in 0.1 M hydrochloric acid, acetate buffer pH 4.5, and phosphate buffer pH 7.4. Published data for AABI in biorelevant media are limited; formulation studies therefore use the measured solubility as the basis for selecting co-solvents such as propylene glycol, polyethylene glycol 300, or ethanol. The final injection is adjusted to pH 7.0–7.8 if the molecule is neutral in that range; otherwise a buffered system is used. Terminal sterilisation at 121 °C for 15 min is acceptable only when forced degradation shows no unspecified impurity exceeding 0.05%. If thermal stability is insufficient, aseptic filtration is employed.
Under ICH Q3C Option 1, residual solvent control in AABI avoids Class 1 solvents. Methanol, acetone, and N,N-dimethylformamide are monitored by headspace gas chromatography using USP <467> or Ph. Eur. 2.4.24. A representative specification is methanol ≤3000 ppm, acetone ≤5000 ppm, and N,N-dimethylformamide ≤880 ppm. Elemental impurities are controlled by inductively coupled plasma mass spectrometry under ICH Q3D; oral and injectable grades use the permitted daily exposure values for cadmium, lead, arsenic, mercury, cobalt, vanadium, and nickel normalized to the maximum daily dose. For a 10 g/day intake, the oral specification corresponds to ≤0.5 µg/g cadmium, ≤0.5 µg/g lead, ≤1.5 µg/g arsenic, ≤3.0 µg/g mercury, ≤5.0 µg/g cobalt, ≤10.0 µg/g vanadium, and ≤20.0 µg/g nickel. The injectable grade applies lower limits for cadmium, mercury, cobalt, vanadium, and nickel because parenteral exposure is more restrictive.
Moisture sorption is evaluated by dynamic vapour sorption from 0 to 90% RH at 25 °C. If the mass gain exceeds 0.5% at 60% RH, packaging includes desiccant and storage is controlled below 60% RH. The product is stored in double polyethylene liners inside a fibre drum. The recommended storage range is 15–25 °C, with short-term excursions to 30 °C permitted if data from ICH Q1A stability protocols support that condition.
For the pharma-grade product, the release specification combines general pharmacopoeial chapters with product-specific acceptance criteria. Because no individual monograph exists, the tests shown in the table are selected from the ICH Q6A universal and specific tests for drug substances produced by chemical synthesis.
| Attribute | Method / Standard | Acceptance criterion |
|---|---|---|
| Appearance | Visual / Ph. Eur. 2.2.1 | Off-white to pale yellow powder |
| Identification | Infrared absorption USP <197K> or Ph. Eur. 2.2.24 | Corresponds to reference spectrum |
| Assay | High-performance liquid chromatography USP <621> | 99.0–101.0% on dried basis |
| Related substances | HPLC area normalisation | Total impurities ≤1.0%; any unspecified impurity ≤0.10% |
| Loss on drying | USP <731> | ≤0.5% oral; ≤1.0% injectable |
| Residue on ignition | USP <281> | ≤0.1% |
| Elemental impurities | ICP-MS ICH Q3D | Route-specific limits as above |
| Residual solvents | USP <467> / ICH Q3C | Methanol ≤3000 ppm; DMF ≤880 ppm |
| Particle size | Laser diffraction ISO 13320:2020 | D90 ≤100 µm for AABI-PM; D90 ≤250 µm for AABI-CG |
| Melting range | USP <741> | Controlled against qualified reference standard |
| Bulk/tapped density | USP <616> | Compressibility index <25 targeted |
| Microbial limits | USP <61> / USP <62> | TAMC ≤100 CFU/g; TYMC ≤10 CFU/g |
| Bacterial endotoxins | USP <85> | ≤0.25 EU/mg injectable grade |
In capsule filling, AABI is processed on dosator-type or tamping-pin machines. The AABI-CG grade is blended at 2–10% drug load with pregelatinized starch, lactose monohydrate, and microcrystalline cellulose to achieve the plug compression required for dosator transfer. Powder bed cohesion is controlled by measuring compressibility index and Hausner ratio; values of 15–25% and 1.15–1.30 reduce weight variation. For capsules containing ≤25 mg AABI, the API is pre-blended with a coloured diluent to allow visual confirmation of distribution. Content uniformity is tested by USP <905>; the acceptance value is ≤15 for 10 units at the initial stage. If the acceptance value is between 15 and 25, 20 additional units are tested. Dissolution testing of capsules uses USP <711> apparatus 2 at 50 rpm in 900 mL of pH 6.8 phosphate buffer with sampling at 15, 30, 45, and 60 min. Immediate-release criteria require mean release of not less than 75% at 45 min for routine quality control, subject to product-specific validation.
For granules for oral suspension, the wet granulation described for tablets is followed by dry sizing and blending with sodium carboxymethylcellulose and sucrose or sorbitol. The granule is packaged in a sachet; redispersion is assessed by pouring into 150 mL water at 25 °C and stirring at 50 rpm. A suspension that passes a 710 µm wet screen without retaining more than 5% residue is considered suitable. The pH of the reconstituted suspension is adjusted to 4.0–6.0 to balance chemical stability and palatability.
Pharma-grade AABI differs from technical-grade material in impurity profile, residual solvent control, and particle engineering. Technical-grade AABI is typically released at 97.0% assay and may contain the parent 5-aminobenzimidazolone at ≥0.5%, along with acetoacetylation side products. Pharma-grade material is recrystallized from ethanol or a water/ethanol mixture to reduce the 5-aminobenzimidazolone precursor to ≤0.10% and total related substances to ≤1.0%. Positional isomers, such as 4-acetoacetylamino benzimidazolone, are controlled by a retention-time marker at ≤0.10% because the substitution pattern affects crystal packing, melting behaviour, and dissolution.
Compared with 5-aminobenzimidazolone, AABI carries the acetoacetyl group and therefore exhibits different hydrogen-bonding interactions and a higher molecular mass. The β-ketoamide arm is reactive toward primary amines and should not be blended with uncured amine-functional excipients without forced compatibility testing. Unlike simple benzimidazolone derivatives that may require micronization to achieve dissolution, the AABI-PM grade is processed under controlled milling to maintain the D90 target without excessive amorphous content. Amorphous content is monitored by dynamic vapour sorption or modulated differential scanning calorimetry; if the amorphous fraction exceeds 10%, recrystallisation can occur during storage and change dissolution. There is no published pharmacopoeial reference standard for AABI; the manufacturer uses a qualified working standard and a two-level HPLC calibration. The product is not interchangeable with pigment-grade AABI of the same CAS number because pigment-grade material is not controlled for elemental impurities, residual solvents, or microbial limits under pharmaceutical quality systems.
During stability evaluation, protocols follow ICH Q1A(R2). Batches are placed in long-term storage at 25 °C/60% RH and accelerated storage at 40 °C/75% RH. The product is retested at 0, 3, 6, 9, 12, 18, 24, and 36 months for oral grade and at 0, 3, 6, 9, and 12 months for injectable grade unless a shorter shelf life is assigned. The API is packaged in double low-density polyethylene liners inside a fibre drum. Each drum is sealed with a tamper-evident closure and labelled with the lot number, retest date, and storage temperature. The product should not be exposed to temperatures above 40 °C for more than 72 h during transport. If cold-chain shipment is used, the product must be equilibrated to 20–25 °C before opening to avoid condensation. Material in process is protected from light because the acetoacetylamino chromophore can undergo photodegradation under intense UV exposure; light protection by amber glass or opaque packaging is used for the injectable solution.
