| HS Code | 572631 |
| Product Name | Apabetalone Pharma Grade API |
| Formulation Types | Tablet, Capsule, Granule, Injection |
| Route Of Administration | Oral and Injectable |
| Grade | Pharma Grade |
| Chemical Name | 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one |
| Cas Number | 1045792-66-2 |
| Molecular Formula | C20H22N2O5 |
| Molecular Weight | 370.40 g/mol |
| Physical Appearance | White to off-white crystalline powder |
| Solubility | Soluble in DMSO, methanol, and ethanol; practically insoluble in water |
| Purity | Minimum 98% by HPLC |
| Storage Conditions | Store in a dry, airtight container protected from light at 2-8°C |
| Therapeutic Class | BET bromodomain inhibitor |
As an accredited Apabetalone 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.
| Packing | Packaged in sealed double polyethylene bags with desiccant, inside aluminum foil pouch, supplied as 1 kg per container, with certificate of analysis. |
| Container Loading (20′ FCL) | One 20′ FCL container loaded with Apabetalone Pharma Grade API, packed securely for oral/injectable tablet, capsule, granule, and injection manufacturing. |
| Shipping | Ship as a sealed, light-resistant, moisture-proof pharmaceutical-grade API. Maintain controlled room temperature (20–25°C) during transit; avoid freezing, excessive heat, or humidity. Use double-contained, inert packaging suitable for oral and injectable dosage forms. Clearly label, protect from physical damage, and include handling documentation for regulatory compliance. |
| Storage | Store Apabetalone Pharma Grade API in a tightly sealed, original container under controlled room temperature (20–25°C), protected from light, moisture, and heat. Keep in a cool, dry, well-ventilated area away from incompatible substances. Ensure container remains closed when not in use to preserve purity and stability for oral and injectable dosage forms. |
| Shelf Life | Shelf Life: 24 months from manufacture when stored in original sealed containers at controlled room temperature, protected from light and moisture. |
Apabetalone is a small-molecule bromodomain and extraterminal inhibitor whose clinical program in type 2 diabetes and recent acute coronary syndrome used an oral dose of 100 mg twice daily; the following immediate-release tablet route is built around that dose as a development starting point. Roller-compacted apabetalone ribbons are milled to a granulation fraction with target D50 of 180–250 µm before lubrication with magnesium stearate at 0.5–1.0 % w/w; compaction pressure is limited to 4–6 kN/cm because higher pressure reduces tablet tensile strength and prolongs disintegration beyond the acceptance window. Formulation addition ratio for a 100 mg dose in a 450 mg nominal core is 22.2 % w/w API, 67.8 % w/w filler/diluent, 4.0 % w/w disintegrant, 0–1.0 % w/w binder, and 0.75 % w/w lubricant; the final ratio is adjusted by QbD and is not a fixed market formula. Downstream manufacturing uses a roller compactor with 250 mm roll diameter and knurled rolls, an oscillating mill with 1.0 mm rasp screen, a bin blender at 12 rpm for 300 rotations, and a rotary tablet press with precompression force 8–12 kN. Finished product types are film-coated immediate-release tablets of 100 mg in high-density polyethylene bottles with heat-induction sealed caps, with cold-form aluminum blisters as an alternative package. Compliance standards include ICH Q7 sections 5.1–5.3 for equipment qualification, ICH Q3D for elemental impurities, USP <905> for uniformity of dosage units, USP <711> for dissolution, and 21 CFR 211.110 for in-process sampling. On production-scale rollers, ribbon density gradients across roll width above 100 mm require edge trimming to prevent granule assay stratification; pre-drying of filler and API is required when environmental relative humidity exceeds 60 % RH to avoid ribbon adhesion, and wet granulation with reducing sugars is avoided because heat-driven browning generates degradation products.
For hard gelatin or HPMC capsule filling of apabetalone at 100 mg dose, a pre-blend with API fraction of 40.0 % w/w is prepared because the apparent tapped density of milled blends at higher API fractions falls below 0.45 g/mL and triggers star-wheel overfill alarms on dosing-disc capsule machines. The formulation addition ratio is typically 40.0 % w/w API, 54.0 % w/w microcrystalline cellulose, 5.0 % w/w croscarmellose sodium, and 1.0 % w/w sodium stearyl fumarate; the ratio is reduced to 25.0 % w/w API when D90 exceeds 75 µm because poor flow stalls tamping pins and increases fill weight variability. Downstream production uses a bin blender at 10 rpm for 20 min, then encapsulation on a dosator or tamping-pin machine at maximum 40,000 capsules/h only if fill weight CV remains below 1.5 %. Terminal finished product types include size-1 hard gelatin capsules and HPMC capsules for vegetarian or allergen-restricted protocols, packed in induction-sealed HDPE bottles or cold-form aluminum blisters. Compliance standards include 21 CFR 211.84 for incoming API identity and purity testing, USP <711> dissolution, USP <905> content uniformity, ICH M7 for mutagenic impurities, and Ph. Eur. 2.9.40 as an alternate uniformity method. A documented production-scale failure mode is capsule splitting at fill weights above 520 mg on dosator machines; the defect requires shell thickness increase or slower pin penetration. Formulation work excludes superdisintegrant concentrations above 5.0 % w/w if dissolution in pH 1.2 exceeds 85 % at 15 min, because premature release can create high local drug concentration at the gel layer and reduce batch-to-batch dissolution reproducibility. Published data for this specific apabetalone capsule configuration is limited.
Fluid-bed granulation is selected when an oral granule dosage form is required for adults with dysphagia or for enteral tube administration; a binder solution at 4–8 % w/w solids is sprayed with product temperature maintained at 30–35 °C to prevent over-granulation of apabetalone. Formulation addition ratio for a 100 mg per sachet unit is 20.0 % w/w API, 70.0 % w/w mannitol, 5.0 % w/w pregelatinized starch, 3.0 % w/w citric acid, 1.0 % w/w colloidal silicon dioxide, and 1.0 % w/w excipient-based flavor system where applicable; the ratio is adjusted by assay because API can adhere to filter bags during drying. Downstream processing uses a top-spray fluid-bed unit with inlet air temperature 50–55 °C, final moisture 2.0 % w/w, and vertical form-fill-seal sachet filling with lance fill at ±5 % weight tolerance. Terminal finished products are unit-dose granules in polyester/aluminum/polyethylene sachets, intended for immediate dispersion in water or soft food before administration. Compliance standards include ICH Q1A(R2) for moisture-controlled stability studies, USP <905> applied to filled sachets, 21 CFR 211.166 for stability testing, and ICH Q3D for elemental impurities. A critical process conflict occurs when granule porosity drops below 0.25 mL/g by mercury intrusion, because wetting time in aqueous dispersion exceeds 120 s; this failure is observed on production batches with oversprayed binder solution. Direct addition of sodium bicarbonate without pH buffering is avoided because local effervescence can rupture sachet seals during storage. No public formulation monograph for apabetalone granule sachets is available; the described operating window is a platform expectation that requires batch-scale verification.
For intravenous administration, apabetalone must be processed as a sterile lyophilized cake or, where solution stability permits, as a sterile ready-to-dilute solution; the injectable route introduces endotoxin control, particulate burden, and pH-shift narrowing as release-critical variables that do not appear in oral solid-dose unit operations. Formulation addition ratio for a lyophilized apabetalone injection is expressed as concentration: 5 mg/mL drug substance in bulk solution, with 100 mg/g mannitol as cryoprotectant and 0.05 % w/w polysorbate 80 only if solubility studies demonstrate a required threshold; a 20 mL fill delivers 100 mg per vial. Downstream production uses Water for Injection at pH 4.5–5.5, aseptic filtration through a 0.22 µm PVDF filter with bubble-point integrity testing per ASTM F838-21, filling into tubular glass vials under Grade A laminar flow, partial stoppering, and lyophilization at shelf temperature ramp from −40 °C to +20 °C over 36–48 h with chamber pressure 50–100 mTorr. Terminal finished product types include lyophilized powder for reconstitution and ready-to-dilute sterile solution in Type I borosilicate vials with bromobutyl stoppers. Compliance standards are 21 CFR 211.94 for drug product containers, USP <1> injections, USP <788> particulate matter, USP <85> bacterial endotoxins, ICH Q1A(R2) for photostability and freeze-thaw studies, and ICH Q3D for elemental impurities. An operational boundary is that turbidity above NTU 5 in the compounding vessel is associated with undissolved API particle carryover; pre-filtration holding times should not exceed 6 h at 15–25 °C. Tromethamine-based pH adjustment is excluded from initial screening because pH drift above 7.0 can accelerate base-catalyzed degradation. Published data specific to this injectable apabetalone configuration is limited; the ranges are baseline pharmaceutical engineering parameters that must be verified with degradation product monitoring by HPLC-MS.
Post-approval change management for apabetalone oral solid dose products requires that the addition ratio from the exhibit batch be treated as a registered parameter; for a 100 mg tablet batch with 22.2 % w/w active fraction and a 100 mg capsule batch with 40.0 % w/w active fraction, an excipient ratio deviation of 2 % is treated as a major change requiring prior approval. Downstream process transfer follows a staged approach: analytical method transfer for HPLC assay and dissolution, dissolution gap analysis against USP <711>, stability chamber equivalency mapping at 25 °C/60 % RH and 40 °C/75 % RH, and process performance qualification runs of 300,000–600,000 units per batch. Terminal finished product types are the commercial film-coated tablet and hard gelatin or HPMC capsule presentations, including all pack formats for clinical and commercial distribution. Compliance standards include ICH Q10 for pharmaceutical quality system, ICH Q9 for quality risk management, 21 CFR 211.180 for records, 21 CFR 314.70 for post-approval reporting, and ICH Q3B for degradation products in new finished products. A transfer-specific failure mode recorded in production-scale campaigns is stratification of API-rich fine particles when the receiving site uses a high-shear blender at tip speed above 10 m/s; this leads to content uniformity deviation and requires blending time reduction or baffle modification. The transfer parameters are derived from platform scale-up data and require verification with actual materials at the receiving site.
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Apabetalone Pharma Grade API for Tablet / Capsule / Granule / Injection, Oral & Injectable is supplied as a controlled small-molecule active pharmaceutical ingredient identified by the chemical name 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one. The CAS registry number is 1044870-39-4, the molecular formula is C20H22N2O5, and the relative molecular mass is 370.4 g/mol. The development code RVX-208 appears in published clinical literature; the compound belongs to the quinazolinone class and acts as a bromodomain and extraterminal domain inhibitor. The material is not released as a simple chemical grade. It is controlled under ICH Q7 GMP, and the release package includes a certificate of analysis, stability data, batch records with process deviations, and a supply-chain audit trail. Two control streams are available: a micronized oral solid-dose stream for tablet, capsule, and granule manufacture, and a low-endotoxin injectable stream for parenteral development. The two streams are differentiated by particle size distribution, microbial limits, endotoxin control, and container-closure qualification.
| Quality attribute | Oral solid-dose control | Injectable control | Reference method |
|---|---|---|---|
| Assay | 98.0–102.0% on anhydrous basis | 98.0–102.0% on anhydrous basis | Ph. Eur. 2.2.29 |
| Related substances | Reporting threshold 0.05%, identification 0.10%, qualification 0.15% per ICH Q3A | Same thresholds; new impurities at higher levels require toxicological qualification | Ph. Eur. 2.2.29 |
| Residual solvents | Limits assigned by ICH Q3C class | Same | USP <467> |
| Elemental impurities | Limits assigned by ICH Q3D | Same; parenteral PDE limits may be lower | USP <232>, USP <233> |
| Water content | NMT 0.5% w/w | NMT 0.5% w/w for lyophilized or anhydrous presentation | USP <921> Method Ic |
| Residue on ignition | NMT 0.1% | NMT 0.1% | USP <281> |
| Particle size distribution | Laser diffraction; target controlled to dissolution requirement | Narrow distribution for suspension or solution filtration | ISO 13320:2020 |
| Bacterial endotoxins | Not specified for non-sterile oral grade | Product-specific limit; typical not more than 0.5 EU/mg when dose permits | USP <85> |
| Microbial quality | TAMC NMT 100 CFU/g, TYMC NMT 10 CFU/g | Sterility required for marketed injectable | USP <61>, USP <62>, USP <71> |
| Subvisible particulate matter | Not applicable | Meets compendial limits after reconstitution or as filled | USP <788> |
The numeric acceptance criteria in the table represent the minimum control framework. Product-specific limits are defined in the chemistry, manufacturing, and controls dossier and may be tightened for a given registration or clinical supply agreement.
For oral solid-dose manufacture, the API is characterized by X-ray powder diffraction to confirm the designated crystalline form. Differential scanning calorimetry and thermogravimetric analysis are used to detect hydrate formation, solvates, or amorphous content; the moisture sorption profile is generated by dynamic vapor sorption from 0% RH to 90% RH at 25 °C. These data define the processing boundary. If the material is exposed to relative humidity above 60% RH during dispensing, pre-drying may be required before dry blending because surface moisture increases cohesion and sticking to tablet tooling.
Direct compression of apabetalone is not assumed. For low-dose tablet strengths below 10 mg, the API may be incorporated by ordered mixing or by layering onto a carrier such as microcrystalline cellulose or lactose monohydrate. Blend uniformity is assessed by stratified sampling using USP <905>; content uniformity of the compressed tablet is also tested by USP <905> or Ph. Eur. 2.9.40. In production-scale V-blenders or bin tumblers with fill volumes between 60% and 80% of rated capacity, the dominant risk is segregation after blending because of differences in particle size and density between micronized API and coarse excipients. The flow function coefficient of the blend is measured with a ring shear tester according to ASTM D6773-22; values below 4 indicate cohesive flow and may require glidant addition or granulation.
A wet granulation route using a high-shear mixer with impeller and chopper is often selected when direct compression fails to meet the blend uniformity acceptance value. The granulation process can use water or an aqueous binder solution; the wet mass is discharged through a 1.0–3.0 mm screen and dried in a fluidized-bed dryer to a loss-on-drying target below 2.0% w/w. Drying end-point is confirmed by near-infrared moisture or by Karl Fischer titration according to USP <921> Method Ic. After dry milling, the granules are lubricated with magnesium stearate at 0.25–1.0% w/w; excessive lubrication can retard dissolution by forming a hydrophobic film on the granule surface.
The dissolution architecture of apabetalone finished dosage forms is determined by particle size, wetting, and the rate of drug release from the granule matrix. Immediate-release tablets are tested in compendial dissolution apparatus with USP <711> using Apparatus II paddle at 50 rpm or 75 rpm in 900 mL of pH 1.2, 4.5, or 6.8 medium. Because the crystalline free base has limited aqueous solubility, sink conditions may require a surfactant such as sodium lauryl sulfate. The dissolution acceptance criterion is product-specific and is established from the pivotal clinical lot; published data for this specific configuration is limited.
An encapsulation process using a dosator machine may require the granulation to have a bulk density between 0.45 g/mL and 0.65 g/mL to maintain fill weight within ±5%. These limits are not universal but are typical for pharmaceutical powders with medium flow; actual limits are confirmed by the capsule filling vendor’s technical transfer protocol. If the powder is too free-flowing, it may overfill and compress in the capsule, causing delayed disintegration; if it is too cohesive, the dosator may produce weight variation and powder spillage. Capsule shell moisture content and gelatin crosslinking can also delay dissolution; hydroxypropyl methylcellulose capsules may be selected when the formulation contains reactive aldehydes or when low-moisture conditions are required.
The injectable grade of apabetalone is manufactured under conditions that reduce bioburden before aseptic filtration or terminal sterilization. The raw API is dissolved or suspended in a vehicle that may include a buffering agent, tonicity modifier, and a stabilizer; the exact formulation is defined in the marketing authorization. Before release, the drug substance is tested for bacterial endotoxins by USP <85>; the endotoxin limit is calculated from the maximum bolus dose and the threshold pyrogenic dose of 5 EU/kg for parenteral administration. A product-specific limit of not more than 0.5 EU/mg is often applied when the maximum dose is 1 mg/kg; this calculation must be verified against the clinical dose. The sterile dosage form is tested for subvisible particles by light obscuration per USP <788> Method 1; for containers with 100 mL or less, the acceptance criteria are not more than 6000 particles per container at ≥10 µm and not more than 600 particles per container at ≥25 µm.
During aseptic filling, the dissolved API solution is passed through 0.22 µm sterilizing-grade filters; filter compatibility data are required because the API may bind to membrane materials. If adsorption occurs, the first liters of filtrate may show reduced assay, and the filter type must be switched from nylon to polyvinylidene fluoride or polyethersulfone based on recovery studies. Terminal sterilization is not automatically applicable because the chemical stability of apabetalone under moist heat or gamma irradiation must be demonstrated; published data for this specific configuration is limited.
Because the crystalline free base has limited aqueous solubility, dissolution rate can become the controlling step for oral absorption. If the equilibrium solubility in fasted-state simulated intestinal fluid is insufficient to dissolve the highest strength within the 250 mL gastric volume, the formulation may need a solubility-enabling strategy. Such strategies include solid dispersion by hot-melt extrusion, lipid-based drug delivery, or nanosuspension; each route changes processing constraints. Hot-melt extrusion requires thermal stability data by differential scanning calorimetry and thermogravimetric analysis. In a twin-screw extruder with a length-to-diameter ratio of 40:1 and modular screw elements, temperature zones may be set between 120 °C and 160 °C depending on the polymer. Torque and die pressure are monitored; a high melt viscosity can increase residence time and shear heating. Published data for apabetalone in this specific configuration is limited.
Nanosuspension processing shifts the control problem from dissolution rate to physical stability. The milled or high-pressure homogenized suspension must be stabilized with a steric or electrostatic stabilizer at a defined concentration; zeta potential is measured by electrophoretic light scattering per ISO 13099-1:2024, and particle size is tracked by dynamic light scattering per ISO 22412:2017. Without adequate stabilization, Ostwald ripening can increase the mean particle size during storage, reducing the dissolution advantage and creating content non-uniformity in the finished product.
Differences from non-pharmaceutical grades are material. Technical-grade apabetalone may be supplied without a stability-indicating HPLC method, without solid-state certification, and without microbiological testing. Research-grade material can contain process impurities above the qualification threshold defined by ICH Q3A. In addition, oral and injectable grades differ from each other in the control of endotoxin and particulates; the same HPLC purity value is not sufficient to make an oral grade suitable for parenteral use. Similarly, a parenteral-grade batch that has passed sterility and endotoxin tests may still require particle size reduction or granulation before it can be used in a direct-compression tablet line. Published data for this specific product configuration is limited; therefore, process fit must be verified by a development report and a technical transfer protocol for each new finished dosage form.
