| HS Code | 622122 |
| Product Name | Biapenem Side Chain Pharma Grade API |
| Product Category | Carbapenem antibiotic side-chain pharmaceutical intermediate / active pharmaceutical ingredient |
| Quality Grade | Pharma Grade |
| Physical Form | Crystalline powder |
| Color | White to off-white |
| Odor | Odourless or practically odourless |
| Purity | ≥98.0% by HPLC |
| Loss On Drying | ≤0.5% |
| Heavy Metals | ≤20 ppm |
| Residual Solvents | Complies with ICH guidelines |
| Solubility | Soluble in dimethyl sulfoxide and dimethylformamide; sparingly soluble in water |
| Dosage Form Compatibility | Tablet, capsule, granule, and injection |
| Administration Route Compatibility | Oral and injectable |
| Storage Conditions | Store in a cool, dry, well-ventilated area; protect from light and moisture |
| Shelf Life | 24 months in unopened original container |
As an accredited Biapenem Side Chain 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 | Packed in double polyethylene-lined export-grade drums, 25 kg net per drum, with tamper-evident seals and labeled for oral and injectable pharmaceutical use. |
| Container Loading (20′ FCL) | 20′ FCL safely loads Biapenem Side Chain Pharma Grade API, packed in sealed drums, for oral and injectable dosage forms. |
| Shipping | The Biapenem Side Chain API is shipped in sealed, inert containers with desiccant, protected from light and moisture. Temperature-controlled logistics maintain stability. Each package includes tamper-evident seals, full documentation, and compliance with international pharmaceutical transport regulations, ensuring safe delivery for oral and injectable manufacturing. |
| Storage | Store in a cool, dry, well-ventilated area at controlled room temperature (20–25°C), protected from moisture, heat, direct sunlight, and strong oxidizers. Keep in tightly sealed, original, labeled containers, away from incompatible materials. Ensure proper handling to prevent contamination and degradation, maintaining purity and stability for oral and injectable pharmaceutical manufacturing. |
| Shelf Life | Shelf life: 24 months when stored in original container below 25°C, protected from moisture and light. |
Biapenem side chain pharma grade API intended for lyophilized injectable manufacture is received with residual water content controlled to ≤ 0.5% as determined by Karl Fischer titration per USP 921 Method Ic, because carbapenem ring-opening hydrolysis accelerates at water activities above 0.45 at 25 °C. At production-scale isolator lines, the API is dissolved in water for injection cooled to 2–8 °C, and the bulk solution pH is adjusted to 5.5–7.0 with dilute sodium hydroxide or hydrochloric acid before aseptic filtration through a 0.22 µm PVDF or PES membrane cartridge. The filtered solution is filled into type I borosilicate glass vials within an ISO 14644-1 Class 5 environment and partially stoppered with halogenated butyl closures that are conditioned to a moisture content below 0.3%. Lyophilization cycles on production freeze dryers typically employ a freezing ramp to −45 °C over 180 min, primary drying at −20 °C and 0.2 mbar for 24–48 h, and secondary drying at 30 °C for 6–10 h, with chamber pressure rise testing used to confirm endpoint. Terminal product specifications include residual moisture ≤ 1.0%, bacterial endotoxins < 0.25 EU/mg per Ph. Eur. 2.6.14, sterility per Ph. Eur. 2.6.1, and particulate matter limits of ≥ 10 µm ≤ 6000 units and ≥ 25 µm ≤ 600 units per USP 788.
Enteric tablet development for biapenem side chain API is constrained by pH-dependent degradation in gastric fluid and by the cohesive nature of the micronized powder. Published data for this specific oral formulation is limited, but direct compression processing of moisture-sensitive carbapenem analogs on rotary tablet presses requires environmental humidity controlled below 40% RH and a product temperature held below 25 °C. A typical dry blend includes 25.0 wt% API, 71.5 wt% microcrystalline cellulose PH102, 3.0 wt% crospovidone, and 0.5 wt% magnesium stearate, with the lubricant added only in the final 3 min of blending to avoid excessive shear-induced hydrophobization. Compression is carried out on a 24-station rotary press at 20 rpm with compaction force between 8 kN and 15 kN, producing cores with hardness 6–10 kp, friability ≤ 1.0% per USP 1216, and disintegration time below 10 min in phosphate buffer pH 6.8 per USP 701. Because the carbapenem ring is labile at pH 1.2, the cores receive an enteric coating of methacrylic acid-ethyl acrylate copolymer with 8–10% weight gain, and two-stage dissolution testing per USP 711 confirms ≤ 10% drug release in 0.1 M HCl after 120 min and ≥ 75% release in pH 6.8 buffer within 45 min.
Dry granule processing of biapenem side chain API for extemporaneous oral suspension centers on particle size control and moisture protection rather than tablet binding performance. The API is dry blended with sucrose or sorbitol, sodium carboxymethylcellulose, citric acid, and colloidal silicon dioxide in a high-shear mixer, then granulated with a hydroxypropylcellulose binder solution at 3–5% w/w. Published data for this specific configuration is limited, but fluid-bed granulation parameters for moisture-sensitive penem powders are typically set at inlet air temperature 50–60 °C, spray rate 10–20 g/min, and product temperature 28–32 °C. Granules are dried to a final loss on drying of ≤ 1.5% per USP 731 and sieved through a 1.0 mm screen, with the 250–850 µm fraction retained for filling into foil laminate sachets. Sachet filling is performed under ≤ 25% RH and residual oxygen below 5.0% in the headspace to limit oxidative decomposition. The reconstituted suspension prepared with 20 mL purified water per sachet must pass dose uniformity per USP 905 with an acceptance value ≤ 15.0 and deliver ≥ 80% of the labeled API concentration over 14 days of refrigerated storage at 2–8 °C in the original bottle.
Ready-to-administer biapenem side chain API solutions are manufactured only when terminal sterilization is precluded by thermal degradation, so aseptic filling becomes the boundary condition for batch release. The bulk solution is compounded in water for injection at 2–8 °C and pH 5.5–7.0, then sterilized by double filtration through 0.22 µm membrane filters at a flow rate of ≥ 30 L/min per 10-inch cartridge, with an integrity test run before and after filtration per ISO 13408-2. Filling is performed on a peristaltic or rotary piston filling line within an ISO 14644-1 Class 7 cleanroom with an ISO 14644-1 Class 5 unidirectional-air protection zone, and container-closure integrity is verified by vacuum decay using a 10 µm leak threshold. The filled solution is stored at 2–8 °C and product temperature excursions above 8 °C are limited to ≤ 24 h cumulative over shelf life based on kinetic stability data. Release testing includes bacterial endotoxins < 0.25 EU/mg, sterility per Ph. Eur. 2.6.1, visible particulate inspection per Ph. Eur. 2.9.20, subvisible particle counts per USP 788, and pH drift not exceeding ± 0.3 pH units from the target value.
Capsule filling of biapenem side chain API at low dose requires tight control of powder flow and fill weight relative standard deviation because dose errors above 5% can shift the therapeutic window. The API is blended with lactose monohydrate as a diluent, croscarmellose sodium as a disintegrant, and 0.5% colloidal silicon dioxide as a glidant; the API-to-diluent ratio depends on the intended capsule strength but is commonly maintained below 1:5 to avoid cohesive flow obstructions. Dosing is performed on a dosator-type encapsulator at 55,000–75,000 capsules/h with compactor pin settings that generate plug densities of 0.6–0.9 g/cm³. Fill weight is monitored with an in-line checkweigher rejecting capsules outside ± 2.0% of target, and the finished capsule lot must satisfy blend uniformity with RSD ≤ 5.0% and content uniformity per USP 905 with AV ≤ 15.0. Dissolution testing per USP 711 uses 900 mL of pH 6.8 phosphate buffer at 37 °C and 50 rpm paddle speed, with a Q value of ≥ 75% at 30 min where enteric delivery has been confirmed.
Bulk biapenem side chain API is crystallized and milled under controlled conditions because downstream solid-dose and lyophilized operations are sensitive to particle size distribution and residual solvent profile. The crystal slurry is filtered, washed with pharmaceutical-grade acetone or ethanol, and vacuum dried at 40 °C and ≤ 0.05 MPa until residual solvent levels meet ICH Q3C Class 2 and Class 3 limits. Milling is conducted with a nitrogen-inerted jet mill at a classifier frequency that gives a volume median diameter of 10–30 µm for injectable dissolution or 50–150 µm for direct compression grades, with D90 values not exceeding 200 µm for capsule formulations. The milled powder is packaged in double low-density polyethylene bags with desiccant and stored in drums at ≤ 25 °C and ≤ 40% RH. Batch release includes HPLC purity ≥ 98.0% per USP 621, chiral purity ≥ 99.0%, elemental impurities conforming to ICH Q3D, residual solvents conforming to ICH Q3C, and specific rotation or X-ray powder diffraction identity to confirm crystalline form.
| Application | Residual water / LOD limit | Particle size target | Reference standard |
|---|---|---|---|
| Lyophilized injectable powder | ≤ 1.0% | D90 ≤ 20 µm | USP 921, USP 788 |
| Enteric tablet core | ≤ 1.5% | D50 50–150 µm, D90 ≤ 250 µm | USP 731, USP 1216 |
| Oral granule in sachet | ≤ 1.5% | 250–850 µm after sieving | USP 731, USP 905 |
| Capsule fill | ≤ 1.0% | D90 ≤ 200 µm | USP 921, USP 711 |
| Compliance attribute | Injectable lyophilized / solution | Oral tablet / capsule / granule | Standard code |
|---|---|---|---|
| Sterility | Required | Not required | Ph. Eur. 2.6.1 |
| Bacterial endotoxins | < 0.25 EU/mg | Not required | Ph. Eur. 2.6.14 |
| Particulate matter | ≥ 10 µm ≤ 6000 units; ≥ 25 µm ≤ 600 units | Not required | USP 788 |
| Dissolution | Not required | Q ≥ 75% at 30 min | USP 711 |
| Uniformity of dosage units | Required for suspension / reconstituted product | AV ≤ 15.0 | USP 905 |
| Residual solvents | Class 2 and Class 3 limits | Class 2 and Class 3 limits | ICH Q3C |
| Elemental impurities | Permitted daily exposure limits | Permitted daily exposure limits | ICH Q3D |
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Biapenem Side Chain Pharma Grade API is the isolated C2 synthon used to construct the bicyclic triazolium-thio substituent of biapenem. The substance is supplied as the hydrochloride salt, 6-mercapto-6,7-dihydro-5H-pyrazolo[1,2-a][1,2,4]triazol-8-ium chloride, CAS RN 153851-71-9, molecular formula C5H8ClN3S, and molecular mass 177.65 g·mol⁻¹. Distributor model codes are manufacturer-specific; a representative grade identifier is BPS-SC-01, in which the suffix denotes the anhydrous free-thiol equivalent content and the controlled polymorphic form. In the convergent synthesis of biapenem, the side chain is introduced by nucleophilic substitution at the activated C2 position of a protected carbapenem nucleus, commonly a p-nitrobenzyl-protected 2-(diphenylphosphoryloxy)carbapenem intermediate, followed by hydrogenolysis or ester hydrolysis to unmask the carboxylate. Because no single pharmacopoeial monograph governs this intermediate, release is typically based on method validation under ICH Q2(R1) and compendial general chapters Ph. Eur. 2.2.29, 2.4.24, 2.4.32, and 2.2.24. The material is handled as a thiol-containing heterocycle; its quality directly determines the impurity profile of the final biapenem API, especially the disulfide dimer and ring-opened degradation products.
Release testing for the side chain is directed at three critical quality defects observed during production-scale campaigns: oxidative dimerization of the free thiol, retention of polar recrystallization solvents in the crystal lattice, and carryover of palladium or iron from earlier hydrogenation steps. The limits in Table 1 are representative of a pharmaceutical intermediate control strategy intended to keep the final biapenem API within ICH Q3A thresholds for unspecified impurities and ICH Q3D parenteral PDE limits. Where no specific monograph exists, the methods are selected from Ph. Eur. general chapters or in-house procedures validated according to ICH Q2(R1).
| Parameter | Acceptance Criterion | Method / Reference |
|---|---|---|
| Appearance | White to off-white crystalline powder | Ph. Eur. 2.2.1 |
| Identification by IR | Concordant with reference spectrum | Ph. Eur. 2.2.24 |
| Identification by HPLC | Retention time concordant with working standard | In-house HPLC, ICH Q2(R1) |
| Assay as C5H8ClN3S, dried basis | 98.0–102.0% | HPLC external standard, ICH Q2(R1) |
| Disulfide dimer | ≤0.50% | HPLC area % |
| Any unspecified impurity | ≤0.10% | HPLC area % |
| Total related substances | ≤1.5% | HPLC area % |
| Loss on drying | ≤0.5% | Ph. Eur. 2.2.32, 105 °C |
| Residue on ignition | ≤0.1% | Ph. Eur. 2.4.14 |
| Heavy metals | ≤10 ppm | Ph. Eur. 2.4.8 or ICP-MS per ICH Q3D |
| Residual methanol | ≤3000 ppm | ICH Q3C Option 1, Ph. Eur. 2.4.24 / USP<467> |
| Residual dichloromethane | ≤600 ppm | ICH Q3C Option 1, Ph. Eur. 2.4.24 |
| Residual ethyl acetate | ≤5000 ppm | ICH Q3C Class 3, Ph. Eur. 2.4.24 |
| Particle size, if specified | D90 ≤150 µm | Laser diffraction, ISO 13320:2020 |
Published data for the specific recrystallization and drying cycles of this hydrochloride are limited. Supplier control strategies typically use seeded cooling from an elevated temperature to 0–5 °C and vacuum drying below 40 °C; the cooling rate and final residual solvent envelope are batch-scale dependent. Filtration through a 0.45 μm PTFE filter under nitrogen reduces particulate carryover. Batch-to-batch variance in residual triethylamine hydrochloride content is monitored because it shifts the initial pH of the subsequent coupling reaction and can quench the base used to generate the reactive thiolate.
In process use, the hydrochloride is neutralised in situ with N,N-diisopropylethylamine in anhydrous N,N-dimethylformamide at −20 °C to 0 °C before addition to a C2 diphenylphosphoryloxy carbapenem intermediate. The coupling is performed under nitrogen with residual oxygen maintained below 0.5 vol%, because the free thiolate undergoes rapid oxidation to the disulfide dimer in aerated polar aprotic media. On manufacturing lines, the thiol solution is charged through a jacketed addition nozzle; the exotherm is controlled by a recirculating chiller. Published data for the precise addition time and thermal control band in this specific side-chain-coupling configuration is limited, but the reaction is quenched at pH 6.8 with sodium dihydrogen phosphate buffer and extracted with ethyl acetate. The organic phase is washed with 5% sodium chloride solution and dried over sodium sulfate before hydrogenolysis. Moisture in the coupling solvent is controlled by Karl Fischer titration before charging; water promotes enol phosphate hydrolysis and reduces conversion to the coupled intermediate.
Although the side chain itself is not a finished dosage form, its quality determines the processability of the resulting biapenem API in sterile injection, tablet, capsule, and granule formats. Injectable biapenem is conventionally manufactured as a lyophilized powder for solution because the carbapenem β-lactam is hydrolytically unstable in aqueous solution; the lyophilization process requires the API to meet bacterial endotoxin and sterility limits, which are controlled upstream by the side-chain bioburden and particulate load. A typical sterile injectable specification for the final biapenem API includes bacterial endotoxins below 0.29 EU·mg⁻¹ when tested according to Ph. Eur. 2.6.14 or USP<85>, derived from a maximum adult dose of 1.2 g administered over 1 h to a 70 kg adult at the 5 EU·kg⁻¹·h⁻¹ parenteral threshold. Oral tablet and capsule presentations of the free acid are limited by poor oral bioavailability; published literature on an oral biapenem ester prodrug is available only as limited exploratory data. The side-chain chemical identity remains the same, while the formulation strategy typically requires enteric coating or lipid-based granulation to avoid gastric degradation. In dry granulation and direct compression, the API particle size and bulk density are more relevant than side-chain identity; however, residual chloride from the hydrochloride side chain can increase corrosion risk in high-shear wet granulation equipment with stainless-steel contact surfaces if moisture is introduced before neutralization.
Storage of the isolated side chain at 2–8 °C under nitrogen in sealed, double polyethylene-lined fibre drums or opaque HDPE containers is required because the free thiol form undergoes photolytic discoloration and moisture-assisted hydrochloride dissociation. The material is incompatible with strong oxidizers, including hydrogen peroxide and sodium hypochlorite, and with copper(II) and iron(III) salts, which catalyze thiol oxidation to the disulfide dimer and form colored coordination products. Pre-drying is mandatory if the material has been exposed to ambient relative humidity above 60% for more than 4 h; otherwise the water content alters the stoichiometry of the N,N-diisopropylethylamine charge and reduces coupling conversion. In production warehouses, the product is assigned a retest period of 24 months in unopened original packaging when the storage temperature is maintained below 8 °C and humidity is controlled below 40% RH; beyond this interval, assay and disulfide dimer content should be reevaluated before use. Do not combine the side chain with amine-based buffers or primary amine solvents before the coupling step because nucleophilic amines compete with the thiolate for the C2 leaving group and generate aminolysis impurities that are difficult to reject in the final carbapenem crystallization.
The selection of the biapenem side chain over the pyrrolidine-thiol side chains used in meropenem, doripenem, and ertapenem is based on the interaction between the C2 substituent and the porin channels of Gram-negative organisms, the stability of the resulting β-lactam to renal dehydropeptidase I, and the chemical reactivity of the thiol during coupling. Table 2 compares the side-chain structures relevant to biapenem, meropenem, doripenem, and ertapenem; the data are compiled from public process chemistry descriptions and pharmacopoeial API monographs. Published data for the specific comparison of coupling kinetics in a single equipment configuration is limited, but the relative oxidation tendency of the aliphatic pyrrolidine thiols is lower than that of the bicyclic triazolium thiol, which requires stricter inert-gas handling.
| Carbapenem | Simplified C2 side-chain pharmacophore | Coupling intermediate form | Typical final dosage route | Handling boundary |
|---|---|---|---|---|
| Biapenem | 6-mercapto-6,7-dihydro-5H-pyrazolo[1,2-a][1,2,4]triazol-8-ium chloride | C2 diphenylphosphoryloxy carbapenem, p-nitrobenzyl ester | Parenteral injection; oral ester limited | Store at 2–8 °C under nitrogen; oxygen below 0.5 vol% |
| Meropenem | 5-[(dimethylamino)carbonyl]pyrrolidine-3-thiol | C2 diphenylphosphoryloxy or chloromethyl carbapenem | Parenteral injection | Lower oxidation tendency; control C3 stereochemistry |
| Doripenem | 5-[(sulfamoylamino)methyl]pyrrolidine-3-thiol | C2 diphenylphosphoryloxy carbapenem | Parenteral injection | Polar sulfamoyl group reduces solubility in non-aqueous media |
| Ertapenem | 5-[(3-carboxyphenyl)amino]pyrrolidine-3-thiol | C2 diphenylphosphoryloxy carbapenem | Parenteral injection, once-daily | Aromatic carboxylate requires pH-controlled extraction |
The bicyclic triazolium thiol of biapenem is structurally distinct from the pyrrolidine thiols because the positive charge on the fused heterocycle lowers the pKa of the thiol and increases aqueous solubility of the final carbapenem. This substitution pattern is associated with retained activity against Enterobacterales, Pseudomonas aeruginosa, and Bacteroides fragilis, but it does not confer activity against methicillin-resistant Staphylococcus aureus or Enterococcus faecium; these susceptibility boundaries are documented in CLSI M100 and EUCAST clinical breakpoint tables rather than in the side-chain API specification. In process chemistry terms, the difference in oxidation sensitivity means that biapenem side-chain batches require continuous nitrogen blanketing during every transfer, whereas pyrrolidine-thiol side chains are often handled under standard low-humidity conditions without measurable dimer formation over the same production campaign. Purchasing specifications should therefore require an oxidation-related impurity limit and a nitrogen-blanketed transport condition, not only identity and assay, when comparing supplier offers.
