| HS Code | 391384 |
| Product Name | Cbz-Amino Acids Pharma Grade API |
| Product Type | Pharmaceutical active ingredient / protected amino acid |
| Chemical Class | N-Carbobenzyloxy amino acids |
| Synonyms | Cbz-amino acids, Z-amino acids, N-CBZ amino acids |
| Protecting Group | Benzyloxycarbonyl (Cbz/Z) |
| Cas Number | Varies by specific Cbz-amino acid |
| Molecular Formula | Varies by amino acid moiety |
| Molecular Weight | Varies by specific derivative |
| Grade | Pharma Grade |
| Purity | ≥98% to ≥99% by HPLC |
| Assay | 98.0% to 102.0% on anhydrous basis |
| Appearance | White to off-white crystalline powder |
| Solubility | Soluble in organic solvents; aqueous solubility varies by amino acid |
| Dosage Form Compatibility | Tablet, capsule, granule, injection |
| Route Of Administration | Oral and injectable |
| Application | Intermediate for peptide synthesis and pharmaceutical API manufacturing |
| Storage Conditions | Store in a cool, dry place, protect from moisture and light |
| Shelf Life | Typically 24 to 36 months when stored properly |
| Packaging | Double polyethylene bags inside fiber drum or as specified |
| Regulatory Compliance | Manufactured under GMP conditions |
| Safety Handling | Use personal protective equipment; avoid inhalation and contact |
| Moisture Content | ≤0.5% |
| Heavy Metals | ≤10 ppm |
| Residue On Ignition | ≤0.1% |
| Optical Rotation | Specific to each Cbz-amino acid |
As an accredited Cbz-Amino Acids 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 | |
| Shipping | |
| Storage |
Pharmaceutical-grade Cbz-amino acids are distributed for six downstream manufacturing routes in oral solid dose and injectable settings. The following scenarios are limited to routes in which Nα-benzyloxycarbonyl-protected chiral intermediates are converted into final peptide APIs or derivative presenters; unrelated industrial sectors are excluded to maintain topic concentration.
Within solid-phase peptide synthesis suites producing LHRH-analog peptide sequences for sterile injectable presentations, Nα-benzyloxycarbonyl-protected amino acids are consumed as orthogonal intermediates rather than as final dosage-form actives. Production-scale campaigns on Wang resin with resin loading between 0.3 mmol/g and 0.7 mmol/g use the protected amino acid at 2.5–3.5 molar equivalents per coupling site when DIC and ethyl cyano(hydroxyimino)acetate in DMF at 20–25°C are applied; increasing the molar excess beyond 4.0 equivalents does not improve coupling yield but raises residual Cbz-related impurities in the crude peptide. Compliance at this stage is governed by ICH Q7 Section 7.3 for in-process controls and 21 CFR 211.84 for incoming raw material verification, with residual solvent levels in the protected intermediate controlled according to ICH Q3C, typically DMF below 880 ppm and dichloromethane below 600 ppm. The downstream process on manufacturing lines often includes six to nine coupling cycles per peptide chain, each cycle requiring Nα-deprotection with 20% v/v piperidine/DMF for Fmoc-based residues, while the Cbz-protected residue is retained for selective later hydrogenolysis using 5–10% Pd/C under 0.2–0.5 MPa hydrogen. Crude peptide is cleaved with TFA/H₂O/triisopropylsilane 95:2.5:2.5, precipitated in cold methyl tert-butyl ether, purified by preparative RP-HPLC on C18 columns, and lyophilized to final residual water below 5.0%. Terminal finished dosage forms from this route include lyophilized injection vials, dual-chamber syringes, and powder-for-suspension kits for intramuscular or subcutaneous administration.
In solution-phase synthesis of short-chain dipeptide derivatives intended for oral modified-release tablets, Cbz-amino acids are coupled to amino acid ester hydrochlorides at 1.0–1.1 molar equivalents relative to the C-terminal nucleophile, with N-methylmorpholine in ethyl acetate at −5 to 0°C to suppress racemization. The critical processing boundary is water content in the reaction medium: above 0.5% w/w, activated O-acylisourea intermediates partition into the aqueous phase and coupling yields fall below 92%, requiring re-crystallization from isopropanol/water to restore chiral purity. Industry compliance for this route references 21 CFR 211.110 for in-process bioburden testing and ICH Q3C for residual ethyl acetate below 5000 ppm in the derived peptide; residual Cbz protecting group is controlled to below 0.10% w/w by HPLC according to ICH Q3A threshold reporting rules. Downstream formulation begins with vacuum drying at 40–45°C for 8–12 h, followed by jet-milling to D90 below 45 µm and direct compression at 8–15 kN with microcrystalline cellulose, dibasic calcium phosphate, and sodium starch glycolate. Dissolution performance is evaluated using USP <711> Apparatus II at 50 rpm in pH 6.8 phosphate buffer. Terminal finished product types include enteric-coated tablets, sustained-release matrix tablets, and mini-tablets for capsule-in-capsule delivery.
Across hard gelatin capsule filling lines for low-dose amino acid derivative prodrugs, the pharma-grade Cbz-protected intermediate is pre-blended at 1.0–2.5% w/w of total capsule fill mass after verification of particle size uniformity. A pre-blend step with colloidal silicon dioxide at 0.25–0.5% w/w and magnesium stearate at 0.5–1.0% w/w in a 600 L bin blender operated at 12–15 rpm for 10–15 min is required to prevent agglomeration; direct addition without pre-blending has been observed on production lines to increase weight variability above ±5% for 25 mg fill weights. Regulatory accountability during filling rests on 21 CFR 211.101 for charge-in accountability and 21 CFR 211.113 for monitoring contaminating bioburden, while elemental impurity levels are aligned with ICH Q3D Option 1 limits for oral products, with nickel and palladium from hydrogenolysis controlled below 25 µg/day and 10 µg/day respectively. Capsule filling is performed on MG2 or Zanasi-type dosators with pin sizes selected for 40–60 mg fill mass; in-process weight sorting rejects capsules outside ±7.5% of target. Terminal dosage forms include hard gelatin capsules, HPMC vegetarian capsules, and clinical trial blister packs for phase I-II studies.
In high-shear wet granulation of oral granules containing Cbz-amino acid-derived short-chain peptide actives, the binder solution is added as PVP K30 at 2.0–4.0% w/w of dry granule mass, with active loadings between 5% and 15% w/w to maintain compressibility and reconstitution dispersibility. Granule growth in a top-drive high-shear mixer at impeller speeds of 250–350 rpm and chopper speeds of 1500–2000 rpm shows a process cliff-edge at liquid-to-solid ratios above 0.18, where median granule size shifts from 180–250 µm to over 600 µm within 30 s, generating oversized granules that fail sieve retention specifications. Compliance references Ph. Eur. 2.9.10 for uniformity of mass of single-dose preparations and ICH Q3C for residual isopropanol below 5000 ppm. Drying in a fluid bed at inlet air 55–65°C targets loss on drying 1.5–2.5%; overcooking above 70°C causes Cbz-derived impurities to rise above 0.15% due to thermal deprotection at the solid surface. Finished products include pediatric oral granules, dispersible sachets, and reconstitutable oral solutions packaged in aluminum foil laminate.
| Parameter | Measurement method | Boundary value | Observed batch effect |
|---|---|---|---|
| Water content in low-hydration coupling reaction | Karl Fischer titration | above 0.5% w/w | coupling yield falls below 92% |
| High-shear granulation liquid-to-solid ratio | torque rheometry | above 0.18 | median granule size rises above 600 µm |
| Fluid bed drying inlet air temperature | in-line thermocouple | above 70°C | Cbz-derived impurity increases above 0.15% |
| Aseptic hold time before filtration | HPLC-UV assay | beyond 96 h | particle count exceeds USP <788> thresholds |
| Microsphere residual methylene chloride | GC headspace | above 600 ppm | release specification failure per ICH Q3C |
For small-molecule amino acid derivative injectable solutions obtained after Cbz hydrogenolysis, terminal steam sterilization is frequently excluded because the free amino group is susceptible to Maillard-type degradation in the presence of reducing sugar excipients at 121°C for 15 min. The process therefore follows aseptic filtration and aseptic filling under EMA Annex 1 and 21 CFR 211.42 environmental certifications. The API is dissolved at 0.1–5.0 mg/mL in Water for Injection, adjusted to pH 4.5–6.5 with 0.1 M HCl or NaOH, and tonicity is set to 280–320 mOsm/kg with sodium chloride at 0.9% w/v. Hold-time studies on production batches indicate that solutions stored at 2–8°C before filtration remain within 98–102% of label claim for up to 72 h; beyond 96 h, particle counts can exceed USP <788> thresholds due to aggregation. Filtration through 0.22 µm PVDF membrane filters with pre-wetted cartridges is followed by filling into depyrogenated glass vials at line speeds of 150–250 vials/min. Terminal finished product types include aqueous injection vials, ampoules, and pre-filled syringes labeled for intravenous or subcutaneous use.
On solvent-extraction lines for long-acting injectable microspheres, Cbz-derived peptide APIs are combined with PLGA 50:50 in methylene chloride at 3–10% w/w peptide relative to polymer mass, with the primary emulsion generated by a rotor-stator homogenizer at 10,000–15,000 rpm for 2–4 min. The external aqueous phase contains 1.0% w/v polyvinyl alcohol as stabilizer; residual methylene chloride in the final microsphere is controlled to below 600 ppm per ICH Q3C, and residual Cbz-related impurities are specified below 0.05% w/w to avoid late-eluting unknown peaks in release testing. Release testing and regulatory controls reference USP <788> and USP <790> for subvisible particulate matter and Ph. Eur. 2.6.14 for bacterial endotoxins with a limit of 0.5 EU/dose. The dried microspheres are sized through a 125 µm oscillating sieve, blended with mannitol and carboxymethylcellulose sodium, and filled as sterile suspension kits requiring reconstitution with Water for Injection. The final presentation is a long-acting injectable depot suspension for intramuscular administration in vials with an injection volume of 1.0–2.5 mL. Published scale-up data for this specific microsphere configuration remains limited; the stated range is derived from current release specifications rather than a harmonized monograph.
Competitive Cbz-Amino Acids Pharma Grade API for Tablet / Capsule / Granule / Injection, Oral & Injectable prices that fit your budget—flexible terms and customized quotes for every order.
For samples, pricing, or more information, please contact us at +8615365186327 or mail to admin@ascent-chem.com.
We will respond to you as soon as possible.
Tel: +8615365186327
Email: admin@ascent-chem.com
Flexible payment, competitive price, premium service - Inquire now!
Cbz-Amino Acids Pharma Grade API for Tablet / Capsule / Granule / Injection, Oral & Injectable comprises N-benzyloxycarbonyl-protected L- and D-amino acid derivatives supplied as crystalline solids with controlled polymorphic form, particle size distribution, residual solvent profile, chiral purity, and endotoxin burden. Model designations generally encode the amino acid abbreviation, salt form, and particle-size grade; commercial lots are available as free acids, hydrochloride salts, sodium salts, and side-chain-protected esters in 100 g, 1 kg, and 5 kg packs. The product line covers Cbz-glycine, Cbz-L-alanine, Cbz-L-valine, Cbz-L-leucine, Cbz-L-isoleucine, Cbz-L-phenylalanine, Cbz-L-proline, Cbz-L-methionine, Cbz-L-tyrosine, Cbz-L-lysine(Cbz), Cbz-L-glutamic acid α-benzyl ester, and Cbz-D-phenylalanine, with custom D-isomer and side-chain-ester variants manufactured to order. Release specifications commonly include assay by HPLC at 98.0% to 100.5% on the dried basis, individual related substances not more than 0.5%, total impurities not more than 1.0%, specific rotation according to Ph. Eur. 2.2.7, loss on drying by Ph. Eur. 2.2.32 at ≤0.5% for non-hydrate lots, residue on ignition by Ph. Eur. 2.4.16 at ≤0.1%, residual solvents by USP <467>, elemental impurities by USP <232>/233 with ICH Q3D-derived limits, and chiral purity by chiral HPLC at ≥99.0% enantiomeric excess. For injectable-grade orders, bacterial endotoxins are controlled to ≤0.25 EU/mg by USP <85>, and the material is handled under controlled bioburden conditions consistent with parenteral API processing.
Because the carbobenzyloxy group is stable to aqueous bases and to trifluoroacetic acid, the Cbz strategy is selected when the amino acid derivative must survive downstream coupling conditions that would cleave the tert-butoxycarbonyl group. Deprotection is carried out by catalytic hydrogenolysis with H₂ over palladium on carbon in neutral or mildly acidic ethanol-water; transfer hydrogenation with ammonium formate is also used. This selective removal profile differs from fluorenylmethyloxycarbonyl chemistry, in which 20% piperidine in dimethylformamide removes the protecting group, and from tert-butoxycarbonyl chemistry, in which trifluoroacetic acid in dichloromethane is standard. In oral solid dosage development, the Cbz route avoids base-catalyzed racemization at the α-carbon during intermediate workup when the N-protected amino acid is converted to a salt or ester. In injectable applications, the absence of secondary amine exposure lowers the risk of residual amine adducts; residual benzyl alcohol and toluene are controlled under USP <467> and Ph. Eur. 2.4.24.
Within a manufacturing batch, the free acid or methyl ester form may be selected according to the downstream route. The free acid is preferred for salt formation and lyophilized injection; the methyl or benzyl ester is preferred when the downstream route requires anhydrous coupling. The selection changes the melting range, solubility in 0.1 N hydrochloric acid, and chromatographic retention. Published dissolution data for Cbz-amino acid lots in physiological media are limited, so solubility screening is performed in phosphate-buffered saline at pH 7.4 and in 0.1 M hydrochloric acid using Ph. Eur. 2.9.3 for oral dosage forms where dissolution testing is applicable. The product is supplied with a certificate of analysis that lists the accepted pharmacopoeial or internally qualified method for each specification.
For tablet and capsule manufacture, the lot-release package includes assay, related substances, residual solvents, moisture, residue on ignition, particle size, polymorph identification by X-ray powder diffraction, and chiral purity. For injection grade, the same core methods are supplemented with bacterial endotoxin, bioburden, and solubility limits. Polymorph stability is assessed by differential scanning calorimetry; if multiple crystalline forms exist, the melt endotherm is used to confirm that milling has not generated amorphous content above 5.0% as measured by modulated DSC. The absence of crystalline form change during wet granulation is checked by XRPD after exposure to 25°C/75% RH for 7 days. The following compliance matrix summarises the release tests and typical limits for tablet, capsule, and injection-grade lots.
| Attribute | Method/Standard | Typical Limit | Dosage-Form Relevance |
|---|---|---|---|
| Assay | HPLC with UV detection, Ph. Eur. 2.2.29 | 98.0–100.5% dried basis | dose verification for tablets and injectable reconstitution |
| Chiral purity | Chiral HPLC, USP <621>; specific rotation Ph. Eur. 2.2.7 | ≥99.0% enantiomeric excess | stereochemical consistency in peptide coupling |
| Residual solvents | USP <467> / Ph. Eur. 2.4.24 | benzyl alcohol ≤0.1%, toluene ≤0.089% if used | ICH Q3C option limits for oral and injectable products |
| Elemental impurities | USP <232>/233; ICH Q3D | Cd ≤0.2 µg/g, Pb ≤0.5 µg/g, As ≤1.5 µg/g, Hg ≤0.3 µg/g; Pd ≤10 µg/g after hydrogenolysis | parenteral risk mitigation and catalyst carryover control |
| Bacterial endotoxins | USP <85> | ≤0.25 EU/mg for injectable lots | parenteral pyrogen control |
| Loss on drying | Ph. Eur. 2.2.32 | ≤0.5% | stoichiometric weighing and ester coupling |
| Residue on ignition | Ph. Eur. 2.4.16 | ≤0.1% | injection clarity and filter blocking |
| Particle size D50 | ISO 13320:2020 laser diffraction | 10–40 µm direct compression; ≤20 µm suspension injection | content uniformity USP <905>; syringeability |
After release, a material-handling sequence for tablet manufacture begins with de-agglomeration through a 600 µm stainless-steel screen followed by pre-blending with lactose monohydrate and microcrystalline cellulose in a bin blender at 15–25 rpm for 20 minutes. If the Cbz-amino acid is deliquescent at relative humidity above 80%, processing is delayed until the granulation suite condition is held below 40% RH. For capsules, powder fill weight is checked against ±3% of target using an in-process gravimetric check; automatic capsule machines with 100,000 capsules/hour throughput require Carr index below 25% to maintain consistent plug formation. Direct compression blends the API with croscarmellose sodium and magnesium stearate, the lubricant added in the final 3 minutes to limit overlubrication. Dry granulation with roller compaction at roll pressure between 5 and 12 kN/cm and gap 1.0–2.0 mm is used when bulk density is too low for high-speed tableting. These parameters are equipment-specific and must be qualified within the manufacturer's process validation, with analytical methods following ICH Q2(R2) and design-space documentation following ICH Q8(R2).
Wet granulation with Cbz-amino acid at 5.0% w/w in a high-shear mixer granulator with an impeller speed of 300 rpm and chopper at 1500 rpm requires careful control of granulation liquid because the free acid can agglomerate into hard lumps under aqueous addition. A starch paste or hydroxypropyl cellulose solution at 3–5% w/w is added at approximately 25 g/min per kilogram of dry powder until a torque rise of 10 N·m is observed; the end point is better detected by power consumption than by visual appearance. The wet mass is milled through a 4.0 mm screen and dried in a fluid-bed dryer at 40°C inlet air temperature until loss on drying is ≤2.0%; final granules between 125 µm and 710 µm are tableted to hardness 60–100 N. The resulting tablets show acceptable disintegration time by Ph. Eur. 2.9.1 under 15 minutes for uncoated cores, but modified-release coating can extend this based on drug-release requirements.
For injectable applications, the Cbz-amino acid is assessed for solubility in water for injection, 0.9% sodium chloride, and co-solvent systems containing propylene glycol or polyethylene glycol. Because some Cbz-amino acids exhibit limited aqueous solubility, final formulation may require salt formation or pH adjustment; pH-dependent solubility is measured by the shake-flask method at 37 ± 0.5°C according to Ph. Eur. 2.9.3 or a validated HPLC solubility method. Terminal sterilization of the Cbz-protected amino acid may not be suitable under all pH and temperature conditions because the carbamate can hydrolyse; therefore, aseptic processing or sterile filtration of a dissolved API after deprotection is more common. For a parenteral-grade raw material, the maximum accepted bioburden before sterile filtration is ≤10 CFU/100 mL according to contamination-control strategies aligned with USP <1115>. Particulate matter after reconstitution is checked by USP <788>, and subvisible particles should remain within the pharmacopoeial limits for the intended fill volume. The material cannot be formulated with strong oxidizing agents because hydrogenolysis may be affected; hydrogenation equipment with palladium catalyst is required for deprotection and is not part of final formulation.
If the Cbz-amino acid is converted to a sodium salt for injection, the final solution pH is typically maintained between 7.0 and 8.5, and filter compatibility is assessed with 0.22 µm membrane filters under USP <665> and USP <1665> for extractables and leachables. Osmolality adjustment with sodium chloride or mannitol is calculated according to USP <785>. Published thermodynamic solubility data for individual Cbz-amino acid salts in parenteral media are limited; therefore, formulation development uses experimentally determined pH-solubility profiles and short-term solution stability rather than predictive software alone.
Compared with Fmoc and Boc intermediates, Cbz-amino acids contain benzyl alcohol and toluene as principal residual solvents, requiring headspace gas chromatography under USP <467> with Class 2 limits. Fmoc derivatives often contain piperidine or dibenzofulvene, while Boc derivatives can retain tert-butanol and isobutylene. The Cbz route can leave palladium below 10 µg/g after hydrogenolysis; inductively coupled plasma mass spectrometry by USP <233> is used for palladium, nickel, and chromium as appropriate to the manufacturing route. The absence of fluoride-containing cleavage reagents in Cbz processing reduces the need for ion chromatography screening for trifluoroacetate, although trace chloride from hydrochloric acid-derived salts must be controlled when chloride content is critical for injection isotonicity.
| Attribute | Cbz | Fmoc | Boc |
|---|---|---|---|
| Protecting-group removal | H₂/Pd-C or transfer hydrogenation | 20% piperidine in dimethylformamide | trifluoroacetic acid/dichloromethane |
| Stability to acid | stable to trifluoroacetic acid | moderately stable; slow loss in trifluoroacetic acid | readily cleaved |
| Stability to base | stable | readily cleaved | stable |
| Principal residual impurities | benzyl alcohol, toluene | dibenzofulvene, piperidine | tert-butanol, isobutylene |
| Typical residual solvent control | USP <467> Class 2 | USP <467> Class 2 for dichloromethane if used | USP <467> Class 2 for tert-butanol if used |
| Special elemental impurity | palladium from hydrogenolysis | no metal catalyst in deprotection | no metal catalyst in deprotection |
| Preferred route when | base-sensitive and acid-stable targets | acid-sensitive targets | base-stable and acid-labile targets |
No single protecting-group strategy is universally compatible across all synthetic sequences. The Cbz group is preferred when the target molecule contains tertiary amine functions that would be lost during Fmoc deprotection, and when catalytic hydrogenation equipment is already installed in the peptide synthesis suite. The Cbz route is contraindicated when the target contains reducible groups such as nitro, azide, or alkene in the side chain unless selective transfer hydrogenation is used; in those workflows, Fmoc base-labile protection may be selected. Differences in residual solvent and catalyst burden should be reviewed against ICH Q3C and ICH Q3D option-based limits before final API selection, especially for injectable products where palladium and endotoxin limits are restrictive.
Packaging for the solid oral grade is selected after accelerated stability studies under 40°C/75% RH for 6 months and long-term studies at 25°C/60% RH. Because the Cbz group can undergo slow hydrolysis in the presence of moisture, lots intended for capsules or tablets are typically packed in aluminium foil-lined low-density polyethylene bags with desiccant. Re-test intervals are assigned from ICH Q1A(R2) data; storage at room temperature is acceptable when the lot remains below 25°C and protected from light. Light exposure can cause photolytic degradation of the benzyloxycarbonyl group, so amber glass or opaque polyethylene containers are used for small-scale laboratory transfers.
For granules, the dry-granulated or wet-granulated intermediate may be filled into sachets with a moisture-barrier film, but fill-weight control for low-dose formulations requires granule particle size between 125 µm and 710 µm to avoid segregation during vibration transit. The sachet fill line is monitored with in-process checkweighers at ±2% of label claim according to the manufacturer's process capability. In tablet compression, the API particle size and bulk density directly affect content uniformity; therefore, the D50 and D90 values are included on the certificate of analysis for formulations where the API proportion is below 5.0% w/w.
