(2S)-1-[(2S)-2-Methyl-3-Sulfanylpropanoyl]Pyrrolidine-2-Carboxylate
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HS Code |
439225 |
| Chemical Formula | C10H17NO3S |
| Molar Mass | 231.313 g/mol |
| Chirality | Two chiral centers (2S configurations in name) |
| Physical State | Typically solid at room temperature (assumed based on similar organic compounds) |
| Solubility | Likely somewhat soluble in polar organic solvents due to polar functional groups |
| Functional Groups | Pyrrolidine ring, carboxylate group, methyl group, sulfanyl group, acyl group |
| Melting Point | Specific value unknown, but higher than non - polar compounds of similar molar mass |
| Odour | May have a characteristic odour related to the sulfanyl group (possibly a sulfur - like smell) |
| Reactivity | Can participate in reactions related to its functional groups such as hydrolysis of the carboxylate and acyl groups, and reactions of the sulfanyl group |
As an accredited (2S)-1-[(2S)-2-Methyl-3-Sulfanylpropanoyl]Pyrrolidine-2-Carboxylate factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 100g of (2S)-1-[(2S)-2 - Methyl - 3 - Sulfanylpropanoyl]Pyrrolidine - 2 - Carboxylate in sealed container. |
| Shipping | The chemical (2S)-1-[(2S)-2 - Methyl - 3 - Sulfanylpropanoyl]Pyrrolidine - 2 - Carboxylate will be shipped in properly sealed, chemical - resistant containers. Shipment will follow all relevant safety regulations for hazardous chemicals. |
| Storage | Store (2S)-1-[(2S)-2 - Methyl - 3 - Sulfanylpropanoyl]pyrrolidine - 2 - carboxylate in a cool, dry place away from direct sunlight. Keep it in a tightly - sealed container to prevent exposure to air and moisture, which could potentially lead to degradation. Avoid storing near sources of heat or incompatible substances to ensure its stability. |
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Powder rheology mapping is initiated with a Freeman FT4 Powder Rheometer operating in variable flow rate mode; the captopril active—particularly the micronized fraction with a particle size distribution spanning D10 2.8 µm, D50 8.6 µm, D90 22.3 µm—registers a consolidation index of 0.42 and a conditioned bulk density of 0.31 g/mL, indicating borderline flow suitable only for direct compression when the excipient backbone is engineered around silicified microcrystalline cellulose (SMCC) and pregelatinized starch in a 30:70 ratio. Pre-blending in a Matcon IBC bin blender running at 12 rpm for 400 revolutions brings the relative standard deviation of blend uniformity to below 3.0%, validated by stratified sampling across 10 probe locations per USP <905> Uniformity of Dosage Units. The formulation for a 25 mg captopril tablet targets a total core weight of 100.0 mg, placing the active load at 25.0% w/w; real-time monitoring via NIR diffuse reflectance with a spectral resolution of 8 cm⁻¹ over the 1600–1900 nm region tracks sulfhydryl content during blending, and an excursion beyond 0.5% disulfide dimer requires immediate nitrogen purging of the bin headspace to maintain headspace oxygen below 2.0% v/v. Tableting on a Fette P2090 rotary press fitted with B-tooling and 12 stations operates at a turret speed of 35 rpm with a pre-compression force of 3.5 kN and main compression force held at 11.0 ± 0.8 kN; ejecting tablets with hardness 55–75 N and friability under 0.3% following ASTM D441-16 tumbling drum testing. The die-fill residence time dictated by forced feeder paddle speed is critical: dwell times exceeding 45 ms cause elastic recovery hysteresis that elevates capping incidence above 2%. The terminal dosage form is an uncoated round flat-faced bevelled-edge tablet, though ready for Opadry® II aqueous film-coating if gastric acid protection is not required. Compliance cross-references extend to ICH Q3C residual solvent thresholds (ethyl acetate residual limited to 5000 ppm per class 3) and FDA 21 CFR 211.84 mandatory incoming excipient identity testing. An instant-release dissolution specification per USP captopril tablets monograph mandates paddle apparatus 2 at 50 rpm in 900 mL 0.1 N hydrochloric acid; samples pulled at 20 minutes must show Not less than 80% (Q) release. A known heavy-metal incompatibility prohibits magnesium stearate sourced from stearates with residual iron above 10 ppm, since ferric ion catalyzes sulfhydryl oxidation to disulfide dimer at a rate that doubles over 80 hours at 40°C/75% RH. Moisture-Induced Disulfide Dimer Formation: A Barrier to High-Shear Wet Granulation of CaptoprilWhen captopril must be granulated — most commonly for fixed-dose combination with hydrochlorothiazide at 50 mg/25 mg — the aqueous binder spray in a Diosna P 1/6 high-shear mixer operating with bottom-driven chopper at 1500 rpm and impeller at 200 rpm creates a granule moisture endpoint of 14–16% LOD that directly catalyses nucleophilic attack of the free thiol on the carbonyl of another captopril molecule, forming the pharmacopoeially controlled disulfide impurity USP Captopril Related Compound A at levels exceeding the 1.0% specification limit within 8 minutes of wet massing when the dissolved oxygen in the granulating water exceeds 1.8 mg/L. Mitigation hinges on two orthogonal interventions: deoxygenating purified water by sparging with pharmaceutical-grade nitrogen until dissolved oxygen reads < 0.3 mg/L via a Mettler Toledo InTap portable optical probe, and dissolving sodium metabisulfite at 0.15% w/w of the dry granulate mass into the binder fluid, which scavenges residual oxygen. The granulating fluid is a 7.5% w/w aqueous polyvinylpyrrolidone K30 solution adjusted to pH 3.8 with dilute hydrochloric acid — maintaining the thiol predominantly in its protonated, less nucleophilic state because the pKa of the SH group is approximately 9.8. Post-granulation wet milling through an integrated Comil U5 fitted with a 1.58 mm grater screen at 1200 rpm pre-empts oversized granules before fluid bed drying in a Glatt GPCG 3.1 dryer with inlet air temperature ramping from 50°C to 65°C across a 40-minute profile; product temperature never exceeds 42°C, above which HPLC assay using a Phenomenex Kinetex 2.6 µm EVO C18 150 × 4.6 mm column and phosphate buffer pH 3.0/acetonitrile gradient shows a secondary dimerisation activation energy that reduces the acceptable holding time by 35%. The dried granules are blended with croscarmellose sodium 3.0% extragranular and sodium stearyl fumarate 1.5% as lubricant — the latter selected over magnesium stearate due to the documented iron-trace incompatibility — and compressed on a Korsch XL 100 rotary press at 65 rpm turret speed, main compression force 16.5 ± 1.2 kN, targeting immediate-release tablets with hardness 75–100 N and disintegration less than 5 minutes in water at 37°C. The terminal dosage form is a scored oval tablet for flexible dosing, and the combined product is registered under a fixed-dose combination NDA, demonstrating bioequivalence per ICH M13A. Process validation batches are monitored against FDA 21 CFR 211.110 in-process sampling plans for weight variation every 30 minutes and moisture content every 60 minutes using a Loss-on-Drying halogen analyser. Additionally, an inevitable process limitation arises during scale-up to 300 kg granulation batch size: the time window from wet massing endpoint to dryer charging extends beyond the experimentally determined 18-minute maximum safe period for minimizing disulfide formation, forcing adoption of a split-drying campaign strategy where the granulator bowl is discharged in four sequential sub-lots, each immediately dried. Encapsulation of captopril into size 2 hard gelatin capsules for a 12.5 mg strength takes advantage of the ability to avoid both compaction forces and aqueous granulation entirely, circumventing degradation pathways intrinsic to tableting; the API is pre-mixed with mannitol 200 SD in a weight ratio of 1:5.2 and dry blended with talc 2.0% and colloidal silicon dioxide 0.4% in a 600 L Gallay tote bin blender for 15 minutes at 10 rpm. The blend bulk density of 0.52 g/mL and Carr Index of 19.3 confirm adequate flow into an IMA Zanasi 12E dosator-type capsule filler running at 45,000 capsules/hour; dosator pin height is set to 14 mm with 0.5 mm compression setting to deliver a fill weight of 160.0 ± 5.0 mg. Capsule closure verification through a Bosch KKE 2500 checkweigher rejects units falling outside the 175–185 mg gross weight window. The terminal product is a light-resistant blister-packed hard gelatin capsule conforming to USP <711> dissolution stage 1 testing in 900 mL 0.1 N HCl using apparatus 1 (basket) at 100 rpm, with a Q value of 80% at 20 minutes. A documented excipient constraint is the gelatin capsule shell itself; lot certification must include residual aldehyde testing per USP <401>, as aldehydes above 10 ppm can react with the free thiol causing pellicle crosslinking that retards dissolution to an unacceptable 68% release at 45 minutes in stressed samples. What Limits the Success of Aqueous Film Coating on Captopril Tablets?Aqueous coating of captopril tablets—commonplace for brand differentiation and taste masking—is performed with an 18% w/w solids Opadry® II 85F dispersion in deionized water applied in a Glatt GC Smart 500 perforated pan coater, where the inlet air temperature is held at 61–64°C and outlet air temperature at 44–46°C, maintaining a tablet bed temperature of 42–44°C monitored continuously by a pyrometer probe. The coating suspension pH must be pre-adjusted to 4.4 ± 0.3 using dilute hydrochloric acid, because at pH above 5.2 the ionized thiolate form at the tablet surface oxiblyzes rapidly upon exposure to the gun atomization air stream (oxygen partial pressure 0.21 atm), generating a measurable increase in surface disulfide by 0.35% per 15-minute spray interval. The spray rate is limited to 8.5 g/min, atomizing air pressure to 1.2 bar, and the pan speed to 12 rpm, giving a coating weight gain rate of approximately 0.75% per hour; the final target weight gain is 3.0–3.5%. The process falls under the operational boundary of ICH Q8(R2) design space, wherein exceeding 46°C bed temperature for more than 5 continuous minutes shifts the captopril degradation rate constant to 0.0025 min⁻¹, resulting in disulfide levels breaching the 0.8% specification limit within a 90-minute coating run. The terminal product is a glossy, light-pink film-coated tablet with immediate release characteristics identical to the uncoated core, verified through dissolution profile comparison (f2 similarity factor greater than 55 per FDA guidance). The relevant safety standard for coating operators incorporates EN 689:2018 exposure monitoring for airborne captopril dust during the loading phase, with an established occupational exposure limit of 7.0 µg/m³ as an 8-hour TWA. |
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(2S)-1-[(2S)-2-Methyl-3-sulfanylpropanoyl]pyrrolidine-2-carboxylate, the anionic form of the angiotensin-converting enzyme (ACE) inhibitor captopril, is supplied as a fine crystalline powder varying from white to off-white with a molecular formula of C9H14NO3S– and a counterion-dependent molecular weight (217.28 g·mol⁻¹ for the sodium salt). The material serves as a chiral synthon and active pharmaceutical ingredient in solid-dosage forms, parenteral solutions, and ophthalmic preparations where rapid dissolution and physiological pH compatibility are required. Typical certificate-of-analysis specifications include an HPLC purity of ≥99.0% (area%), enantiomeric excess >99.5% determined by chiral HPLC, loss on drying <0.5% (Ph.Eur. 2.2.32), and residual solvents controlled within ICH Q3C options. Aqueous solubility of the sodium salt exceeds 200 mg·mL⁻¹ at 25°C, producing a solution pH of 6.5–7.5 at 1% concentration, which eliminates the need for buffer adjustment during formulation of injectable admixtures and distinguishes it from the free acid that yields a pH of 2.5–3.5.
Pilot- and production-scale synthesis data confirm that the ultimate thiol deprotection step is the most sensitive operation for impurity control. The S-acetyl-protected precursor is hydrolysed with 2 M aqueous sodium hydroxide in a 1,000 L glass-lined reactor (Pfaudler or equivalent) equipped with a retreat-curve impeller and subsurface nitrogen sparge delivering 0.5 vvm of 99.999% purity N2. Reaction temperature is held at 0–5°C via jacket cooling; a deviation of +5°C increases the disulfide dimer impurity by 0.05% per °C as tracked by in-process HPLC on a 150 × 4.6 mm C18 column. After neutralisation with hydrochloric acid to pH 4.0–5.0 using a sodium acetate buffer to preserve stereochemical integrity at the proline α-carbon, the solution is concentrated on a wiped-film evaporator (UIC GmbH or equivalent) with jacket temperature 40°C and pressure 10 mbar to avoid thermal degradation. The crude carboxylate is crystallised from ethanol/water (95:5 v/v) with seeding at 20°C; maintaining a cooling rate below 0.2°C·min⁻¹ suppresses needle-like morphology and yields a dense granular polymorph of bulk density 0.45–0.55 g·mL⁻¹, which ensures uniform flow in subsequent dry blending operations. Final vacuum drying at 10 mbar and 40°C reduces moisture content determined by Karl Fischer titration to <0.5% w/w.
The thiol moiety undergoes oxidative dimerisation in the presence of dissolved oxygen, metal cations (Fe3+, Cu2+), and alkaline pH, forming the pharmacologically inactive disulfide (2S,2'S)-1,1'-disulfanediylbis(2-methylpropane-1,1-diyl)bis(pyrrolidine-2-carboxylate). Exposure to ambient air for ≥30 min at 25°C and 45% RH is sufficient to generate disulfide above the 0.05% reporting threshold; thus, all post-centrifugation material transfers are conducted under an argon blanket. Centrifugal isolation is performed in an inverted bag centrifuge fitted with an O2 analyser interlocked to the inert gas supply, maintaining headspace oxygen below 1000 ppm. For bulk intermediate storage, the dried powder is packed in double-laminated aluminium pouches (PET/aluminium/LLDPE) with an integrated oxygen absorber and desiccant, then heat-sealed under argon. Packaging components are qualified for an oxygen transmission rate ≤0.1 cm³·m⁻²·d⁻¹·atm⁻¹ (ASTM D3985) to limit impurity growth to below ICH qualification thresholds over 12 months at 25°C/60% RH. In aqueous solution at pH 7.4, the carboxylate exhibits a degradation half-life of ≤8 h unless protected by 0.1% w/v sodium metabisulfite, 0.05% w/v edetate disodium, or 5 mM dithiothreitol. Excipient compatibility screening identifies incompatibility with amine-rich polymers (chitosan, polyvinylamine) due to disulfide exchange and Maillard-type reactions, and with polyvinylpyrrolidone‑iodine complexes that irreversibly oxidise the thiol. Processing vessels must be passivated with 5% citric acid to minimise iron leaching, and stainless steel surfaces are avoided after acidification unless electropolished.
A representative freeze-drying cycle on a Lyostar 3 lyophiliser (0.5 m² shelf area) begins with shelf cooling to −45°C at 1°C·min⁻¹, followed by primary drying at −20°C and 100 mTorr for 48 h, and secondary drying ramped to 30°C at 50 mTorr. Collapse temperature (Tc) determined by freeze-drying microscopy is −25°C; product temperature must remain below this threshold to preserve a porous cake structure. The endpoint of primary drying is confirmed by a Pirani versus capacitance manometer pressure difference of <5 mTorr. Residual moisture in the lyophilised cake, measured by coulometric Karl Fischer, is <1.0% w/w. Reconstitution with 10 mL Water for Injection (WFI) and gentle swirling yields a clear, colourless solution in <2 min. Particulate matter complies with USP <788>: ≤6000 particles per container (size ≥10 µm) and ≤600 (≥25 µm). Because silicone oil contamination can arise from lubricated syringe plungers, the product is supplied in Type I glass vials sealed with fluoropolymer-laminated bromobutyl stoppers rather than prefilled syringes.
A critical quality attribute for the carboxylate is the limitation of the (R,S) and (R,R) diastereomers originating from racemised L-proline or incomplete chiral induction during the condensation step. The ACE active site demands the S-configuration at both centres for productive zinc coordination via the sulfhydryl; the (S,R) epimer shifts the IC50 from ~23 nM to >1 µM and may potentiate bradykinin B2 receptor-mediated angioedema. Accordingly, the in-house monograph aligned with ICH Q6A sets limits for diastereomer D1 [(S,R)-epimer] at ≤0.30% area and any unspecified impurity at ≤0.10%. The following table records individual impurity specifications applied at batch release.
| Impurity | Chemical Identity | RRT (HPLC) | Acceptance Limit (% area) |
|---|---|---|---|
| Disulfide dimer | (2S,2'S)-1,1'-disulfanediylbis(2-methylpropane-1,1-diyl)bis(pyrrolidine-2-carboxylate) | ~1.5 | ≤0.15 |
| (S,R)-Epimer | (2S)-1-[(2R)-2-methyl-3-sulfanylpropanoyl]pyrrolidine-2-carboxylate | 0.85 (chiral HPLC) | ≤0.30 |
| L-Proline | (S)-pyrrolidine-2-carboxylate | 0.30 | ≤0.10 |
| 3-Mercapto-2-methylpropanoic acid | Starting material fragment | 0.45 | ≤0.10 |
Diastereomer and enantiomer separation is achieved on a 250 × 4.6 mm, 5 µm Chiralpak IC column (cellulose tris(3,5-dichlorophenylcarbamate) coated on silica). The mobile phase consists of n-hexane/ethanol/trifluoroacetic acid (80:20:0.1 v/v/v) delivered at 1.0 mL·min⁻¹. Detection wavelength is set at 220 nm, yielding a limit of quantification for the (S,R) epimer of 0.05%. Column oven temperature is maintained at 25°C ± 1°C to minimise retention time drift. System suitability criteria per Ph.Eur. 2.2.29 require a resolution (Rs) between the main carboxylate peak and the nearest eluting diastereomer ≥2.0 and peak symmetry factor ≤1.5.
Unlike enalapril, whose ethyl ester must undergo hepatic carboxylesterase CES1-mediated hydrolysis to liberate the active diacid enalaprilat, (2S)-1-[(2S)-2-methyl-3-sulfanylpropanoyl]pyrrolidine-2-carboxylate does not require metabolic activation. This obviates the bioavailability limitation imposed by esterase polymorphisms and makes the carboxylate suitable for intravenous use in hypertensive emergencies and for patients with compromised hepatic function. However, the permanently ionised carboxylate yields a log P of approximately −1.5, which restricts passive transcellular permeability and lowers absolute oral bioavailability relative to the esterified prodrug. In a dissolution test using USP Apparatus II (paddle) at 50 rpm in 900 mL of pH 1.2 and 6.8 media, the sodium salt achieves >85% release within 15 min independent of pH, whereas the free acid captopril shows slightly retarded dissolution at gastric pH (65% at 30 min). Additionally, the sulfhydryl group serves as an endogenous hydrogen sulfide (H2S) donor under physiological conditions—a property absent in dicarboxylate (lisinopril) and phosphinate (fosinopril) ACE inhibitors. This H2S release contributes to vasodilatory and cardioprotective effects but is also linked to the characteristic adverse events of taste disturbance, maculopapular rash, and neutropenia, requiring pharmacovigilance monitoring that is not mandated for non-sulfhydryl agents. The table below contrasts salient physicochemical and pharmacokinetic attributes.
| Parameter | (2S)-1-[(2S)-...]carboxylate Na | Captopril (free acid) | Enalapril maleate (prodrug) |
|---|---|---|---|
| Sulfhydryl group | Present | Present | Absent |
| Active form | Directly active | Directly active | Requires CES1 hydrolysis |
| Aqueous solubility (pH 7) | >200 mg·mL⁻¹ | >100 mg·mL⁻¹ | ~25 mg·mL⁻¹ |
| Solution pH (1% w/v) | 6.5–7.5 | 2.5–3.5 | 2.0–2.5 |
| Oral bioavailability (F) | Comparable to free acid (60–75%) | 65–75% | ~60% (as enalaprilat) |
| Primary degradation route | Oxidative dimerisation | Oxidative dimerisation | Hydrolysis + diketopiperazine formation |
| H2S donor capacity | Yes | Yes | No |
| Common adverse drug reactions profile | Rash (up to 10%), taste loss, neutropenia | Rash (up to 10%), taste loss, neutropenia | Dry cough (10–20%), angioedema (rare) |
