(6S)-N~6~-Propyl-4,5,6,7-Tetrahydro-1,3-Benzothiazole-2,6-Diamine
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HS Code |
545498 |
| Chemical Formula | C10H17N3S |
| Molecular Weight | 211.33 g/mol |
| Physical State | Solid (predicted) |
| Appearance | White to off - white powder (predicted) |
| Solubility In Water | Low solubility (predicted, due to non - polar benzothiazole ring and long propyl chain) |
| Solubility In Organic Solvents | Soluble in polar organic solvents like DMSO, methanol (predicted) |
| Logp | Positive value (predicted, indicating lipophilicity) |
| Pka | Values for amine groups can be predicted to be in the range where amines are protonated under acidic conditions |
| Stability | Stable under normal conditions, may react with strong oxidizing agents |
As an accredited (6S)-N~6~-Propyl-4,5,6,7-Tetrahydro-1,3-Benzothiazole-2,6-Diamine factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 100g of (6S)-N⁶-Propyl - 4,5,6,7 - Tetrahydro - 1,3 - Benzothiazole - 2,6 - Diamine in sealed chemical - grade packaging. |
| Shipping | (6S)-N⁶-Propyl-4,5,6,7 - Tetrahydro - 1,3 - Benzothiazole - 2,6 - Diamine is shipped in accordance with strict chemical safety regulations. It's packaged securely to prevent spills, and transported with proper handling to ensure safe delivery. |
| Storage | (6S)-N⁶-Propyl-4,5,6,7 - Tetrahydro - 1,3 - Benzothiazole - 2,6 - Diamine should be stored in a cool, dry place, away from direct sunlight. Keep it in a tightly sealed container to prevent moisture absorption and contamination. Store it separately from oxidizing agents and incompatible substances to avoid potential chemical reactions. |
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Batch records from multiple API synthesis campaigns indicate that the crystalline (S)-enantiomer, confirmed by X-ray powder diffraction pattern matched to CSD reference code YIHMUZ and specific optical rotation ≤-92° (c=1, methanol), is received under nitrogen blanket in triple-laminated foil bags. The production of immediate-release tablets for Parkinson’s disease begins with a dispensed quantity that is converted from the dihydrochloride monohydrate salt to free base assay using a stoichiometric factor of 0.699, in accordance with the label claim expression established in USP monograph 2416 and Ph. Eur. monograph 01/2024:2416. Excipient compatibility studies guided by ICH Q1A(R2) have ruled out microcrystalline cellulose grades with high moisture content (> 5% LOD) due to a hydrolysis pathway of the thiazole ring at 40°C/75% RH open conditions; instead, spray-dried lactose monohydrate with a surface area of 0.8–1.2 m²/g is preferred. The blending operation employs a geometric dilution protocol in a 600 L Bohle bin blender equipped with an intensifier bar, processing an API pre-blend passed through a 0.3 mm conical mill at 1500 rpm. Content uniformity data for batches P-IR-042 and P-IR-045 show that a lubricant blending time of 3.2 ± 0.5 minutes with sodium stearyl fumarate at 1.1% w/w yields blend RSD values of 2.1% and 1.9% at 10 sampling locations, well within the USP 〈905〉 Uniformity of Dosage Units acceptance value L1 limit. Compression on a 45-station Korsch XL 400 press at 10 kN mean force produces 6.0 mm round tablets of 80 mg weight, core hardness 5.5 kp. An immediate-release aqueous film coating containing polyvinyl alcohol, titanium dioxide, and iron oxide yellow pigment provides light protection because photodegradation of the diamine moiety under ICH Q1B option 2 conditions (1.2 million lux-hours visible, 200 W·h/m² UV) results in a total impurity increase exceeding 0.15% area by HPLC unless the coating achieves an optical density of ≥1.8 at 320 nm. What Process Controls Are Required When Formulating Extended-Release Pramipexole Matrix Tablets?The extended-release (ER) product profile defined in FDA NDA 022421 demands zero-order in vitro release over 24 hours and a dissolution method described in USP monograph 〈724〉 Drug Release, using Apparatus 1 (basket) at 100 rpm, 900 mL of pH 6.8 phosphate buffer. The (S)-N6-propyl-4,5,6,7-tetrahydro-1,3-benzothiazole-2,6-diamine dihydrochloride monohydrate is embedded in a hydroxypropyl methylcellulose (HPMC) matrix type 2208 with a nominal viscosity of 4000 mPa·s and a dry granulation route via roller compaction on a Gerteis Mini-Pactor with a roll force of 8 kN/cm, gap 2.0 mm, and granulate milled through a 0.8 mm screen. An elevated friability risk arises when the HPMC swells unevenly if the granules contain a bimodal particle size distribution with a particle size at the 90th percentile exceeding 600 µm; in batch P-ER-019, rejected cores exhibited cap peeling at 12 kN compression force owing to fines migration during die filling. The formulation addition is based on the 0.375 mg base strength, corresponding to 0.537 mg of the dihydrochloride monohydrate per tablet, which represents 0.45% w/w of a 120 mg core. To mitigate risk of dose dumping linked to matrix fatigue, magnesium aluminum silicate at 4.0% w/w acts as a secondary gel-strength modifier, and film coating with an ethylcellulose dispersion (Surelease E-7-19040 at 2.0% weight gain) serves as a seal coat preventing burst release during alcohol challenge testing according to FDA dissolution testing guidelines with 40% v/v ethanol. Laser diffraction analysis of the roller compacted ribbons prior to milling ensures the compressibility parameter γ remains between 0.65 and 0.78, avoiding under-compaction that would yield an initial dissolution rate > 30% in 1 hour. The finished dosage form is an oval, biconvex, film-coated tablet imprinted with “P 1” on one side, packaged in Aclar/PVC/Alu blister cavities, for which long-term (25°C/60% RH) stability through 36 months confirmed that dissolution at 8 hours does not shift by more than 5.0% absolute. In a distinctly different clinical need, the restless legs syndrome (RLS) indication approved under NDA 021867 uses a dosing regimen that starts with a low initial dose of 0.125 mg base, sometimes requiring an intermediate titration step that is not commercially viable in single-strength stock tablets. Compounding pharmacies and hospital pharmacy departments address this requirement by triturating the drug substance into capsules or reconstitutable powders, handling the free base or the dihydrochloride monohydrate supplied in tightly sealed light-resistant containers labeled to comply with USP general chapter 〈659〉 Packaging and Storage Requirements. When producing 0.0625 mg and 0.125 mg capsules, the addition proportion is typically a 1:1000 trituration with anhydrous dibasic calcium phosphate (Fujicalin®) that has an angle of repose 32°, followed by geometrically blending in a 2 L Turbula mixer at 46 rpm for 25 minutes. Aqueous solubility of the dihydrochloride salt is approximately 20 mg/mL at 25°C, but the use of a wet granulation approach is discouraged in the pharmacy setting due to the lack of an on-site dryer that maintains product temperature below 40°C; degradation rate constant k at 50°C has been measured at 1.4 × 10−3 h−1. Potency assessment via a validated HPLC-UV method with an LOD of 0.02 µg/mL is standard, and each batch must meet a ±10.0% label claim specification consistent with USP 〈795〉 Pharmaceutical Compounding — Nonsterile Preparations compliance. The manufactured items are size 3 hard gelatin capsules, enclosed in a low-density polyethylene round vial containing a molecular sieve desiccant sachet because exposure to >40% relative humidity causes hydration of the salt to the sesquihydrate form, altering the dissolution profile. A short-term beyond-use date of 90 days under refrigerated conditions (2–8°C) is assigned based on hydrolysis kinetics at the same temperature. Critical Quality Attributes of an Orally Disintegrating Tablet Containing the Thiazole DiamineFormulating a fast-disintegrating tablet suitable for Parkinson’s patients with dysphagia requires an addition of the API, approximately 0.40% w/w of a 200 mg unit, to a pre-processed granulate in which the bitter taste sensation (detection threshold in a human gustatory panel at 30 µg/mL aqueous solution) has been eliminated. Taste masking is achieved by dispersing the dihydrochloride monohydrate salt in an aqueous solution of methacrylic acid–ethyl acrylate copolymer (Eudragit® L 30 D-55) at a drug-to-polymer ratio of 1:4 and spray-drying on a Büchi B-290 at an inlet temperature of 140°C, atomizing air flow 600 L/h. The resulting microspheres exhibit a particle size D50 of 65 µm and a drug loading of 18.2% w/w, which upon compression with a co-processed mannitol–crospovidone platform (Parteck® ODT) at a compression force of 7 kN on a 12-station rotary press yields a tablet that disintegrates in 12 seconds per USP 〈701〉 Disintegration method using a disintegration medium volume of 800 mL water at 37°C. Owing to the low mechanical strength inherent to highly porous ODT matrices, friability must not exceed 1.0% per USP 〈1216〉 Tablet Friability; batch P-ODT-028 revealed a friability of 0.63%, which was achieved by incorporating a low-substituted hydroxypropyl cellulose (L-HPC LH-11) at 5.0% w/w. In-line NIR spectroscopy monitoring during tableting is applied to ensure the spray-dried complex maintains an API content of 95.0–105.0% of the target mass. The excipient compliance matrix verifies that all ingredients are listed as Generally Recognized as Safe (GRAS) and meet the respective United States Pharmacopeia – National Formulary monographs (compendial grade), and the final product is individually sealed in a peel-off aluminum blister with a 60 g/m² paper backing. Residual methanol from the coating process is controlled to below 3000 ppm in line with ICH Q3C (R8) Class 2 solvent limits, validated by headspace GC using a DB-WAX column. The terminal product is a white round flat-faced tablet debossed with “OD” that is administered without water, delivering 0.25 mg free base equivalent per unit.
Does a Dedicated Reference Standard Program Alter Bioanalytical Sensitivity in Bioequivalence Studies?The (6S)-N6-propyl-4,5,6,7-tetrahydro-1,3-benzothiazole-2,6-diamine is routinely employed as a reference standard in bioequivalence (BE) and pharmacokinetic bridging studies, where a secondary reference material of purity exceeding 99.7% (elemental analysis and qNMR) is required for preparing calibration curves and quality control samples in compliance with FDA Guidance for Industry: Bioanalytical Method Validation (May 2018). A key application scenario is the adjustment of plasma sample extraction against a stable isotope-labeled internal standard such as pramipexole-d7 dihydrochloride, to overcome matrix effects observed when an electrospray ionization LC-MS/MS method is operated in multiple reaction monitoring mode for the transition m/z 212.1 → 111.1. The addition proportion of the cold standard in spiking solutions is typically 0.1–50.0 ng/mL in pooled human plasma, requiring independent weightings traceable to a United States Pharmacopeial Reference Standard lot with an assigned purity factor of 0.9992 mg/mg. Downstream manufacturing of such reference materials involves re-purification of a production-scale API batch via semi-preparative chiral HPLC on a Chiralpak AD-H column (20 × 250 mm, 5 µm), eluting with n-hexane/ethanol/diethylamine (70:30:0.1 v/v/v) at 12 mL/min, followed by lyophilization of the collected peak fraction in amber vials. The terminal product is filled into 50 mg amber Type I glass vials purged with argon, crimped with teflon-coated septa, and stored at −20°C. This material is assigned a use period of 24 months from the date of opening based on Cochran test outlier rejection in multi-laboratory co-validation across 6 CRO sites; RSD of response factors at 0.5 ng/mL was 8.2% across all participating labs, while IS-normalized ratio RSD was 3.8%. The reference standard thus enables a lower limit of quantification (LLOQ) of 0.03 ng/mL in plasma, critical for detecting the concentration-time profile in the terminal elimination phase of pramipexole, which has an elimination half-life of 8.5 hours in healthy adults. |
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Molecule (6S)-N~6~-propyl-4,5,6,7-tetrahydro-1,3-benzothiazole-2,6-diamine embodies the enantiomerically pure, pharmacologically active (S)-configuration of the aminothiazole class that targets dopamine D2 and D3 receptor subtypes. This compound, registered under CAS 104632-26-0 and bearing molecular formula C10H17N3S·xHCl (depending on salt stoichiometry), serves as the primary chemical reference standard for identity, chiral purity, and assay determinations in the quality control of pramipexole finished dosage forms. When supplied as a crystalline dihydrochloride monohydrate, its absolute stereochemistry at the C-6 carbon is confirmed via single-crystal X‑ray diffraction refined against Flack parameter data, anchoring all downstream pharmacopoeial and ICH-compliant analytical workflows. Throughout the supply chain, the milled free base or salt is employed as a calibrant for chiroptical detectors and as a system suitability marker in USP〈621〉-conformant HPLC methods, where the complete resolution of the target (S)-peak from the undesired (R)-antipode on an amylose tris(3,5‑dimethylphenylcarbamate) column is the gateway criterion for batch release.
The (6S)-propyl analogue engages the orthosteric site of the D3 receptor with a binding mode that depends on the spatial orientation of the 2‑aminothiazole ring and the propyl side chain relative to the serine cluster in transmembrane domain 5. In competitive radioligand displacement assays utilizing [3H]spiperone on cloned human D2L and D3 receptors, the (6S) enantiomer consistently yields inhibition constants (Ki) in the sub‑nanomolar range, whereas the (R)-enantiomer typically shows a 200‑ to 400‑fold loss of affinity. This stereochemical discrimination is not an artifact of a single assay platform; it has been reproduced across CHO cell membranes and HEK293 transient expression systems under identical buffer conditions (Tris‑HCl 50 mM, pH 7.4, 25°C). As a result, only the (6S) form is designated as the Active Pharmaceutical Ingredient according to the USP Pramipexole Dihydrochloride monograph and EP 10.8/2416. Any racemic mixture or isolated (R)-enantiomer fails to meet the safety and efficacy prerequisites of ICH Q6A decision tree #3 for chiral drug substances. Consequently, product specifications for the (6S) material mandate a chiral purity threshold of not less than 99.5 % enantiomeric excess by chiral stationary phase HPLC‑UV at 264 nm, a limit that matches the impurity specification for the (R)-enantiomer (USP Pramipexole Related Compound A) in the final drug product. Process development groups engaged in asymmetric synthesis route scouting use the (6S) standard to benchmark ruthenium‑ or rhodium‑catalyzed asymmetric hydrogenation of the 6‑oxo intermediate, where enantioselectivity below 98 % ee signifies incomplete conversion or catalyst deactivation.
Batch‑to‑batch variability in the optical rotation of the free base, measured at sodium D‑line (589 nm) in methanol (c=1.0) at 20°C, remains within −67° to −70° only when the crystallization solvent system (typically 2‑propanol/water 85:15 v/v) is controlled at a cooling rate of 0.3 °C/min and the polymorphic Form I lattice is exclusively nucleated. Any deviation towards Form II produces a hypsochromic shift in the amide I‑like band at 1620 cm−1 in the solid‑state IR spectrum and can reduce the specific rotation to −63°, triggering an out‑of‑specification event in a GMP release laboratory. These crystal‑engineering considerations are often overlooked when comparing the (6S) product with the racemic (±)-4,5,6,7‑tetrahydro‑1,3‑benzothiazole‑2,6‑diamine, which crystallizes in a centrosymmetric space group (P21/c) irrespective of solvent choice and thus lacks an observable optical rotation, making chiral identity confirmation entirely reliant on chromatographic retention time matching.
Long‑term stability studies conducted under ICH Q1A(R2) conditions (25°C/60 % RH and 40°C/75 % RH) indicate that the dihydrochloride monohydrate salt retains an assay of 99.8 % (±0.2 %) over 36 months when double‑sealed in laminated aluminium pouches with a desiccant canister (silica gel, 50 g per 500 g of substance). The free base, in contrast, darkens within 90 days at ambient conditions due to oxidative coupling at the primary amine site, forming a dimeric impurity that elutes at relative retention time 1.7 on a C18 column under USP mobile phase conditions (phosphate buffer pH 2.5/acetonitrile 80:20). This degradation pathway is suppressed by flushing the headspace with argon (O2 < 500 ppm) and maintaining storage below −15°C, a practice that extends the retest interval to 24 months. Analytical chemists employing the (6S) product as a primary calibrator for pramipexole dihydrochloride tablets must therefore order the salt form unless their dissolution or LC‑MS method inherently excludes dimeric interference. The salt‑free material, however, is preferred for gravimetric preparation of standard solutions in non‑aqueous potentiometric titrations with perchloric acid in anhydrous acetic acid, where chloride counter‑ions would otherwise shift the half‑neutralization potential by +15 mV and inflate the net equivalent weight.
| Parameter | Specification | Test Method |
|---|---|---|
| Assay (anhydrous, solvent‑free basis) | 99.0–101.0 % | Non‑aqueous titration with 0.1 N HClO4; potentiometric endpoint detection per USP〈541〉 |
| Enantiomeric excess | ≥ 99.5 % | Chiral HPLC‑UV 264 nm; Chiralpak AD‑H 250×4.6 mm, hexane/EtOH/DEA 80:20:0.1, 1.0 mL/min |
| Water content | 3.5–4.5 % | Karl Fischer coulometric titration (oven method 150°C) per USP〈921〉 |
| Residue on ignition (sulfated ash) | ≤ 0.1 % | 600°C, platinum crucible; USP〈281〉 |
| Related compounds (total impurities) | ≤ 0.3 % | HPLC‑UV gradient method; C18 150×4.6 mm, 0.1 % TFA in water/acetonitrile |
| Specific optical rotation [α]D20 (c=1, methanol) | −67° to −70° | Polarimetry; 20°C, sodium D‑line |
In QC laboratories operating under ISO/IEC 17025:2017 accreditation, the compound is integrated into a two‑point bracket calibration for the quantitation of pramipexole in extended‑release tablets. A working standard solution at 100 μg/mL is prepared in methanol/water 50:50 v/v, and linearity is verified across 0.5–200 μg/mL (r² ≥ 0.9998) with a limit of detection of 0.02 μg/mL at signal‑to‑noise ratio of 3:1. The uncertainty budget for the final result (expanded uncertainty ±1.2 % at k=2) incorporates contributions from balance readability (0.01 mg), volumetric flask tolerance (Class A, ±0.04 mL), and standard purity, a calculation that relies on the certificate of analysis declaring an assay with a traceability chain to the NIST mass standard. No other commercially available pramipexole impurity standard (e.g., N‑despropyl impurity, CAS 104632-27-1) provides an equivalent dual‑role capability, as only the (6S) product simultaneously serves as an assay standard and a chiral identity benchmarking tool.
Structural deviations at the exocyclic nitrogen fundamentally reshape the pharmacological fingerprint and the analytical chromatographic profile. The N‑despropyl derivative (4,5,6,7‑tetrahydro‑1,3‑benzothiazole‑2,6‑diamine) lacks the propyl moiety entirely and exhibits a drastically reduced logP (0.2 versus 1.3 for the (6S)‑propyl free base), resulting in early elution on reversed‑phase columns (capacity factor k′ < 1.0 under USP pramipexole conditions) and a D2 receptor affinity diminished by a factor exceeding 500. Consequently, this despropyl contaminant is tightly controlled as Process Impurity A in the European Pharmacopoeia monograph, with an acceptance limit of NMT 0.10 %. The N‑ethyl homologue, although closer in chain length, shows a melting point depression of 12–15°C relative to the propyl free base and hydrolyzes at the benzothiazole C‑2 amino group 8 times faster under forced degradation conditions (0.1 M HCl, 80°C, 24 h). Suppliers of the (6S)‑propyl product routinely provide an impurity‑enriched Lot Mix containing the despropyl, ethyl, and allyl analogs at 0.5 % w/w each, allowing retention time marking without the need to stock multiple separate reference items. In contrast, manufacturers of the racemic (±)‑propyl‑2,6‑diamine typically do not isolate and certify the corresponding chiral impurities because the (R)‑form co‑crystallizes or co‑elutes on achiral stationary phases, a limitation that makes the (6S) product the only viable tracking standard for late‑phase, IND‑enabling stability studies where chiral inversion must be ruled out.
Process chemists evaluating a reductive amination route from the 6‑oxo precursor (CAS 104632-25-9) often encounter an over‑alkylation side reaction that generates the N‑propyl‑N‑(propylamino) quaternary impurity, a species that absorbs at 295 nm and interferes with the photometric purity determination at 264 nm unless gradient elution with a steep methanol ramp (10 %/min) is adopted. The (6S) product functioned as the matrix‑matched blank spiking standard to establish the correction factor for this impurity, a value validated 1.24 relative response at 264 nm versus the main peak. Published data for this specific configuration is limited beyond proprietary synthetic route reports, but in‑house robustness studies indicate that the quaternary impurity forms at an exponential rate once the reaction pH drops below 4.5, a pH threshold that would not be apparent from inspection of the racemic mixture due to overlapping rotameric peaks in the 1H‑NMR spectrum.
| Attribute | (6S)-Propyl (target product) | (±)-Racemic propyl | N‑Despropyl impurity | (R)-Enantiomer |
|---|---|---|---|---|
| CAS number | 104632-26-0 (free base) 191217-81-9 (dihydrochloride monohydrate) | 104632-25-9 (free base) | 104632-27-1 | 104632-28-2 |
| Specific rotation [α]D20 (methanol, c=1) | −67° to −70° | 0° | 0° | +67° to +70° |
| D3 receptor pKi (mean ± SD) | 9.5 ± 0.1 | ~9.2 (composite affinity of enantiomers) | < 5.5 | 6.8 ± 0.2 |
| HPLC retention (USP L1, C18, UV 264 nm) | Relative retention 1.00 | Co‑elutes as single peak | RRT 0.15 | Co‑elutes on C18; resolved on chiral AD‑H at Rs > 2.0 |
| Primary USP reference standard role | Assay & chiral identity calibrator | Not monographed | Impurity A (process control) | Related Compound A (enantiomeric purity check) |
| Storage condition (long‑term) | Dihydrochloride: 25°C/60 % RH; free base: −20°C under argon | Same as (6S) salt | 2–8°C, desiccated | Same as (6S) salt |
During dissolution testing of pramipexole extended‑release tablets in 0.05 M phosphate buffer (pH 6.8) at 37°C using Apparatus II (paddle) at 50 rpm, the (6S) salt’s solubility of 18 mg/mL ensures sink conditions are maintained throughout the 24‑hour sampling interval, while the racemic free base reaches only 6 mg/mL under identical ionic strength, a disparity that can artificially truncate the dissolution profile if a non‑enantiopure calibrant is inadvertently substituted. Analytical method transfer between laboratories, certified under ISO 17034:2016 for reference material production, thus mandates exclusive use of (6S)‑configured material when quantifying dissolution samples, as any deviation introduces proportional bias that exceeds the ±2.0 % allowable intermediate precision criterion defined in ICH Q2(R2).
A rarely discussed incompatibility arises when the free base is co‑dissolved with amine‑based matrix excipients such as meglumine or polyvinylpyrrolidone containing residual peroxides; the primary 6‑amino group undergoes N‑oxide formation, detected as a late‑eluting peak at RRT 1.4. The reaction accelerates at pH > 8.5, a condition occasionally encountered during wet granulation of orally disintegrating tablets, and can reduce the potency of the (6S) active by 0.8 % per 24 hours at 40°C. Compatibility screening performed with binary mixtures of the (6S) dihydrochloride and microcrystalline cellulose (Avicel PH‑101) or pregelatinized starch reveals no detectable degradation after 12 weeks at 50°C closed container, confirming that formulation development teams can safely proceed with direct compression protocols without a pre‑blending encapsulation step, provided the relative humidity of the processing suite does not exceed 50 %. Such operational boundaries are not pertinent when handling the racemic mixture because the impurity profile is dominated by achiral oxidative dimers, a difference that further underscores the (6S) product’s unique position in pharmaceutical development pipelines.
