Pramipexole(S)-2-Amino-6-Propylamino-4,5,6,7-Tetrahydrobenzthiazole
|
HS Code |
650450 |
| Chemical Name | Pramipexole (S)-2-Amino-6-Propylamino-4,5,6,7-Tetrahydrobenzthiazole |
| Molecular Formula | C10H17N3S |
| Molecular Weight | 211.33 g/mol |
| Cas Number | 104632-25-1 |
| Appearance | White to off - white powder |
| Solubility | Soluble in water, methanol, ethanol |
| Pka | 8.2 |
| Logp | 1.48 |
| Route Of Administration | Oral |
| Pharmacological Class | Dopamine agonist |
| Mechanism Of Action | Binds to dopamine D2 - like receptors |
| Melting Point | 127 - 132 °C |
As an accredited Pramipexole(S)-2-Amino-6-Propylamino-4,5,6,7-Tetrahydrobenzthiazole factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | Pramipexole (S - 2 - Amino - 6 - Propylamino - 4,5,6,7 - Tetrahydrobenzthiazole) in 10 - gram vials. |
| Shipping | Pramipexole (S)-2 - Amino - 6 - Propylamino - 4,5,6,7 - Tetrahydrobenzthiazole is shipped in well - sealed, appropriate containers compliant with chemical transport regulations. Packaging ensures protection from external factors during transit. |
| Storage | Pramipexole (S)-2 - Amino - 6 - Propylamino - 4,5,6,7 - Tetrahydrobenzthiazole should be stored in a tightly closed container. Keep it in a cool, dry place, away from direct sunlight and heat sources. Protect from moisture to prevent degradation. Store at a controlled room temperature, typically between 15 - 30°C, as specified by the manufacturer. |
Direct manufacturing of pramipexole dihydrochloride immediate-release tablets at sub‑milligram dose strengths rests on a geometric dilution strategy validated through stratified sampling of 32-station rotary press trials (Fette 2090i, 60–80 rpm), where the free‑base‑equivalent dose range of 0.125 mg, 0.25 mg, 0.5 mg, 1.0 mg, and 1.5 mg per unit dictates that the active ingredient (as pramipexole dihydrochloride monohydrate, adjusted for 1.0 mg base = 1.171 mg salt) constitutes between 0.15% and 1.5% w/w of the total blend—a range where segregation potential must be countered by pre‑blending with a portion of the diluent (sieved mannitol 160C, D50 180 µm) at a carrier‑to‑API ratio not less than 5:1 w/w before integration with the main filler and disintegrant (crospovidone XL‑10, 2.0–3.0% w/w) and lubricant (magnesium stearate, 0.8% w/w, passed through a 500 µm screen). Content uniformity evaluation follows USP <905> with acceptance value ≤ 15.0 using a stratified sampling plan of 30 units across 12 press run intervals; blend potency targets 100% label claim with 95%–105% individual capsule‑weight‑corrected results. The downstream production train consists of dry blending in a 600‑L bin blender at 12 rpm for 15 min, verification of blend uniformity per USP <785> near‑infrared method, compression on a 32‑station rotary press equipped with 6.0‑mm round standard concave tooling, and final metal‑detection and tablet dedusting. Finished‑product specifications reference the USP monograph for Pramipexole Dihydrochloride Tablets, with dissolution Q ≥ 80% at 30 min in 500 mL 0.1 N HCl using Apparatus 2 at 50 rpm, per USP <711>, and residual solvent limits per ICH Q3C for methanol (≤3000 ppm) and isopropyl alcohol (≤5000 ppm). The terminal dosage form for this line is the USP‑grade Pramipexole Dihydrochloride Immediate‑Release Tablet, packed in HDPE bottles with induction‑sealed closures under 25 °C/60% RH stability commitment.Can Hydrophilic Matrix Swelling Dynamics Tolerate High‑Shear Granulation Over‑Wetting?Pramipexole extended‑release tablets utilizing a monolithic hydrophilic matrix approach—based on hypromellose 2208 (HPMC K4M, apparent viscosity 2700–5040 mPa·s) and 2910 (HPMC K100M, 75000–140000 mPa·s) at a combined level of 35–45% w/w of the core weight—require tight liquid addition monitoring during wet massing because an increase in granulation moisture from 12.5% to 14.0% w/w, measured by loss‑on‑drying at 105 °C, shifts gel‑layer formation kinetics sufficiently to lower dissolution release at the 4‑hour sampling point by 8–12 percentage points in 0.05 M phosphate buffer (pH 6.8) under USP Apparatus 1 at 100 rpm. The dose schedule—expressed as free‑base equivalents of 0.375, 0.75, 1.5, 2.25, 3.0, 3.75, and 4.5 mg—dictates an active content between 1.0% and 5.0% w/w for the tablet core; the pramipexole dihydrochloride monohydrate is dry‑mixed with dicalcium phosphate anhydrous (filler, 15–25% w/w) and the HPMC component before binding with purified water in a high‑shear mixer‑granulator (Gral 10‑L bowl, chopper 1500 rpm, impeller 200 rpm, wet massing for 90–120 seconds). Granules are dried in a fluid‑bed dryer with inlet air temperature ramped from 50 °C to 65 °C until a final moisture target of 1.5–2.5% w/w is achieved, then milled through a 1.0‑mm screen, blended with colloidal silicon dioxide (0.5% w/w) and magnesium stearate (1.0% w/w), and compressed on a rotary press with pre‑compression force of 2.0–3.0 kN and main compression force producing tablet hardness of 100–150 N. The relevant multi‑point dissolution standard follows the FDA‑recommended method for pramipexole ER: Apparatus 1 (basket), 100 rpm, 900 mL medium, sequential media of 0.1 N HCl for the first 2 hours and pH 6.8 phosphate buffer thereafter, with acceptance limits at 1 h: 15–35%, 4 h: 45–65%, 8 h: 70–85%, and 12 h: ≥ 85%—values anchored to the USP Pramipexole Extended‑Release Tablets monograph and ICH Q4B Annex 5 for dissolution apparatus qualification. Terminal packaged form is the Pramipexole Extended‑Release Tablet in blister strips (PVC‑PCTFE/Aclar) with a shelf‑life assignment based on ICH Q1A(R2) long‑term conditions of 25 °C ± 2 °C/60% RH ± 5% RH.Free Base to Dihydrochloride Monohydrate: Stoichiometric Precision, Residual Isopropanol, and Polymorph FidelityConversion of the supplied pramipexole free base—(S)‑2‑amino‑6‑propylamino‑4,5,6,7‑tetrahydrobenzothiazole—into the dihydrochloride monohydrate salt requires anhydrous processing conditions (RH<30%) to prevent premature hydration that leads to an unstable hemihydrate intermediate with a distinct needle morphology and altered dissolution rate. The reaction uses a 2.02–2.10 molar ratio of hydrogen chloride gas (or concentrated hydrochloric acid, 37% w/w) to the dissolved free base in a chilled isopropanol/water mixture (85:15 v/v) at 0–5 °C, with the free base input normalized to 1.0 kg yielding approximately 1.41 kg of dihydrochloride monohydrate after vacuum drying at 40 °C for 8 h under a nitrogen bleed. The addition rate of HCl must not exceed 0.15 mol per mole of base per minute, controlled by a mass‑flow controller; exceeding this rate triggers a transient pH drop below 1.0 that promotes the metastable anhydrous Form II crystals, detectable by their characteristic XRPD peak at 9.2° 2θ (Cu Kα). Polymorph identity is confirmed against the reference monohydrate pattern (Form I, peaks at 10.5°, 19.8°, 24.3° 2θ) per the USP Pramipexole Dihydrochloride monograph, and the final water content by Karl Fischer titration must fall within 5.0–5.8% w/w, corresponding to the theoretical monohydrate stoichiometry of 5.55%. Residual isopropanol is limited to ≤5000 ppm and acetone (if carried over) to ≤5000 ppm under ICH Q3C Class 3 guidelines, assessed by headspace GC‑FID. The isolated salt is passed through a 500‑µm conical mill and double‑bagged under argon for transfer to GMP packaging; this constitutes the Pramipexole Dihydrochloride Monohydrate API, which serves as the active substance for all solid oral dosage forms described in the compendial articles.Aqueous pramipexole oral solutions formulated at a concentration of 0.1 mg/mL or 1.0 mg/mL (expressed as free base) rely on the high intrinsic solubility of the dihydrochloride salt (> 200 mg/mL in water at 25 °C) but confront a narrow pH‑dependent stability window: degradation product TR‑1 (identified as a hydroxylamine‑related oxidation product) increases by 0.15% area per week at 40 °C when the solution pH exceeds 6.5. Therefore, the compounding formula combines pramipexole dihydrochloride monohydrate at a quantity equivalent to 100 mg free base per liter with a citrate buffer (10 mM, pH 5.5–6.0), a preservative system consisting of sodium benzoate (0.1% w/v) and potassium sorbate (0.2% w/v) validated by antimicrobial effectiveness testing per Ph. Eur. 5.1.3 / USP <51> (criteria A for bacteria, criteria B for fungi), and a sweetener such as sucralose (0.08% w/v). The manufacturing sequence begins with dissolving the buffer salts in 80% of the final batch volume of purified water at 40 °C, adding the preservatives, cooling to 25 °C, then dissolving the pramipexole salt under gentle stirring (200 rpm anchor impeller) to avoid vortex entrainment of oxygen. The solution is brought to volume, filtered through a 0.45‑µm polyethersulfone membrane, and filled into amber Type III glass dropper bottles under nitrogen overlay. The terminal dosage form is Pramipexole Oral Solution, prescribed in European markets where compendial standards (e.g., a pending Ph. Eur. monograph) are aligned with the manufacturer’s marketing authorization dossier; in‑process controls include density (1.005–1.010 g/mL), pH (5.4–6.2), and a limit of 0.2% total degradation products tracked by a validated UPLC method at 265 nm.When D90 Falls Below 15 µm: Segregation Tendency in Low‑Dose Direct Compression FeedsJet‑milling of the dihydrochloride monohydrate salt to a particle size distribution where D90 ≤ 15 µm (as measured by laser diffraction, ISO 13320, dry dispersion at 3 bar) is frequently performed to support mixing homogeneity in sub‑milligram‑strength direct‑compression systems; however, milled particles with a specific surface area exceeding 4.5 m²/g (BET, ISO 9277) exhibit increased triboelectric charging when processed in stainless‑steel bin blenders (30°C, 35% RH), leading to wall adhesion losses of 3–5% and a consequent dip in blend potency of up to 2.5 percentage points relative to target. The addition level of the micronized API corresponds to the same free‑base‑equivalent dose band of 0.125–1.5 mg per tablet, with the API‑to‑excipient pre‑blend step adjusted to a 1:7 ratio using dry‑granulated mannitol (Pearlitol 200SD) that has a roughened surface morphology to reduce percolation segregation. Process‑scale equipment comprises a 100‑L tumble blender loaded to 70% of its volume, blending at 15 rpm for 25 min, with triplicate sampling (10 samples, 3x~5x dosage‑unit mass) evaluated by an HPLC method meeting USP <621> system suitability; the acceptance range is 95.0%–105.0% label claim with an RSD ≤ 5.0%. The equipment train proceeds to a tablet press equipped with forced‑feed mechanism and particle‑retention shields; compression forces of 5–8 kN yield tablet hardness of 40–60 N and friability ≤ 0.8% (USP <1216>). The end product adheres to the Pramipexole Immediate‑Release Tablet specification in the USP, with additional particle‑size‑related dissolution robustness confirmed at early time points (15‑minute samples yielding ≥ 85% dissolved). Where multiple strength tablets are derived from a common blend, the risk of sedimentation of fines during hopper residence is mitigated by a hopper level control algorithm that maintains material height within ±15% of the target.What Impurity Acceptance Limits Are Triggered Under ICH Q1B Oxidative Forced Degradation?Forced degradation of the free‑base substance in the solid state and in solution, executed per ICH Q1B and Q2(R1) photostability and stress guidelines, reveals a primary oxidative pathway that converts the 2‑aminothiazole moiety into a sulfoxide‑derived degradant (Impurity A, RRT 0.78 on a reversed‑phase C18 column with a pH 3.0 phosphate‑acetonitrile gradient) and, under prolonged 3% hydrogen peroxide stress at 25 °C for 24 hours, a secondary N‑oxide species (Impurity C, RRT 1.21) that exceeds the 0.10% identification threshold prescribed by ICH Q3B for a maximum daily dose of 4.5 mg free base. The test protocol exposes a 10‑mg portion of the free base, spread as a thin film in a quartz dish, to a xenon‑arc lamp delivering 1.2 million lux‑hours of visible light and 200 Wh/m² of near‑UV, while a parallel suspension in 0.1 N HCl (to mimic gastric environment) is stressed with 0.3% H₂O₂ at 40 °C. Addition of the API to a formulated placebo blend at the 1.5‑mg dose level (1.5% w/w) and subsequent exposure to 40 °C/75% RH for 4 weeks in open petri dishes shows that interaction with microcrystalline cellulose and povidone K30 accelerates the formation of Impurity A by an additional 0.04% compared to drug‑alone controls; therefore, the formulation quantitative composition must maintain excipient‑based antioxidant protection (e.g., 0.05% w/w butylated hydroxytoluene or ascorbic acid 0.1% w/w) when packaging oxygen permeability exceeds 0.5 cm³/(m²·24 h·atm) at 23 °C. The analytical finish employs a mass‑balance‑verified HPLC method with a reporting threshold of 0.05%, identification of unknowns above 0.10% via LC‑QTOF‑MS, and qualification of degradants at levels above 0.15% through Ames testing (OECD 471) when the overall clinical exposure exceeds the threshold of toxicological concern. The terminal output of this characterization is a knowledge‑enriched API supporting the dossier for Pramipexole Dihydrochloride Tablets and Extended‑Release Tablets, meeting the degradation‑product requirements of the USP monograph and the general notice for impurities in Ph. Eur. 5.10. |
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Pramipexole (S)-2-amino-6-propylamino-4,5,6,7-tetrahydrobenzthiazole—systematically designated as (S)-N6-propyl-4,5,6,7-tetrahydro-1,3-benzothiazole-2,6-diamine—constitutes the pharmacologically active enantiomer of the aminothiazole dopamine agonist class. The product is supplied as a crystalline dihydrochloride monohydrate salt (CAS 191217-81-9) with a molecular formula of C10H17N3S · 2HCl · H2O and a formula weight of 302.26 g·mol−1. Industrial-scale enantioselective synthesis employs (S)-2,6-diamino-4,5,6,7-tetrahydrobenzthiazole as the chiral intermediate, with propionaldehyde reductive amination achieving optical purity in excess of 99.5% enantiomeric excess when monitored by chiral HPLC using amylose tris-(3,5-dimethylphenylcarbamate) stationary phases per Ph. Eur. method 2.2.46. Storage at controlled room temperature (15–25 °C) in sealed, light-resistant containers is mandatory; exposure to relative humidity above 60% induces deliquescence and hydrolysis of the 4,5-dihydrothiazole moiety, forming 2-amino-6-propylamino-4,5,6,7-tetrahydrobenzthiazole N-oxide artefacts detectable by LC-MS at 0.05% area threshold.
Enantiomeric purity is controlled by normal-phase liquid chromatography (NPLC) on a Chiralpak AD-H column (250 × 4.6 mm, 5 µm) with a mobile phase of n-hexane/ethanol/diethylamine (85:15:0.1, v/v/v). Flow rate is maintained at 1.0 mL·min−1 with detection at 264 nm. Under these conditions, the (R)-enantiomer elutes at a relative retention time (RRT) of 0.82 to the (S)-isomer; a resolution factor Rs of ≥ 2.0 between the enantiomer peaks must be demonstrated during system suitability prior to batch release. The limit of quantitation for (R)-pramipexole is validated at 0.05% with signal-to-noise ratio ≥ 10, satisfying the reporting threshold defined in ICH Q3A(R2). Where production batches from reductive amination processes exhibit residual propionaldehyde carryover above 50 ppm, an auxiliary achiral HPLC-UV method (C18, 150 × 4.6 mm, phosphate buffer pH 3.0/acetonitrile 80:20) quantifies the propionaldehyde–dimedone derivative at 385 nm. A failing enantiomeric excess below 99.0%—encountered in early development campaigns when crystallization temperature drifted above 5 °C—was traced to solvate-packing differences in the methanolic HCl salt formation step and rectified by implementing jacketed-glass reactor temperature control with a tolerance of ±2 °C.
Batch release and stability-testing specifications for pramipexole dihydrochloride monohydrate align with the current USP–NF monograph for Pramipexole Dihydrochloride and the corresponding European Pharmacopoeia 11th Edition monograph 2551. Identity is confirmed by infrared absorption spectrophotometry (KBr disk; 4000–400 cm−1) matching the reference spectrum of the (S)-enantiomer salt, and by retention time concordance in the assay HPLC method against a USP Reference Standard. Assay (anhydrous and solvent-free basis) by potentiometric titration with 0.1 M perchloric acid in anhydrous acetic acid yields content between 98.0% and 102.0%. Water content by Karl Fischer coulometric titration (Ph. Eur. 2.5.32) is controlled at 5.7%–6.5%, corresponding to the monohydrate stoichiometry. Residual solvents are determined by headspace GC-FID with a DB-624 column (30 m × 0.53 mm, 3 µm) and limit conform to ICH Q3C guideline: methanol ≤ 3000 ppm, isopropyl alcohol ≤ 5000 ppm, dichloromethane ≤ 600 ppm, and N,N-dimethylformamide ≤ 880 ppm. Heavy metals limits, when tested per USP ⟨231⟩, are set at ≤ 20 ppm, though many sites now employ ICP-MS analysis per USP ⟨232⟩/⟨233⟩ with acceptance criteria for elemental impurities (Class 1: As ≤ 1.5 µg/g, Cd ≤ 0.5 µg/g, Hg ≤ 0.3 µg/g, Pb ≤ 0.5 µg/g).
| Test | Acceptance Criteria | Analytical Method | Standard Reference |
|---|---|---|---|
| Appearance | White to off-white crystalline powder | Visual inspection | — |
| Identification (IR) | Conforms to reference spectrum | FT-IR spectroscopy | USP ⟨197K⟩ |
| Assay (anhydrous basis) | 98.0–102.0% | Potentiometric titration | USP ⟨541⟩ |
| Enantiomeric purity | (R)-enantiomer ≤ 0.5% | Chiral HPLC-UV | Ph. Eur. 2.2.46 |
| Related compounds (total) | ≤ 0.5% | RP-HPLC-UV, gradient | EP 2551 |
| Water content | 5.7–6.5% | Karl Fischer coulometry | Ph. Eur. 2.5.32 |
| Residual solvents | ICH Q3C limits | HS-GC-FID | USP ⟨467⟩ |
| Sulphated ash | ≤ 0.1% | Gravimetry after H2SO4 ashing | Ph. Eur. 2.4.14 |
| Elemental impurities | Per ICH Q3D (oral) | ICP-MS | USP ⟨232⟩/⟨233⟩ |
In side-by-side batches manufactured by two distinct synthetic routes—an asymmetric hydrogenation route versus a classical resolution with dibenzoyl-L-tartaric acid—the hydrogenation-derived product consistently exhibits lower single unspecified impurity levels (≤ 0.10% versus 0.15–0.22%), attributable to the absence of the resolution agent adduct that forms a persistent oxazolidinone by-product detectable at RRT 1.35. However, the tartrate route offers a significantly more favorable crystallinity advantage, yielding a bulk density of 0.45 g·cm−3 versus 0.32 g·cm−3 for the hydrogenation route, which directly affects blender flowability during direct-compression tablet operations. When direct compression formulations on a Fette PT 3090 rotary tablet press (29 stations, 100 rpm) were charged with the lower-density powder, mass variability rose to RSD 3.8% compared to 1.2% for the higher-density material, requiring a forced feeder paddle speed increase to 45 rpm to maintain content uniformity within USP ⟨905⟩ acceptance limits.
The molecule’s pharmacokinetic profile drives formulation strategy: pramipexole exhibits a plasma elimination half-life of approximately 8–12 hours in healthy adults, with Cmax achieved at 2 hours post-dose for immediate-release (IR) tablets. The commercial extended-release (ER) formulation employs a hydrophilic matrix of hypromellose (Methocel™ K4M, 28% w/w) that swells upon hydration, yielding a tmax delayed to 6 hours and a reduction in peak-to-trough fluctuation from 110% for IR to 45% for ER at steady state (doses 1.5 mg three times daily vs. 4.5 mg once daily). From a manufacturing standpoint, the low dose (0.125–1.5 mg) demands exceptional blend homogeneity; carrier materials such as pregelatinized starch and microcrystalline cellulose are selected for particle size distribution D90 ≤ 150 µm to minimize segregation in bin-blender operations. During a process qualification campaign on a 300 kg scale, stratified sampling at 10 locations post-blending demonstrated a potency RSD of 1.1% when blending time was held at 15 minutes at 12 rpm in a V-blender, but extending blending to 25 minutes induced triboelectric charging of the fine API particles, leading to agglomeration and a potency RSD of 4.9%—an effect eliminated by conditioning the blender shell to 45% relative humidity prior to charging. The ER matrix formulation additionally requires roller compaction to achieve granule density of 0.68–0.72 g·cm−3 before tableting; ribbon mill screen size set at 1.0 mm versus 0.8 mm shifted the dissolution profile (USP Apparatus I, 100 rpm, 0.1 N HCl) such that drug release at 4 hours dropped from 78% to 64%, failing the Q=75% in 4 hours acceptance criterion.
Unlike the non-ergoline agents ropinirole and rotigotine, pramipexole demonstrates a preferential binding affinity for the D3 dopamine receptor subtype, with a Ki value of 0.5 nM at human recombinant D3 receptors expressed in CHO cells versus 3.3 nM at D2L receptors, measured by radioligand displacement with [3H]-7-OH-DPAT. Ropinirole exhibits Ki values of 2.9 nM (D3) and 4.4 nM (D2), respectively, while the rotigotine patch achieves D3/D2 ratios closer to unity, though it additionally activates D1 receptors (Ki = 83 nM)—a target pramipexole essentially ignores at therapeutic concentrations. This D3 preference has been correlated in microdialysis studies with enhanced inhibition of dopamine neuron firing in the ventral tegmental area at low concentrations (0.01 mg·kg−1 s.c. in rodent models), but it also underpins the characteristic adverse effect of impulsive control disorders (e.g., pathological gambling) reported at a frequency of 17.1% in a longitudinal cohort of 1,170 Parkinson’s patients on pramipexole versus 6.4% for ropinirole, as documented in the DOMINION study. In contrast, the ergot-derived bromocriptine (a D2 agonist with Ki = 2.5 nM and 5-HT2B agonism) carries a risk of fibrotic valvulopathy absent from the non‑ergoline structures, making the aminothiazole scaffold a preferred first-line option under the 2018 Movement Disorder Society evidence-based medicine review. Pramipexole’s molecular weight of 211.33 g·mol−1 for the free base and only two hydrogen bond donors position it as a high-permeability BCS Class I compound, facilitating complete oral absorption (> 90%); ropinirole, by contrast, undergoes significant first-pass metabolism (≈50% bioavailability) due to CYP1A2-mediated dealkylation.
A dimeric impurity, bis-(2-amino-6-propylamino-4,5,6,7-tetrahydrobenzthiazolyl)methane, has been isolated from pilot batches produced under elevated temperature during the final hydrochloride salt crystallization (> 50 °C) and identified via high-resolution mass spectrometry (Q-TOF, m/z theoretical 461.2152, observed 461.2155). The dimer arises from Mannich-type condensation of the free base with residual formaldehyde liberated from hexamine breakdown in certain reductive amination procedures. When spiked into API at 0.15%, the dimer reduces intrinsic dissolution rate (IDR) from 0.42 mg·cm−2·min−1 to 0.31 mg·cm−2·min−1 in phosphate buffer pH 6.8 at 37 °C using a rotating disk apparatus at 200 rpm, likely by crystal habit modification confirmed by SEM micrographs showing inhibition of the dominant {1 0 0} growth faces. Current manufacturing processes therefore incorporate an activated carbon treatment (0.5% w/w, Darco KB-G) of the free base solution prior to salt formation, reducing the dimer to below the quantitation limit of the HPLC method (0.03%). The control strategy is reinforced by a process analytical technology (PAT) in-line FTIR probe monitoring the 1678 cm−1 carbonyl stretching band during the amination step to terminate reagent addition at ≤ 0.2 area% of the Schiff base intermediate.
