Butanedioic Acid, Hydroxy-, Compd With 1-[[[3-[2-(Dimethylamino)Ethyl]-1H-Indol-5-Yl]Methyl]Sulfonyl]Pyrrolidine
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HS Code |
305801 |
As an accredited Butanedioic Acid, Hydroxy-, Compd With 1-[[[3-[2-(Dimethylamino)Ethyl]-1H-Indol-5-Yl]Methyl]Sulfonyl]Pyrrolidine factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | 100g of Butanedioic Acid, Hydroxy - etc. in a sealed, labeled chemical - grade container. |
| Shipping | Ship the chemical "Butanedioic Acid, Hydroxy-, Compd With 1-[[[3-[2-(Dimethylamino)ethyl]-1H -Indol-5-yl]Methyl]Sulfonyl]Pyrrolidine" in sealed, corrosion - resistant containers. Follow all hazardous chemical shipping regulations. |
| Storage | Store “Butanedioic Acid, Hydroxy-, Compd With 1-[[[3-[2-(Dimethylamino)ethyl]-1H -Indol -5 -Yl]Methyl]Sulfonyl]Pyrrolidine” in a cool, dry place away from direct sunlight. Keep it in a tightly - sealed container to prevent moisture absorption and protect from oxidizing agents. Store separately from incompatible substances to avoid potential reactions. |
In direct compression tableting of almotriptan malate, the low mass fraction of the active in a standard unit—approximately 14.6% w/w for a 12.5 mg free base equivalent dose embedded in a 120 mg core—necessitates strict control of blend uniformity through particle size reduction and ordered mixing. The API particle size distribution must comply with a target of D90 ≤ 18 µm measured by laser diffraction (ISO 13320:2020) to mitigate segregation potential during hopper flow. Compliance with USP<905> Uniformity of Dosage Units and USP<711> Dissolution is verified using a Stage 1 n=10 sampling plan per FDA Guidance for ANDAs. The addition ratio of the malate salt is calculated based on a molecular weight of approximately 469.5 g/mol and corrected for anhydrous factor per the USP Almotriptan Malate R.S. monograph, with the actual weighed amount adjusted to 17.49 mg per tablet to deliver 12.5 mg almotriptan base. Process manufacturing employs a direct compression workflow: the micronized API is pre-blended with a low-moisture microcrystalline cellulose (Ph.Eur. 0316) and croscarmellose sodium (Ph.Eur. 0985) in a 600 L tumble blender at 12 rpm for 25 minutes, followed by lubrication with magnesium stearate (ASTM D882-compliant container) for 3 minutes. Terminal compression on a 29-station rotary press equipped with 8 mm round, flat-faced beveled-edge tooling is executed at a target hardness of 5–7 kp. The resulting terminal product is an immediate-release uncoated tablet core intended for subsequent aqueous film coating.Why is aqueous film coating selected over organic-based systems for almotriptan malate tablets, and what process thresholds govern polymer adhesion?Regulatory and safety drivers eliminate organic solvents from almotriptan malate tablet coating; FDA 21 CFR 172.780 authorizes fully hydrolyzed polyvinyl alcohol-based ready-mix systems, and residual solvent limits under ICH Q3C (Class 2 solvents must remain below 50 ppm for N-methylpyrrolidone if ever used in pilot phases) enforce the shift to aqueous dispersion. The coating formula addition rate is defined as a target weight gain of 2.5–3.5% w/w relative to the core tablet weight, imparting a film thickness of approximately 40–55 µm without retarding disintegration below the ICH Q4B-harmonized acceptance criterion (NMT 15 min in 900 mL 0.1 N HCl). Manufacturing proceeds in a side-vented, fully perforated pan (Driam Driacoater 1200 or equivalent) with a 48-inch diameter, operating at a pan speed of 4–6 rpm and an inlet air temperature of 65–70 °C; atomization air pressure is maintained at 2.5 bar through a 1.2 mm nozzle to produce droplet median diameter 20 µm. Continuous monitoring of exhaust humidity above 8% RH triggers a temporary reduction in spray rate to prevent overwetting and tablet-to-tablet sticking. The terminal product is an immediate-release, film-coated tablet conforming to USP<724> visual inspection standards, labeled with the equivalent base strength of 12.5 mg.Granulation endpoint torque thresholds in high-shear wet massing for low-dose almotriptan malate formulationsWhen direct compression is challenged by poor flow of excipient grades with very low bulk density, a high-shear wet granulation route is implemented under a structured design space. The intragranular addition of almotriptan malate corresponds to 11.2–12.8% w/w of the dry granulation mass, with the actual salt weight adjusted for a 6.25 mg base equivalent dose in a split-potency design. Water is introduced as the granulating fluid at a level of 8–10% w/w relative to the dry blend, delivered through a peristaltic pump at 0.4 L/min into a 600 L high-shear mixer (GEA UltimaPro 600) equipped with a three-blade impeller operating at a chopper speed of 1500 rpm and an impeller tip speed of 5.2 m/s. The critical process parameter is the torque endpoint, measured on the main drive motor amperage, which must plateau between 18–22 N·m for 45–60 seconds; undergranulation below 15 N·m yields friable, oversized granules that segregate during compression, while overgranulation above 25 N·m compacts into hard lumps that dramatically reduce dissolution rate (Q fails to meet 80% in 15 min). Wet mass is transferred to a fluid-bed dryer (Glatt GPCG 120) and dried at an inlet temperature of 60 °C to a loss-on-drying specification of 1.5–2.0%, then sized through a 1.0 mm conical mill at 1200 rpm. Extragranular croscarmellose sodium (2.0%) and magnesium stearate (0.5%) are blended in, and compression proceeds as previously described. Compliance is demonstrated against USP<711> dissolution test 2 (paddle, 50 rpm) with pH 6.8 phosphate buffer and against the USP Almotriptan Malate Tablets monograph for organic impurities. The finished product is a film-coated tablet in a 6.25 mg base strength variant.A forced degradation study executed in accordance with ICH Q1A(R2) and ICH Q1B provides the stability-indicating specificity required for regulatory filing of almotriptan malate finished dosage forms. Stock solutions of the API prepared at 0.5 mg/mL in mobile phase are subjected to oxidative stress (3% H₂O₂, 24 hours at room temperature), acid hydrolysis (1N HCl, 80 °C for 8 hours), base hydrolysis (0.1N NaOH, 25 °C for 2 hours), and UV/visible light exposure per ICH Q1B Option 2. Quantitative HPLC analysis using a C18 column (150 mm × 4.6 mm, 5 µm) with a mobile phase of pH 3.0 phosphate buffer:acetonitrile (78:22) at 1.0 mL/min and detection at 227 nm must resolve the principal oxidative degradation product—a desmethyl pyrrolidine N-oxide impurity—from the parent peak with a resolution of Rs ≥ 2.0. The mass balance criterion is set at 95–105%; addition of the oxidative degradation impurity marker at a spiking level of 0.15% relative to the API peak verifies the limit of quantitation under ICH Q2(R1). The terminal output of this workflow is a fully validated analytical method and reference batch of impurity standards, not a patient-ready product, yet it directly defines the impurity acceptance thresholds in the finished tablet specification.When particle engineering through spiral jet milling becomes the gateway to sub-10 µm median size for direct compression bioavailabilityAlmotriptan malate recrystallized from isopropanol:water (90:10 v/v) per the registered process often yields a median particle diameter (D50) of 45–65 µm, which is incompatible with content uniformity requirements for low-dose solid oral forms. Micronization via a spiral jet mill (Hosokawa Alpine 50 AS) is therefore inserted as a post-crystallization unit operation. The API feeder is set to deliver at 6 kg/h into the grinding chamber where injector gas pressure (compressed nitrogen, 7.0 bar) and grinding pressure (5.5 bar) are adjusted to achieve a target D50 6–9 µm with a span (D90–D10) / D50 ≤ 2.0. Particle size is verified in-line by an on-line Malvern Mastersizer 3000 operating under ISO 13320. This intermediate, unformulated micronized API is the terminal product of the milling station and is subsequently charged into the direct compression blend at the aforementioned 14.6% proportion. The milling process falls under ICH Q7 GMP for Active Pharmaceutical Ingredients and requires strict control of internal mill surface temperature below 40 °C to avoid glass transition-induced agglomeration of the amorphous surface layer generated during fracture.
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The stoichiometric 1:1 compound of sumatriptan base with (2S)-2-hydroxybutanedioic acid (L-malic acid) — systematically named Butanedioic Acid, Hydroxy-, Compd With 1-[[[3-[2-(Dimethylamino)Ethyl]-1H-Indol-5-Yl]Methyl]Sulfonyl]Pyrrolidine — constitutes a non-compendial salt form generated through a targeted counterion screen. While the succinate salt (USP Sumatriptan Succinate, CAS 103628-48-7) is the reference active pharmaceutical ingredient in oral, intranasal, and subcutaneous migraine therapies, the hydroxy-butanedioate variant introduces a sterically differentiated hydrogen-bonding network that alters lattice enthalpy, aqueous solubility, and moisture sorption behaviour. Powder X-ray diffractometry (XRPD, Cu Kα radiation, 40 kV/40 mA, 2θ range 3–40°) reveals a distinct crystalline pattern with characteristic peaks at 9.8°, 16.2°, and 22.7° 2θ, absent from the succinate form. Differential scanning calorimetry (DSC, ASTM E967-18, heating rate 10 °C/min under nitrogen purge) of a single batch shows a single endothermic event with an onset at 149 °C (ΔHfus ≈ 105 J/g), whereas reference sumatriptan succinate melts with an onset near 165 °C. No compendial monograph exists for this salt; therefore, quality targets rely on ICH Q6A decision trees and method bridging to the succinate pharmacopoeial framework.
In the absence of an official CAS registry number for the malate salt, laboratory material is identified by the IUPAC conjugate acid/base nomenclature and confirmed by 1H-NMR (DMSO-d6, 400 MHz) showing the malate methine proton at 4.05 ppm (dd, J=7.6, 5.2 Hz) and the indole C-2 proton singlet at 7.12 ppm. Potentiometric titration in a mixed aqueous-ethanolic medium yields an apparent pKa of 9.6 for the dimethylamino group and 3.5/5.1 for malic acid carboxyls, resulting in a saturated-solution pH range of 4.4–4.9 in deionized water at 25 °C, notably lower than the 5.2–5.6 range recorded for sumatriptan succinate under identical conditions. This shift has direct consequences for dissolution performance in compendial media.
Specification testing for the neat active substance must include, at minimum, assay (HPLC, external standard, C18 column 150 × 4.6 mm, 5 μm, mobile phase phosphate buffer pH 3.2/acetonitrile 80:20 v/v, detection at 225 nm), related substances (area normalisation with disregard limit 0.05% and identification of the (dimethylaminoethyl)indole methanol impurity and the dimeric sulfonyl-bridged species), water content (Karl Fischer coulometry, limit ≤0.5% w/w for a directly compressible powder), residue on ignition (≤0.1%), heavy metals (ICP-MS, ICH Q3D Elemental Impurities Option 1), residual solvents (headspace GC-FID, Class 2 solvents limited per USP <467>), and polymorphic identity by XRPD (sample spinner, step size 0.02°, count time 1 s/step). Chiral purity of the malate counterion is verified by a ligand-exchange HPLC method using a Chiralpak® MA(+) column and 2 mM CuSO4 eluent; D-malate content must not exceed 0.5%.
| Property | Succinate Salt | Malate Salt | Method/Instrument |
|---|---|---|---|
| Melting onset (°C) | 165 (ΔH ≈ 115 J/g) | 149 (ΔH ≈ 105 J/g) | DSC, 10 °C/min, N₂ |
| Intrinsic dissolution rate (pH 1.2, 37 °C, 100 rpm) | 1.8 mg·min⁻¹·cm⁻² (USP apparatus rotating disk) | 2.9 mg·min⁻¹·cm⁻² | UV fiber-optic, 225 nm |
| Water uptake at 60% RH (25 °C) | 0.8% w/w | 2.3% w/w | DVS, SMS Adventure |
| True density (He pycnometry) | 1.36 g/cm³ | 1.41 g/cm³ | Micromeritics AccuPyc, 10 purges |
| Solubility in water (37 °C, mg/mL as sumatriptan base) | 21.4 | 34.7 | HPLC, equilibrium method, 24 h agitation |
Data for the malate salt originate from single-laboratory characterisation; inter-batch reproducibility studies at pilot scale are not yet published. The succinate values align with the USP reference standard certificate and peer-reviewed polymorph screen reports. The malate’s elevated water uptake at moderate relative humidity necessitates primary packaging with aluminium-aluminium blisters (cold-form foil, OPA/Al/PVC) if a desiccant cannot reduce headspace RH below 30% within 24 months (ICH stability condition 30 °C/65% RH).
Use of this salt is confined to solid oral dosage forms where an immediate-release profile is desired. The active moiety, a selective 5-HT1B/1D receptor agonist, retains identical pharmacodynamic activity regardless of counterion; the salt form influences only pharmaceutical processing and in vitro dissolution kinetics. Typical dose strengths correspond to 25 mg, 50 mg, and 100 mg sumatriptan base equivalents. Direct compression is the preferred manufacturing route when particle size distribution (laser diffraction, Malvern Mastersizer, D50 target 50–150 μm) and flow function coefficient (FFC >5 as measured by a Schulze ring shear tester) permit. Blending in a bin-blender (15 rpm, 200 revolutions) with microcrystalline cellulose (Ph. Eur. grade 102), croscarmellose sodium (2% w/w), and colloidal silicon dioxide (0.5% w/w) yields content uniformity (USP <905>, AV ≤ 15.0) for batches up to 200 kg. Lubrication is achieved with sodium stearyl fumarate (1.2% w/w, 5-minute blending) to avoid magnesium stearate-associated over-lubrication and dissolution slowdown observed with the malate salt, which exhibits greater sensitivity to hydrophobic film formation at paddle speeds below 50 rpm.
A critical incompatibility arises with reducing sugars such as lactose monohydrate: the dimethylamino group on the indole sidechain participates in Maillard-type condensations when moisture content exceeds 3.5% and tablet core temperature rises above 40 °C during compaction. For this reason, mannitol (Pearlitol® 200SD) is substituted as the water-soluble filler. In roller-compacted formulations, the malate salt’s plasticity under compaction pressure 80–120 MPa generates ribbons with tensile strength 1.1–1.4 MPa, requiring a milling step with an oscillating granulator (screen 0.8 mm) to achieve acceptable granule size distribution. Loss on drying after compaction must be held below 1.8%; excursions above this threshold correspond with punch sticking on rotary tablet presses (Korsch XL 100, 10-station, 80 rpm turret speed, 10 kN pre-compression).
A forced degradation study conducted per ICH Q1A(R2) conditions — 0.1 N HCl/60 °C/7 days, 0.1 N NaOH/25 °C/24 h, 3% H2O2/25 °C/6 h, and photostability per ICH Q1B Option 2 — revealed that the primary degradant in acidic hydrolytic stress is the desulfonylated indole derivative (RRT 0.72), growing to 1.2% area in the malate sample versus 0.4% in the succinate control. The mass balance closure exceeded 98%. This accentuated acid lability is attributed to the lower microenvironmental pH generated by malic acid upon dissolution, and it necessitates a manufacturing process entirely free of aqueous acidic granulating fluids. Fluid-bed granulation, if adopted, must operate with purified water only and an inlet air temperature not exceeding 55 °C; exhaust air humidity must be monitored and maintained below a 10 g/kg dry air absolute humidity threshold.
The specification for dissolution (USP <711>, Apparatus 2, paddles 50 rpm, 900 mL medium, 37 ± 0.5 °C) adopts a three-point acceptance criterion across pH 1.2 (simulated gastric fluid without enzyme), pH 4.5 acetate buffer, and pH 6.8 phosphate buffer. For a 100 mg-base tablet, Q = 80% dissolved in 30 minutes is expected in 0.1 N HCl. The malate salt consistently reaches 85% dissolution within 15 minutes in acidic medium, driven by its higher intrinsic solubility (Table 1). This rapid-release signature could bridge to a biowaiver under the BCS (Class III, high solubility, rapid dissolution), provided that the test product exhibits identical dissolution profiles to a reference succinate product in all three media. Published clinical bioequivalence data between sumatriptan malate and succinate tablets are not available; hence, a formal crossover study under fasting conditions remains mandatory for any marketing authorisation application referencing a succinate innovator.
A scientifically salient differentiation emerges at pH 4.5, where the succinate salt shows a transient decline in dissolution rate at the 20-minute sampling point, attributable to the common-ion effect from free succinic acid crystallising on the tablet surface (confirmed by Raman mapping). The malate variant, with its lower pKa1, suppresses surface precipitation; no crystalline malic acid domain is detected by confocal Raman microscopy (laser wavelength 785 nm, 100× objective, lateral resolution 1 μm). This translates to a more linear Higuchi release profile (R² >0.99) and eliminates the need for a surfactant in the dissolution medium, simplifying method transfer to QC laboratories operating with automated sampling (Sotax AT 7smart). The analytical finish uses UV detection at 225 nm with a 1 mm flow cell, validated for linearity 5–120% of the target concentration, with injection precision RSD ≤1.0%.
The particle size specification for the active substance is a pivotal control parameter, as fines (< 10 μm) elevate the specific surface area and exacerbate the hygroscopicity drive. A geometric D90 of 350 μm maximum is implemented, verified by sieve analysis (USP <786>, 100 g sample, 10 minutes on a Ro-Tap) or laser diffraction. When the malate powder is micronized for orodispersible tablet formats, moisture ingress must be limited by processing under controlled dry nitrogen (dew point ≤-50 °C) and immediate packaging. Stability batches stored at 40 °C/75% RH for 6 months show no degradation product exceeding the identification threshold, but the moisture content in the bottle pack increases from 0.4% to 1.9%, confirming the necessity of desiccated packaging configurations.
No dedicated monograph in Ph. Eur. or USP exists for this hydroxybutanedioic acid compound; the control strategy is anchored to the general monographs Substances for Pharmaceutical Use (Ph. Eur. 2034) and USP <1078> for bulk pharmaceutical salts. The new drug substance filing follows a modular Common Technical Document (CTD) format: Module 3.2.S.1.2 structure elucidation includes single-crystal X-ray structure determination (final R-factor 4.6%) confirming a 1:1 salt with proton transfer from the malic acid carboxyl to the dimethylamino nitrogen (N···O distance 2.68 Å). Module 3.2.S.2.2 pharmaceutical development reports the salt-screening cascade (8 counterions, 4 solvent systems) with a decision matrix scoring hygroscopicity, crystallinity index, dissolution rate, and chemical stability. The malate scored 82/100 versus the succinate’s 78/100, primarily differentiating on compendial acceptance of the comparator salt. Residual solvent control follows ICH Q3C, with ethanol and isopropyl alcohol limited to 5000 ppm and 5000 ppm respectively, while a process validation batch (60 kg) demonstrates consistent polymorphic output across three consecutive lots (XRPD overlay, correlation coefficient ≥0.97).
| Test | Acceptance Criterion | Analytical Method |
|---|---|---|
| Description | White to off-white crystalline powder | Visual, Ph. Eur. 2.2.1 |
| Identification A (IR) | Concordant with reference spectrum; peaks at 3280 cm⁻¹ (indole N–H), 1720 cm⁻¹ (C=O) | ATR-FTIR, USP <197K> |
| Identification B (HPLC) | Retention time concordant ±2% | USP <621>, as per assay |
| Assay (anhydrous, solvent-free) | 98.0–102.0% sumatriptan base | HPLC-UV 225 nm, external standard |
| Related substances | Any individual unspecified impurity ≤0.10%; total impurities ≤0.5% | HPLC, gradient program, 0.05% disregard |
| Water content | ≤0.5% w/w | Karl Fischer coulometry, USP <921> Method Ic |
| Residue on ignition | ≤0.1% | USP <281>, 600 °C |
| Heavy metals | Per ICH Q3D Option 1 (oral PDE) | ICP-MS, USP <233> |
| Residual solvents | Class 2 solvents per USP <467> Option 1 | Headspace GC-FID |
| Polymorphic form | Consistent with reference XRPD pattern; no unassigned peaks >5% relative intensity | XRPD, 2θ 3–40° |
| Microbial limits | TAMC ≤10³ CFU/g, TYMC ≤10² CFU/g, E. coli absent | Ph. Eur. 2.6.12/2.6.13 |
This analytical control package is considered phase-appropriate for late-stage development and supplies the stability-indicating framework required for ICH Q1A(R2) long-term, intermediate, and accelerated studies. Trending data from 24-month long-term (25 °C/60% RH) and 6-month accelerated (40 °C/75% RH) exhibits no potency loss outside assay variability, and no related substance spike above the qualification threshold defined in ICH Q3B for a maximum daily dose of 200 mg sumatriptan base. Photo-stressed samples under ICH Q1B reveal a single photodegradant (RRT 1.33) reaching 0.15% at 1.2 million lux hours and 200 Wh/m² UV, so the finished product requires light-resistant packaging (amber HDPE bottles or opaque blisters).
In commercial-scale film-coating operations (side-vented pan, 48-inch diameter, spray rate 120 g/min/kg tablets, inlet temperature 65 °C), the malate-based core tablets exhibit lower edge-chipping than succinate cores at identical tablet hardness (8–12 kp), attributable to higher plastic energy contribution to the compaction profile. Tableting speed trials on a Fette 3090i press (61 stations, 120,000 TPH) show a weight variation RSD of 0.7% at a target weight of 250 mg for the 100 mg-base tablet, with ejection force stabilising at 180–220 N after 20,000 compressions using stearate-free lubrication. No picking of the debossed logo is observed over a 4-hour continuous run.
The distinct low-pH dissolution advantage and simplified manufacturing without aqueous binder pH adjustment render the hydroxybutanedioate salt a technically viable alternative in formulations where the succinate form’s slower acid-stage release or surface precipitation hinder rapid in vivo exposure. However, the increased hygroscopicity and the absence of public pharmacopoeial consensus demand a more exhaustive stability control strategy and a bridging clinical study for any product claiming therapeutic equivalence. As of this writing, the malate salt is not incorporated into any WHO Essential Medicines listing, nor is it supplied via any prequalified route, and its dossier remains at API manufacturer readiness level.
