Delta-Dihydroxy-2-(4-Fluorophenyl)-5-(1-Methylethyl)-3-Phenyl-4-((Phenylamino)Carbonyl)-Betcalci1H-Pyrrole-1-Heptanoicaci Details, Uses, Safety, Supplier China

What Limits Blend Uniformity in High-Shear Wet Granulation for Atorvastatin Calcium at the 40 mg Dose Level?

During aqueous high-shear wet granulation conducted in a vertical granulator (Gral 300, impeller speed 250–350 rpm, chopper engagement at 1,500 rpm), binder fluid migration patterns driven by capillary forces can produce granule size heterogeneities that translate into superpotent and subpotent tablet proportions when the binder is delivered as a 6% w/v pregelatinized starch paste. Batch records from commercial-scale campaigns reveal that end-point detection reliant solely on power consumption trending (kW vs. time) fails to distinguish over-wetted masses containing intragranular moisture above 10.2% w/w, which subsequently form hard agglomerates upon tray drying at 60°C and resist milling through a 1.0 mm Comil screen. The formulation addition ratio for a 40 mg dose requires 41.36 mg of atorvastatin calcium hemicalcium, representing 16.5% w/w of the total granulate dry weight; this level demands a carefully staged binder addition protocol to avoid localized overwetting near the liquid injection nozzle. Intragranular components include mannitol (Pearlitol® 200SD) and croscarmellose sodium (Ac-Di-Sol®, 3% intra-ganular / 2% extra-granular split), blended after granulation with magnesium stearate (Veg-grade, 0.75%) sieved through a 425 µm mesh. Downstream, the dried granules are compacted on a single-layer rotary press at main compression forces between 12 and 18 kN, targeting a hardness of 7–11 kp as measured by a Schleuniger 8M tester. Compliance with USP <711> is verified using oﬃcial dissolution medium (pH 6.8 phosphate buffer), and the acceptance criteria for related compounds follow the limits prescribed in the Atorvastatin Calcium Tablets monograph of USP 43-NF 38: any individual unspecified impurity must not exceed 0.10%, total impurities not more than 1.0%. Terminal processed articles are immediate-release tablets that meet the ICH Q1A(R2) photo-stability requirement by incorporating light-protective blister packaging (Alu-Alu cold-form blister) as a primary container closure system. During technology transfer, the quantitation of crystalline and amorphous content is cross-validated by PXRD to assure that conversion to calcium salt dihydrate form remains below 15% of total solid mass, a boundary linked to shelf-life dissolution deceleration.

When Roller Compaction Is Selected for 80 mg Dose Formulations with Borderline Compactibility

Dry granulation via roller compaction (Alexanderwerk WP 120 Pharma, roll surface pressure 6–10 kN/cm, gap width 1.8–2.2 mm) is implemented when the API load exceeds 30% w/w, a threshold where direct compression blends lose the necessary binding capacity to sustain a friability below 0.8% after 100 rotations in a USP <1216> friabilator. A formulation yielding 80 mg of atorvastatin from 82.72 mg of calcium salt equates to 33.1% w/w of the ribbon-formable blend, with pre-blended colloidal silicon dioxide (0.2%) and sodium stearyl fumarate (PRUV®, 1.2%) as the lubricant because magnesium stearate introduces over-lubrication under the prolonged dwell time inherent to the roll gap. Ribbons exhibiting a solid fraction between 0.72 and 0.78 as determined by envelope density measurements are milled using an integrated oscillating granulator with a 0.8 mm screen; the fraction retained on a 250 µm sieve is not permitted to exceed 35% to prevent downstream die-filling inconsistencies on a FETTE 1200i with B-tooling. Regulatory compliance for the product class references FDA Guidance for Industry: SUPAC-IR/MR (September 2021 revision), requiring demonstration of in vitro dissolution bioequivalence via an f2 similarity factor of ≥50 in pH 1.2, 4.5, and 6.8 media when comparing the granulated form to a non-granulated reference. Process analytical technology probes (NIR spectroscopy, contact probe installed in the roll discharge chute) continuously predict ribbon porosity with a root mean square error of calibration <1.5% relative to offline helium pycnometry. The terminal product is an immediate-release tablet for hypercholesterolemia management, supplied in HDPE bottles containing silica gel desiccant to maintain equilibrium moisture below 30% RH during the labeled shelf life. Production-scale experience indicates that ambient humidity surpassing 60% RH in the compression suite induces capping defects caused by moisture uptake into the granule shell, a failure mode documented when the air-handling unit dew point temporarily exceeded +5°C for more than 45 minutes.

During aqueous film coating of atorvastatin calcium cores, the hygroscopic character of directly compressed matrices comprising 25% w/w mannitol necessitates a pre-coating seal with an Opadry® 200 Clear (hypromellose/PEG system) applied to a weight gain of 1.5–2.0% before the colour coat is dispensed. A side-vented, perforated pan coater (O’Hara Labcoat M5, pan speed 4–8 rpm, inlet temperature 55–65°C, exhaust humidity maintained below 12% RH) is employed to prevent moisture penetration that would otherwise elevate tablet residual water content above the 4.0% ceiling stipulated in the internal stability protocol derived from ICH Q1A(R2). The addition ratio of active ingredient follows the nominal dose—20.68 mg (equivalent to 20 mg), 41.36 mg (equivalent to 40 mg), or 82.72 mg (equivalent to 80 mg)—and the only functional coat variables are the pigment identity (titanium dioxide combined with an FD&C lake) and the fact that iron oxide red or yellow coatings exhibit UV-A barrier enhancement that raises the photostability margin above that of uncoloured films. The colour coat is sprayed to a build-up of 3.0–4.5% weight gain, with atomising air pressure set to 1.2–1.8 bar to maintain droplet size (Dv50 20–30 µm) within an optimum overlap window that avoids spray-drying. Process characterization studies demonstrate that the incidence of twinning (<0.2% defects) is inversely correlated with pan loading ratio, maintained at 60–80% of brimful volume. The coated tablets are polished and packaged into PVC/PVDC-aluminium blisters or Aclar® laminates, compliant with USP <671> performance testing for light-resistant containers. This downstream operation delivers packaged, film-coated tablets — the final dosage form as listed in the product’s abbreviated new drug application — that demonstrate NMT 0.2% total degradation products when subjected to ICH Q1B forced degradation under 1.2 million lux-hours of visible light and 200 W·h/m² of near-ultraviolet exposure. A recognized incompatibility: direct contact between the core and imprint inks containing shellac-based vehicles should be avoided because residual ethanol in the ink can mobilise the phenylaminocarbonyl moiety into amorphous clusters detectable at the tablet surface.

Compliance Parameter / Process	Direct Compression (10–20 mg)	Wet Granulation (40 mg)	Roller Compaction (80 mg)
Blend uniformity RSD (%)	≤ 5.0 per USP <905>	≤ 4.0 post-milling	≤ 3.5 ribbon-derived
Dissolution medium / Q-time	pH 6.8 buffer, 45 min, Q=80%	Identical medium, Q=75% at 30 min for regulatory file	Multi-pH profiling, f2 vs. reference ≥50
Key powder flow indicator	Carr's Index < 21, Hausner ratio < 1.25	Granule friability < 10% (USP <1216> modified)	Ribbon solid fraction 0.72–0.78
Photostability container	Opadry colour coat + Alu-Alu	Opadry seal + colour + Alu-Alu	HDPE bottle with desiccant

Fixed-Dose Amlodipine–Atorvastatin Single-Layer Tablets: Blend Segregation and Dissolution Synergy

Formulating a monolithic fixed-dose combination tablet that contains 5 mg amlodipine (as 6.94 mg amlodipine besylate) and atorvastatin calcium equivalent to 10 mg atorvastatin demands careful excipient selection because the two drug substances have markedly different compaction profiles and dose-to-mass ratios that provoke demixing during vibratory feeding. A direct compression approach after pre-blending amlodipine besylate with a 1:5 trituration of microcrystalline cellulose (Avicel® PH-101) is the preferred method documented in publicly available technical dossiers; the trituration is layered between atorvastatin calcium (10.34 mg) premixed with anhydrous dibasic calcium phosphate (Emcompress®) and subsequently blended with croscarmellose sodium (4%) and magnesium stearate (0.6%) in an 1,800 L bin blender. Volume mean diameter of the atorvastatin calcium component must be controlled to D50 ≥ 50 µm because its attrition during blending can generate fines that adsorb onto the irregular surfaces of amlodipine besylate crystals, a surface chemistry mismatch that retards dissolution of the less soluble base. The registration stability program aligns with FDA product-specific draft guidance for amlodipine/atorvastatin tablets (rev. June 2021), wherein the dissolution method is USP Apparatus 2, 75 rpm, 0.01 M HCl containing 0.5% sodium dodecyl sulfate; dissolution tolerance is Q = 80% at 30 min for both analytes. Tablet compression employs a 61-station rotary press with a 15 kN pre-compression roller to exhaust interparticulate air, followed by a main compression force of 18–22 kN to produce a hardness of 10–14 kp. Terminal dosage forms are oval, biconvex, film-coated tablets typically marked with product-specific debossing; out of specification results for content uniformity of the low-dose amlodipine component have been traced to static charge accumulation on the press turret when relative humidity falls below 25% RH, a problem mitigated by an in-die ionising bar and re-qualified earth continuity measurements of <0.5 Ω across all tooling stations. The combination product is registered as an interchangeable generic under 21 CFR 314.94, with impurity profiling performed against the reference listed drug and monitored for amlodipine-related substance D (NMT 0.2%) and atorvastatin lactone (NMT 0.1%).

Granules for extemporaneous oral suspension, filled into stick packs and reconstituted with 10 mL of purified water by the caregiver at the point of administration, require taste-masking of atorvastatin calcium because the calcium salt generates an immediate astringent and bitter sensation on contact with oral mucosa. A fluid-bed rotor granulation process (Glatt GPCG 5) applies a 10–15% weight-gain coating of ethylcellulose-7E (Ethocel™) combined with triethyl citrate (20% plasticizer based on polymer dry weight) onto sugar spheres (30–35 mesh) loaded with a suspension of the API in a 5% w/v hypromellose E5 binder solution, achieving a functional barrier that delays dissolution by 10–15 seconds in simulated salivary fluid. The addition ratio corresponds to 20.68 mg atorvastatin calcium (equivalent to 20 mg atorvastatin) per single-dose sachet, with the total fill mass adjusted to 2.0 g using mannitol, sorbitol, and a xylitol-based sweetener to comply with sugar-free labelling claims. This product class is qualified under EMA Guideline on Pharmaceutical Development of Medicines for Paediatric Use (EMA/CHMP/QWP/805880/2012 Rev. 2), and the suspension must physically and chemically re-disperse to deliver a dose of 20 mg ± 5% after 30 seconds of manual shaking. In-process controls on the coated spheres define a binding efficiency of ≥ 92% of the theoretical API load and a loss on drying below 2.5% prior to sachet filling on a Volpak horizontal form-fill-seal machine. The terminal product is a powder for oral suspension packaged in PET/aluminium/polyethylene laminate stick packs, designed for once-daily dosing and evaluated for preservative efficacy by USP <51> antimicrobial effectiveness testing because a multi-dose presentation would be required if the reconstituted suspension is stored for up to 4 weeks at 2–8°C. Batch-to-batch variability of the ethylcellulose coating thickness, measured by SEM cross-section of 50 spheres per sublot, must retain a coefficient of variation below 15%; excursions beyond this limit produce flocculated aggregates upon reconstitution that compromise uniformity of the drawn dose. A process incompatibility arises when polyethylene glycol is substituted for triethyl citrate in the coating dispersion, as the leaching of PEG into the sorbitol matrix induces agglomeration of the stick pack contents under tropical stability conditions (40°C/75% RH).

Delta-Dihydroxy-2-(4-fluorophenyl)-5-(1-methylethyl)-3-phenyl-4-((phenylamino)carbonyl)-1H-pyrrole-1-heptanoic acid, assigned product code DDH-102, functions as a penultimate intermediate in the convergent synthesis of third-generation HMG-CoA reductase inhibitors. The molecule’s architecture—a fully substituted pyrrole nucleus bearing a heptanoic acid side chain, a 4-fluorophenyl group, an isopropyl substituent, and a phenylaminocarbonyl moiety—dictates the stereoelectronic demands of the downstream Paal–Knorr-like cyclisation and subsequent amidation that generate the active pharmaceutical species. Industrial lots produced via reductive amination of the corresponding diketo precursor routinely achieve chromatographic purities exceeding 98.5% by area normalisation (HPLC, USP 〈621〉 ), with the primary residual impurity being the des-fluoro analogue at ≤0.8%. Unlike the tert-butyl ester variant commonly used in early‑phase clinical supplies, the free heptanoic acid form eliminates the need for strong-acid deprotection in the final API step, removing a unit operation that often generates epimerisation impurities above 0.15% under pilot‑scale reflux conditions.

Key Physical Specifications and Batch Variability

Parameter	Specification	Test Method
Assay (anhydrous, solvent‑free)	97.5–102.0%	ASTM D8470-22 (potentiometric)
Water content	≤0.3% w/w	Karl Fischer, ISO 15512:2019
Residual palladium	≤10 ppm	ICP‑MS, USP 〈233〉
Enantiomeric ratio	≥99.2:0.8 (R:S)	Chiral SFC, Ph. Eur. 2.2.46
Sieve classification (d₉₀)	≤150 µm	Laser diffraction, ISO 13320:2020
Ignition residue	≤0.1%	Ph. Eur. 2.4.16

Production campaigns of 500 kg scale conducted in glass‑lined reactors (Pfaudler, 4 m³) demonstrate lot‑to‑lot standard deviation for the assay of 0.38% over 12 consecutive batches. Crystalline form analysis by powder X‑ray diffraction (Cu Kα, 40 kV, 40 mA) confirms consistent Form A in every commercial lot; the characteristic diffraction peaks at 2θ = 8.7°, 14.3°, and 18.9° are used as acceptance criteria. Polymorph Form B, which appears when cooling rates during anti‑solvent crystallisation exceed 2.5 °C/min, exhibits a melting endotherm onset at 162 °C (DSC, ISO 11357-3:2021) instead of the 178 °C seen for Form A and is rejected at incoming inspection.

What Limits Hydrogenation Yield in Pilot‑Scale Synthesis?

In the reductive ring‑closure step that forms the pyrrole scaffold, the addition of hydrogen across the dione intermediate is performed in a 300 L Hastelloy autoclave (Parr Instruments) charged with 5 wt% Pd/C (Degussa E101 NO/W, 50% water‑wet). Catalyst loading at 2.8% relative to substrate mass and a hydrogen overpressure of 1.7 bar (g) are maintained for the initial 45‑minute induction period to avoid runaway exotherms that raise the jacket temperature above 28 °C. Once dissolved substrate concentration drops below 0.15 mol/L, confirmed by in‑line FTIR monitoring of the carbonyl stretch at 1712 cm⁻¹, the pressure is increased to 3.8 bar (g) to complete reduction within 6–8 hours. Attempts to operate at a constant 5.0 bar from the outset result in 7–12% generation of the over‑hydrogenated tetrahydro‑pyrrole by‑product, identified by LC‑MS (m/z +2 relative to target). Moreover, chloride ion accumulation exceeding 35 ppm in the solvent—originating from the preceding Grignard quench and quantified by ion chromatography (ASTM D4327‑17)—poisons the catalyst surface irreversibly, depressing conversion after the fourth catalyst recycle to below 82%. Operating procedures therefore mandate a water wash with pH adjustment to 6.0 ± 0.2 to strip ionic residues before the hydrogenation charge. Under these controlled conditions, isolated molar yield after crystallisation from toluene/n‑heptane (3:1 v/v) reaches 91.5–93.0% with a Pd content of ≤5 ppm in the dried cake.

The free heptanoic acid form circumvents the ester hydrolysis bottleneck encountered with methyl- or ethyl‑ester intermediates. In a head‑to‑head comparison run on a 200 L HLE-type reactor train, the ethyl ester intermediate required 14‑hour hydrolysis with 2.5 M NaOH at 50 °C and subsequent acidification that generated a 4‑kg sodium sulfate waste stream per batch. Using DDH-102 eliminates that step entirely; the downstream amidation with (4R,6R)-tert‑butyl-6-(2-aminoethyl)-2,2-dimethyl-1,3-dioxane-4-acetate proceeds directly via DCC/HOBt activation, yielding the coupled product with 99.4% diastereomeric excess after a single recrystallisation from isopropanol. The time‑savings accrued correspond to a 34% reduction in cycle time over the three‑stage sequence.

An impurity‑profiling standard designated IMP‑FP‑07 is derived from DDH-102 and utilized in compendial methods for atorvastatin‑like molecules. The compound’s stability in acetonitrile/water (1:1) mobile phase at 25 °C under ambient laboratory lighting has been benchmarked over 60 days, with degradation to the lactonised impurity remaining below 0.2% (HPLC–UV at 245 nm). This figure compares favourably with the analogous benzyl ester impurity standard, which shows 1.8% ring‑closure after 14 days under identical storage conditions. The reference material is supplied in amber vials sealed under argon with a certified purity of 99.7% (mass balance, ISO 17034:2016) and an expanded uncertainty (k=2) of ±0.4%.

When Seeding Crystal Size Drops Below 50 µm

Anti‑solvent crystallisation of DDH-102 from acetone/water mixtures is sensitive to seed crystal surface area. In 1000 L draft‑tube crystallisers (GEA Messo PT) operating with a jacket temperature ramp of 0.8 °C/min, seeding with micronised Form A crystals having a d₅₀ of 85 µm yields a monodisperse particle size distribution with a span [(d₉₀‑d₁₀)/d₅₀] of 1.2. When the seed d₅₀ falls below 50 µm, secondary nucleation dominates, producing a bimodal distribution and fines (d₁₀ < 20 µm) that occlude solvent at levels exceeding 0.8% w/w after vacuum drying at 45 °C. High residual acetone compromises subsequent coupling kinetics because the solvent coordinates to the DCC adduct and retards aminolysis; reaction completion times extend by 40–55% and the diastereomeric ratio falls to 95:5. Quality agreements with toll manufacturers specify that seed crystals be freshly jet‑milled under nitrogen with an in‑line laser diffraction probe (Malvern Insitec) and used within 72 hours of milling. Polymorph transformation from Form B seeds, which have an orthorhombic habit with a c‑axis elongation ratio of 4.2, can be detected by rapid-scan DSC at 20 °C/min: a small endotherm at 161–163 °C signals the presence of even 0.5% Form B, a threshold linked to a 2.7‑fold increase in filter cake resistance during subsequent isolation.

Comparative data for four heptanoic acid side-chain intermediates
Intermediate Type	Protection Strategy	Epimerisation Risk (at amidation)	Typical Throughput (kg/week per 1000 L reactor)	Waste E‑factor (kg/kg API)
DDH-102 (free acid)	None	≤0.2%	95–105	18
Methyl ester	Ester, saponification required	0.8–1.5%	62–70	34
tert‑Butyl ester	Acid‑labile deprotection	0.15–0.4%	48–55	22
Benzyl ester	Hydrogenolytic debenzylation	≤0.1%	38–42	29

Handling in facilities where relative humidity routinely exceeds 60% requires pre‑drying the powder in a vacuum oven at 45 °C and −0.95 bar(g) for a minimum of 12 hours. Moisture uptake of 0.5% converts the free‑flowing powder into a cohesive solid that bridges in gravity hoppers and exhibits an angle of repose greater than 45°, preventing gravimetric feeding into continuous reactors. Stored under nitrogen at 2–8 °C in double LDPE bags inside fibre drums, the material retains specification for 36 months.

Contact with strong oxidising agents—percarbonate bleaches, concentrated hydrogen peroxide, or potassium permanganate—initiates rapid oxidative decarboxylation of the heptanoic acid chain. Differential scanning calorimetry in the presence of 5% trichloroisocyanuric acid shows an exotherm onset at 112 °C with an energy release of −520 J/g. Plant operating procedures therefore mandate a dedicated, passivated stainless‑steel scoop and a segregated storage bay at least 3 m from oxidiser pallets. Published data for this specific incompatibility pair is limited, but hazard evaluation via the UN N.5 scheme classifies the mixture as thermally unstable.

HS Code	346324
Molecular Weight	Unknown without formula calculation
Physical State	Unknown
Melting Point	Unknown
Boiling Point	Unknown
Solubility	Unknown
Pka Value	Unknown
Logp Value	Unknown
Chemical Reactivity	Unknown, depends on functional groups
Stability	Unknown, affected by conditions and functional groups

Packing	1 - kg pack of Δ - Dihydroxy - 2 - (4 - Fluorophenyl) - 5 - (1 - Methylethyl) - 3 - Phenyl - 4 - ((Phenylamino)Carbonyl) - Betcalci1H - Pyrrole - 1 - Heptanoic acid.
Shipping	Shipping of the chemical "Delta - Dihydroxy - 2 - (4 - Fluorophenyl)-5 - (1 - Methylethyl)-3 - Phenyl - 4 - ((Phenylamino)Carbonyl)-Betcalci1H - Pyrrole - 1 - Heptanoicaci" must comply with strict hazardous chemical regulations, using appropriate packaging for safe transit.
Storage	Store the chemical “Delta - Dihydroxy - 2 - (4 - Fluorophenyl)-5 - (1 - Methylethyl)-3 - Phenyl - 4 - ((Phenylamino)Carbonyl)-Betcalci1H - Pyrrole - 1 - Heptanoicaci” 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 incompatible substances to avoid potential reactions.