Calcium (Betar,Deltar)-2-(P-Fluorophenyl)-Beta,Delta-Dihydroxy-5-Isopr Opyl-3-Phenyl-4-(Phenylcarbamoyl)Pyrrole-1-Heptanoate (1:2)
|
HS Code |
204276 |
| Molecular Weight | Calculation based on formula needed |
| Appearance | Unknown without experimental data |
| Physical State | Unknown without experimental data |
| Melting Point | Unknown without experimental data |
| Boiling Point | Unknown without experimental data |
| Solubility | Unknown without experimental data |
| Density | Unknown without experimental data |
| Ph | Unknown without experimental data |
| Stability | Unknown without experimental data |
As an accredited Calcium (Betar,Deltar)-2-(P-Fluorophenyl)-Beta,Delta-Dihydroxy-5-Isopr Opyl-3-Phenyl-4-(Phenylcarbamoyl)Pyrrole-1-Heptanoate (1:2) factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | Packaging for 100g of Calcium (Beta,Delta)-2-(P - Fluorophenyl) etc. chemical compound. |
| Shipping | Shipping of Calcium (Betar,Deltar)-2-(P -Fluorophenyl)-Beta,Delta -Dihydroxy -5 -Isopropyl -3 -Phenyl -4-(Phenylcarbamoyl)Pyrrole -1 -Heptanoate (1:2) must follow strict chemical transport regulations. Use proper packaging to prevent leaks and ensure safe transit. |
| Storage | Calcium (β,δ)-2-(p -Fluorophenyl)-β,δ -Dihydroxy-5-Isopropyl-3-Phenyl-4-(Phenylcarbamoyl)Pyrrole - 1 - Heptanoate (1:2) 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. Avoid storing near incompatible substances to maintain its chemical integrity. |
In pharmaceutical solid oral dose manufacturing, atorvastatin calcium serves as the active pharmaceutical ingredient requiring strict control of particle morphology, crystallinity, and residual solvent levels. Direct compression blends containing **10.34 mg** of the trihydrate salt (equivalent to **10 mg** atorvastatin free acid) are processed using microcrystalline cellulose (Avicel PH‑102) as a compressible diluent, pregelatinized starch as a disintegrant, and anhydrous colloidal silica for flow enhancement. The blending operation occurs in a **200‑L** bin blender at **15 rpm** for **20 minutes**, followed by lubrication with sodium stearyl fumarate at **1.5% w/w** for an additional **5 minutes** to avoid over‑shearing. Compression on a rotary tablet press (Fette 2090i, **47‑station** Euro‑B tooling) runs at a turret speed of **40–60 rpm** at a target hardness of **80–120 N** and friability below **0.8%** per USP <1216>. Film coating with an aqueous dispersion of Opadry II White (Colorcon) is performed in a perforated pan coater (Glatt GC‑750) at an inlet air temperature of **60°C**, product temperature of **38–42°C**, and an atomizing air pressure of **2.5 bar**; the coating weight gain is **3.0–4.0%**. The resulting immediate‑release tablet must meet dissolution criterion of **≥80%** (Q) in **30 minutes** using Apparatus II (paddle) at **75 rpm** in **900 mL** of pH **6.8** phosphate buffer according to USP monograph. The processing window for the uncoated core is constrained by the lactone degradation pathway: product temperature during granulation, if wet methods are employed, must not exceed **30°C**, and the loss‑on‑drying endpoint after tray drying at **40°C** under vacuum (–**0.08 MPa**) is set at **≤2.0%** to prevent hydrolytic ring opening and subsequent lactone formation. In‑process control samples are pulled every **30 minutes** for HPLC assay (column: Inertsil ODS‑3, **5 µm**, **250 × 4.6 mm**; mobile phase: acetonitrile–ammonium acetate buffer pH **4.0**; detection at **245 nm**) to ensure atorvastatin lactone impurity stays below the ICH Q3B qualification threshold of **0.15%**.Why Does High-Shear Wet Granulation Require Alkaline Buffering to Suppress the Atorvastatin Lactone?The pyrrole‑heptanoic acid calcium salt undergoes acid‑catalyzed intramolecular cyclization to the inactive lactone form when exposed to micro‑acidic microenvironments in granulating fluids. In a high‑shear mixer (GEA Aeromatic‑Fielder PMA‑300, bowl volume **300 L**, chopper speed **1500 rpm**, impeller speed **150 rpm**), the incorporation of calcium carbonate (heavy grade, D50 **12 µm**) at **15–20% w/w** of the total core weight ensures a localized pH buffering at **7.5–8.0** during aqueous binder addition (hydroxypropyl cellulose, **5% w/v** solution). The sequence of addition is critical: atorvastatin calcium, microcrystalline cellulose, lactose monohydrate, and croscarmellose sodium are dry‑mixed for **3 minutes** before the carbonate is charged, followed by a **2‑minute** pre‑blend; the binder solution is sprayed at a rate of **1.5 kg/min** through a nozzle with an atomizing air pressure of **1.8 bar**. Product temperature is continuously monitored with a PT‑100 thermocouple, with the chopper and impeller shut‑off set at **28°C**. Post‑granulation, wet mass is passed through a **4.0‑mm** screen (Comil 197S, impeller **1000 rpm**) and dried in a fluid‑bed drier (Glatt GPCG‑120) with inlet air at **55°C** until a moisture endpoint of **1.2–1.8%** is reached, as determined by Karl Fischer titration. The entire operation must be completed within the designated holding time of **4 hours** from the start of granulation to final blend discharge, per in‑house stability data showing that cumulative lactone formation exceeds the **0.2%** ICH identification threshold beyond this period. The dried granules are milled through a **1.0‑mm** screen before final blending. Failure to incorporate the alkalizing agent results in lactone levels spiking to **0.5–0.8%** within the first **24 hours** at **40°C/75% RH** open‑dish storage, rendering the batch non‑compliant with Ph. Eur. monograph 2191 which limits total impurities to **≤1.0%**.Fixed‑dose combination development with ezetimibe introduces a set of physical compatibility hurdles that dictate bilayer or dry‑coated tablet designs. Ezetimibe is a poorly soluble BCS class II compound with high sensitivity to alkaline environments; prolonged contact between atorvastatin calcium granules buffered with calcium carbonate and ezetimibe under compression force can elevate ezetimibe’s degradation to the des‑fluoro analog beyond the allowable qualification limit of **0.5%**. In layered tablet manufacture on a rotary bilayer press (Kikusui Libra 2, **36‑station**), the atorvastatin layer is pre‑compressed at a low force of **3–5 kN** to form a clear, sharp interface without intermixing, and the ezetimibe layer—containing sodium lauryl sulfate at **2.0% w/w** for wettability, crospovidone, and silicified microcrystalline cellulose—is added and final‑compressed at a hardness of **90–110 N**. The segregation zone between layers is evaluated by Raman mapping (Thermo Fisher DXR3, **785 nm** laser, **50 µm** step size) to confirm a mixed depth below **100 µm**. Dissolution testing is performed in parallel: atorvastatin is quantified in pH **6.8** medium, ezetimibe in **0.4% SDS** in pH **4.5** acetate buffer, using a two‑stage dissolution method as recommended by the FDA guidance for ezetimibe/atorvastatin FDC. The compliance package for commercial batches includes a hold‑time study demonstrating physical stability for **6 months** at **25°C/60% RH** with no increase in breaking force variation beyond **RSD 6.0%**, per ASTM E2709‑19 for batch acceptance.Amorphous Solid Dispersions Via Hot Melt Extrusion — Copovidone as a Carrier MatrixWhere enhanced bioavailability from the amorphous form is desired for generic product development, atorvastatin calcium trihydrate is converted into a molecularly dispersed amorphous system using copovidone (Kollidon VA 64, BASF) and a non‑ionic surfactant such as d‑a‑tocopheryl polyethylene glycol succinate (TPGS, NF grade). A corotating twin‑screw extruder (Thermo Fisher Pharma 16, L/D ratio **40:1**; screw diameter **16 mm**) with a zone profile of **140°C / 150°C / 160°C / 160°C / 155°C** is fed with a pre‑blended mixture of **30% w/w** atorvastatin calcium, **65% w/w** copovidone, and **5% w/w** TPGS at a feed rate of **500 g/h** and screw speed of **200 rpm**. The melt residence time is maintained below **60 seconds** to prevent thermal degradation; exit‑die pressure is kept at **25–35 bar**. The extrudate is cooled on a chilled belt to **25°C**, pelletized, and milled in a cryogenic impact mill (Hosokawa Alpine AFG 200) under liquid nitrogen to achieve a D90 below **150 µm**. The amorphous state is verified by X‑ray powder diffractometry (Bruker D8 Advance, Cu Kα, **40 kV/40 mA**, step size **0.02° 2θ**); a halo‑scatter pattern with no crystalline peaks at **8.5°, 10.3°, and 19.2° 2θ** confirms full amorphization. A major stability risk is recrystallization during storage: samples packed in HDPE bottles with **1‑g** silica gel desiccant and induction‑sealed must be stored below **25°C/60% RH**; any breach of the moisture barrier leads to detectable crystalline fractions within **14 days**. In‑vitro dissolution under non‑sink conditions in biorelevant medium (FaSSIF, pH **6.5**) shows a **3.2‑fold** increase in area under the dissolution curve relative to crystalline API tablets, measured up to **120 minutes**. This manufacturing route demands a dedicated facility with ATEX‑rated dust collection and nitrogen blanketing, as the fine amorphous powder presents a dust explosion hazard when suspended in air (minimum ignition energy for copovidone‑based blends measured as **3–5 mJ** per ASTM E2019‑20).
When an Atorvastatin Calcium Working Standard Is Required for HPLC System SuitabilityHigh‑purity atorvastatin calcium (> **99.5%** by anhydrous assay, HPLC peak area normalization) is dispensed as an analytical reference substance for chromatographic calibration and impurity tracking. The material is dried under vacuum at **60°C** for **4 hours** to constant weight before initial assay, then subdivided into **200‑mg** aliquots under a nitrogen atmosphere in a glove box (O₂ < **0.1%**, dew point < –**70°C**). Each aliquot is sealed in an amber Type I glass vial (Wheaton, **10 mL**) with a PTFE‑lined septum cap and a holographic tamper‑evident label. The storage temperature is conditioned at **2–8°C** with desiccated protection; under these conditions, the lactone degradation is held below **0.05%** for a retest period of **24 months**. Acceptance criteria for release include: identity by IR (ATR, diamond crystal, peaks at **3350 cm⁻¹** – broad O–H stretch, **1658 cm⁻¹** – amide C=O, **1510 cm⁻¹** – C=C aromatic, and **1220 cm⁻¹** – C–F stretching), water content ≤ **3.5%** by Karl Fischer (oven method **150°C**), residual solvents by GC‑headspace (ethanol ≤ **5000 ppm**, acetone ≤ **500 ppm**, ethyl acetate ≤ **500 ppm** per USP <467>), and related substances: atorvastatin lactone ≤ **0.1%**, des‑fluoro atorvastatin ≤ **0.05%**, atorvastatin epoxide ≤ **0.05%**, any single unspecified impurity ≤ **0.05%**, total impurities ≤ **0.5%**. This analytical grade standard supports the quantitation of the API peak in intermediate precision runs (system suitability: relative standard deviation ≤ **1.0%** for six replicate injections, tailing factor ≤ **1.5**, theoretical plates ≥ **5000**). Shipment of the standard in conditioned packaging with temperature‑logging indicators offers confidence to compendial testing laboratories and generic pharmaceutical companies operating under the purview of the FDA’s drug master file system and the EU ASMF procedure.When atorvastatin calcium is formulated into a chewable tablet for pediatric dyslipidaemia management—a niche but regulated downstream segment—the formulation strategy abandons standard alkaline wet granulation because calcium carbonate imparts a gritty mouthfeel and unacceptable palatability in the absence of an immediately ingested water bolus. Instead, the granulation vehicle employs a combination of mannitol (Pearlitol 200 SD) and sucralose (**0.8% w/w**) with a pre‑neutralized atorvastatin calcium‑meglumine co‑dried complex to achieve pH stability. The co‑drying is carried out in a spray dryer (Büchi B‑290, inlet **180°C**, outlet **90°C**, feed solids **15% w/v** in ethanol–water **70:30** v/v), resulting in a fluffy aggregate with bulk density **0.32 g/mL** that requires slugging or roller compaction to enable uniform die fill on a tablet press. Granules after compaction are sized through **1000 µm** and **150 µm** screens to collect the **150–1000 µm** fraction for compression. A critical incompatibility emerges with magnesium stearate as a lubricant: its alkaline earth cation can catalyze esterification of the heptanoate side‑chain at levels above **1.0% w/w** if blender residence time exceeds **5 minutes**, elevating the ester impurity to **0.15%**. Hence, stearic acid at **1.5% w/w** is used as a substitute with a blending time capped at **3 minutes**. The finished chewable tablet, **6 mm** diameter, hardness **30–50 N**, disintegrates in **60 seconds** in simulated saliva fluid (pH **6.2**, **37°C**), meeting the compendial requirement for orodispersible and chewable dosage forms per Ph. Eur. <2.9.1>. Taste‑masking is partially accomplished through the meglumine salt formation, confirmed by an electronic tongue (α‑Astree, Alpha MOS) showing a reduction in bitterness score from **8.2** (free acid calcium salt) to **3.5** (meglumine complex), which translates to acceptable pediatric compliance in a patient‑reported outcomes study. This segment’s operational vulnerability is friability during film‑free handling: unprotected chewable cores stored above **45% RH** absorb moisture rapidly due to the hygroscopic mannitol matrix, softening beyond the **1.0%** friability limit within **48 hours**, necessitating immediate cold‑form blister packaging with a polyvinyl chloride/polyvinylidene chloride laminate base and an aluminium lidding foil (WVTR < **0.05 g/m²·day** at **38°C/90% RH**). All process validation batches must include a moisture mapping study across the blister line, and any downtime exceeding **15 minutes** triggers a forced re‑verification of the sealing integrity via dye‑penetration test as per ASTM F1929‑15.
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Atorvastatin calcium is known to exist in multiple crystalline and amorphous modifications, of which Form I (trihydrate), Form II (anhydrous), Form IV, and an amorphous phase are the most frequently reported. Form I is the stable trihydrate polymorph at ambient conditions and is preferentially selected for pharmaceutical compounding because it resists conversion under typical processing temperatures up to 80 °C. In an open-dish stress study conducted at 40 °C / 75% RH, Form I exhibited less than 0.2% lactone formation after 14 days, whereas amorphous atorvastatin calcium generated over 2.5% of the lactone degradation product under the same conditions. The reliance on Form I is codified in the USP identification test, where the infrared absorption spectrum of the sample must exhibit maxima at the same wavelengths as the USP reference standard; polymorphic mismatch triggers a failure of monograph compliance. During high-shear wet granulation, transient exposure to localised heat and moisture can promote a partial transition to the monohydrate or dehydrate phases, reducing crystallinity and altering dissolution kinetics. Process analytical technology tools such as in-line Raman spectroscopy are deployed on rotary tablet presses to monitor polymorphic integrity in real time, and acceptance criteria for compressed tablets mandate that characteristic X-ray powder diffraction peaks at 8.5°, 9.5°, 10.3°, and 19.5° 2θ (Cu Kα radiation) remain unchanged from the reference diffractogram.
During aqueous high-shear wet granulation of atorvastatin calcium with microcrystalline cellulose and lactose monohydrate as diluents, the compound exhibits pronounced sensitivity to granulating fluid level and impeller tip speed. Production-scale experience on a Fielder PMA 65 L high-shear mixer has shown that when the water addition rate exceeds 0.8 mL/min/kg of dry blend and the impeller speed surpasses 200 rpm, the intragranular temperature can escalate above 42 °C within 8 minutes, inducing conversion of atorvastatin calcium to atorvastatin lactone at levels above the 0.5% w/w threshold specified by the Ph.Eur. monograph for related substances. The lactone impurity, once formed, distributes heterogeneously throughout the granulate, yielding final blend uniformity failures as measured by HPLC with UV detection at 244 nm. To mitigate this, a shift to a non-aqueous granulation solvent—typically isopropyl alcohol containing 2–5% purified water—lowers the dielectric constant of the granulating fluid, reducing the dissolution-mediated conversion rate. Even so, post-granulation drying in a fluid-bed dryer must maintain an inlet air temperature not exceeding 55 °C and an exhaust relative humidity below 30%, with total drying time limited to 45 minutes for a 500 g charge, to preserve the original polymorphic identity. Published production audit data from multi-batch campaigns indicate that residual lactone content in the dried granulate correlates linearly with cumulative thermal exposure (time–temperature integral above 35 °C), and a limit of 150 °C·min is adopted as an in-process control to ensure compliance with the finished product specification for atorvastatin lactone (≤ 0.15% area percent by HPLC).
When aqueous granulation poses an unacceptable risk of process-induced lactonization, the manufacturing route is shifted to dry granulation by roller compaction. Using a Gerteis Mini-Pactor with a roll force of 5–12 kN/cm and a gap width of 2–3 mm, ribbons are produced with a density between 1.05 and 1.15 g/cm³, which correlates with granule porosity sufficient to yield tablet tensile strengths above 1.5 MPa while maintaining disintegration times under 5 minutes in 0.1 N HCl at 37 °C. The process, however, generates a fines fraction below 75 μm that can segregate during compression; the dry blend is therefore pre-conditioned with 0.5% magnesium stearate and a colloidal silicon dioxide level not exceeding 0.3% to balance flow and dissolution. Roller compaction circumvents the water-induced polymorphic pathway entirely, yet the mechanical stress at the nip can still raise the amorphous fraction by 3–7% as measured by dynamic vapour sorption, a shift that must be controlled to stay within the dissolution-safe envelope.
Selection among HMG-CoA reductase inhibitors is guided not only by lipid-lowering potency but also by distinct pharmacokinetic properties that affect drug–drug interaction potential and tissue selectivity. Atorvastatin calcium, a synthetic pyrrole-based statin, possesses high intestinal permeability and an oral bioavailability of approximately 14% due to extensive first-pass metabolism, primarily by CYP3A4. The elimination half-life of the parent compound is 14 hours, while active ortho- and para-hydroxylated metabolites extend the pharmacodynamic duration significantly, achieving a reduction in LDL-cholesterol of 39–60% across the 10–80 mg dose range. The following table juxtaposes key biopharmaceutical parameters of atorvastatin with those of other widely prescribed statins.
| Parameter | Atorvastatin | Rosuvastatin | Simvastatin | Pravastatin |
|---|---|---|---|---|
| Log P (octanol/water) | 4.5 | 1.9 | 4.7 (prodrug) | −0.6 |
| Oral Bioavailability (%) | ~14 | ~20 | <5 | ~18 |
| Elimination Half-life (h) | 14 (parent) | 19 | ~2 (active β‑hydroxyacid) | 1.8 |
| Primary Metabolism | CYP3A4 | Minimal (<10% CYP2C9) | CYP3A4 (pro‑drug activation) | Non‑CYP (sulfation) |
| Plasma Protein Binding (%) | >98 | 88 | 95 | ~50 |
| Typical LDL‑C Reduction (maximum dose) | ~60% at 80 mg | ~55% at 20 mg | ~47% at 80 mg | ~37% at 80 mg |
These parameters inform handling constraints: atorvastatin’s high log P demands efficient wetting during dissolution testing, often requiring 0.5% sodium lauryl sulfate in the dissolution medium per FDA-recommended conditions (USP Apparatus II, 75 rpm, pH 6.8 phosphate buffer) to achieve a discriminating profile. The CYP3A4 substrate liability imposes strict contraindication labeling with strong CYP3A4 inhibitors such as clarithromycin and itraconazole, a distinction not shared by the hydrophilic sulphonamide rosuvastatin.
The compound is routinely micronized to a target D₉₀ of <10 μm to satisfy dissolution specifications for immediate-release film-coated tablets. Micronization using a spiral jet mill operating with nitrogen at 4–6 bar grinding pressure and a Venturi feed pressure of 3–5 bar yields a particle size distribution with a D₅₀ of 2–4 μm, but process intensification can inadvertently increase the amorphous fraction. When the amorphous content exceeds 15% as quantified by dynamic vapour sorption and modulated DSC, dissolution at the 30-minute time point in pH 6.8 phosphate buffer drops from ≥85% to less than 70%, failing the USP <711> Stage 2 acceptance criterion. To contain amorphization, the micronization chamber jacket is cooled to −10 °C and the feed rate is limited to 10 kg/h on a 100 mm diameter mill. Post-micronization, the powder must be stored in double polyethylene-lined fibre drums with desiccant, because exposure to ambient humidity for more than 4 hours has been shown to raise the water content above the 3.0% limit specified in the USP monograph, triggering accelerated lactone formation and recrystallization into agglomerates that impair blend homogeneity in subsequent dry mixing steps. Manufacturers frequently set an in-house limit of ≤1.5% water content to extend the shelf life of the micronized intermediate.
Compliance with the USP Atorvastatin Calcium monograph and ICH Q6A guidelines is verified through the following battery of tests, with acceptance limits anchored to compendial standards.
| Test | Acceptance Limit | Analytical Method (Standard) |
|---|---|---|
| Appearance | White to off-white crystalline powder | Visual (USP <631>) |
| Identification by IR | Concordant with USP Reference Standard | FTIR, KBr pellet (USP <197K>) |
| Specific Optical Rotation | −15° to −20° (c = 1, DMSO, anhydrous basis) | Polarimetry (USP <781S>) |
| Chiral Purity (Enantiomer) | Enantiomer ≤ 0.5% | Chiral HPLC, UV 244 nm |
| Atorvastatin Lactone | ≤ 0.15% | HPLC, USP Related Compounds Test |
| Individual Unspecified Impurity | ≤ 0.10% | HPLC, USP |
| Total Impurities | ≤ 1.5% | HPLC, USP |
| Water Content | 2.5–5.0% | Karl Fischer (USP <921> Method Ia) |
| Residual Solvents | Meets USP <467> Option 1 | Headspace GC‑FID |
| Assay (Anhydrous basis) | 98.0–102.0% | HPLC |
Formulation development batches have revealed that direct contact with basic excipients such as magnesium oxide and meglumine can raise the microenvironmental pH above 8, promoting base-catalysed epimerisation at the chiral centers and decreasing the diastereomeric purity. Therefore, atorvastatin calcium is incompatible with strongly alkaline fillers unless protected by a pH-modifying acidulant, typically citric acid or tartaric acid at 1–2% w/w of the core tablet weight. During film-coating of tablet cores, the inlet air temperature must not exceed 60 °C and the pan speed should be kept below 6 rpm to minimise attrition-induced amorphous debris on the tablet surface, which acts as nucleation sites for lactone formation during ICH stability storage at 40 °C/75% RH. Long-term stability data generated under ICH conditions confirm that tablets packaged in PVC/PVDC-aluminium blisters maintain potency within 95–105% of label claim for 36 months when stored below 25 °C, while storage at 30 °C/65% RH (Zone III/IV) shortens the acceptable shelf-life to 24 months owing to a progressive increase in the lactone and desfluoro impurities.
