Quercetin 95% Pharma Grade API for Tablet / Capsule / Granule / Injection, Oral & Injectable

Model QRC-95 is a purified 3,3′,4′,5,7-pentahydroxyflavone, CAS 117-39-5, molecular weight 302.24 g/mol, released on the anhydrous basis. The product appears as a yellow to greenish-yellow crystalline powder. Unlike unstandardized flavonoid extracts, the pharma-grade designation is operationally defined by the certificate of analysis, not by the assay number alone. A 95.0% HPLC assay on the dried basis carries a corresponding related-substances budget of ≤5.0%, residual solvent limits under ICH Q3C, and a defined residual moisture specification of ≤1.0%. The material is intended as an active pharmaceutical ingredient for direct compression and granulated solid oral dosage forms, and—when additional bacterial endotoxin and sub-visible particulate controls are applied—for injectable formulations. Downstream behavior is constrained by aqueous solubility below 0.1 mg/mL at 25°C, poor intrinsic flow, and pH- and oxygen-sensitive degradation of the catechol B-ring. Table 1 summarizes the release specification that separates this grade from lower-cost dietary supplement inputs.

What Distinguishes a 95% Pharma-Grade Quercetin from Dietary Supplement Grades?

A dietary supplement grade of quercetin dihydrate may carry the same 95% label claim on a UV or titration basis, but without a related-substances fingerprint the number does not control the composition of the remaining 5%. In QRC-95, HPLC profiling under ICH Q2(R1) resolves quercetin from kaempferol, isorhamnetin, and later-eluting oxidative dimers. When total related substances approach 5.0%, three quality risks become measurable. First, hydrophobic enrichment of oxidized impurities at the crystal surface can slow dissolution in pH 1.2 or pH 4.5 media in USP <711> apparatus 2 at 50 rpm. Second, injectable formulations may develop sub-visible particles after terminal sterilization because impurity aggregates act as nucleation sites. Third, batch-to-batch variance in the impurity profile complicates ICH Q3A reporting because the unspecified impurity threshold of 0.10% may be crossed by multiple minor peaks. For modified-release solid oral products, the internal release target is often tightened to total related substances ≤3.0% and the individual unspecified impurity limit to ≤0.50%. Published data for the impurity-dissolution relationship specific to QRC-95 is limited; therefore the tightened target is a development boundary, not a compendial requirement.

Solid Oral Processing Windows and Equipment-Dependent Failure Modes

Direct compression of QRC-95 without particle engineering is prone to weight variation and sticking. The powder typically has a Hausner ratio between 1.25 and 1.45 and a Carr index between 20% and 31%. On a rotary tablet press equipped with 10 mm round concave tooling, acceptable tablets with hardness 40–80 N and friability ≤1.0% are obtained at compression forces of 8–18 kN when the formulation contains silicified microcrystalline cellulose at 30–50 wt% and colloidal silicon dioxide at 0.5–1.5 wt%. If magnesium stearate exceeds 1.0 wt%, dissolution at the 45-minute point in 0.1 N HCl can fall below 75%. Because quercetin is poorly compressible and sensitive to alkaline granulating fluids, wet granulation is preferably performed with a binder solution of pregelatinized starch or low-viscosity hypromellose at 5–8 wt%, using a high-shear granulator at impeller tip speed 3–6 m/s. Fluid-bed drying at inlet air temperature 45–55°C to a final LOD of ≤2.0% minimizes oxidative browning. Drying temperatures above 60°C with residual moisture above 3% have been observed on production-scale fluid-bed dryers to accelerate assay loss and increase yellow-brown discoloration.

For capsule filling, the low bulk density creates fill-weight variability on dosator-type machines unless the powder is pre-compacted. A slug solid fraction of 0.55–0.70 is typically required for size 0 capsules at total fill weights of 300–500 mg. Blend uniformity acceptance value should be ≤15.0 under USP <905>. If the incoming QRC-95 particle size D90 exceeds 120 µm, a pin mill with classifier speed 5000–8000 rpm may be used, but over-micronization can reduce bulk density below 0.30 g/mL and increase electrostatic adhesion to stainless steel contact surfaces.

If a Liquid Injectable Is Required, Terminal Sterilization Is Not the Default Route

Quercetin undergoes oxidative degradation in neutral-to-alkaline aqueous media, and autoclaving at 121°C for 15 minutes can increase related substances beyond an injection release limit. Aseptic filtration through a 0.22 µm polyvinylidene fluoride membrane after pH adjustment to 5.0–6.5 is preferred for solutions. Because the aqueous solubility of the uncomplexed aglycone is below 0.1 mg/mL, injectable solutions require a solubilizing system. Hydroxypropyl-β-cyclodextrin at a molar ratio of 1:5 to 1:10 can raise solubility above 5 mg/mL in phosphate buffer at pH 6.0, but the complexation efficiency must be confirmed by phase-solubility analysis. Cosolvent systems containing propylene glycol and polysorbate 80 may also be used, with the limitation that polysorbate-containing formulations are susceptible to oxidative degradation and should be nitrogen-sparged. For a nanosuspension, high-pressure homogenization at 1000–1500 bar for 10–20 passes with 0.1–0.2 mm zirconium oxide beads can reduce the D50 to 200–400 nm; the resulting suspension must meet particulate limits under USP <788> and endotoxin limits under USP <85>. Lyophilized injectable cakes should be formulated with a cryoprotectant such as mannitol at 4–6 wt% and dried to residual moisture ≤1.0%. If the API is designated for injection, the certificate of analysis should include bacterial endotoxins and sub-visible particulate matter, because the solid oral release specification does not automatically cover these attributes.

Correcting the Anhydrous-to-Dihydrate Mass Conversion During Weighing

The anhydrous-to-dihydrate mass conversion is a frequent source of batch assay error when a manufacturer switches from an unspecified quercetin hydrate to QRC-95. Quercetin dihydrate has molecular weight 338.27 g/mol and water content 10.0–12.0%. To deliver 100 mg of anhydrous quercetin, a dihydrate input requires 111.9 mg when the label claim has not been corrected for water. QRC-95 is released as the anhydrous form with water ≤1.0%; the same weigh-boost is not required. The anhydrous form is more hygroscopic than the crystalline dihydrate and should be stored in double polyethylene bags inside a sealed aluminum foil laminate. At 25°C/60% RH for 24 hours, the water content can rise by 1–2%, increasing tablet sticking and punch filming during compression. If conversion of the dihydrate to the anhydrous form is performed in-house, vacuum drying at 60–65°C under −0.08 MPa for 8–12 hours is a typical starting point, but overdrying or excessive mechanical shear can generate amorphous domains with reduced chemical stability. This hydrate difference also affects the assay certificate: a 95% dihydrate material is not equivalent to a 95% anhydrous material on an as-is basis.

The 5% Impurity Window Is Not Inert and Alters Dissolution Stability

The 5% impurity window is not inert and should be treated as a formulation variable rather than a fixed excipient background. Related flavonoids and oxidized quercetin species can change surface wetting, dissolution, and chemical stability. Contact-angle measurements on compacts prepared from lots with total related substances ≤2.0% versus lots near 5.0% show higher hydrophobicity for the impurity-enriched powder. This correlates with slower disintegration in phosphate buffer at pH 6.8 and more tablet core discoloration after 6 months at 40°C/75% RH in aluminum/PVC blister packaging. If QRC-95 is used in a modified-release formulation, a narrower internal release target of total related substances ≤3.0% and unspecified impurities ≤0.50% may reduce the need for dissolution re-validation across API lots. Injectable formulations are even more sensitive because quinone-like oxidative impurities can participate in redox cycling and generate reactive oxygen species under pH stress. Published data for the specific QRC-95 impurity-performance relationship is limited; therefore, formulation development should include deliberate use of impurity-enriched or aged lots to challenge the downstream process, not just fresh-lot qualification.