Compound (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-[4-chloro-3-(4-ethoxybenzyl)phenyl]tetrahydro-2H-pyran-3,4,5-triyl triacetate is the per-O-acetylated C-aryl glucoside commonly referenced as dapagliflozin tetraacetate. The CAS registry number 461432-25-7 identifies the defined stereoisomer; the molecular formula is C₂₉H₃₃ClO₁₀ and the molecular weight is 577.03 g mol⁻¹. The four acetyl groups mask the secondary and primary alcohols of the free C-aryl glucoside, yielding a non-ionizable, lipophilic crystalline solid. The substance is handled as a pharma-grade advanced intermediate under ICH Q7 and Q11 cGMP controls. It is not a compendial active pharmaceutical ingredient with an official USP or Ph. Eur. monograph; specification limits are therefore supplier and contract defined.

The stereochemical descriptors (2R,3R,4R,5S,6S) correspond to the D-gluco C-aryl series after numbering the tetrahydropyran ring with oxygen as position 1. The aryl group is attached at the anomeric carbon through a C–C bond. This C-aryl linkage is chemically distinct from O-glycosidic linkages in conventional glucosides and is not cleaved by ordinary glycoside hydrolases. The acetyl esters, however, are hydrolytically labile under alkaline conditions and are removed to generate the active SGLT2 inhibitor dapagliflozin. The theoretical free-base equivalent of the tetraacetate is 70.86% w/w, based on the molecular weight of dapagliflozin base 408.88 g mol⁻¹.

What Limits Direct Use of the Tetraacetate in Finished-Dose Formulation?

Direct blending of the tetraacetate into tablet, capsule, granule, or injectable matrices is not supported by public finished-dose monographs. The substance is practically insoluble in water, and its four acetate esters introduce hydrolytic instability in aqueous vehicles and wet granulation processes. Moisture ingress above 0.5% w/w is capable of liberating acetic acid, shifting related-substance profiles and lowering assay. The free C-aryl glucoside dapagliflozin, not the tetraacetate, is the active moiety; therefore weight-for-weight substitution into an oral dosage form would require a correction factor and would still require in vivo equivalence data unless the protected form were deliberately developed as a prodrug. Published data for the tetraacetate as a finished-dose prodrug is limited.

The tetraacetate is used primarily as a protected intermediate in the synthesis of dapagliflozin. The protecting groups improve crystallinity and simplify purification, but they also require quantitative removal before salt formation and final formulation. In a typical downstream step, the tetraacetate is treated with catalytic sodium methoxide in methanol at ambient temperature under nitrogen. The pH is maintained above 10 until HPLC shows disappearance of the starting tetraacetate. The mixture is then neutralized with acetic acid or an acidic ion-exchange resin, extracted into ethyl acetate, and crystallized as dapagliflozin base or converted to dapagliflozin propanediol monohydrate.

Release specifications for this protected intermediate are not published by pharmacopoeias. A representative cGMP release package includes identity, assay, related substances, residual solvents, water, residue on ignition, and elemental impurities. Analytical methods are generally validated according to ICH Q2(R2). HPLC area normalization is used for assay and impurity control because the aryl chromophore gives reliable UV response. The table below summarizes representative controls used in industrial supplier agreements for dapagliflozin tetraacetate.

The acceptance criteria above are representative of cGMP release for an advanced synthetic intermediate; they are not a formal regulatory specification. Because no public pharmacopoeial monograph exists, exact limits can vary by manufacturer and by the synthetic route used. The impurity profile is route-dependent and should be reviewed for deacetylated homologues, positional isomers, and residual metal catalysts.

Residual Solvent and Elemental Impurity Control Points

Residual solvent control follows ICH Q3C. Methanol, ethyl acetate, dichloromethane, and tetrahydrofuran are common process solvents in the acetylation and purification sequence. The ICH Q3C Class 2 limits for methanol, ethyl acetate, dichloromethane, and tetrahydrofuran are 3000 ppm, 5000 ppm, 600 ppm, and 720 ppm, respectively. Class 1 solvents such as benzene must be absent or controlled below 2 ppm unless a route-specific justification is provided.

Elemental impurities are assessed against ICH Q3D using the intended deprotection and salt conversion sequences. Palladium is relevant when a palladium-catalyzed coupling or hydrogenation step is used in the synthesis of the C-aryl glucoside. A route-dependent palladium limit of ≤10 ppm is commonly applied because the metal can persist through crystallization and interfere with the final dapagliflozin propanediol monohydrate specification. Cadmium, lead, arsenic, and mercury are controlled as Class 1 elemental impurities. Because the tetraacetate is not an injectable final product, the Q3D parenteral risk assessment is not applied until the deprotected form is converted to a parenteral-grade salt if such a formulation is developed.

For injectable use, the tetraacetate itself is not suitable without hydrolysis and salt selection. After deprotection, residual methanol and methylene chloride must meet ICH Q3C limits, and the final injectable grade would require additional control of endotoxins, bioburden, and particulate matter according to Ph. Eur. 2.6.14 or USP <85>. No approved parenteral dapagliflozin finished product is described in major pharmacopoeias; published data for this specific configuration as an injectable API is limited.

When the Deprotected API Replaces the Tetraacetate in Oral and Injectable Processing

The difference between the tetraacetate and the final active is not merely molecular weight. The tetraacetate is neutral, crystalline, and organic-solvent soluble; dapagliflozin base is a polar C-aryl glucoside with poor aqueous solubility and a high hydrogen-bonding capacity. For oral solid dosage forms, the free base is typically isolated as dapagliflozin propanediol monohydrate, CAS 960404-59-5, with molecular weight 502.98 g mol⁻¹. This salt form provides better crystallinity and handling than the free base. The approved oral tablets contain 5 mg or 10 mg of dapagliflozin as the propanediol monohydrate.

Process conversion from the tetraacetate to dapagliflozin propanediol monohydrate requires strict control of the deacetylation endpoint. Incomplete deprotection leaves acetylated impurities that may cocrystallize with the final salt. Over-exposure to base can generate oxidized impurities at the benzylic methylene position. The reaction is therefore monitored by HPLC at an early time point and at endpoint, with intermediate sampling to confirm the disappearance of mono-, di-, and triacetyl intermediates. The anomeric C–C bond is stable under the alkaline deprotection conditions; the principal side reactions are ester hydrolysis and oxidation rather than anomerization or C–glycosidic cleavage.

After deprotection and salt formation, the final dapagliflozin API can be processed by direct compression or wet granulation for tablets. Granule-based oral dosage forms require particle-size control of the active after milling; laser diffraction according to USP <429> or ISO 13320 is commonly used to monitor d₁₀, d₅₀, and d₉₀. Capsule and granule formulations may be developed from the same milled API, but the tetraacetate is not used directly in these operations because it would require a stoichiometric correction for the free-base equivalent and because the acetyl groups would introduce a different dissolution and stability profile.

For injectable development, the deprotected API would require salt selection, aqueous solubility assessment, pH stability profiling, and terminal sterilization or aseptic processing. No public injectable monograph or approved injectable formulation for dapagliflozin exists; therefore any injectable application of the tetraacetate-derived material would require full pharmaceutical development, including compatibility with parenteral excipients, container closure systems, and endotoxin control. The tetraacetate is not interchangeable with the propanediol monohydrate salt on a weight basis, and the two materials have different residual solvent, moisture, and impurity risk profiles.

Storage of the tetraacetate is normally conducted in sealed, moisture-resistant containers under nitrogen at controlled room temperature or 2–8 °C, depending on the manufacturer’s stability data. The material should not be exposed to open atmospheric moisture for extended periods, because acetyl hydrolysis can occur at the powder surface. When the compound is transferred to production, containers should be warmed to ambient temperature before opening to avoid condensation. These handling controls are particularly important when the tetraacetate is intended for conversion to a final active rather than for direct formulation, because residual moisture and free acetic acid can affect downstream pH adjustment and crystallization behavior.