The product plant extracts diosmin Pharma Grade API for Tablet / Capsule / Granule / Injection, Oral & Injectable is a purified semisynthetic flavonoid active pharmaceutical ingredient obtained from hesperidin extracted from Citrus aurantium var. amara or equivalent Rutaceae biomass, followed by oxidative dehydrogenation. The chemical entity is diosmetin 7-O-rutinoside, molecular formula C₂₈H₃₂O₁₅, relative molecular mass 608.5 g/mol, CAS registry number 520-27-4. The substance is a yellowish to pale yellow powder, practically insoluble in water, very slightly soluble in ethanol, and soluble in dimethyl sulfoxide. Four process-oriented grades are supplied: DSN-90P non-micronized powder for wet-granulation and capsule processing; DSN-90M micronized powder for dissolution-limited oral solid-dose manufacturing; DSN-90DC direct-compression agglomerate for dry tablet and capsule processing; and DSN-90I injectable-suitable powder with reduced bioburden and endotoxin controls. Release testing conforms to the current Ph. Eur. monograph for diosmin, with assay controlled by liquid chromatography in the range 90.0–102.0% dried basis.

The pharmacognostic starting material is not a crude extract. It is controlled for botanical identity, pesticide residues, and residual flavonoid profile before chemical conversion. Oxidative dehydrogenation of hesperidin creates the flavone double bond at C2–C3 and reduces molecular weight by two hydrogen atoms relative to hesperidin. This structural difference changes chromatographic retention and ultraviolet absorption, making diosmin distinguishable from hesperidin, rutin, quercetin, naringenin, and crude citrus bioflavonoids. Because the API is derived from plant biomass and then refined by solvent crystallisation, the residual solvent profile must be evaluated against ICH Q3C and the elemental impurity profile against ICH Q3D. Plant-derived routes can introduce pesticide residues and related flavonoids that must be controlled in the final API, while fully synthetic routes may introduce metal catalysts or different solvent residues. Pharma-grade diosmin is therefore not interchangeable with non-pharmacopoeial citrus bioflavonoid powders, which may contain variable total flavonoid content, hygroscopic fractions, and poorly compressible plant constituents.

Why does particle size control diosmin tablet dissolution and compression beyond simple flow?

Diosmin is a poorly water-soluble flavone. Its dissolution from tablet and capsule matrices is surface-area dependent during the initial minutes after disintegration. The DSN-90P grade typically has particle size D90 in the range 40–100 µm, low bulk density, and poor flow. Jet milling to DSN-90M reduces D90 to ≤15 µm and D50 to 5–8 µm, increasing the specific surface area available for wetting. Particle-size control is performed by laser diffraction according to Ph. Eur. 2.9.31 or USP <429>; this method is more robust than sieving for detecting the fine fraction. The micronized grade may show a Hausner ratio above 1.40 and compressibility index above 25% under Ph. Eur. 2.9.36, creating sticking and weight variation if compressed directly at high turret speed. Particle-size reduction is therefore a formulation trade-off between dissolution and process robustness. For capsule filling with dosator machines, a Carr index below 20 is usually required; otherwise auger or vacuum fill systems require powder-conditioning steps such as forced feeding or pre-compaction.

Dissolution testing of finished tablets containing micronized diosmin is commonly performed using USP <711> apparatus II at 50 rpm or 75 rpm in 900 mL of 0.1 M HCl or pH 6.8 phosphate buffer with a surfactant concentration justified by solubility data. Without surfactant, sink conditions may not be achieved and variability increases. Method development should include solubility in media containing 0.25–1.0% sodium lauryl sulfate. Production-scale observations on a 27-station rotary tablet press equipped with 11 mm round B-tooling show that direct compression of DSN-90P at turret speeds above 40 rpm generated weight RSD values above 2.0%. The same process with DSN-90DC at 40 rpm maintained weight RSD below 1.5%. Tablet hardness was set at 80–120 N, friability below 1.0% by Ph. Eur. 2.9.7, and disintegration below 15 min by Ph. Eur. 2.9.1 for uncoated tablets. These are process observations observed during technology transfer, not API release specifications.

For granule manufacture, non-micronized DSN-90P disperses better in aqueous binder solutions. Top-spray fluid-bed granulation with inlet air temperature 60–70 °C and product temperature 32–40 °C is typical; the exact spray rate must be adjusted for batch size and binder viscosity. Aqueous binder viscosity between 5–15 mPa·s at 25 °C reduces nozzle blocking while controlling agglomerate size. The direct-compression grade DSN-90DC is not intended for wet granulation because its agglomerates break down under high-shear wet massing and lose the flow advantage.

For injectable manufacture, DSN-90I is not a sterile API. It is a low-endotoxin, controlled-particulate active ingredient intended for further processing into terminal sterilisation or aseptic filtration. Bacterial endotoxin acceptance follows Ph. Eur. 2.6.14 or USP <85>; an example limit is ≤0.25 EU/mg where the maximum daily dose supports this value, but the limit must be calculated from the finished-product dose and route. Subvisible particulate matter after reconstitution of the formulated solution is assessed by Ph. Eur. 2.9.19 or USP <788>. Because diosmin is practically insoluble in water, direct dissolution of crystalline powder in WFI is not a feasible manufacturing step. Solubilised systems such as cosolvent dilution, phospholipid complexation, cyclodextrin inclusion, or liposome encapsulation require validation of precipitation risk upon dilution with saline; free active material can precipitate within seconds at high dilution. Membrane adsorption must also be studied. PES and PVDF filters may bind flavones, and published data for diosmin-specific adsorption to these membranes is limited. The injectable grade should be stored at controlled humidity; above 60% RH, particle aggregation and reduced powder dosing accuracy can occur even if deliquescence does not.

When tablet compression requires a lower Hausner ratio than the supplied powder

If the selected DSN-90M micronized powder has a Hausner ratio above 1.35 or compressibility index above 25%, direct compression without dry granulation or excipient selection is not recommended. The first corrective action is to blend with colloidal silicon dioxide at 0.5–2.0% w/w and magnesium stearate at 0.25–1.0% w/w. Overlubrication can occur after blending for more than 15 min following stearate addition, resulting in slower disintegration and lower tablet tensile strength. DSN-90DC has a bulk density of 0.45–0.60 g/cm³ and a Hausner ratio of 1.15–1.25, permitting consistent hopper discharge on a rotary press. In tableting, a force feeder speed of 20–40 rpm and press speed of 30–60 rpm are typical for 10–12 mm round tooling, but the exact values depend on tablet mass and friability limits. For capsule filling, DSN-90DC can be filled with dosator settings if the powder plug retains shape; DSN-90M may require a tamping-pin machine or pre-roller compaction. Segregation tendencies are higher for DSN-90P because its broad particle-size distribution includes both coarse and fine fractions. Blend uniformity should follow USP <905> or Ph. Eur. 2.9.40 for finished units and API blend sampling during scale-up.

For wet-granulated tablets, DSN-90P is preferred because its larger D90 and lower initial specific surface reduce binder demand. The granulate should be dried to loss on drying ≤2.5% w/w before compression; residual moisture above 3.0% w/w can increase sticking on punch faces. Drying end point is confirmed by Ph. Eur. 2.2.32 or a rapid moisture balance correlated to the same method. Compared with hesperidin, diosmin has a flavone core instead of a flavanone core. Hesperidin molecular weight is 610.6 g/mol; diosmin is 608.5 g/mol. The two-hydrogen difference may appear small, but the C2–C3 double bond changes molecular shape and reversed-phase HPLC retention. Hesperidin is usually controlled as impurity A with a limit of ≤0.5% in the diosmin monograph. Crude citrus extracts may contain both flavonoids; therefore a defined HPLC method is required to separate them. Unlike rutin, quercetin, or naringenin, pharma-grade diosmin is not interchangeable in formulation, because disintegration, dissolution, compactability, and chromatographic release profiles differ.

Comparative grade parameters across oral and injectable processing routes

Three oral-process grades and one injectable grade differ primarily in particle size, flow, and microbiological control. The table summarises typical release or characterisation values; each batch CoA controls the pharmacopoeial criteria, and particle-size values are informational for process fit.

Particle-size values are not pharmacopoeial release limits but process-control values obtained by Ph. Eur. 2.9.31/USP <429>. The injectable grade is controlled for subvisible particles only as part of the finished formulation; the API itself is not tested against USP <788> except after solubilisation. The release specification matrix below lists analytical techniques and representative limits applied at batch release. For parenteral applications, bioburden and endotoxin are added to the standard oral release tests.

Storage is controlled at ≤25 °C and ≤60% RH in sealed HDPE or aluminium-lined containers. Re-testing after the retest date requires at least identity, assay, related substances, loss on drying, and microbial enumeration for oral grades. The micronized and direct-compression grades should not be exposed to strong alkaline granulating media above pH 9.0 unless stability data are generated; the flavone structure may undergo hydrolytic or oxidative degradation under extreme pH. Avoid mixing diosmin with strong oxidizing agents during cleaning or formulation. Trace peroxide incompatibility can generate degradation products that are not part of the standard related-substance profile. These operational boundaries are manufacturing constraints, not clinical indications.