| HS Code | 520435 |
| Product Name | Fructose Diphosphate Pharma Grade API (intended for tablet, capsule, granule, and injection; oral and injectable dosage forms) |
| Chemical Name | D-Fructose-1,6-bisphosphate (fructose-1,6-diphosphate; commonly supplied as sodium or calcium salt) |
| Cas Number | 488-69-7 (free acid); 81028-90-2 (sodium salt) |
| Molecular Formula | C6H14O12P2 (free acid); C6H11Na3O12P2 (trisodium salt) |
| Molecular Weight | 340.12 g/mol (free acid); 406.06 g/mol (anhydrous trisodium salt) |
| Appearance | White or almost white crystalline powder; generally odourless |
| Solubility | Freely soluble in water; slightly soluble or practically insoluble in ethanol; insoluble in ether and chloroform |
| Ph | Aqueous solution (1% w/v) typically has a pH of 4.0 to 6.0 |
| Assay Hplc Purity | 98.0% to 102.0% on dried/anhydrous basis |
| Residual Solvents | Conforms to ICH Q3C requirements and pharmacopoeial limits |
| Specific Surface Particle Property | Suitable for direct or granulation-based manufacture of tablets/capsules; practical grade for parenteral dissolution |
| Storage | Store in tight, light-resistant containers at controlled room temperature, protected from moisture |
| Shelf Life | Typically 24 months under recommended storage conditions |
| Therapeutic Functional Use | Active pharmaceutical ingredient used as an energy-metabolism carbohydrate product in oral and injectable pharmaceutical formulations |
As an accredited Fructose Diphosphate Pharma Grade API for Tablet / Capsule / Granule / Injection, Oral & Injectable factory, we enforce strict quality protocols—every batch undergoes rigorous testing to ensure consistent efficacy and safety standards.
| Packing | Packaged in sealed double polyethylene-lined drums, 25 kg net per drum, with tamper-evident closure and labeled identification. |
| Container Loading (20′ FCL) | 20′ FCL loaded with Fructose Diphosphate Pharma Grade API in sealed drums/pallets, secured, temperature-controlled, safe for oral/injectable use. |
| Shipping | Ship fructose diphosphate pharma-grade API in sealed, moisture-proof, light-resistant containers, suitable for oral and injectable formulations. Ship at ambient temperature in dry conditions, away from direct sunlight and extreme heat. Include Certificate of Analysis, MSDS, and GMP documentation. Ensure secure, compliant packaging to prevent contamination and maintain stability during transit. |
| Storage | Store Fructose Diphosphate Pharma Grade API in tightly sealed, original containers away from light, moisture, and heat. A cool, dry, well-ventilated area is required; avoid temperatures above 25°C and do not freeze unless specified. Keep protected from oxidation and incompatible substances. Ensure containers remain undamaged and opened only under clean, dry conditions to maintain stability for oral and injectable dosage production. |
| Shelf Life | Shelf Life: 24 months when stored as recommended in the original unopened container, protected from light and moisture. |
On rotary tablet press lines producing immediate-release FDP sodium tablets of 200 mg label claim, the API’s hygroscopicity and platelet-like crystal habit determine whether direct compression or dry granulation is selected. FDP sodium is freely soluble in water, so dissolution rate is not the primary formulation constraint; the main failure modes observed on production batches are sticking to upper punches, weight variation during high-speed compression, and capping when residual moisture exceeds 2.5%. A representative direct compression blend contains 40.0% FDP sodium, 52.5% microcrystalline cellulose PH102, 5.0% croscarmellose sodium, 1.5% colloidal silicon dioxide, and 1.0% sodium stearyl fumarate. After blending in a 600 L bin blender at 12 rpm for 20 min, the blend is compressed on a 45-station rotary press with force feeder speed 15 rpm and mean compression force 18 kN. Tablets are specified at hardness 70–100 N, friability not more than 1.0% per USP <1216>, and disintegration not more than 15 min per USP <701>. Dissolution testing uses USP <711> Apparatus 2 at 50 rpm in 900 mL water at 37 ± 0.5°C, with a typical Q value of 75% at 30 min. Content uniformity is assessed per USP <905> with acceptance value not more than 15.0. Assay is performed by HPLC with charged aerosol detection or evaporative light scattering detection because FDP sodium lacks a strong UV chromophore; free inorganic phosphate is controlled by ion chromatography. The API must be protected from ambient humidity above 40% RH during dispensing and lubrication because surface moisture films accelerate punch filming and increase edge chipping.
When the drug load rises above 60%, direct compression becomes unreliable because flow deteriorates and tablet weight RSD can exceed 2.0%. Dry granulation by roller compaction is then used at roll pressure 40–60 bar, roll speed 3–5 rpm, and screen milling at 1.0 mm aperture. The resulting granules are specified at bulk density 0.55–0.65 g/mL and tapped density 0.70–0.80 g/mL, producing Carr index 15–20%. Dry granulation avoids the sticky granule growth and hydrate conversion observed when FDP sodium undergoes aqueous wet granulation with povidone or starch paste. Batch records require in-process moisture checks by Karl Fischer titration per USP <921> before compression; moisture above 2.0% requires vacuum tray drying at 40–45°C for not more than 4 h to limit phosphate ester hydrolysis.
The moisture exchange between FDP sodium granules and empty hard gelatin shells is a dominant source of fill weight drift on intermittent-motion capsule filling machines with dosator or tamping-pin systems. Empty hard gelatin shells contain 13–16% w/w moisture; hygroscopic FDP sodium granules above 4.5% water activity can transfer moisture to the shell, causing softening at the body rim and loss of cap friction. The filling room is maintained at 20–25°C and ≤35% RH, while the powder hopper is purged with dry air through a desiccant bed at 0.5 L/min. Preferred powders are dry-granulated FDP sodium with 0.5% sodium stearyl fumarate and 1.0% talc; this reduces sticking to dosator surfaces and yields capsule fill weight RSD below 2.5% for size 0 shells. HPMC capsules with residual moisture 4–6% w/w are used where gelatin cross-linking from aldehyde-containing excipients must be eliminated, although their lower water content can make the shell more brittle at 25–30% RH. In-process controls include capsule weight sorting on a checkweigher with ±2 mg accuracy and disintegration testing per USP <701> in 900 mL water at 37°C. A desiccant sachet of silica gel or molecular sieve is added to HDPE bottles to maintain headspace RH below 30% over a 24-month shelf life. Formulators must confirm that the desiccant does not shift capsule brittleness below the shell glass transition; this failure mode appears as split caps during automatic blister packing.
Oral granules filled into PET/aluminum/LLDPE laminate stick packs require a free-flowing, non-friable granule with tightly controlled particle-size distribution. FDP sodium is not compatible with wet granulation when drug load exceeds 40% w/w because the dissolved API forms a hard, glassy agglomerate during tray drying, producing granules that break into fines and cause fill weight variation. Roller compaction is therefore the preferred process, using roll force 30–50 kN, roll gap 1.5–2.5 mm, and an oscillating mill equipped with 1.0 mm rasping screen. The resulting granules are specified at D10 0.15 mm, D50 0.45–0.65 mm, and D90 1.00 mm; bulk density is held at 0.50–0.60 g/mL to permit filling of 1.0–2.0 g unit doses with fill weight RSD below 1.5%. Fill-seal lines are configured with auger fillers and vibration trays, and the laminate must exhibit water vapor transmission rate below 0.1 g/m²/24 h at 38°C/90% RH per ASTM F1249. The seal strength is tested per ASTM F88 with a target burst pressure above 0.4 bar. Taste-masking is achieved by adding 0.3% sodium saccharin and 0.1% menthol flavor, but FDP sodium retains a mildly salty taste that cannot be fully masked by high-intensity sweeteners alone. Reconstitution in 50 mL water at 20°C should produce a clear solution in 2 min; undissolved fines indicate overcompacted granules or hydrolysis-derived sticky fines and require batch rejection. Microbial limits for oral granules are tested per USP <61> and USP <62>, with water activity controlled below 0.6 to prevent microbial growth during storage.
For injectable FDP sodium powder filled into 10 mL Type I glass vials, the manufacturing route is aseptic filtration followed by lyophilization. Terminal steam sterilization at 121°C for 15 min is avoided because the phosphate ester bonds in FDP sodium hydrolyze above 60°C, increasing free inorganic phosphate and fructose-6-phosphate impurities. The bulk solution is prepared by dissolving FDP sodium in Water for Injection at 20–25°C to a concentration of 100 mg/mL, adjusting the pH to 6.5 ± 0.3 with dilute hydrochloric acid or sodium hydroxide, and filtering through a 0.22 µm polyethersulfone membrane. Vials are filled with 5 mL solution and partially stoppered with chlorobutyl lyophilization stoppers. The freeze-drying cycle uses shelf temperature ramped from -40°C to -20°C over 2 h, primary drying at -20°C and chamber pressure 0.15–0.25 mbar for 24–36 h, and secondary drying at 30°C for 6–8 h until the product temperature remains above 25°C for at least 3 h. The lyophilized cake is specified as white to off-white, intact, and free of meltback or shrinkage; residual moisture by Karl Fischer titration is not more than 2.0%. Reconstitution with 10 mL Water for Injection should yield a clear solution within 2 min, with particulate matter controlled per USP <788> and subvisible particle counting by light obscuration. Elemental impurity controls follow ICH Q3D, residual solvents follow ICH Q3C, and bacterial endotoxins are tested per USP <85>. The lyophilization stopper and vial combination must maintain container closure integrity after crimping; dye ingress testing is performed per USP <1207> during validation.
| Stage | Setpoint | Critical quality attribute | Acceptance criterion |
|---|---|---|---|
| Freezing | -40°C for 2 h | Cake structure | No meltback or collapse |
| Primary drying | -20°C, 0.15–0.25 mbar, 24–36 h | Residual moisture | ≤ 2.0% via USP <921> |
| Secondary drying | 30°C, 6–8 h | Product temperature | ≥ 25°C for 3 h |
| Reconstitution | 10 mL WFI at 20°C | Clarity and reconstitution time | Clear solution in 2 min |
Cardiopulmonary bypass circuits and cardioplegic admixtures represent a specialized parenteral application in which FDP sodium is added as a metabolic substrate during ischemia-reperfusion. In this configuration, the API is diluted into crystalloid or colloid priming solutions in the operating room, not manufactured as a fixed combination product in most markets. The primary compatibility risk is precipitation of calcium phosphate when free inorganic phosphate present as an impurity contacts calcium chloride or calcium gluconate in the cardioplegic diluent. Free inorganic phosphate in the FDP sodium API is commonly controlled to not more than 0.5% by ion chromatography before clinical admixture, and concentrated FDP sodium solution is diluted in half-normal saline before mixing with calcium-containing solutions. In-line filtration with a 0.2 µm polypropylene filter is used during cardioplegia preparation to retain particulate matter above 200 nm. Visual inspection and particulate matter testing per USP <788> are required after mixing; turbidity or Tyndall scatter indicates incompatibility and requires the admixture to be discarded. Published clinical evaluation of FDP sodium in cardioplegic solutions is limited to small cohorts and experimental ischemia-reperfusion models; the absence of a harmonized monograph for this specific admixture means that batch-specific stability and compatibility data must be generated before hospital preparation. Assuming the API is supplied as the trisodium salt, a 200 mg oral dose contributes approximately 34 mg sodium, and a 5 g parenteral dose contributes approximately 850 mg sodium. This sodium load must be accounted for in pump prime calculations and in oral dosage labeling where sodium content is specified by the applicable regulatory format.
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Fructose Diphosphate Pharma Grade API, designated FDP-PG-API and supplied as the trisodium salt octahydrate with molecular formula C₆H₁₁Na₃O₁₂P₂·8H₂O and molecular weight 550.18 g/mol, is a white to almost white crystalline powder intended for the manufacture of oral tablets, capsules, and granules and for sterile injectable preparations. The product contains the phosphorylated hexose fructose-1,6-diphosphate with phosphate ester groups at the C-1 and C-6 positions; it is freely soluble in water and practically insoluble in ethanol. The manufacturer differentiates the API into model subgrades FDP-PG-API-T for direct compression, FDP-PG-API-C for dry granulation and capsule filling, FDP-PG-API-G for wet granulation, and FDP-PG-API-I for injectable processing. These subgrades are distinguished by particle size distribution, bulk density, bioburden, and bacterial endotoxin limits rather than by a change in the base pharmacopoeial assay acceptance criterion of 98.0–102.0% on the anhydrous, solvent-free basis. The aqueous pH of a 5% solution is controlled between 6.0 and 8.0, and the related substances profile limits fructose-6-phosphate, fructose-1-phosphate, glucose, and inorganic phosphate. Identification is performed by infrared absorption spectrophotometry against the current pharmacopoeial FDP reference standard and by a sodium flame test. Residual solvents are controlled according to ICH Q3C Option 1 limits by headspace gas chromatography, and elemental impurities are controlled according to ICH Q3D Class 1 and Class 2A limits using USP <233>. The product differs from food-grade fructose diphosphate powders and from non-phosphorylated carbohydrate APIs in the combined control of endotoxin, elemental impurities, residual solvents, and related phosphorylated impurities that affect the safety of injectable and high-dose oral use.
| Model subgrade | Primary intended dosage form | Particle size D90 by USP <429> | Bulk density by USP <616> | Bacterial endotoxins by Ph. Eur. 2.6.14 | Total aerobic microbial count by USP <61> |
|---|---|---|---|---|---|
| FDP-PG-API-T | Direct-compression tablet | ≤ 150 µm | 0.50–0.70 g/mL | ≤ 0.50 IU/mg | ≤ 100 CFU/g |
| FDP-PG-API-C | Dry granulation and capsule filling | ≤ 180 µm | 0.45–0.70 g/mL | ≤ 0.50 IU/mg | ≤ 100 CFU/g |
| FDP-PG-API-G | Wet granulation and tablet compression | ≤ 250 µm | 0.40–0.65 g/mL | ≤ 0.50 IU/mg | ≤ 100 CFU/g |
| FDP-PG-API-I | Injectable and lyophilized preparation | ≤ 75 µm | 0.30–0.55 g/mL | ≤ 0.050 IU/mg | ≤ 10 CFU/g |
Aqueous fructose-1,6-diphosphate solutions are not compatible with terminal steam sterilization. The phosphate ester bonds at C-1 and C-6 undergo pH- and temperature-dependent hydrolysis to fructose-6-phosphate, fructose-1-phosphate, and inorganic phosphate. Published pH-rate profiles indicate a minimum degradation rate near pH 6.5 and faster hydrolysis below pH 3.0 and above pH 8.5. Terminal steam sterilization at 121°C for 15 min exceeds the thermal stability limit for the aqueous solution, producing assay loss, increased free phosphate, and visible turbidity in accelerated studies. Consequently, FDP-PG-API-I is processed by aseptic filtration through 0.22 µm membrane filters and, when a powder-filled vial is required, lyophilization. Production-scale lyophilization cycles maintain the product temperature below −25°C during primary drying to prevent cake collapse and to reduce hydrolytic degradation in the residual moisture film. The freeze-dried cake is amorphous, and final water content is controlled below 2.0% by Karl Fischer titration according to USP <921>, Method Ic. The sterile subgrade FDP-PG-API-I is controlled for total aerobic microbial count at ≤ 10 CFU/g before sterile filtration and bacterial endotoxins at ≤ 0.050 IU/mg by Ph. Eur. 2.6.14. The final injectable endotoxin limit is derived from the maximum intended daily dose.
During aseptic manufacturing of FDP injection, the bulk solution is typically held in a jacketed stainless steel vessel at 2–8°C to reduce microbial growth and hydrolysis. Filter compatibility is confirmed with polyvinylidene fluoride or polyethersulfone 0.22 µm membranes; nylon membranes may be unsuitable at low pH because of leachable interactions. The filling line is operated under a laminar airflow cover and maintained to fill weight variability within ±1.0%. Lyophilized vials are stoppered under partial vacuum or nitrogen to protect the amorphous cake from moisture. For injectable finished product, the reconstituted solution is tested for particulate matter according to USP <788> and for sterility according to USP <71>. The pH after reconstitution is maintained at 5.5–7.5. The bulk solution is prepared in water for injection at concentrations typically between 100 mg/mL and 200 mg/mL, filtered through a bioburden-reduction filter, and held under validated time limits to limit microbial proliferation. Because the molecule is a reducing sugar phosphate, the solution should not be mixed with primary amine-containing components or with strongly alkaline buffers; such combinations produce phosphate migration and Maillard-type browning.
In dry granulation processing on a production-scale roll compactor with 150 mm roll diameter and 50 mm roll width, FDP-PG-API-C with a D90 below 180 µm was processed at roll pressure settings between 4 MPa and 8 MPa. The resulting granular bulk had a Carr index of 15–25, measured by USP <1174>, and was compressed on a rotary tablet press fitted with 10.0 mm flat-faced bevelled tooling. Because the API is hygroscopic, direct compression at relative humidity above 60% caused sticking and weight variability; pre-drying the powder in a vacuum dryer at 40°C for 4 h and maintaining the compression suite at 35–45% RH restored acceptable tablet weight uniformity. Aqueous wet granulation is not recommended unless the binder solution is buffered near pH 6.5; acidic granulation fluids accelerate phosphate ester hydrolysis. Roller compaction or slugging remains the preferred granulation route because it avoids the heat and moisture profile that destabilizes the phosphorylated sugar. Capsule filling of the dried granulate on an automatic capsule machine with size 0 or size 1 capsules is performed after addition of 0.5–1.0% silica dioxide and 0.25–0.5% magnesium stearate. These addition levels are within conventional pharmaceutical ranges and are expected to produce a powder with acceptable flow, although published data for this exact formulation configuration is limited.
The fines fraction below 45 µm should be limited to 10–20% to prevent segregation and capping. A bulk density below 0.50 g/mL typically requires roller compaction rather than direct compression. Target hardness for 500 mg tablets is 60–100 N, with disintegration tested according to USP <701> and dissolution tested according to USP <711> in water at 37°C. Granules for oral solution or suspension are prepared by dry granulation and filled into single-dose sachets; the granulate is blended with a sweetener and a silica-based desiccant to protect the hygroscopic API. Sachet packaging uses aluminium/polyethylene laminate with moisture vapor transmission rate below 0.5 g/m²/day.
FDP-PG-API is not interchangeable with food-grade fructose diphosphate, glucose-6-phosphate, or fructose-1-phosphate. Food-grade FDP powders may be recovered from fermentation broths without the ion-exchange purification steps used for pharmaceutical manufacture, leaving higher levels of fermentation-derived peptides, endotoxin, and inorganic phosphate. The pharmacopoeial FDP product is crystallized and dried under conditions that protect the phosphate ester groups. In ion-pair high-performance liquid chromatography with evaporative light-scattering or refractive index detection, the retention time of FDP is distinct from those of fructose-6-phosphate and fructose-1-phosphate, and the method must produce baseline resolution with a resolution of not less than 2.0 between FDP and the nearest related phosphorylated impurity. A confirmation assay using aldolase and triose phosphate isomerase is specific for fructose-1,6-diphosphate and can distinguish the product from other phosphorylated sugars. Fructose-2,6-bisphosphate is a different positional isomer with phosphate groups at C-2 and C-6; it is not a substitute for FDP and is not supplied as an oral or injectable API. Glucose-6-phosphate and fructose-1-phosphate have a single phosphate group and different metabolic roles; they would fail the FDP infrared and enzymatic identification criteria.
| Control parameter | FDP-PG-API pharma grade | Food-grade fructose diphosphate | Test standard |
|---|---|---|---|
| Assay | 98.0–102.0% | ≥ 95.0% | Ion-pair HPLC, ELSD/RID |
| Related substances | fructose-6-phosphate ≤ 1.0%; inorganic phosphate ≤ 0.5% | not controlled | Ion-pair HPLC |
| Bacterial endotoxins | injectable grade ≤ 0.050 IU/mg; oral grade ≤ 0.50 IU/mg | not controlled | Ph. Eur. 2.6.14 |
| Microbial enumeration | injectable TAMC ≤ 10 CFU/g; oral TAMC ≤ 100 CFU/g | TAMC ≤ 1000 CFU/g | USP <61> |
| Elemental impurities | Class 1 and Class 2A limits per ICH Q3D | not controlled | USP <233> |
| Residual solvents | ICH Q3C Option 1 limits | not controlled | USP <467> headspace GC |
| Water content | oral octahydrate 24.0–28.0%; injectable lyophile ≤ 2.0% | not controlled | USP <921> |
| Particle size | model-specific D90 as in Table 1 | not controlled | USP <429> |
Storage and handling boundaries follow from the same physicochemical profile. The API should be stored in sealed aluminium foil bags with desiccant below 25°C and protected from moisture. At relative humidity above 60%, the powder forms agglomerates and can adhere to stainless steel contact surfaces. The API should not be milled in unventilated equipment without verification that the surface temperature remains below 40°C, because local frictional heating can release water of hydration and promote hydrolysis. The octahydrate has theoretical water content of 26.2%; partial dehydration during milling changes particle surface energy and can reduce flowability in direct-compression formulas. For aqueous processing, the solution should be buffered to pH 6.0–7.0 and protected from prolonged exposure to temperatures above 25°C. Incompatibilities include strongly acidic or alkaline conditions, primary amine-containing excipients, and oxidizing agents. Under long-term storage at 25°C/60% RH and accelerated storage at 40°C/75% RH, product-specific stability data are required before assigning retest dates; published data for this exact hydrate and dosage-form configuration is limited.
