Adenosine-5′-diphosphate disodium salt: pharma-grade API for oral and parenteral dosage forms

Identified by CAS registry number 16178-48-6 and molecular formula C₁₀H₁₃N₅Na₂O₁₀P₂, the product is adenosine-5′-diphosphate disodium salt, a pharma-grade active pharmaceutical ingredient intended for tablet, capsule, granule, and injection manufacturing. The nominal molecular weight is 471.16 g/mol. The commercial designation is Adenosine-5′-Diphosphate Disodium Salt nucleic acid /protein synthesis Pharma Grade API for Tablet / Capsule / Granule / Injection, Oral & Injectable. The material is supplied as a white to off-white crystalline powder and is not sterile bulk API. The disodium counterion provides reproducible aqueous solubility and a weakly acidic solution pH suitable for subsequent formulation. As an adenosine diphosphate, the molecule contains one β–α phosphoanhydride bond; this linkage is the principal hydrolytic liability during aqueous processing and high-moisture storage. Because the compound is hygroscopic, dispensing should be conducted in an environment with relative humidity below 40% and with minimal open-container residence time. The product is intended for oral solid dosage forms or for injectable formulations after validated sterilization or aseptic filtration.

In nucleic acid and protein synthesis applications, the material serves as a phosphorylated adenosine substrate in kinase, synthetase, and ATP-regenerating systems. In finished drug forms, it supports nucleotide-dependent metabolic or receptor-mediated pathways when formulated as an oral solid or parenteral product. Published data for this specific grade in individual formulation matrices are limited; compatibility and stability studies should be generated for each dosage form.

Compared with adenosine triphosphate disodium salt, the compound carries two phosphate groups rather than three and therefore has a lower non-enzymatic phosphate-transfer potential. Compared with adenosine monophosphate sodium salt, it supplies the pyrophosphate moiety required for certain enzymatic transformations. These structural differences influence aqueous stability, ionic strength, and the regulatory release tests that apply to the finished product.

What release specifications apply to the oral and injectable ADP disodium salt API?

Actual lot values may differ because crystallization solvent, drying endpoint, and milling conditions shift water content and particle size. The specification above is not a compendial monograph; it is a supplier release profile aligned with ICH Q3C, ICH Q3D, and relevant USP general chapters. For injectable products, the endotoxin limit should be recalculated from the maximum dose and the intended route using the dose-based criterion in USP <85>.

Storage and bulk handling of non-sterile ADP disodium salt require segregation from strong oxidizers, acids, and moisture. The powder is best stored in a sealed double polyethylene liner inside a fiber drum with a desiccant pouch at 2–8 °C or lower. Long-term research-grade nucleotide storage often uses −20 °C under nitrogen; pharmaceutical warehouse storage should be justified with ICH Q1A(R2) stability data at 25 °C/60% RH and 40 °C/75% RH. At relative humidity above 60%, the crystalline surface may develop sufficient free moisture to reduce flow and increase water activity. If caking or a visible surface film is observed, direct compression without re-drying is not advisable. Re-drying should be performed only under vacuum or dry nitrogen at low wall temperature because excessive thermal input can promote cleavage of the phosphoanhydride bond and increase free phosphate impurity.

For controlled low-dose blending, the API may be pre-sieved through a 500 µm stainless-steel screen and blended in a bin blender at 60% fill volume and 12 rpm. If the particle size distribution is broad, segregation can occur; stratified blend uniformity samples should be taken from at least 10 positions. A lot with Carr index above 25 or Hausner ratio above 1.35 should not be loaded directly onto a rotary press without a flow aid or granulation step. Magnesium stearate at 0.5–1.0% w/w with blending time not exceeding 5 min is typical for low-dose nucleotide blends, but over-lubrication can slow aqueous dissolution because the phosphate-containing surface becomes hydrophobic.

Aqueous dissolution, solution pH, and injectable formulation constraints are governed by diphosphate ionization

Dissolution for injectable compounding is performed in Water for Injection at 15–25 °C in a jacketed stainless-steel vessel. A 10 mg/mL solution typically exhibits pH 4.0–6.0; pH adjustment with sodium hydroxide or sodium phosphate should be made slowly to prevent local alkaline hydrolysis of the β–α phosphoanhydride bond. At 50 mg/mL, complete dissolution is often achieved within 15 min under 150–300 rpm pitch-blade agitation, although lot-specific crystallinity can extend the wetting time. Aqueous solubility of the disodium salt exceeds 100 mg/mL in purified water at room temperature; saturation is temperature-dependent and should be confirmed for concentrated liquid formulations.

The diphosphate group has multiple ionizable sites; exact pKa values are buffer- and ionic-strength-dependent, so the solution pH must be measured rather than calculated from stoichiometry alone. For parenteral manufacturing, the bulk API is not sterile and must be filtered through a 0.22 µm polyethersulfone or polyvinylidene fluoride membrane. Filter integrity testing by bubble point or diffusion flow is performed before and after filtration. If terminal moist-heat sterilization is proposed, a cycle of 121 °C for 15 min may increase assay loss through hydrolysis. Aseptic filtration is therefore preferred for heat-labile nucleotide solutions. If autoclaving is unavoidable, the formulation should be buffered at pH 6.0–7.0 and the F0 exposure minimized within regulatory requirements. Lyophilized products typically use mannitol or trehalose as bulking agents; primary drying at shelf temperature −30 to −10 °C and chamber pressure 50–150 mTorr is a common starting range, but cycle design depends on the complete formulation matrix.

The disodium salt contributes approximately 9.76% w/w sodium. A 10 mg/mL solution therefore contains about 0.98 mg/mL sodium ions. Injectable osmolality should be measured by freezing-point depression per USP <785>; sodium load and electrolyte balance should be considered in high-dose or infusion products. Divalent cations such as calcium or magnesium can form insoluble phosphate complexes; compatibility with total parenteral nutrition admixtures should be evaluated by visual precipitation testing and particulate matter assessment per USP <788>.

Protection from light is recommended; ultraviolet exposure can accelerate photochemical degradation of the adenine chromophore. Aqueous holding should be minimized, with unpreserved solutions used within a validated hold time, typically not exceeding 8 h at 2–8 °C, unless stability data support longer storage.

For tablet and capsule manufacture, ADP disodium salt is typically incorporated at low dose by pre-blending with microcrystalline cellulose, lactose monohydrate, or mannitol. Direct compression is feasible only when lot-specific flow characterization demonstrates acceptable flow; otherwise dry granulation by roller compaction or slugging is preferred. Roller compaction starting conditions include roll force 8–12 kN/cm, roll speed 2–5 rpm, and milling screen 0.8 mm. Wet granulation with aqueous binder is not preferred because water addition can accelerate diphosphate hydrolysis and produce a sticky granule bed. If wet granulation is unavoidable, the granulation moisture should be controlled at 25–35% w/w and the product temperature during fluid-bed drying should not exceed 40 °C. Tablet compression on a rotary press may require precompression 6–10 kN and main compression 10–20 kN, depending on tooling diameter and target hardness. Film coating with an HPMC-based system may be performed in a perforated pan at inlet air 60–70 °C provided that tablet-bed temperature does not exceed 40 °C.

Finished tablets and capsules can be tested using USP <711> Apparatus II at 50 rpm in 900 mL medium at 37 °C. Aqueous media with pH 4.5–6.8 are common starting points because the API has high solubility; sink conditions should be confirmed by the Noyes–Whitney criteria with at least 3 times the saturation volume. Content uniformity is typically evaluated under USP <905> with acceptance value not exceeding 15. If the tablet is coated, dissolution should be performed after the coating is shown to disintegrate or dissolve in the intended medium.

Granules may be produced by high-shear granulation or fluid-bed granulation. Aqueous binder systems are feasible for short granulation times if the drug load is low and the granule water activity is reduced quickly. Alcohol or hydroalcoholic binder systems can reduce the exposure of the phosphoanhydride bond to water but require explosion-proof equipment and residual solvent controls. The final granule loss on drying should be ≤2.0% before compression or encapsulation, and the dried granules should be equilibrated to 20–25 °C before final blending to reduce moisture migration.

Automatic capsule filling with a dosing-disc or dosator machine can handle low-dose ADP blends if the powder bed height and fill weight are controlled. The hopper should be fitted with a low-humidity purge, and relative humidity during encapsulation should be maintained below 40%. For hard gelatin capsules, moisture content above 14% in the shell can lead to brittleness or crosslinking; for HPMC capsules, the water activity specification of the blend should be compatible with the shell manufacturer’s stated range.

In bioreactor applications, ADP disodium salt is typically dissolved in the buffer rather than added as a solid to avoid local pH shift. Enzymatic ATP regeneration systems using acetate kinase or pyruvate kinase show pH optima near 7.0–7.5, and process temperature is generally 30–37 °C depending on the enzyme source. The dissolved oxygen tension, agitation, and feeding rate are determined by the biological system, not by the nucleotide salt. Because published kinetic data for this specific grade in whole-cell protein synthesis are limited, conversion yield and phosphate release should be verified in small-scale experiments before pilot or production batches.

When formulation requires ATP replacement or direct ADP-mediated activity, the disodium salt differs from other adenosine phosphates and counterion grades

ADP disodium salt contains one phosphoanhydride bond; ATP disodium salt contains two; AMP sodium salt contains none. The reduced high-energy phosphate transfer capacity of ADP relative to ATP is formulation-relevant when non-enzymatic phosphate donation must be minimized before administration. Aqueous ATP can undergo stepwise dephosphorylation to ADP and then AMP; ADP is the intermediate and therefore can present a more limited route of hydrolysis under comparable conditions. Published comparative stability data for all three nucleotides in a single formulation matrix are limited, and the relative hydrolysis rate will depend on buffer species, ionic strength, temperature, and pH.

The disodium salt differs from the free acid and from alternative counterion grades. The disodium form provides consistent stoichiometry and higher aqueous solubility than the free acid, while the sodium load must be included in parenteral electrolyte calculations. Potassium or magnesium salts may be selected for reduced sodium load or for specific ion compatibility; these forms are not identical to the disodium product and should not be substituted without redevelopment of osmolality, pH, and dissolution specifications. Compared with adenosine base, the phosphate groups increase water solubility and molecular weight, and they introduce chelation potential for divalent cations.

For oral solid dosage forms, the API may be released as non-sterile with microbial enumeration and specified pathogen testing. For injectable products, the same chemical entity is tested for bacterial endotoxins and particulate matter, and the final dosage form must be rendered sterile by filtration or terminal sterilization. The oral and injectable grade designation indicates that the base chemistry can enter both supply chains; it does not imply that the bulk container is sterile, depyrogenated, or ready for immediate parenteral filling.

Manufacturing under ICH Q7 requires batch records traceable to raw materials, equipment cleaning validation, change control, and stability testing. The API should be supplied with a certificate of analysis, safety data sheet, residual solvent and elemental impurity data, and a statement of GMP status. For regulatory submissions, a Type II drug master file or certificate of suitability may be referenced where available. Residual solvent limits follow ICH Q3C(R8); elemental impurities follow ICH Q3D and USP <232>/<233>. Microbiological release uses USP <61>/<62>. Parenteral dosage form developers should apply USP <85> endotoxin limits on a dose-based calculation and USP <788> particulate standards for finished injectable products. The material is incompatible with strong oxidizing agents, strong acids, and prolonged contact with high-moisture environments. Contact with calcium- or magnesium-containing parenteral solutions may create insoluble phosphate complexes; compatibility testing should be completed before pharmacy admixture or manufacturing scale-up.