Ozagrel Sodium Pharma Grade API is the sodium salt of (E)-3-[4-(1H-imidazol-1-ylmethyl)phenyl]propenoic acid, CAS 130952-60-4, molecular formula C13H11N2NaO2, molecular weight 250.23 g/mol. The material is supplied as a white to off-white crystalline powder manufactured under ICH Q7 GMP and released against pharmacopoeial identification, related substance, residual solvent, water content, residue on ignition, and heavy metal controls. The active moiety functions as a selective thromboxane A2 synthase inhibitor; this mechanism reduces thromboxane A2-mediated platelet aggregation and vasoconstriction without directly blocking cyclooxygenase-derived prostacyclin formation. For ordering and release control, the product is distinguished as oral-grade and injectable-grade material. The two grades use the same crystalline form and synthesis route; injectable grade adds routine bacterial endotoxin testing, a tighter heavy metal acceptance criterion, and stricter microbial enumeration. The pharmaceutical-grade designation is therefore a release-control model rather than a separate chemical entity. The product is suitable for development of tablets, capsules, granules, oral solutions, and sterile injectable presentations when the corresponding route-specific specification is selected.

In the solid state, the (E)-configuration of the propenoic acid side chain is controlled as the active geometric isomer. Typical release testing employs gradient HPLC with UV detection and a C18 stationary phase; the (Z)-isomer and other related substances are reported as area percentages relative to the principal peak. The sodium salt form is selected for parenteral and oral products because it provides a solution pH in the range 6.0–8.0 at 1% concentration when tested according to Ph. Eur. 2.2.3; this avoids the acidic pH excursion encountered with some hydrochloride salts and permits direct compounding with neutral buffers. The API should not be equated with technical-grade ozagrel sodium; technical material may lack validated residual solvent, endotoxin, and particulate controls, and is not released with a pharmacopoeial certificate of analysis.

What release specification and impurity controls define injectable-grade ozagrel sodium?

Injectable-grade material differs from oral material primarily in the routine application of bacterial endotoxin testing and stricter microbial enumeration. The matrix below lists representative pharmacopoeia-aligned acceptance limits for oral and injectable release. Compendial monographs, regional registration files, or customer quality agreements may impose tighter values; the table is therefore a release-control framework rather than a universal regulatory standard.

Residual solvent monitoring follows ICH Q3C Option 2 because the synthesis does not use Class 1 solvents; ethanol or isopropanol, when present as Class 3 solvents, are controlled below 0.5%. Elemental impurities are controlled under ICH Q3D Option 1. If a transition-metal catalyst is used, the process includes extraction and carbon treatment, and the residual palladium limit is set below 10 ppm for oral grade and below 5 ppm for injectable grade, with routine ICP-MS verification. A nitrosamine risk assessment is maintained; no nitrosating agent is used in the current synthesis, and the specification includes a limit for N-nitrosodimethylamine below 0.03 ppm by LC-MS/MS where the regional filing requires it.

For sterile injectable manufacturing, the API is dissolved in Water for Injection and filtered through a 0.22 µm sterilizing-grade membrane. Sub-visible particulate matter is controlled on the reconstituted solution per Ph. Eur. 2.9.19 or USP <789>. Solution pH is maintained at 6.0–8.0; below 4.0, acid-catalysed double-bond migration or imidazole protonation can generate related substances, while above 9.0 the salt may lose sodium at the solution surface. These boundaries derive from forced degradation studies under acidic and alkaline stress conducted as part of an ICH Q1A(R2) program; published data for this specific formulation configuration are limited where formulation-specific degradation thresholds are concerned. The API is not supplied as sterile powder; injectable-grade ozagrel sodium is a low-burden API intended for terminal sterilizing filtration during compounding. If an aseptic API is required, the customer must request sterile API manufactured under aseptic conditions; this is outside the default release model.

Process-related impurities include the (Z)-isomer, the free acid, and imidazole-related starting material. All are controlled by area normalization in the related substances test. The (Z)-isomer is of particular concern because it lacks the pharmacologically active trans geometry; its limit is included in the unspecified impurity threshold of ≤0.10%. The free acid can form during improper salt formation or exposure to acidic solution; it is not considered a safety risk but is monitored to assure salt stoichiometry and dissolution performance.

Manufacturing is performed in a facility with dedicated charging booths and mobile isolators for final milling. Campaign cleaning is validated to a carryover limit of 10 ppm by swab and rinse sampling, with recovery factors established per ICH Q7 and PIC/S recommendations. Equipment trains include vacuum dryers with jacket temperature control at 50–60°C and nitrogen-purged sifters; the API is milled under nitrogen when low water content must be maintained. Batch-to-batch variance observed at production scale is principally linked to recrystallization cooling rate and drying endpoint; slow cooling tends to produce a coarser crystal habit and faster filtration, while rapid cooling can increase fines and surface moisture. These differences are controlled by in-process particle size and water analysis before final packaging.

In tablet and capsule manufacture, the sodium salt is usually dry-mixed or wet-granulated. For direct compression, particle size is controlled to D90 below 150 µm, and sieve analysis or laser diffraction is performed according to Ph. Eur. 2.9.38. If high-shear granulation is selected, the API is dry-mixed in a 600 L top-driven granulator at low impeller speed before aqueous binder addition; the wet mass is dried in a fluid-bed dryer with inlet air temperature not exceeding 60°C to maintain water content at or below 0.5%. At relative humidity above 60%, the sodium salt can adsorb surface moisture; pre-drying at 50–60°C for 2–4 hours and immediate resealing of intermediate bulk containers are required. Blend uniformity is verified by Ph. Eur. 2.9.5, and the final granulate is sized through a 1.0 mm screen before compression.

For capsule filling, the powder is transferred under controlled humidity to a dosator or tamping-pin machine. Bulk density measured by Ph. Eur. 2.2.42 and tapped density by Ph. Eur. 2.2.43 are recorded because they affect die filling and tamping-pin compression ratios. Granule presentations, including sachet formulations, use the same wet granulation or dry granulation route; after drying and sizing, the granulate is filled by volume after confirming loss on drying is below 0.5%. Loss on drying is determined according to Ph. Eur. 2.2.32. If the granulate is compressed on a rotary tablet press, compression force is set between 8 kN and 15 kN for a 10 mm round tooling, with pre-compression force between 2 kN and 4 kN. These parameters are tooling-dependent and require formulation trial confirmation; published production data for this specific API at larger commercial scale are limited.

When the sodium salt is compared with aspirin, clopidogrel, or the hydrochloride salt

The primary pharmacological difference is that aspirin irreversibly acetylates platelet cyclooxygenase-1, suppressing both thromboxane A2 and endothelial prostacyclin, whereas ozagrel sodium selectively blocks thromboxane A2 synthase. This targeted inhibition leaves prostacyclin-mediated vasodilation more intact in the mechanistic model. Clopidogrel acts at the platelet P2Y12 ADP receptor and requires hepatic biotransformation to an active metabolite; ozagrel sodium does not depend on CYP2C19 activation and therefore does not share that genetic polymorphism liability. Ozagrel sodium is not an anticoagulant and cannot substitute for heparin or direct factor Xa inhibitors in extracorporeal circuits.

Between the sodium and hydrochloride salts, the selection is driven by the formulation pH target and the route of administration. The hydrochloride salt may release chloride and lower solution pH; this can create compatibility constraints with enteric coatings or pH-sensitive lyophilized matrices. The sodium salt provides a neutral-to-weakly alkaline pH range and is preferred when a sterile solution must be compounded without aggressive pH adjustment. Both salts contain the same (E)-configured active moiety and are subject to identical related substance concerns.

Among thromboxane A2 synthase inhibitors, ozagrel sodium is distinguished from early imidazole derivatives such as dazoxiben by its (E)-propenoic acid side chain and its formulation-ready sodium salt. Dazoxiben has historically been investigated as an oral inhibitor, but its development was limited by short duration of action and formulation challenges; ozagrel sodium’s pharmacopoeial monograph provides a compendial release basis that many early inhibitors lack. The product is not an interchangeable substitute for ticagrelor or prasugrel, which target the platelet ADP pathway via different receptors and exhibit distinct pharmacodynamic profiles.

Particle size, crystallinity, and moisture protection in solid-dose and lyophilized forms

Crystallinity is monitored by X-ray powder diffraction, and release material is expected to show characteristic reflections of the sodium salt without a broad amorphous halo. If rapid dissolution is required for a chewable or orally disintegrating tablet, a nitrogen-fed jet mill operating at 7–10 bar can reduce D90 to 10–20 µm; the milled lot exhibits higher electrostatic charge and moisture uptake, and should be tested for blend flowability and water content before compression. Micronization is not a default operation for injectable grade because the API is fully dissolved before sterile filtration; particle size control is more relevant to blend uniformity in solid-dose processing.

For lyophilized injectable presentations, ozagrel sodium is dissolved with bulking agents such as mannitol or sucrose, filtered, filled, and freeze-dried. The cycle must stay below the formulation-specific collapse temperature; published data for this specific formulation configuration is limited, so pilot freeze-drying microscopy is recommended before scale-up. Terminal sterilization by autoclaving at 121°C for 15 min should not be assumed acceptable without moisture and degradation data; aseptic processing with sterilizing-grade filtration is the conservative route unless the drug product has submitted terminal sterilization validation data.

Operational boundaries are explicit: do not expose the sodium salt to unbuffered acidic media below pH 4.0 for more than brief dissolution intervals; avoid anhydrous acidic excipients such as citric acid at high concentration unless a compatibility study demonstrates no related substance increase; do not mix with strong oxidizers such as peroxides or hypochlorites in cleaning operations. The API should not be milled in a hammer mill at temperatures above 60°C because localized heating may generate the (Z)-isomer and increase total impurities. These incompatibilities are based on forced degradation and cleaning compatibility data rather than long-term stability studies.

Primary packaging for oral and injectable API is double low-density polyethylene bags heat-sealed under nitrogen, enclosed in an aluminium foil laminate bag with desiccant. Shipping cartons carry CAS 130952-60-4, net weight, retest date assigned from 24-month stability data at 25°C/60% RH, and a GMP statement referencing ICH Q7. Receiving sites should sample under relative humidity below 40%; opened bulk containers should be resealed under nitrogen within 30 min and returned to controlled storage. Campaign cleaning in the API facility is validated to a carryover limit of 10 ppm by swab and rinse sampling to prevent cross-contamination with other antiplatelet or imidazole-containing products.