| HS Code | 791999 |
| Product Name | CORTİPOL 250 Mg I.M./I.V. Powder and Solvent for Preparing Injection Solution |
| Brand Name | CORTİPOL |
| Active Ingredient | Hydrocortisone sodium succinate |
| Chemical Name | Hydrocortisone 21-sodium succinate |
| Strength | 250 mg |
| Dosage Form | Powder and solvent for preparing injection solution |
| Route Of Administration | Intramuscular (I.M.) and intravenous (I.V.) |
| Pharma Grade | Pharma Grade API |
| Formulation Suitability | Tablet, capsule, granule, injection, oral and injectable |
| Therapeutic Class | Glucocorticoid / Corticosteroid |
| Atc Code | H02AB09 |
| Cas Number | 125-04-2 |
| Molecular Formula | C25H33NaO8 |
| Molecular Weight | 484.52 g/mol |
| Indications | Severe allergic reactions, adrenal insufficiency, shock, inflammatory and autoimmune conditions |
| Mechanism Of Action | Binds to glucocorticoid receptors and suppresses inflammatory and immune responses |
| Contraindications | Systemic fungal infections, hypersensitivity to hydrocortisone, live virus vaccines |
| Side Effects | Hyperglycemia, hypertension, immunosuppression, adrenal suppression, osteoporosis, edema |
| Appearance | White to off-white powder |
| Solubility | Soluble in water |
| Ph | 7.0 to 8.0 after reconstitution |
| Packaging | Vial containing powder and ampoule with solvent |
| Storage Conditions | Store below 25°C and protect from light |
| Shelf Life | Typically 24 months from manufacturing date |
| Prescription Status | Prescription only |
| Manufacturer | Mustafa Nevzat İlaç (MN Pharmaceuticals) |
As an accredited CORTİPOL 250 Mg I.M./ I.V. POWDER AND SOLVENT FOR PREPARING INJECTION SOLUTION 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.
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Inside a Grade A unidirectional airflow workstation located within an ISO 14644-1 Class 5 cleanroom certified under EU GMP Annex 1, hospital pharmacy aseptic compounding of the 250 mg Cortipol powder begins with reconstitution using the supplied solvent. The vial is brought to 18–22 °C before the diluent is introduced through a 21 G sterile needle attached to a 10 mL syringe. Reconstitution to a nominal concentration of 62.5 mg/mL is followed by controlled swirling rather than mechanical shaking to reduce shear-induced foam formation and oxidative surface denaturation. The resulting solution is transferred into an infusion container of 0.9% w/v sodium chloride or 5% w/v glucose, with final infusion concentrations commonly in the 0.1–1 mg/mL range. Compatibility of the admixture with PVC and polyolefin containers is assessed under USP <797> risk-level assignments; when protected from light and stored at 2–8 °C, the beyond-use date is assigned not to exceed 24 h. Visual inspection of the prepared admixture is conducted per USP <790>; if visible particulate matter is observed, the unit is discarded and a new vial is reconstituted. Aseptic process simulation and media-fill validation are maintained under 21 CFR 211.167 and 21 CFR 211.42, with terminal certification of the compounding area documented at each shift. The terminal article is a ready-to-administer intravenous infusion labelled with patient-specific identifiers, route, diluent, concentration, and beyond-use date.
Wet granulation of the 250 mg parenteral powder as an oral granule intermediate is constrained by the susceptibility of the ester linkage to pH- and heat-catalyzed hydrolysis. In a high-shear mixer-granulator with bowl capacity 10–50 L, impeller speed 200–400 rpm, and chopper speed 1,500–3,000 rpm, a binder solution above pH 6.5 accelerates hydrolytic cleavage, while jacket temperatures above 40 °C increase free corticosteroid formation and reduce content uniformity. Granulation of the ester-form API is therefore confined to a binder solution buffered at pH 5.0–6.0, wet massing time not exceeding 5 min, and a final loss on drying of ≤ 2.0% w/w measured by USP <731>. Drying in a fluid-bed dryer uses inlet air at 50–60 °C and product temperature held at 35–40 °C; the two-stage profile with initial drying at 50 °C for 15 min followed by 60 °C for 10 min reduces residual moisture without inducing excessive granule attrition. The dried mass is passed through an oscillating sieve with aperture 0.8 mm, and fines below 105 µm are controlled to ≤ 25% w/w to avoid downstream segregation. Binder selection is validated according to ICH Q8 design-of-experiment protocols; pregelatinized starch at 5% w/w or povidone K30 at 3% w/w is used only when compatibility screening confirms no ester hydrolysis after 24 h at 40 °C/75% RH. If the target oral dosage form specifies the free-alcohol corticosteroid rather than the ester form, the sodium succinate ester must be converted before granulation, after which the hydrophobic free alcohol requires a different wetting strategy and high-shear dispersing. The terminal output is a dried granule intermediate suitable for tablet compression or unit-dose sachet filling, with batch-to-batch variance in granule D50 held within 200–400 µm.
When the 250 mg powder-derived corticosteroid is targeted to a low-dose oral tablet in the 0.5–20 mg strength range, direct compression is evaluated before wet processing because the micronized API can exhibit high surface energy and sticking on rotary press tooling. Micronization is performed in a spiral jet mill using grinding gas pressure of 6–8 bar, yielding a particle size D90 of ≤ 10 µm; this size reduction is necessary to meet USP <711> dissolution criteria in 0.1 N HCl with Apparatus II at 50 rpm. Dry granulation by roll compaction is conducted at a specific compaction force of 8–16 kN/cm and roll speed of 3–8 rpm, producing ribbons with solid fraction 0.60–0.75. The milled granulate is blended with lactose monohydrate, microcrystalline cellulose PH102, croscarmellose sodium at 2% w/w, and magnesium stearate at 0.5% w/w; final lubrication is limited to 3 min to avoid overlubrication and dissolution retardation. Compression on a 16-station rotary tablet press targets tablet hardness of 50–80 N and friability of ≤ 1.0% w/w per USP <1216>. Content uniformity is verified using USP <905>, with an acceptance value of ≤ 15 for all tested units. Because the ester salt is hygroscopic, processing relative humidity is maintained at ≤ 30% and direct compression is stopped if excipient moisture content exceeds 5.0% w/w. The terminal compressed unit is an immediate-release tablet sealed in PVC/PVDC-aluminium blister packaging with moisture-protective barrier properties validated under USP <671>.
| Format | Parameter | Target range | Standard |
|---|---|---|---|
| Reconstituted IV solution | Reconstitution temperature | 18–22 °C | USP <797> |
| Wet granulation | Final loss on drying | ≤ 2.0% w/w | USP <731> |
| Direct compression | Tablet breaking force | 50–80 N | USP <1217> |
| Capsule filling | Fill weight RSD | ≤ 2.0% | USP <905> |
| Lyophilization | Residual moisture | ≤ 1.0% w/w | USP <921> |
| I.M. injection | Sub-visible particles ≥25 µm per container | ≤ 600 | USP <788> Method 1 |
Capsule filling of a low-dose corticosteroid blend derived from the 250 mg powder presentation introduces powder-flow segregation risk before chemical degradation risk. Micronized API with D90 ≤ 10 µm and bulk density below 0.3 g/mL causes dosator weight fluctuation when capsule machine speed exceeds 30,000 capsules/h. A granulated capsule blend with bulk density adjusted to 0.55–0.65 g/mL, Carr index 15–25, and flow through a 10 mm orifice at 8–12 g/s is used to maintain die-fill consistency. Capsule filling is performed on a tamping-pin machine at speeds up to 60,000 capsules/h; fill weight relative standard deviation is held at ≤ 2.0%. The active content per capsule is typically 2–10 mg, so geometric dilution with lactose monohydrate is performed before final blending to prevent segregation and to satisfy USP <905> uniformity of dosage units. Hard gelatin capsule shells of size 3 or 4 are selected; empty capsule moisture is controlled at 12.5–16.0% w/w because lower moisture raises brittleness and higher moisture transfers to the hygroscopic ester. Dissolution release testing uses USP <711> Apparatus II at 50 rpm in 900 mL of 0.1 N HCl, with an acceptance criterion of Q = 80% in 30 min. Published data for this specific powder in hypromellose capsule shells is limited; compatibility screening is therefore required under ICH Q8 before a commercial formula is locked. The filled capsule is a low-dose oral unit intended for immediate release and packaged in HDPE bottles with desiccant or cold-form aluminium blisters.
Scale-up of the lyophilization cycle for the 250 mg injection presentation from a clinical 2 mL vial to a commercial 10 mL vial alters the vial heat transfer coefficient and the resistance of the dried cake to vapour flow. The design space for primary drying must be re-established because a fixed shelf-temperature programme can produce collapse in the larger vial if product temperature exceeds the collapse temperature of the maximally freeze-concentrated solute, typically reported for similar succinate ester formulations in the range −35 °C to −30 °C. Freezing is performed at a shelf ramp rate of 0.5 °C/min to −45 °C, followed by an annealing step at −10 °C to −15 °C for 2–4 h to promote larger ice crystal growth and reduce primary drying time. Primary drying is run at shelf temperature −20 °C to −25 °C and chamber pressure 10–20 Pa, with product temperature monitored by thermocouple and comparative pressure measurement using Pirani and capacitance manometer gauges. Secondary drying at 25–30 °C for 4–6 h reduces residual moisture to ≤ 1.0% w/w by Karl Fischer titration under USP <921>. Vial stoppering is performed under partial vacuum in the lyophilizer, and container closure integrity is verified by USP <1207> methods after capping. The terminal sealed unit is a lyophilized powder vial ready for reconstitution, with a cake appearance specification demanding uniform colour, absence of collapse, and full dissolution within 2 min after solvent addition at 18–22 °C.
For I.M. administration, the reconstituted solution is drawn into a 2 mL or 3 mL syringe fitted with a 21 G or 23 G needle; syringeability depends on the post-reconstitution viscosity, which remains in the 2–5 mPa·s range at 25 °C. Injectable viscosity below 5 mPa·s is necessary to keep injection force below 20 N when measured by texture analyzer at an extension rate of 100 mm/min through a 21 G needle. Sub-visible particulate matter is evaluated according to USP <788> Method 1; the acceptance limit for small-volume parenterals is ≤ 6,000 particles ≥10 µm and ≤ 600 particles ≥25 µm per container. The diluent and reconstituted solution are inspected for visible particulates per USP <790> before withdrawal, and syringes with silicone oil lubricant are assessed for droplet aggregation because the ester salt can interact with silicone oil at the interface. The prepared syringe is labelled for deep gluteal intramuscular injection and assigned a beyond-use date consistent with USP <797> compounding risk category. The discharged unit is a patient-specific I.M. syringe in which the plunger force, needle gauge, and solution volume have been recorded on the batch compounding log.
| Requirement | Standard/clause | Application |
|---|---|---|
| Sterile drug manufacturing | 21 CFR 211.167, EU GMP Annex 1 | Hospital and commercial injectables |
| Aseptic compounding | USP <797> | IV and I.M. preparation |
| Particulate matter in injections | USP <788> | Reconstituted solution |
| Dissolution of oral solid dosage | USP <711> | Tablet and capsule |
| Uniformity of dosage units | USP <905> | Tablet, capsule, granule |
| Loss on drying | USP <731> | Granule intermediate |
| Elemental impurities | ICH Q3D | All oral and parenteral formats |
As soon as the formulation is transferred from the parenteral powder-solvent kit to a unit-dose oral granule sachet, the primary technical constraint moves from sterile barrier maintenance to moisture exclusion and dose uniformity across a free-flowing powder bed. The granule intermediate is filled at ambient temperature 15–25 °C and relative humidity ≤ 35%, with sachet filling machine weight control set to reject any unit outside ± 3% of target mass. Granule size distribution is controlled at D50 200–400 µm with fines below 105 µm not exceeding 15% w/w; this band prevents settling during transit and ensures complete pouring of a single dose. Sachet laminate barrier is selected with water vapour transmission rate below 0.5 g/m²/24 h at 38 °C/90% RH according to USP <671>, and the sealed sachet is leak-tested by vacuum decay or dye penetration. Dissolution of the oral granule is evaluated by USP <711> using 0.1 N HCl as medium, with the dispersed granule required to pass a 0.5 mm sieve opening after 30 min of stirred contact. Stability of the ester in the sachet is monitored at 40 °C/75% RH for 6 months with related substances quantified by USP <621> chromatographic purity methods. The filled sachet is a single-dose oral granule presentation in which each pouch contains the declared labelled content and an individual desiccant pouch is inserted when the outer carton is not considered an adequate moisture barrier.
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CORTİPOL 250 mg I.M./I.V. powder and solvent for preparing injection solution is presented as a sterile pharmaceutical-grade active pharmaceutical ingredient presentation comprising a lyophilized or sterile crystalline powder component and a separate solvent phase intended for reconstitution immediately before intramuscular or intravenous administration. The product identifier encodes a nominal active moiety content of 250 mg per container, distinguishing the presentation from other strengths and from oral solid-dose feedstock. The designation “Pharma Grade API for Tablet / Capsule / Granule / Injection, Oral & Injectable” indicates that the active moiety is available in a controlled form for multiple downstream routes; it does not imply that a single physical batch is simultaneously optimized for every route. Injectable-grade material is manufactured under aseptic or terminal sterilization conditions, tested for bacterial endotoxin and subvisible particulate matter, and packaged in a container-closure system that maintains sterility through reconstitution. Oral-grade material is instead controlled for bioburden, particle size distribution for solid-dose processing, and granulation or direct compression behavior.
The product model includes the dosage form phrase “powder and solvent for preparing injection solution” to distinguish a dry powder reconstitution kit from a ready-to-use injectable solution and from a lyophilized plug intended for single-vial reconstitution. In the kit configuration, the solvent is a secondary container with separate identity testing, extractable profile, and closure compatibility. The dry powder presentation reduces hydrolysis, oxidation, and polymorphic transformation during storage relative to an aqueous ready-to-inject formulation, but it transfers reconstitution risk to the compounding site. The prepared solution must meet USP <1> Injections general chapter requirements for clarity, dose uniformity, and leachables. It is not used if visible precipitate, phase separation, or color change occurs.
Reconstitution uses the solvent provided in the kit. The solvent is typically water for injection with or without a buffering agent; the total volume is selected to yield the intended concentration for I.M. or I.V. administration. The transfer should occur in a Grade A / ISO Class 5 environment as defined in EU GMP Annex 1 and ISO 14644-1. The reconstituted solution is inspected immediately for visible particles; acceptance is zero visible particles per container under the conditions of Ph. Eur. 2.9.20. Subvisible particle testing is conducted by light obscuration or membrane microscopy under USP <788> and Ph. Eur. 2.9.19. The small-volume parenteral limit is no more than 6000 particles per container at ≥10 µm and no more than 600 particles per container at ≥25 µm. These limits apply after reconstitution and, if applicable, after dilution with isotonic infusion fluid.
Sterility is confirmed by membrane filtration or direct inoculation according to USP <71> and Ph. Eur. 2.6.1 with an incubation period of 14 days. Bacterial endotoxin testing follows USP <85>/Ph. Eur. 2.6.14 using a limulus amoebocyte lysate assay; the limit is calculated using the formula K/M, where K is 5 EU/kg for parenteral routes and M is the maximum bolus dose per kg. A product intended for both I.M. and I.V. use must satisfy the more conservative I.V. limit when the same solution can be administered by that route. These release criteria separate the injectable presentation from oral-grade API, which is controlled by bioburden and specified indicator organism counts under USP <61>/<62>, not by sterility and endotoxin.
The solvent for injection meets water for injection specifications under USP <1231> and Ph. Eur. 0169: conductivity ≤1.3 µS/cm at 25 °C, total organic carbon ≤0.5 mg/L, and bacterial endotoxin ≤0.25 EU/mL. The solvent container is tested for particulate and endotoxin after withdrawal. Container closure integrity is verified by dye ingress or vacuum decay per USP <1207> and ASTM F2338-09, with defect-positive controls at a leak size of approximately 5 µm when the container is exposed to pressure differentials. For a powder-solvent kit, integrity is verified after sealing and again after simulated reconstitution, because puncture of the stopper creates a temporary breach that must not compromise sterility.
In routine production, a major operational boundary is moisture. Lyophilized injectable powders are hygroscopic and can absorb atmospheric water during transfer if the relative humidity exceeds 60% RH. Uncontrolled moisture uptake alters reconstitution time, accelerates hydrolytic degradation, and increases the risk of insoluble particulate formation. Handling areas for powder subdivision and filling are typically maintained at 35%–45% RH at 18 °C–22 °C, with pre-drying of vials and closures. Karl Fischer water content is monitored under USP <921>/Ph. Eur. 2.5.12; lyophilized parenteral powders of this class commonly carry a release limit of ≤1.0% w/w, but the exact value is product-specific and established through stability data rather than a fixed compendial requirement.
| Attribute | Injectable powder-solvent criterion | Oral solid-dose criterion | Reference method |
|---|---|---|---|
| Sterility | No growth after 14-day incubation | Not required; bioburden ≤1000 CFU/g | USP <71>, Ph. Eur. 2.6.1 / USP <61> |
| Bacterial endotoxin | Dose-dependent; IV/IM limit based on K/M with K = 5 EU/kg | Not assigned | USP <85>, Ph. Eur. 2.6.14 |
| Subvisible particulate | ≤6000/container ≥10 µm; ≤600/container ≥25 µm | Not assigned | USP <788>, Ph. Eur. 2.9.19 |
| Visible particulate | No visible particles per container | Not assigned | Ph. Eur. 2.9.20 |
| Water content | Product-specific Karl Fischer limit; lyophilized parenterals commonly control ≤1.0% w/w | Product-specific; oral granulates often control ≤3.0% w/w | USP <921>, Ph. Eur. 2.5.12 |
| Residual solvents | ICH Q3C Class 1 and Class 2 limits; no added capacity beyond labeling | Same ICH Q3C limits but oral daily intake calculation may permit higher concentration | USP <467>, Ph. Eur. 2.4.24 |
Analytical identity is confirmed by infrared absorption spectrophotometry according to USP <197>/Ph. Eur. 2.2.24, and chromatographic purity by high-performance liquid chromatography using a C18 column with UV detection at the wavelength in the product specification. Related substances are controlled to ICH Q3A thresholds for a maximum daily dose ≤2 g: reporting 0.05%, identification 0.10%, and qualification 0.15%. For higher daily doses, the thresholds are adjusted as specified in the guideline. This purity profile is not route-specific but is interpreted against the highest intended route; parenteral products often apply the stricter qualification threshold because impurities enter the systemic circulation without first-pass metabolism.
After solvent transfer, the solution is expected to be clear and free of undissolved residue when the active moiety is soluble. pH is adjusted to a range compatible with intravenous infusion, generally 5.0–8.0, and osmolality is controlled between 270 and 330 mOsm/kg for peripheral administration. Solutions with osmolality outside this range may require central venous access. Filtration through a sterile 0.22 µm polyethersulfone or polyvinylidene fluoride membrane is used when terminal sterilization of the reconstituted solution is not validated. The filter is selected after evaluating membrane binding, extractables, and flow decay; low surface-area filters can exhibit throughput decline above 100 mL/min at 20 °C when the solution viscosity exceeds 1.2 cP, but actual performance is concentration-dependent.
Reconstitution temperature is a critical process variable. Below 20 °C, wetting of the cake can require extended agitation; above 30 °C, degradation kinetics may accelerate for thermolabile active moieties. For this reason, the solvent is often equilibrated to 20 °C–25 °C before transfer. Gentle swirling is preferred over vigorous shaking to minimize foam and the generation of subvisible particles. If a vacuum transfer needle system is used, the pressure differential across the stopper is minimized during withdrawal to avoid cavitation and particle formation.
Compatibility of the reconstituted solution with 0.9% sodium chloride injection and 5% dextrose injection is assessed by mixing, pH, and particulate testing over 24 h at ambient temperature. pH shifts beyond 0.5 units and precipitation at the interface are early indicators of incompatibility. The solution should not be mixed with strongly alkaline solutions above pH 8.5 or with amine-containing buffers if the active moiety is susceptible to base-catalyzed degradation.
The injectable powder-solvent presentation differs from oral-grade material in particle size distribution, polymorphic purity, residual solvent profile, and microbial specification. Oral solid-dose processing can tolerate a broader particle size distribution and may require flowable, compressible crystals with a D90 in the range of 50 µm to 250 µm to ensure adequate content uniformity and direct compression. Injectable solution preparation, by contrast, requires complete dissolution; therefore, particle size is relevant only insofar as it affects reconstitution rate and polymorph-dependent solubility. A poorly soluble polymorphic fraction that is acceptable in a tablet formulation may fail the clear-solution inspection or produce subvisible particles in an injectable.
Residual solvents present another route-dependent distinction. Injectable formulations are constrained by ICH Q3C limits, but the route of exposure changes the permitted daily intake calculation. A solvent such as dichloromethane may be present at 600 ppm in an oral-grade input without exceeding the ICH Class 2 permitted daily exposure for an oral product of low daily mass, but the same level may be unacceptable for an injectable product because the same PDE is applied to a smaller administration volume and because the route lacks first-pass metabolic clearance.
Elemental impurities are controlled under USP <232>/<233> and ICH Q3D using option 2A for permitted daily exposure. For parenteral products, the daily exposure limit for cadmium is 2 µg/day, lead 5 µg/day, arsenic 15 µg/day, and mercury 4 µg/day, when not otherwise excipient-limited. The manufacturing flow uses a risk assessment across all raw materials, water, and container systems; if oral and injectable routes are produced in shared facilities, a matrix calculation is required because oral PDE values differ from parenteral for some elements.
The API is also designated for tablet, capsule, and granule processing. When the same active moiety is used for oral solid-dose manufacturing, the material is not necessarily identical to the injectable powder. On a high-shear granulator with a 250 L vessel and impeller tip speed of 5 m/s to 10 m/s, the injectable-grade powder may exhibit poor flow and require dry sieving after cold storage; oral-grade material is usually conditioned to 20 °C–25 °C for 24 h before use. Capsule filling on a dosator machine may require powder bed depth and pin settings to be adjusted when the bulk density shifts from 0.35 g/mL to 0.65 g/mL. These adjustments are standard operational measures, not product failures.
Wet granulation of the oral-grade API is performed in a top-spray fluid-bed granulator at inlet air temperature of 50 °C–70 °C and product temperature of 30 °C–40 °C, using a binder solution with viscosity 10–100 mPa·s. The injectable-grade material is not optimized for this unit operation because its particle morphology and residual moisture are controlled for reconstitution rather than granule formation. Therefore, a direct substitution of injectable-grade API into an oral granulation process without re-validation may alter granule size distribution and compressibility. Published data for this specific CORTİPOL configuration in oral granulation is limited; the general equipment ranges are provided from standard granulation practice.
For downstream compression on a rotary tablet press, precompression force and main compression force are adjusted to tablet crushing strength of 50 N to 120 N and friability ≤1.0% under USP <701>/Ph. Eur. 2.9.7. Capsule disintegration is controlled under USP <2040>/Ph. Eur. 2.9.1 using 0.1 N hydrochloric acid at 37 °C. These oral dosage form tests do not apply to the injectable solution but are relevant when the multi-route API is used in solid oral formulations.
