Drug master file for Sildenafil citrate
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DRUG MASTER FILE (DMF)
Sildenafil Citrate
DMF Type: Type II (Active Pharmaceutical Ingredient)
Prepared in accordance with: ICH Q8, Q9, Q10, Q11; FDA 21 CFR 314.420; EU CTD Module 3
SECTION 1 — ADMINISTRATIVE INFORMATION
| Field | Details |
|---|---|
| Drug Substance Name | Sildenafil Citrate |
| INN (Nonproprietary Name) | Sildenafil |
| Brand Names | Viagra® (ED); Revatio® (PAH) |
| DMF Type | Type II — Drug Substance (API) |
| Regulatory Authority | U.S. FDA / EMA / CDSCO (as applicable) |
| Pharmacopeial Status | USP, BP, EP monograph available |
| CAS Number | 171599-83-0 (Sildenafil Citrate) |
| ATC Code | G04BE03 |
SECTION 2 — DRUG SUBSTANCE INFORMATION
2.1 Nomenclature
| Type | Name |
|---|---|
| IUPAC Name | 5-[2-Ethoxy-5-(4-methylpiperazin-1-ylsulfonyl)phenyl]-1-methyl-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-7(4H)-one, 2-hydroxypropane-1,2,3-tricarboxylate |
| Molecular Formula (free base) | C₂₂H₃₀N₆O₄S |
| Molecular Formula (citrate salt) | C₂₂H₃₀N₆O₄S · C₆H₈O₇ |
| Molecular Weight (free base) | 474.58 g/mol |
| Molecular Weight (citrate salt) | 666.70 g/mol |
2.2 Structural Formula
Sildenafil is a pyrazolo[4,3-d]pyrimidinone derivative. Its core structure mimics the purine ring of cGMP, which is the basis for its selective competitive inhibition of PDE5.
Pyrazolopyrimidinone core
- N1-methyl substituent
- C3-propyl substituent
- C5-aryl group bearing:
• 2-ethoxy group
• 5-(4-methylpiperazin-1-ylsulfonyl) group
Citrate counter-ion for salt form
2.3 Physicochemical Properties
| Property | Value / Description |
|---|---|
| Physical Appearance | White to off-white crystalline powder |
| Odour | Odourless |
| Taste | Slightly bitter |
| Solubility | Slightly soluble in water; freely soluble in DMSO; slightly soluble in methanol |
| pKa | ~6.5 (basic amine) |
| Log P (octanol/water) | ~1.9 (free base) |
| Melting Point | ~187–189°C (citrate salt) |
| Hygroscopicity | Non-hygroscopic under standard conditions |
| pH (1% aqueous solution) | ~3.5–4.0 (acidic due to citrate) |
| UV Absorption | λmax ~293 nm (in methanol) |
| BCS Classification | Class II (low solubility, high permeability) |
| Polymorphism | Multiple polymorphic forms reported; Form I most stable |
| Stereochemistry | Achiral (no stereocentre) |
SECTION 3 — SYNTHESIS AND MANUFACTURING
3.1 Synthetic Route (Overview)
Sildenafil citrate is synthesised via a multi-step organic synthesis. The key chemical steps are:
Step 1 — Preparation of 5-amino-1-methyl-3-propylpyrazole-4-carboxamide intermediate
- Condensation of propionaldehyde with ethyl cyanoacetate
- Cyclisation with methylhydrazine
Step 2 — Sulfonylation
- Reaction of 2-ethoxybenzenesulfonyl chloride with 4-methylpiperazine to introduce the piperazinylsulfonyl moiety at position 5 of the phenyl ring
Step 3 — Coupling and Cyclisation
- Coupling of the pyrazole intermediate with the sulfonylated aryl compound
- Intramolecular cyclisation under acidic/basic conditions to form the pyrazolopyrimidinone bicyclic core
Step 4 — Salt Formation
- Dissolution of the free base in suitable solvent
- Addition of citric acid (1:1 molar ratio)
- Precipitation and recrystallisation of Sildenafil Citrate
- Filtration, washing, and drying under vacuum
Key Starting Materials:
- 4-Methylpiperazine
- 2-Ethoxybenzenesulfonyl chloride
- Propionaldehyde
- Methyl hydrazine
- Citric acid (anhydrous)
3.2 Process Controls
| Stage | Critical Process Parameter | Acceptance Criterion |
|---|---|---|
| Cyclisation | Reaction temperature | Controlled within ±5°C of target |
| Sulfonylation | Residual solvent (DMF, THF) | Per ICH Q3C limits |
| Salt formation | Molar ratio (free base : citric acid) | 1.00 ± 0.02 |
| Drying | Residual moisture | NMT 0.5% w/w (KF) |
| Final API | Polymorphic form | Confirmed by XRPD |
3.3 Reagents, Solvents, and Catalysts
All reagents, solvents, and catalysts are of pharmaceutical or analytical grade. Residual solvents are controlled per ICH Q3C. Heavy metal catalysts (if any) are controlled per ICH Q3D guidelines.
SECTION 4 — IMPURITY PROFILE
4.1 Process-Related Impurities
| Impurity | Type | Control |
|---|---|---|
| Des-methyl sildenafil | Synthetic by-product | Specification NMT 0.1% |
| N-oxide sildenafil | Oxidative degradant | Specification NMT 0.1% |
| Desmethylpiperazine analogue | Related substance | Specification NMT 0.15% |
| Unreacted starting materials | Process impurity | Specification NMT 0.05% each |
4.2 Degradation Products (Stress Testing — ICH Q1A)
| Stress Condition | Major Degradant | Observation |
|---|---|---|
| Acid hydrolysis (1M HCl, 60°C) | Hydrolytic cleavage products | Moderate degradation |
| Alkali hydrolysis (1M NaOH, 60°C) | Desulfonyl product | Minor degradation |
| Oxidative (3% H₂O₂, RT) | N-oxide impurity | Significant |
| Photolysis (ICH Q1B) | Minimal change | Stable to light |
| Thermal (60°C, open dish) | Minimal change | Thermally stable |
| Humidity (75% RH, 40°C) | Minimal change | Not hygroscopic |
4.3 Mutagenic Impurities (ICH M7)
All potential mutagenic impurities are identified, risk-assessed, and controlled to Threshold of Toxicological Concern (TTC) levels (≤1.5 µg/day for lifetime exposure).
SECTION 5 — QUALITY SPECIFICATIONS
5.1 API Specification (In-House / Aligned with USP/EP)
| Test | Method | Specification |
|---|---|---|
| Description | Visual | White to off-white crystalline powder |
| Identity (IR) | FT-IR vs. reference standard | Conforms |
| Identity (HPLC Retention Time) | RP-HPLC | Conforms |
| Assay (Sildenafil Citrate) | RP-HPLC | 98.0%–102.0% (dried basis) |
| Related Substances (Total) | RP-HPLC | NMT 0.5% |
| Any individual unknown impurity | RP-HPLC | NMT 0.10% |
| Residual Solvents | GC-Headspace | Per ICH Q3C |
| Heavy Metals | ICP-MS | Per ICH Q3D |
| Water Content | Karl Fischer Titration | NMT 0.5% |
| Residue on Ignition (Sulphated Ash) | Ph. Eur./USP | NMT 0.1% |
| Polymorphic Form | XRPD | Form I confirmed |
| Particle Size Distribution | Laser diffraction | D90 ≤ 150 µm |
| Microbial Limits | USP <61> / <62> | TAMC ≤ 1000 cfu/g; TYMC ≤ 100 cfu/g; No E. coli |
5.2 Analytical Methods
| Method | Technique | Purpose |
|---|---|---|
| Assay & Related Substances | RP-HPLC, C18 column, UV 293 nm | Quantification |
| Identification | FT-IR, UV-Vis, HPLC | Confirmation of identity |
| Residual Solvents | GC-FID / Headspace | Solvent control |
| Water Content | Karl Fischer coulometric | Moisture control |
| Particle Size | Laser diffraction (Malvern Mastersizer) | Physical characterisation |
| Crystal Form | XRPD | Polymorphism |
| Elemental Impurities | ICP-MS | ICH Q3D compliance |
SECTION 6 — STABILITY DATA
6.1 Stability Protocol (ICH Q1A)
| Condition | Temperature / Humidity | Duration |
|---|---|---|
| Long-term | 25°C / 60% RH | 24 months (ongoing) |
| Intermediate | 30°C / 65% RH | 12 months |
| Accelerated | 40°C / 75% RH | 6 months |
6.2 Stability Results Summary
Sildenafil Citrate demonstrates satisfactory stability under all conditions tested:
- Assay: Remains within 98.0–102.0% throughout long-term storage
- Related substances: No significant increase
- Physical form: No polymorphic conversion observed
- Appearance, colour, and odour: No change
Proposed Re-test Period: 36 months from date of manufacture when stored as specified.
6.3 Storage Conditions
- Store in tightly closed containers
- Protect from light and moisture
- Store at controlled room temperature: 15°C–30°C
- Keep away from direct sunlight and humidity
SECTION 7 — PACKAGING AND CONTAINER-CLOSURE SYSTEM
| Parameter | Details |
|---|---|
| Primary Packaging | Double polyethylene bags (inner: LDPE, outer: HDPE) |
| Secondary Packaging | Fibre drum with tight-fitting lid |
| Container Size | 1 kg, 5 kg, 10 kg, 25 kg |
| Desiccant | Silica gel sachets included |
| Labelling | Batch no., manufacturing date, re-test date, storage conditions, net weight, hazard symbols |
| Container-Closure Integrity | Tested per USP <1207> |
SECTION 8 — PHARMACOLOGY
8.1 Mechanism of Action
Sildenafil is a potent and selective competitive inhibitor of phosphodiesterase type 5 (PDE5), the enzyme responsible for degradation of cyclic guanosine monophosphate (cGMP) in smooth muscle cells.
Pathway:
- Sexual stimulation → nitric oxide (NO) release from penile nerve terminals and vascular endothelium
- NO activates guanylyl cyclase → cGMP formation from GTP
- cGMP → smooth muscle relaxation of corpus cavernosum → vasodilation → penile erection
- PDE5 normally degrades cGMP; sildenafil inhibits this degradation
- Result: sustained cGMP levels → prolonged and enhanced smooth muscle relaxation
Sildenafil structurally mimics the purine ring of cGMP, providing >1000-fold selectivity for PDE5 over other PDE isoforms, though there is some cross-reactivity with PDE6 (retinal) at higher concentrations, explaining visual side effects.
— Goodman & Gilman's The Pharmacological Basis of Therapeutics
In pulmonary arterial hypertension (PAH): PDE5 is abundant in pulmonary arterial smooth muscle cells (PASMCs). Sildenafil inhibits PDE5 → elevated cGMP → pulmonary vasodilation and reduced pulmonary vascular resistance.
8.2 Pharmacodynamics
- Vasodilation: Selective effect on smooth muscle via the NO–cGMP–PKG pathway
- Cardiac effects: Mild reductions in systemic blood pressure (~5–10 mmHg); no direct chronotropic or inotropic effect at therapeutic doses
- Platelet aggregation: Some inhibitory effect on platelet aggregation (via PDE5 in platelets)
- Antifibrotic activity: Has demonstrated antifibrotic activity tested in lung disease models
8.3 Therapeutic Indications
| Indication | Dose | Regimen |
|---|---|---|
| Erectile Dysfunction (ED) | 25 mg, 50 mg, 100 mg | As needed, ~1 hour before sexual activity; max once daily |
| Pulmonary Arterial Hypertension (PAH) | 20 mg (Revatio®) | Three times daily |
| Off-label: Female sexual dysfunction | As per male dosing | Limited evidence |
| Off-label: SSRI-induced anorgasmia | 50 mg | As needed |
SECTION 9 — PHARMACOKINETICS (ADME)
| Parameter | Details |
|---|---|
| Absorption | Rapidly absorbed after oral administration |
| Tmax | ~1 hour (fasted); delayed by high-fat meal |
| Bioavailability | ~41% (mean absolute oral bioavailability) |
| Distribution | Vd ≈ 105 L; highly protein bound: 96% (to plasma proteins) |
| Metabolism | Hepatic, primarily via CYP3A4 (major) and CYP2C9 (minor) |
| Active Metabolite | N-desmethyl sildenafil (pharmacologically active; ~50% potency of parent) |
| Terminal Half-life (t½) | ~4 hours (both parent and N-desmethyl metabolite) |
| Excretion | Predominantly faecal: 73–88% (as metabolites); urinary: ~13%; unmetabolised drug not detected in urine or faeces |
| Elderly (>65 years) | Reduced clearance → increased AUC for parent and metabolite → starting dose of 25 mg recommended |
| Hepatic impairment | Reduced clearance; dose adjustment for severe impairment |
| Renal impairment | Moderate increase in AUC; starting dose of 25 mg in severe impairment |
— Goodman & Gilman's The Pharmacological Basis of Therapeutics; Kaplan & Sadock's Synopsis of Psychiatry
SECTION 10 — DRUG INTERACTIONS
| Interacting Drug/Class | Mechanism | Effect | Clinical Management |
|---|---|---|---|
| Organic nitrates (nitroglycerine, isosorbide) | Both ↑ cGMP → additive vasodilation | Severe, potentially fatal hypotension | ABSOLUTE CONTRAINDICATION |
| Amyl nitrate ("poppers") | Same as above | Severe hypotension, MI risk | CONTRAINDICATED |
| Riociguat (sGC stimulator) | Additive hypotension | Severe hypotension | CONTRAINDICATED |
| CYP3A4 inhibitors (ketoconazole, itraconazole, erythromycin) | Reduced metabolism | ↑ Sildenafil plasma levels | Dose reduction; start at 25 mg |
| Cimetidine (non-specific CYP inhibitor) | Reduced metabolism | Plasma sildenafil ↑ 56% | Monitor; consider dose reduction |
| Erythromycin | CYP3A4 inhibition | Plasma sildenafil ↑ 182% | Dose reduction required |
| Bosentan (CYP3A4 inducer) | Induced metabolism | Substantial ↓ sildenafil levels | Monitor efficacy |
| Rifampicin (CYP3A4 inducer) | Induced metabolism | Plasma sildenafil ↓ | May require dose increase |
| Alpha-blockers | Additive vasodilation | Significant hypotension | Use with caution; start at lowest dose |
| Antihypertensives | Additive vasodilation | Enhanced hypotension | Monitor blood pressure |
— Kaplan & Sadock's Synopsis of Psychiatry; Goodman & Gilman's
SECTION 11 — SAFETY PROFILE
11.1 Adverse Effects
| System | Adverse Effect | Frequency |
|---|---|---|
| CNS | Headache | Very common (>10%) |
| Vascular | Flushing | Common |
| GI | Dyspepsia, nausea, diarrhoea | Common |
| Respiratory | Nasal congestion | Common |
| Visual | Coloured tinge (blue hue), blurred vision, photosensitivity | Common at higher doses |
| CV | Hypotension, palpitations | Uncommon |
| Ophthalmic | Non-arteritic anterior ischaemic optic neuropathy (NAION) | Rare (~1/1,000,000) |
| Auditory | Sudden hearing loss | Rare |
| Genitourinary | Urinary tract infection | Uncommon |
11.2 Contraindications
- Concurrent use of any organic nitrate (in any form, at any frequency)
- Concurrent use of amyl nitrate or riociguat
- Severe hepatic impairment (Child-Pugh C)
- Hypersensitivity to sildenafil or any excipient
- Recent history (within 6 months) of MI, stroke, or life-threatening arrhythmia (use with caution)
- Severe hypotension or hypertension
- Retinitis pigmentosa (relative contraindication)
- Non-arteritic anterior ischaemic optic neuropathy (NAION) history
11.3 Special Populations
| Population | Recommendation |
|---|---|
| Elderly (>65 years) | Start at 25 mg due to reduced clearance |
| Hepatic impairment | 25 mg starting dose; avoid in severe (Child-Pugh C) |
| Renal impairment (CrCl <30 mL/min) | Starting dose 25 mg |
| Pregnancy | Not indicated; safety not established |
| Paediatrics | Not recommended for ED; specific paediatric PAH formulations exist |
SECTION 12 — REGULATORY AND COMPLIANCE INFORMATION
| Aspect | Details |
|---|---|
| Original Approval | FDA approved Viagra® (sildenafil citrate) for ED on March 27, 1998 |
| PAH Approval | FDA approved Revatio® (20 mg sildenafil) for PAH in 2005 |
| Patent Expiry | Original Pfizer patent expired 2012 (US); generic manufacturing commenced |
| ICH Guidelines Compliance | Q1A (Stability), Q3A/B (Impurities), Q3C (Residual Solvents), Q3D (Elemental Impurities), Q6A (Specifications), Q7 (GMP for API), Q11 (Development and Manufacture of Drug Substances) |
| GMP Compliance | Manufactured under ICH Q7 / 21 CFR Part 211 / EU GMP Part II |
| DMF Holder Obligations | Authorization letter required before regulatory agencies can reference this DMF; annual updates required |
| CEP Status | Certificate of Suitability (CEP) from EDQM available for EP compliance |
SECTION 13 — GLOSSARY
| Term | Definition |
|---|---|
| API | Active Pharmaceutical Ingredient |
| BCS | Biopharmaceutics Classification System |
| cGMP | Cyclic Guanosine Monophosphate |
| CEP | Certificate of Suitability to the European Pharmacopoeia |
| DMF | Drug Master File |
| ICH | International Council for Harmonisation |
| NAION | Non-arteritic Anterior Ischaemic Optic Neuropathy |
| PAH | Pulmonary Arterial Hypertension |
| PDE5 | Phosphodiesterase Type 5 |
| XRPD | X-Ray Powder Diffraction |
SECTION 14 — REFERENCES
- Goodman & Gilman's The Pharmacological Basis of Therapeutics, 14th Ed. — PDE5 Inhibitors section
- Lippincott Illustrated Reviews: Pharmacology — Phosphodiesterase-5 Inhibitors
- Kaplan & Sadock's Synopsis of Psychiatry — Drug Interactions & Dosage Guidelines
- Campbell-Walsh-Wein Urology — Modulation of Antitumescence Pathways
- Murray & Nadel's Textbook of Respiratory Medicine — PDE5 Inhibitors in PAH
- ICH Q1A(R2): Stability Testing of New Drug Substances and Products
- ICH Q3A(R2): Impurities in New Drug Substances
- ICH Q7: Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients
- ICH Q11: Development and Manufacture of Drug Substances
- ICH M7(R1): Assessment and Control of DNA Reactive (Mutagenic) Impurities
- USP Monograph: Sildenafil Citrate
- FDA Drug Approval History: Viagra® NDA 020895; Revatio® NDA 021845
Key highlights of this DMF:
- CAS: 171599-83-0 | MW (citrate salt): 666.70 g/mol | BCS Class II
- Mechanism: Selective competitive PDE5 inhibitor (>1000-fold selectivity) — sustains cGMP-mediated smooth muscle relaxation
- ADME: Rapid oral absorption (Tmax ~1h), t½ ~4h, 96% protein bound, CYP3A4/2C9 metabolism, active N-desmethyl metabolite, predominantly faecal excretion (73–88%)
- Critical drug interaction: Absolute contraindication with organic nitrates — risk of severe/fatal hypotension
- Stability: Stable under ICH conditions; proposed retest period 36 months at 15–30°C
- Regulatory: FDA-approved 1998 (ED) and 2005 (PAH); compliant with ICH Q1A, Q3A/B/C/D, Q6A, Q7, Q11, M7
Disclaimer: This DMF is compiled for reference and study purposes from published pharmacology textbooks and regulatory frameworks. An actual regulatory submission DMF must include original analytical data, batch records, validated method reports, and site master file details generated by the manufacturing facility. It must be authored and signed by qualified pharmaceutical scientists.
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