Sildenafil 4.0—Integrated Synthetic Chemistry, Formulation and Analytical Strategies Effecting Immense Therapeutic and Societal Impact in the Fourth Industrial Era
Abstract
:1. Introduction
2. Chemical Synthesis of Sildenafil
3. Physiochemical Properties
3.1. Solubility
3.2. Permeability
3.3. Thermogravimetric Analysis (TGA)
3.4. Differential Scanning Calorimetry (DSC)
3.5. Infrared Spectroscopy (IR)
3.6. X-ray Crystallography Data
3.7. NMR Spectroscopy
4. Pharmacology and Clinical Applications
4.1. Treatment of Erectile Dysfunction
4.2. Treatment against Pulmonary Arterial Hypertension
4.3. Sildenafil as a Potential Treatment Option for COVID-19
4.4. Potential Sildenafil Effectiveness on Cancer Treatment and Type 2 Diabetes
5. Pharmacokinetic and Pharmacodynamic Profile
5.1. Pharmacokinetic Profile of Sildenafil
5.2. Pharmacodynamic Properties
5.3. Drug Interactions
5.4. Pharmacokinetic/Pharmacodynamic Interactions
5.5. Pharmacokinetic Interactions with Endothelin Receptor Antagonists
5.6. Administration to Special Populations
5.6.1. Elderly
5.6.2. Patients with Renal and Hepatic Impairment
5.6.3. Patients with Pulmonary Arterial Hypertension (PAH)
5.6.4. Pediatric Populations
6. Alternative Administration Schemes
6.1. Oral Administration
6.1.1. Orally Disintegrating Tablets (ODT)
6.1.2. Oro-Dispersible Film (ODF)
6.1.3. Sublingual Delivery Systems
6.1.4. Oral Pediatric Suspensions
6.1.5. Chewable Tablets
6.1.6. Dry Foam Tablets
6.2. Intranasal Microemulsions
6.3. Inhalables of Controlled Release
6.4. Transdermal
6.5. Intravenous
7. Analytical Strategies for the Determination of Sildenafil in Pharmaceutical and Biological Matrices
7.1. Pharmaceutical Applications
7.1.1. Optical Methods
Spectrophotometric Methods
Other Spectroscopic Methods
7.1.2. Electroanalytical Methods
7.1.3. Chromatographic Methods
7.1.4. Specifications in an Assessment Report
API’s Specifications
Stability of API
Specifications of Tablet Formulations
Stability of Tablets Formulation
7.2. Bioanalytical Applications
7.2.1. LC-MS/MS
7.2.2. HPLC-UV
7.2.3. Voltammetry
8. Discussion
9. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Pharmaceutical Compositions | Ref. | |
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sildenafil hydrochloride sildenafil hydrogensulphate sildenafil hemisulphate sildenafil hemitratrate sildenafil esylate sildenafil fumarate | Salts | [17] |
sildenafil-ACNI sildenafil ACNII | Solvates | [15] |
sildenafil lactate | [18,19] | |
sildenafil saccharinate CH3CN sildenafil oxalate sildenafil fumarate trihydrate sildenafil succinate sildenafil glutarate sildenafil adipic acid sildenafil pimelic acid sildenafil suberic acid sildenafil sebacic acid | Solvate Salt Salt Salt Salt Cocrystal Cocrystal Cocrystal Cocrystal | [20] |
Sildenafil-acetylsalicylic-acid | Cocrystal | [21] |
sildenafil-salicylic acid | Cocrystal | [22] |
sildenafil resorcinol | Cocrystal | [23] |
sildenafil Sacharinate with: CH3NO2, CH3CN, HCONH2, HOC2H4OH, C4H8O2 | Solvates of salts | [24] |
sildenafil-quercetin sildenafil-3,4-dihydroxybenzoic acid sildenafil-resorcinol sildenafil-tartaric acid sildenafil-caffeic acid sildenafil-methyl gallate sildenafil-3-hydroxybenzoic acid | Cocrystals | [25] |
Tablets | -Stability -Accurate Dosing -Easy Manufacturing -Small Packaging Size -Easy Handling | -Poor Patient Compliance Due to Swallowing Difficulties -First Pass Metabolism |
---|---|---|
Orally disintegrating tablet /film | -disintegration friendly, in the oral cavity, limited volume of saliva -no need of water -easy self-administration | -bitter taste |
Sublingual tablets | - first past metabolism elimination | |
Chewable tablets | -easy swallowing -easy self-administration | -first pass metabolism |
Dry foam tablets | - bioavailability enhancement | -poor patient compliance due to swallowing difficulties -first pass metabolism |
Intranasal | - first pass metabolism elimination | -poor permeability across nasal mucosa -mucociliary clearance |
Inhalable | -local action, first pass metabolism elimination | -rapid clearance from the pulmonary compartment |
Transdermal | -controlled released - first pass metabolism elimination -easy self-administration -avoidance of efflux transporters -improved patient compliance -avoidance of gastrointestinal harsh environment - reduction of dosing frequency -stable plasma levels -extended duration of action | slow absorption rate |
Intravenous | -highest bioavailability and Cmax | -difficult, demanding process - needle may be painful being the source of infectious disease |
Formulation | Route | Dose (mg), (mg/mL) | Excipients | Condition | Name | Market Holder | Authorization Date | EPAR |
---|---|---|---|---|---|---|---|---|
Film-coated tablets | oral | 25, 50, 100 | Microcrystalline cellulose, Silica, hydrophobic colloidal Croscarmellose sodium, Magnesium stearate Indigo carmine aluminum lake (E132), Sucralose Mannitol, Crospovidone, Polyvinyl acetate, Povidone Flavoring contains: Maltodextrin, Dextrin Natural flavoring contains: Maltodextrin, Glycerol (E422), Propylene glycol (E1520), Lemon flavoring contains: Maltodextrin, Alpha-tocopherol (E307) | ED | Viagra | Pfizer | 1998 | [127] |
Film-coated tablets | oral | 25, 50, 100 | Tablet core Microcrystalline cellulose, Calcium hydrogen phosphate Croscarmellose sodium, Magnesium stearate Film-coat, Poly(vinyl alcohol), Titanium dioxide (E171) Macrogol 3350, Talc | ED | Sildenafil Teva | Teva | 2009 | [128] |
Orodispersible tablets | oral | 25, 50, 100 | Hydroxypropyl cellulose (E463), Mannitol (E421) Aspartame (E951), Neohesperidin-dihydrochalcone (E959), Spearmint oil, Peppermint oil (containing sorbitol (E420)), Crospovidone, Calcium silicate, Magnesium stearate (E572) | ED | Vizarsin | Krka d.d. | 2009 | [129] |
Orodispersible film | oral | 25, 50, 75, 100 | Maltodextrin, Glycerol, Polysorbate 20, Propylene glycol monocaprylate, Polyvinyl acetate dispersion 30%, Lemon and Grapefruit flavors (Lemon essential oil, Citral, Linalool, Grapefruit essential oil, Orange essential oil, Nootkaton, Butylated hydroxyanisol E320, Ascorbic acid E300, Maltodextrin, Arabic gum E414), Sucralose, Titanium dioxide, Indigotine | ED | Sildenafil Sandoz ODF | IBSA | 2013 | [130] |
Chewable tablets | oral | 25, 50, 100 | Polacrilin potassium, silica colloidal anhydrous, lactose monohydrate, povidone K-30, aspartame (E951), croscarmellose sodium, peppermint flavor, magnesium stearate, potassium hydroxide (for pH adjustment) or hydrochloric acid (for pH adjustment). | ED | Sildenafil Portfarma | Portfarma | 2012 | [131] |
Solution for injection | IV | 0.8 mg/mL | Glucose Water for injections | PAH | Revatio | Upjohn EESV | 2005 | [132] |
Powder for suspension (after reconstitution) | oral | 10 mg/mL | Powder for oral suspension: Sorbitol Citric acid anhydrous, Sucralose, Sodium citrate, Xanthan gum, Titanium dioxide (E171), Sodium benzoate (E211), Silica, colloidal anhydrous Grape flavor: Maltodextrin, Grape juice concentrate, Gum acacia, Pineapple juice concentrate, Citric acid anhydrous, Natural flavoring | PAH | Revatio | Upjohn EESV | 2005 | [132] |
Stationary Phase | Mobile Phase | Flow Rate/Temp | LOD (ng mL−1) | UV (nm) | Ref |
---|---|---|---|---|---|
Monolithic column Chromolith® RP-18e, (100 × 4.6 mm I.D) | Acetonitrile/water, 60/40, v/v | 2 mL min−1/Ambient | 25 | 292 | [152] |
RP C18 | Phosphate buffer 10 mM (pH 6.5)/MeOH, gradient | 1 mL min−1/40 °C | 1.49 | 286 | [154] |
Bondapak C18 (300 × 3.9 mm, 10 μm) | CH3COONH4 0.2 M (pH 7.0)/CH3CN, 50/50 v/v | 1 mL min−1/Ambient | 0.413 | 240 | [153] |
Spherisorb® silica-C18 (250 × 4.6 mm, 5 μm) | TEA 0.2% v/v (pH = 3) with OPA and ACN (60/40 v/v) | 1 mL min−1/Ambient | 0.3 | 230 | [155] |
Inertsil C18 (150 × 4.6 mm, 5 μm) | CH3CN/phosphate buffer (70/30 v/v, pH 7.0) | 0.8 mL min−1/Ambient | 1.8 | 228 | [156] |
Inertsil®ODS-3; (250 × 4.6 mm, 3 μm) | CH3COONH4 0.2M (pH 7.0)/CH3CN, 50/50 v/v | 1.0 mL min−1/25 °C | 3.82 | 245 | [157] |
Poroshell 120 EC-C18 (150 × 4.6 mm, 4 μm) | CH3COONH4 0.03M/CH3CN gradient | 1.0 mL min−1/40 °C | 0.67 | 230 | [158] |
Analyte LC-MS | Sample | Sample Preparation | Analytical Parameters | Detection | LOD/LOQ | Ref |
---|---|---|---|---|---|---|
Sildenafil, N-desmethyl sildenafil | Human plasma | Protein precipitation using acetonitrile | Gradient elution using water and acetonitrile both containing 0.1% v/v formic acid Column: Gemini NX-C18 (50 × 4.6 mm i.d., 5 μm) + Gemini C18 guard column (4 × 3 mm i.d., 5 μm) Flow rate: 0.3 mL min−1 Temperature: 35 °C | MS/MS (MRM 1) | NM 2/2 ng mL−1 | [164] |
Sildenafil, tadalafil, bosentan, ambrisentan, macitentan | Human plasma | (1) Protein precipitation using acetonitrile (2) SPE 3 (Oasis® HLB 96 well-plate) | Isocratic elution: 5 mM CH3COONH4/acetonitrile, 50/50 v/v Column: Symmetry C18 (150 × 2.1 mm i.d., 5 μm) Flow rate: 0.3 mL min−1 Temperature: 40 °C | MS | NM/1 ng mL−1 | [165] |
Sildenafil, tadalafil, avanafil, vardenafil | Human plasma, urine | Magnetic SPE using citric acid coated iron oxide nanoparticles | Gradient elution using 10 mM HCOONH4 (pH 4.6) and acetonitrile containing 0.1% formic acid Column: Agilent Poroshell 120 EC-C18 (150 × 3.0 mm i.d., 2.7 μm) Flow rate: 0.55 mL min−1 Temperature: NM | QTOF-MS/MS | 0.74/2.45 ng g−1 | [166,167] |
Sildenafil, tadalafil, vardenafil and avanafil | Human plasma, urine | Magnetic SPE using citric acid coated iron oxide nanoparticles | Gradient elution using 10 mM HCOONH4 (pH 4.6) and acetonitrile containing 0.1% formic acid Column: Agilent Poroshell 120 EC-C18 (150 × 3.0 mm i.d., 2.7 μm) + Agilent Zorbax Eclipse guard column (12.5 × 2.1 mm, 5 μm) Flow rate: 0.55 mL min−1 Temperature: NM | QTOF-MS/MS | 0.14/0.47 ng g−1 | [168] |
Sildenafil, tadalafil, vardenafil and avanafil | Human urine, simulated gastric fluid | Dilution | Gradient elution using 10 mM HCOONH4 (pH 4.6) and acetonitrile containing 0.1% formic acid Column: Agilent Poroshell 120 EC-C18 (150 × 3.0 mm i.d., 2.7 μm) + Agilent Zorbax Eclipse guard column (12.5 × 2.1 mm, 5 μm) Flow rate: 0.55 mL min−1 Temperature: 40 °C | QTOF-MS/MS | 2.19/7.28 ng g−1 | [170,171,172,173] |
Sildenafil, rosiglitazone | Rat plasma | Protein precipitation using methanol | Gradient elution using water and methanol both containing 0.1% formic acid Column: Kinetex C18 (50 × 2.1 mm i.d., 1.3 μm) Flow rate: 0.25 mL min−1 Temperature: 40 °C | MS/MS (MRM) | NM/5 ng mL−1 | [174,175,176] |
Sildenafil, N-desmethyl sildenafil | Human plasma | Protein precipitation using acetonitrile | Gradient elution using water and acetonitrile both containing 0.05% formic acid Column: Acquity UPLC® HSS T3 C18 (150 × 2.1 mm i.d., 1.8 μm) Flow rate: 0.4 mL min−1 Temperature: 40 °C | MS/MS (MRM) | 1.95/3.9 ng mL | [30] |
Sildenafil, mirodenafil, tadalafil, udenafil, vardenafil and their metabolites | Animal hair | Digestion with 5M HCl methanolic solution followed by mixed-mode SPE using C18 and strong ion exchange polymeric sorbents | Gradient elution using water and acetonitrile containing 0.1% formic acid Column: Agilent Poroshell 120 EC-C18 (50 × 3.0 mm i.d., 2.7 μm) Flow rate: 0.3 mL min−1 Temperature: 30 °C | MS/MS (MRM) | 0.05/0.1 ng mg−1 | [177,178,179] |
Sosentan, ambrisentan, sildenafil, tadalafil | Human plasma | SPE using Oasis WAX cartridges | Isocratic elution using 5 mM CH3COONH4 (pH 5.0)/acetonitrile, 55/45 v/v Column: Cadenza CD-C18 (75 × 2.0 mm i.d., 3 μm) + Phenomenex Security guard column Flow rate: 0.2 mL min−1 Temperature: 40 °C | MS/MS (MRM) | NM/2 ng mL−1 | [180] |
Sildenafil | Human plasma | Protein precipitation using acetonitrile followed by heating at 60 °C | Gradient elution using 50 mM CH3COONH4/3% trifluoroacetic acid/methanol/acetonitrile, 68/2/15/15 v/v/v/v Column: Agilent Poroshell 120 EC-C18 (50 × 3 mm i.d., 2.7 μm) Flow rate: 0.3 mL min−1 Temperature: 30 °C | MS/MS (MRM) | 7.25/10 ng mL−1 | [181] |
Sildenafil | Dried blood spot | LLE 4 using diethyl ether | Isocratic elution using 2 mM CH3COONH4 (pH 5.0)/acetonitrile, 65/35 v/v Column: BEH C18 (50 × 2.1 mm i.d., 1.7 μm) Flow rate: 0.3 mL min−1 Temperature: 40 °C | MS/MS (MRM) | NM/5 ng mL−1 | [182] |
Sildenafil, N-desmethyl sildenafil | Human plasma | LLE using methyl terb-butyl ether | Isocratic elution using 0.02% formic acid/acetonitrile, 30/70 v/v Column: Thermo Hypersil Gold (50 × 2.1 mm i.d., 5 μm) Flow rate: 0.5 mL min−1 Temperature: 35 °C | MS/MS (MRM) | NM | [183] |
Sildenafil | Human plasma | SPE using Sep-Pak tC18 | Isocratic elution using 5 mM ammonium formate/acetonitrile, 60/40 v/v Column: Thermo Hypersil Gold (50 × 2.1 mm i.d., 5 μm) Flow rate: 0.5 mL min−1 Temperature: 35 °C | MS | NM/5 ng mL−1 | [184] |
HPLC-UV | ||||||
Sildenafil, avanafil, apomorphine, trazodone, yohimbine, tramadol, dapoxetine | Human plasma | Protein precipitation using acetonitrile | Gradient elution using sodium octanesulfonate, EDTA aqueous solution (pH 3.0) and acetonitrile or ethanol Column I: Chromolith Performance RP-18e (100 × 4.6 mm i.d. Column II: Poroshell core-shell EC-C18 (150 × 4.6 mm i.d., 2.7 μm) Flow rate: 1 or 2 mL min−1 Temperature: 35 °C | UV@210nm | 200/500 ng mL−1 (using Column I) 200/500 ng mL−1 (using Column II) | [167] |
Sildenafil, tramadol | Rabbit plasma | SPE using Oasis HLB | Isocratic elution using 10 mM phosphate buffer (pH 7.5)/acetonitrile, 55/45 v/v Column: ODS Discovery HS C18 (150 × 4.6 mm i.d. 5 μm) Flow rate: 0.8 mL min−1 Temperature: Ambient | UV@220nm | 0.01/0.03 μg mL−1 | [169] |
Sildenafil | Rat plasma | Protein precipitation | Isocratic elution using a mixture of acetonitrile and water (57.5/42.5 v/v) containing 0.675 mL trimethylamine (pH 7 with H3PO4) Column: Sepax Gp-C18 (150 × 4.6 mm i.d. 5 μm) Flow rate: 1 mL min−1 Temperature: 30 °C | UV@230nm | NM/20 ng mL−1 | [171] |
Sildenafil, N-desmethyl sildenafil | Human plasma | LLE using ethyl acetate | Isocratic elution using a mixture of 30 mM phosphate buffer (pH 6.0)/acetonitrile, 53/47 v/v Column: Inertsil ODS2 C18 (150 × 4.6 mm i.d. 5 μm) Flow rate: 1 mL min−1 Temperature: 25 °C | UV@230nm | 0.5/1 ng mL−1 | [172] |
Sildenafil | Human plasma | LLE using diethylacetate followed by back-extraction with 5% HClO4 aqueous solution | Isocratic elution using a mixture of water and acetonitrile (63/37 v/v) containing 0.1% TEA (pH 7.7) Column: Hypersil BDS-C18 (150 × 4.6 mm i.d. 5 μm) Flow rate: 1 mL min−1 Temperature: 25 °C | UV@230nm | NM/2 ng mL−1 | [175] |
Sildenafil | Rat plasma | LLE using ethyl acetate/hexane (30/70 v/v) followed by back-extraction with mixture of methanol/0.1 M H2SO4 aqueous solution (10/90 v/v) | Isocratic elution using a mixture of 50 mM KH2PO4 (pH 4.5) and acetonitrile, 75/25 v/v Column: Supelcosil PCN cyanopropyl (250 × 4.6 mm i.d. 5 μm) Flow rate: 1 mL min−1 Temperature: 22 °C | UV@230nm | 5/10 ng mL−1 | [176] |
aliskiren, prasugrel, rivaroxaban, rednisolone, propranolol, ketoprofen, nifedipine, naproxen, terbinafine, ibuprofen, diclofenac, sildenafil, acenocoumarol | Human urine | SPE using 17 different silica- and polymeric-based sorbents | Gradient elution using water and acetonitrile both containing 0.05% trifluoroacetic acid Column: Hypersil Gold C18 (50 × 2.1 mm i.d., 1.9 μm) Flow rate: 0.5–1.0 mL min−1 Temperature: 25 °C | UV@228nm | 66/198 ng mL−1 | [179] |
Sildenafil, N-desmethyl sildenafil | Human plasma | LLE using ethyl acetate | Isocratic elution using a mixture of 30 mM KH2PO4 (pH 4.5) and acetonitrile, 53/47 v/v Column: μBondapack C18 (150 × 3.9 mm i.d. 5 μm) Flow rate: 0.8 mL min−1 Temperature: 21 °C | UV@230nm | 1/10 ng mL−1 | [185] |
Sildenafil, vardenafil, aildenafil | Human plasma | Ionic liquid-based dispersive liquid liquid microextraction followed by back-extraction with 10% acetic acid | Isocratic elution using a mixture of water and methanol both containing 1% acetic acid, 60/40 v/v Column: Shimazdzu RP-C18 (250 × 4.6 mm i.d. 5 μm) Flow rate: 1.2 mL min−1 Temperature: NM | UV@254nm | 0.17/NM | [186] |
Voltammetry | ||||||
Sildenafil | Human serum | Dilution | Screen-printed electrode with carbon working and auxiliary electrodes and silver reference electrode Potential range: −0.75 to 1.55 V Scan rate: 175 mV s−1 Sample medium: 0.15 M acetate buffer (pH 5.0) | − | 5.9 × 10−10/2.0 × 10−9 mol L−1 | [151] |
Sildenafil | Human serum | NM | Square wave voltammetry using polycrystalline gold (surface area 0.5 cm2), gold wire and saturated calomel electrode as working, counter and reference electrodes respectively Sample medium: 0.05 M NaHCO3 | − | 0.031/0.106 μmol L−1 | [173] |
Sildenafil | Simulated human urine | Dilution | Cyclic voltammetry using screen-printed glassy carbon electrode modified gold nanoparticles via electrodeposition Sample medium: Britton-Robinson buffer (pH 7.3) | − | 5.2 × 10−10 mol L−1/NM | [178] |
Batch Spectrophotometry | ||||||
Sildenafil | Human urine | Dispersive solid-phase microextraction using Mn@ CuS/ZnS nanocomposite loaded on activated carbon | − | NM | 2.5/8.35 ng mL−1 | [181] |
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Ouranidis, A.; Tsiaxerli, A.; Vardaka, E.; Markopoulou, C.K.; Zacharis, C.K.; Nicolaou, I.; Hatzichristou, D.; Haidich, A.-B.; Kostomitsopoulos, N.; Kachrimanis, K. Sildenafil 4.0—Integrated Synthetic Chemistry, Formulation and Analytical Strategies Effecting Immense Therapeutic and Societal Impact in the Fourth Industrial Era. Pharmaceuticals 2021, 14, 365. https://doi.org/10.3390/ph14040365
Ouranidis A, Tsiaxerli A, Vardaka E, Markopoulou CK, Zacharis CK, Nicolaou I, Hatzichristou D, Haidich A-B, Kostomitsopoulos N, Kachrimanis K. Sildenafil 4.0—Integrated Synthetic Chemistry, Formulation and Analytical Strategies Effecting Immense Therapeutic and Societal Impact in the Fourth Industrial Era. Pharmaceuticals. 2021; 14(4):365. https://doi.org/10.3390/ph14040365
Chicago/Turabian StyleOuranidis, Andreas, Anastasia Tsiaxerli, Elisavet Vardaka, Catherine K. Markopoulou, Constantinos K. Zacharis, Ioannis Nicolaou, Dimitris Hatzichristou, Anna-Bettina Haidich, Nikolaos Kostomitsopoulos, and Kyriakos Kachrimanis. 2021. "Sildenafil 4.0—Integrated Synthetic Chemistry, Formulation and Analytical Strategies Effecting Immense Therapeutic and Societal Impact in the Fourth Industrial Era" Pharmaceuticals 14, no. 4: 365. https://doi.org/10.3390/ph14040365