Bimonthly, Established in 1959
Open access journal

Sildenafil: Integrated Synthetic Chemistry, Formulation and Analytical Strategies Effecting Immense Therapeutic and Societal Impact in the Fourth Industrial Era

Abstract

Sildenafil is a reversible selective phosphodiesterase type 5 (PDE5) inhibitor approved for the treatment of erectile dysfunction and pulmonary arterial hypertension by medical regulatory authorities in most countries of the world. Sildenafil was initially approved by the US Food and Drug Administration (USFDA) as a US-developed drug. Today, the relevance of the use of Sildenafil has not decreased. This drug is entering the fourth industrial era, summarizing decades of advances in the treatment of erectile dysfunction (ED) and pulmonary hypertension (PD). To date, detailed data from numerous clinical trials of sildenafil, as well as two other PDE5 inhibitors (tadalafil and vardenafil) released on the international pharmaceutical market, highlight the significant therapeutic and commercial achievements of sildenafil. Today, sildenafil is available in different dosage forms, from tablets to bolus suspensions and gels, which are taken in a wide variety of ways, from oral to intravenous administration, with respective advantages and disadvantages. The purpose of this article is to highlight interdisciplinary elements that span the areas of knowledge about the chemical synthesis of sildenafil, its physicochemical properties, pharmacology, routes of administration, the various routes of administration, and the analytical strategies currently used to guide the development of other formulations based on sildenafil.
Keywords: sildenafil, fourth industrial era, efficacy, safety, improved solubility, nanomaterial, formulation, PDE5 inhibitors, side effects

Introduction

Sildenafil has made its way from an accidentally discovered substance that was intended to treat pulmonary hypertension to the first effective drug against erectile dysfunction, which became possible to take orally. In the world, this remedy is known under the trade name Viagra. Sildenafil is also used to treat pulmonary arterial hypertension (PAH) under the brand name Pfizer Revatio. The possible efficacy of sildenafil against pulmonary fibrosis, which is one of the formidable complications of COVID-19, is currently being considered.
Sildenafil belongs to the II class of the biopharmaceutical classification system. Sildenafil has a common metabolic pathway with many drugs, therefore, when used together with some of them, it leads to a strong drug interaction.
Oral sildenafil is most commonly used in clinical practice, and is available in tablet (pill), chewable, capsule, suspension (gel) and liquid forms. The tablet form provides the most accurate correspondence to the technological recipe, although other forms also have their own specific advantages. More non-standard forms of release include bioequivalent formulations that are absorbed by the sublingual, supra-lingual, intranasal, inhalation, transdermal and intravenous routes of administration [1].
Today, there are several analytical protocols for the precise determination of the presence and amount of sildenafil in pharmaceutical products, herbal products and biological matrices. In this work, we attempt to study chemical synthesis, physicochemical properties, pharmacology, clinical applications, biopharmaceutical profile, multiple route of administration approach, and analytical strategies used to develop new sildenafil-based formulations.

Sildenafil – Chemical Synthesis

Sildenafil is notable for being the first pharmacological substance to be developed using computer-aided drug design protocols. They successfully promoted the synthesis of a substance that inhibits type 5 phosphodiesterase isoenzyme (PDE-5).
The commercial synthesis of sildenafil was further developed in the context of the 4.0 Green Chemistry Directives, which aim to improve the environmental performance of this drug on an industrial scale. The revamped sildenafil synthesis process resulted in a pure cyclization reaction as the final step. In addition to this, how the use of water instead of organic solvents to produce sulfonamide has also reduced the environmental burden of production. As a result, the CO2 emissions associated with the reaction of thionyl chloride or oxalyl chloride with ethyl acetate have been reduced, and potentially toxic substances have been eliminated, which contributes to the high quality and environmental friendliness of the product. The yield of sildenafil citrate resulted in 75%, while this value was not previously thought to be possible.

Sildenafil – Physiochemical Properties

Sildenafil base and sildenafil citrate are white to off-white (yellowish or grayish) crystalline solids with densities of 1.60 and 1.17 g/cm3, respectively.
Thermal decomposition of sildenafil citrate occurs at a temperature of 189.5°C. At the same time, the resulting decomposition product melts. The endothermic peak of anhydrous form I of sildenafil occurs at 188 – 189°C.
For a quick and qualitative analysis of the reliability or falsification of various plant products (aphrodisiacs), allegedly containing sildenafil, infrared measurements are used [3, 4]. Also, this method is used to detect counterfeit pills.
To date, several methods have been tested to accelerate the crystallization process of sildenafil, namely crystallization of the solution, addition of an anti-solvent, boiling under reflux, and slow evaporation of the solvent. The main molecule of sildenafil, compared to salts, exhibits poor crystallinity, forming rod-shaped crystals. The crystalline structure of sildenafil free base is a monoclinic system, while the crystalline system of sildenafil citrate is orthorhombic. The crystal structure of anhydrous sildenafil citrate is currently unknown [5].
Studies have been conducted that included complex comparisons of sildenafil citrate and sildenafil base. In particular, the spectra of sildenafil in solution, in solid state and in pharmaceutical dosage forms were studied. Notably, 13C-NMR spectroscopy shows chemical shifts that are different for the different states of sildenafil.

Pharmacology and Methods of Clinical Use

Sildenafil in ED Treatment

Sildenafil citrate belongs to the group of selective phosphodiesterase type 5 (PDE-5) inhibitors. This enzyme is responsible for the hydrolysis of cyclic guanosine monophosphate (cGMP), which is found mainly in the corpus cavernosum of the penis. Also, this substance is present in the smooth muscle cells of the walls of blood vessels and lung tissue. Sexual stimulation is accompanied by the release of nitric oxide by the nerves of the penis and the endothelium and activates soluble guanylate cyclase, which mediates the conversion of guanosine triphosphate (GPD) to cyclic guanosine monophosphate (cGMP). Thus, the smooth muscle relaxes due to the increase in cGMP by minimizing the intracellular calcium concentration. The strength and duration of this process is controlled by type 5 phosphodiesterases, which destroy cGMP. Inhibition of PDE-5 by sildenafil with local release of nitric oxide against a background of sexual arousal contributes to a high level of cGMP availability in the corpus cavernosum due to vasodilation and an increase in local blood circulation [6].

Sildenafil in PAH Treatment

Under the brand name Revatio, Sildenafil is used to treat pulmonary arterial hypertension (PAH). In contrast to erectile dysfunction, the sildenafil regimen for PAH involves taking 20 mg three times daily to achieve a more consistent level of sildenafil in the body. PAH is a blood vessel disease that occurs in the main pulmonary artery, which is responsible for transporting blood volumes from the right ventricle of the heart to the lungs. In PAH, there is a sustained increase in pulmonary systolic pressure (>30 mmHg during physical activity), mean pressure> 25 mmHg. Art at rest and wedge pressure <15 mm Hg. Sildenafil helps to relax the walls of the pulmonary arteries, which leads to a controlled decrease in pulmonary arterial pressure [7].

Sildenafil in COVID-19 Treatment

Sildenafil is currently being considered for the treatment of pulmonary fibrosis arising as a complication of COVID-19 due to the high level of PDE-5 expression in the lung tissue and the proven vasodilatory activity of sildenafil. It is assumed that sildenafil inhibits intrapulmonary vasoconstriction caused by the regulation of the Ang II receptor type I (AT1) due to the binding of SARS-CoV-2-ACE2 to alveolar cells, bronchial epithelium and vascular endothelium. It is also believed that sildenafil, by inhibiting PDE-5 receptors, helps prevent the spread of local inflammation by reducing the release of pro-inflammatory cytokines. Clinical trials of sildenafil are currently underway in patients with COVID-19 and postcoid pulmonary fibrosis. The use of sildenafil in COVID-19 treatment protocols has not yet received approval, as there is a need for further extensive clinical trials [8].

Potential of Sildenafil for the Treatment of Cancer and Type 2 Diabetes Mellitus (T2DM)

Recently, a number of studies have demonstrated the antitumor efficacy of sildenafil. It is hypothesized that it can be used as a chemoprotective approach in colorectal cancer [9]. Clinical studies are underway in mice, as well as on human cells in vitro and in vivo. Sildenafil inhibits the proliferation of tumor cells, causing cell cycle arrest and apoptosis with increased levels of intracellular reactive oxidative forms (ROS). Sildenafil may also prove to be a promising treatment for chronic lymphocytic leukemia, prostate cancer and breast cancer. Some studies show that sildenafil may enhance the effectiveness of other chemotherapy drugs for bladder and pancreatic cancer [10].
The administration of sildenafil to patients with type 2 diabetes mellitus, especially men, improves endothelial function, increases metabolic control, and decreases vascular inflammation. According to one clinical study, daily intake of 100 mg of sildenafil per day in men with T2DM resulted in increased glucometabolic control [11].

Pharmacokinetic and Pharmacodynamic Profile of Sildenafil

Sildenafil is selective for the PDE-5 enzyme. Its activity against PDE-5 is about 10 times higher than against PDE-6, that is, the enzyme responsible for the retinal phototransduction pathway, and more than 700 times higher than against other isozymes of the phosphodiesterase family. After the administration of sildenafil, in most patients, due to the vasodilating effect, there is a moderate decrease in both systolic and diastolic blood pressure, while the heart rate does not decrease. The main side effects associated with taking sildenafil, including headache and facial flushing, are also associated with vasodilation. Visual impairments, including color impairments, are associated with small but present inhibition of PDE-6.
Since inhibition of PDE-5 by sildenafil enhances the hypotensive effect of nitric oxide, it is contraindicated to take sildenafil in combination with organic nitrates.
Pharmacokinetic interactions between sildenafil and protease inhibitors, namely ritonavir and saquinavir, show that both of these drugs increase the systemic exposure of sildenafil and the active metabolite, therefore their combination is not recommended [12].
Substances that can affect first-pass metabolism controlled by CYP3A4, such as grapefruit, which claim to have a significant inhibitory effect, can also alter the pharmacokinetics of sildenafil. Relevant clinical studies have shown that taking sildenafil with grapefruit juice causes an increase in the bioavailability of sildenafil by 23% due to a decrease in its metabolism during the first pass and the resulting delay in absorption.

Sildenafil in Special Populations

Data from clinical studies indicate differences in the pharmacokinetic profile of sildenafil and its main metabolite between young/middle-aged and older men. Elderly men show a 38% higher plasma concentration of free sildenafil and an increase in its half-life.
In patients with mild to moderate cirrhosis of the liver, as well as with severe kidney damage, it is recommended to reduce the dose of sildenafil by 25 mg due to the increased half-life of sildenafil.
Patients with PAH show twice the plasma concentration of sildenafil compared to healthy volunteers, indicating a decrease in clearance and an increased oral bioavailability [13].
Body mass index plays a decisive role in the systemic effect of sildenafil in children. For persons under 18 years of age, sildenafil is recommended for treatment of PAH only in situations where the potential benefit outweighs the risk [14].

Possible Administration Schemes

Modern researchers are focusing on modernizing existing oral dosage forms of sildenafil and looking at intranasal, transdermal and intravenous routes.
In order to eliminate the inconvenience of swallowing and increase bioavailability, the development of orodispersible formulations, mainly sublingual and supra-lingual, is underway. Oral disintegrating tablets (ODT) disintegrate within 2-3 minutes after contact with saliva in the mouth and do not require swallowing. This form of release retains the advantages of conventional tablets, such as precise dosing, ease of manufacture and ease of administration. Disadvantages include high first pass metabolism, bitter taste, and significant interaction with food.
Oro Dispersible Film (ODF) tablets are thin-film composites that are placed directly on the surface of the tongue. They quickly break down in the mouth, they do not need to be washed down with water or chewed [15].
The Sheu pharmaceutical group is developing sublingual sildenafil in the form of granular sprays adsorbed on a silicate substrate. It has a higher absolute bioavailability.
The challenge is to prepare a safe and stable liquid formulation for use in children with PAH. This can be an oral redispersible suspension or a clear glucose-free solution. The main problem with these formulations is long-term storage without lowering the concentration of sildenafil.
Sildenafil in the form of chewable tablets demonstrates pharmacokinetic properties similar to tablet forms, and is a complete alternative to them.
The dry-foam tablets exhibit bioavailability about 1.5 times that of film-coated tablets [16].
The main advantage of sildenafil intranasal microemulsions is the fastest possible absorption. However, the bioavailability of the drug is limited by such factors as poor permeability of the drug through the nasal mucosa and mucociliary clearance. In this regard, sildenafil nasal preparations are still not on the market.
Oral administration of sildenafil in the treatment of pulmonary arterial hypertension causes systemic exposure to the drug and undesirable side effects. A method is being developed for the administration of sildenafil using submicron particles delivered to the respiratory tract using a Micro-Sprayer(R) system integrated into an inspiratory tube system with a nebulizer tip approximately 1 cm above the tracheal bifurcation [17].
Transdermal delivery of sildenafil nanocarriers significantly increases the initial available concentration followed by controlled release. This route of administration has the potential for faster onset of action and longer duration of drug action.

Discussion

High selectivity of PDE-5 in relation to sildenafil can be achieved through the independent regulation of PDE5 in an unactivated form. Despite the fact that sildenafil is well absorbed into the blood, the absolute bioavailability does not exceed 40% due to the extensive effect of first-pass metabolism.
Oral administration of sildenafil in tablet/pill form is the main route of administration for this medication. While this method has the advantages of accurate dosing and ease of manufacture, it is also associated with a slow dissolution rate and alarming levels of first pass metabolic effect. With the aim of improving the latter parameters, attention has recently been focused on new orodispersible formulations such as gels, lozenges and chewable softgels. They have the advantages of tablets for oral administration while also having a higher bioavailability.

Conclusions

The role of pharmaceutical science in optimizing the biopharmaceutical profile of sildenafil while reducing toxicity and side effects remains unresolved. It is of interest to develop an optimal method for drug delivery into the body. The focus is on reducing the metabolic load of sildenafil on the liver.
In 2018, Viagra became the first erectile dysfunction drug to be allowed over-the-counter in UK pharmacies as a generic drug under the brand name Connect. More countries are expected to follow Britain’s lead in the future. One of the contributing factors to this is that sildenafil is often counterfeited.
Discovered twenty years ago, sildenafil has revolutionized the treatment of pulmonary hypertension and erectile dysfunction, and has even had significant social impact. With the advent of the fourth industrial era, characterized by unprecedented levels of automation and virtual social media, a significant expansion of the sector can be predicted to encompass the development of new products based on sildenafil.

References

[1] Dunn P.J., Galvin S., Hettenbach K. The development of an environmentally benign synthesis of sildenafil citrate and its assessment by Green Chemistry metrics. Green Chem. 2004;6:43 – 48. doi: 10.1039/B312329D.
[2] Corbi P.P., Cuin A., Cavicchioli M. Physicochemical properties of sildenafil citrate (Viagra) and sildenafil base. J. Pharm. Sci. 2003;92:2140 – 2143. doi: 10.1002/jps.10469.
[3] Nugroho A., Febriana Y., Septiwi M., Pratiwi D.A. Rapid analysis of adulterated sildenafil citrate in marketed herbal aphrodisiacs using infrared spectroscopy. AIP Conf. Proc. 2018;2026:020003. doi: 10.1063/1.5064963.
[4] Neto J.C., Lisboa F.L.C. ATR-FTIR characterization of generic brand-named and counterfeit sildenafil- and tadalafil-based tablets found on the Brazilian market. Sci. Justice. 2017;57:283 – 295. doi: 10.1016/j.scijus.2017.04.009.
[5] Abraham A., Apperley D.C., Byard S.J., Ilott A.J., Robbins A.J., Zorin V., Harris R.K., Hodgkinson P. Characterising the role of water in sildenafil citrate by NMR crystallography. CrystEngComm. 2016;18:1054 – 1063. doi: 10.1039/C5CE02234G.
[6] Ballard S.A., Gingell C.J., Tang K., Turner L.A. Effects of sildenafil on the relaxation of human corpus cavernosum tissue in vitro and on the activities of cyclic nucleotide phosphodiesterase isozymes. J. Urol. 1998;159:2164 – 2171. doi: 10.1016/S0022-5347(01)63299-3.
[7] Maclean M.R., Johnston E.D., Mcculloch K.M., Pooley L., Houslay M.D., Sweeney G. Phosphodiesterase isoforms in the pulmonary arterial circulation of the rat: Changes in pulmonary hypertension. J. Pharmacol. Exp. Ther. 1997;283:619 – 624.
[8] Qiao Z., Zhang H., Ji H.F., Chen Q. Computational view toward the inhibition of SARS-CoV-2 spike glycoprotein and the 3CL protease. Computation. 2020;9:53. doi: 10.3390/computation8020053.
[9] Islam B.N., Sharman S.K., Hou Y., Bridges A.E., et al. Sildenafil suppresses inflammation-driven colorectal cancer in mice. Cancer Prev. Res. 2017;10:377 – 388. doi: 10.1158/1940-6207.CAPR-17-0015.
[10] Das A., Durrant D., Mitchell C., Mayton E., Hoke N.N., Salloum F.N., Park M.A., Qureshi I., Lee R., Dent P., et al. Sildenafil increases chemotherapeutic efficacy of doxorubicin in prostate cancer and ameliorates cardiac dysfunction. Proc. Natl. Acad. Sci. USA. 2010;107:18202 – 18207. doi: 10.1073/pnas.1006965107.
[11] Grover-Páez F., Rivera G.V., Ortíz R.G. Sildenafil citrate diminishes microalbuminuria and the percentage of A1c in male patients with type 2 diabetes. Diabetes Res. Clin. Pract. 2007;78:136 – 140. doi: 10.1016/j.diabres.2007.02.006.
[12] Muirhead G.J., Wulff M.B., Fielding A., Kleinermans D., Buss N. Pharmacokinetic interactions between sildenafil and saquinavir/ritonavir. Br. J. Clin. Pharmacol. 2000;50:99 – 107. doi: 10.1046/j.1365-2125.2000.00245.x.
[13] Muirhead G.J., Wilner K., Colburn W., Haug-Pihale G., Rouviex B. The effects of age and renal and hepatic impairment on the pharmacokinetics of sildenafil citrate. Br. J. Clin. Pharmacol. 2002;53:21S – 30S. doi: 10.1046/j.0306-5251.2001.00029.x.
[14] Dodgen A.L., Hill K.D. Safety and tolerability considerations in the use of sildenafil for children with pulmonary arterial hypertension. Drug. Healthc. Patient Saf. 2015;7:175 – 183.
[15] Dey P., Maiti S. Orodispersible tablets: A new trend in drug delivery. J. Nat. Sci. Biol. Med. 2010;1:2 – 5. doi: 10.4103/0976-9668.71663.
[16] Sawatdee S., Atipairin A., Yoon A.S., Srichana T., Changsan N., Suwandecha T., Chanthorn W., Phoem A. Oral bioavailability and pharmacokinetics of sildenafil citrate dry foam tablets in rats. Cogent Med. 2018;5 doi: 10.1080/2331205X.2018.1510821
[17] Li B., He W., Ye L., Zhu Y., Tian Y., Chen L., Yang J., Miao M., Shi Y., Azevedo H.S., et al. Targeted delivery of sildenafil for inhibiting pulmonary vascular remodeling. Hypertension. 2019;73:703 – 711. doi: 10.1161/HYPERTENSIONAHA.118.11932.