Sildenafil 4.0—Integrated Synthetic Chemistry, Formulation and Analytical Strategies Effecting Immense Therapeutic and Societal Impact in the Fourth Industrial Era

Abstract

Sildenafil is a potent selective, reversible inhibitor of phosphodiesterase type 5 (PDE5) approved for the treatment of erectile dysfunction and pulmonary arterial hypertension. Whilst twenty years have passed since its original approval by the US Food and Drug Administration (USFDA), sildenafil enters the fourth industrial era catalyzing the treatment advances against erectile dysfunction and pulmonary hypertension. The plethora of detailed clinical data accumulated and the two sildenafil analogues marketed, namely tadalafil and vardenafil, signify the relevant therapeutic and commercial achievements. The pharmacokinetic and pharmacodynamic behavior of the drug appears complex, interdependent and of critical importance whereas the treatment of special population cohorts is considered. The diversity of the available formulation strategies and their compatible administration routes, extend from tablets to bolus suspensions and from per os to intravenous, respectively, inheriting the associated strengths and weaknesses. In this comprehensive review, we attempt to elucidate the multi-disciplinary elements spanning the knowledge fields of chemical synthesis, physicochemical properties, pharmacology, clinical applications, biopharmaceutical profile, formulation approaches for different routes of administration and analytical strategies, currently employed to guide the development of sildenafil-based compositions.

Development of a Nanocrystal Formulation of a Low Melting Point API Following a Quality by Design Approach

“…The effects of formulation variables and process parameters governing ball milling comminution coupled with spray drying of Fenofibrate nanosuspensions at temperatures approaching melting point were investigated. The resolved operating conditions supported by experimental and theoretical approaches, suggest that API submicron crystals of approximately 887 nm of average hydrodynamic diameter, bearing the ζ-potential of −16.49 mV, are efficiently obtained employing the Fenofibrate to Pharmacoat/mannitol weighted optimum ratios of 4.075% and 0.75%, respectively, dried at the preferred temperature of 77 • C. Reduction of particle API size below the 1 µm will generate nanocrystals, improving both drug solubility and bioavailability [37]. Therefore, the rationalization of the formulated material's behavior via the proposed QbD methodology assisted by theoretical calculations minimizes the risk of temperature-related degradation of uniformity, at same time reducing development costs by narrowing the focus of the operational space.…”

“…The resolved operating conditions supported by experimental and theoretical approaches, suggest that API submicron crystals of approximately 887 nm of average hydrodynamic diameter, bearing the ζ-potential of −16.49 mV, are efficiently obtained employing the Fenofibrate to Pharmacoat/mannitol weighted optimum ratios of 4.075% and 0.75%, respectively, dried at the preferred temperature of 77 °C. Reduction of particle API size below the 1 µm will generate nanocrystals, improving both drug solubility and bioavailability [37]. Therefore, the rationalization…”

Pharma 4.0-Artificially Intelligent Digital Twins for Solidified Nanosuspensions

“…Specifically, different APIs provide different experimental data and consequently different ANN weights and physichochemical parameters must be plugged to the system’s agent. ANNs, however, carry the flexibility to link different input types with desired outputs, and as such various physicochemical properties can be utilized, constituting this digital twin as a universal predictive platform suitable for BCS II drugs [ 29 ], whereas the iterated processes are examined. Pharma 4.0 capacitating digital twins fused with artificial wisdom will in the future decrease the need for the implementation of experiments and exploit real time manufacturing process data towards the constant adjustment of the tuning parameters, succeeding the control and prediction of the process’s progress and material’s quality attributes in time.…”

New Psychoactive Substances: Major Groups, Laboratory Testing Challenges, Public Health Concerns, and Community-Based Solutions

“…Although most NPSs have been stimulants, anabolic steroids, or hallucinogens, the diversity of likely compounds seem limited by patent and scientifc literature; recent years have been characterized by the extensive range of substances sold as NPS [6,7], which include several synthetic sedatives (e.g., premazepam, methylmethaqualone), synthetic stimulants (e.g., geranamine, mephedrone, desoxypipradrol), and synthetic analogues of Viagra (sildenafl), reported as herbal aphrodisiac products' active compounds [71,72]. Synthetic cannabinoids that are believed to have emerged in December 2008 include two compounds, (C8)-CP 47,497 and JWH-018, frst reported as active components in blends for herbal smoking, and sold as alternatives tomarijuana [73].…”