Chapter 8 - Tadalafil

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Abstract

Tadalafil is PDE5 inhibitor that has recently been approved for the treatment of ED. The mechanism of action of tadalafil is similar to sildenafil and vardenafil through the inhibition of PDE. In both chemical structure and PDE subtype selectivity profile, tadalafil differs markedly from sildenafil and vardenafil. Compared with sildenafil and vardenafil, tadalafil exhibits a prolonged plasma residence and window of therapeutic response. The physical properties, spectroscopic data and chromatographic methods of determination of tadalafil are documented.

Section snippets

Uses and Applications

Erectile dysfunction (ED), a common and widespread health problem that affects approximately 30 million men in the United States [1], is suggested to represent an early clinical manifestation of a diffuse vascular disease [2], [3].

Tadalafil (Cialis®) [4], [5], [6], [7], [8], [9], [10], [11], which is a cyclic guanosine monophosphate (cGMP) specific Type V phosphodiesterase (PDE5) inhibitor similar to sildenafil (Viagra®) [12] and vardenafil (Levitra®) [13], has an improved PDE5/PDE6 selectivity

Chemical name

  • (6R,12aR)-6-(1,3-Benzodioxol-5-yl)-2,3,6,7,12,12a-hexahydro-2-methylpyrazino[1′,2′:1,6]pyrido[3,4-b]indole-1,4-dione.

  • (6R,12aR)-2,3,6,7,12,12a-Hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)pyrazino[2′,1′:6,1]pyrido[3,4-b]indole-1,4-dione.

Generic name [17]

Tadalafil

Trade name

Cialis.

Empirical

C22H19N3O4

Structural

Molecular weight, HRMS and CAS registry number [17,18]

  • MW = 389.40

  • (6R,12aR)-(+)-Tadalafil (1); HRMS calcd M+ for C22H19N3O4 389.1376; found 389.1386

  • (6S,12aR)-(+)-Tadalafil (8); HRMS calcd M+ for C22H19N3O4 389.1376, found 389.1387 (6-epi-tadalafil)

  • CAS = 171596-29-5

Optical rotation [17,18]

  • (6R,12aR)-(+)-Tadalafil (1); [

Melting point

  • (6R,12aR)-(+)-Tadalafil (1); 302–303 °C

  • (6S,12aR)-(+)-Tadalafil (8); 286–288 °C (6-epi-tadalafil)

  • (6R,12aS)-(−)-Tadalafil (11); 295–296 °C (12a-epi-tadalafil)

Solubility

Practically insoluble in water; very slightly soluble in ethanol.

Appearance

A white crystalline powder.

Peak plasma concentration

378 ng/mL occurs 2 h postdose

Apparent volume of distribution (Vd/F)

62.6 L

Apparent oral clearance (CL/F)

2.48 L/h.

The mean elimination half-life

17.5 h.

Duration of action

36 h

Method of Preparation

(+)-(6R,12aR)-2,3,6,7,12,12a-Hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-pyrazino-[2′,1′:6,1]pyrido[3,4-b]indole-1,4-dione; Cialis; 1 [(+)-Tadalafil] is one of the well-known PDE5 inhibitors indicated for the treatment of ED [7], [8], [9].

Infrared spectrum

  • The FT-IR spectrum of (+)-tadalafil (1) as KBr disc is presented in Fig. 8.2. Principal peaks at wave numbers IR (KBr film) 3328, 2904, 1677, 1649, 1489, 1438, 1401, 1323, 1269, 1242, 1152, 1097, 1041, 939, 922, 746 cm 1.

  • The IR spectrum of (−)-12a-epi-tadalafil (11) as KBr film was 3326, 2902, 1676, 1649, 1489, 1437, 1400, 1323, 1269, 1241, 1150, 939, 922, 746 cm 1.

Nuclear magnetic resonance spectra

1H, 13C NMR, and other 2D spectra were recorded in DMSO-d6 at 500MHz, Brucker instrument (Brucker Company, USA); chemical shifts are

X-ray powder diffractometry of tadalafil with poloxamer 407

The XRPD pattern of tadalafil displayed intense and sharp peaks (Fig. 8.13A), indicating its crystalline nature. Relative decrease in crystallinity (RDC value) was determined by comparing some representative peak heights in the diffraction patterns of the binary systems with those of a reference (pure tadalafil). Tadalafil (Fig. 8.13A) showed sharp peaks at 7.33, 12.62, 14.47, 14.56, 18.49, and 21.14° (2θ) with peak intensities of 2798, 243, 1043, 1282, 353, and 246, respectively. The

HPLC/UV

A simple and sensitive high-performance liquid chromatographic (HPLC) method for the determination of tadalafil in 50 μL of rat plasma was described [33]. Tadalafil and the internal standard lamotrigine were extracted with 0.5 mL of tert-butyl methyl ether, after the samples alkalinized with 20 μL of sodium hydroxide solution (1 N). Chromatographic separation was achieved on a C18 column with the mobile phase of acetonitrile: water containing 20 mM phosphate buffer (pH 7) (35/65, v/v), at a flow

An overview

The term pharmacodynamics covers all actions of a drug on the different body organs and in turn their functions (e.g., blood pressure, heart rate, vision). The pharmacodynamic interactions of any drug are influenced by the number of receptors available in the target organ and the affinity of the compound to the receptors in question. The most important parameters concerning the pharmacodynamic properties of a drug are its biochemical potency and its organ (PDE) selectivity [1], [2], [3], [52],

An overview

Tadalafil is a potent and selective PDE5 inhibitor under regulatory review for the treatment of ED. In a clinical trial, tadalafil showed a clinical response in erectile function for up to 24 h postdosing.

In both chemical structure and PDE subtype selectivity profile, tadalafil differs markedly from sildenafil and vardenafil. These disparities are indicated by the respective suffixes: dalafil and denafil. Compared with sildenafil and vardenafil, tadalafil exhibits a prolonged plasma residence

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