Why sildenafil and sildenafil citrate monohydrate crystals are not stable?

Abstract

Sildenafil citrate was crystallized by various techniques aiming to determine the behavior and factors affecting the crystal growth. There are only 2 types of sildenafil obtaining from crystallization: sildenafil (1) and sildenafil citrate monohydrate (2). The used techniques were (i) crystallization from saturated solutions, (ii) addition of an antisolvent, (iii) reflux and (iv) slow solvent evaporation method. By pursuing these various methods, our work pointed that the best formation of crystal (1) was obtained from technique no. (i). Surprisingly, the obtained crystals (1) were perfected if the process was an acidic pH at a cold temperature then perfect crystals occurred within a day. Crystals of compound (2) grew easily using technique no. (ii) which are various polar solvents over a wide range of pH and temperature preparation processes. The infrared spectroscopy and nuclear magnetic resonance spectra fit well with these two X-ray crystal structures. The crystal structures of sildenafil free base and salt forms were different from their different growing conditions leading to stability difference.

Physicochemical Properties of Bosentan and Selected PDE-5 Inhibitors in the Design of Drugs for Rare Diseases

“…Figure 5 indicates that TA analysed in the present study conforms to form I. The influence of the crystallization process on the properties of SIL crystals was studied in details by Sawatdee et al (36). A survey of the literature data on BOS reveals that about eight crystalline forms of BOS have been described so far (Table III) (34,35).…”

Preparation and physicochemical characterization of sildenafil cocrystals

“…The free base sildenafil was crystallized from methanol as parallelogram plate crystals and compared the crystal appearance that described elsewhere. [ 18 ] The sildenafil crystals are also confirmed by nuclear magnetic resonance (NMR) results.…”

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

“…Sildenafil citrate and sildenafil base produce similar spectra except from the broad bands, i.e., lower than 3411 cm −1 , which represent the O-H stretching of the citrate [ 35 ]. The most characteristic peak of both substances is due to the -C=O vibration, appearing in a band of strong intensity at 1703 cm −1 .…”

“…The most characteristic peak of both substances is due to the -C=O vibration, appearing in a band of strong intensity at 1703 cm −1 . Other characteristic bands are considered: the stretching of the secondary amides N-H at 3300 cm −1 , the N-H bending vibration at 1650-1580 cm −1 , the asymmetrical stretch of S=O at 1359 cm −1 and the symmetrical one at 1172 cm −1 [ 35 ]. IR measurements have been widely used as a fast qualitative method for the analysis of adulteration of natural products (marketed herbal aphrodisiacs) with sildenafil [ 36 , 37 ] and also for the detection of counterfeit tablets [ 38 , 39 ].…”

“…Several methods have been tested to advance the crystallization process of sildenafil i.e., solution crystallization, antisolvent addition, reflux and slow solvent evaporation [ 35 ]. The molecule is built around a rigid central core fragment which consists of a π-conjugated bicyclic pyrazolopyrimidone and a phenyl ring.…”