Salt and Cocrystals of Sildenafil with Dicarboxylic Acids: Solubility and Pharmacokinetic Advantage of the Glutarate Salt

Abstract

Sildenafil is a drug used to treat erectile dysfunction and pulmonary arterial hypertension. Because of poor aqueous solubility of the drug, the citrate salt, with improved solubility and pharmacokinetics, has been marketed. However, the citrate salt requires an hour to reach its peak plasma concentration. Thus, to improve solubility and bioavailability characteristics, cocrystals and salts of the drug have been prepared by treating aliphatic dicarboxylic acids with sildenafil; the N-methylated piperazine of the drug molecule interacts with the carboxyl group of the acid to form a heterosynthon. Salts are formed with oxalic and fumaric acid; salt monoanions are formed with succinic and glutaric acid. Sildenafil forms cocrystals with longer chain dicarboxylic acids such as adipic, pimelic, suberic, and sebacic acids. Auxiliary stabilization via C-H···O interactions is also present in these cocrystals and salts. Solubility experiments of sildenafil cocrystal/salts were carried out in 0.1N HCl aqueous medium and compared with the solubility of the citrate salt. The glutarate salt and pimelic acid cocrystal dissolve faster than the citrate salt in a two hour dissolution experiment. The glutarate salt exhibits improved solubility (3.2-fold) compared to the citrate salt in water. Solubilities of the binary salts follow an inverse correlation with their melting points, while the solubilities of the cocrystals follow solubilities of the coformer. Pharmacokinetic studies on rats showed that the glutarate salt exhibits doubled plasma AUC values in a single dose within an hour compared to the citrate salt. The high solubility of glutaric acid, in part originating from the strained conformation of the molecule and its high permeability, may be the reason for higher plasma levels of the drug.

Solubility Enhancement of Lornoxicam by Crystal Engineering

“…The most common causes of low oral bioavailability are poor solubility and low permeability of active pharmaceutical ingredient (API) [1] . Multiple approaches have been adopted to improve the solubility of poorly water soluble APIs including micronization [2] , complexation with cyclodextrins [3] , cosolvency [4,5] , solid dispersions [6] , salt forms [7] , nanoparticles [8] and surfactants [9] , etc. Cocrystals are a class of multicomponent molecular crystals demonstrated to enhance the solubility, bioavailability and/or stability of API, which has been proposed as a unique crystal engineering approach to alter the physicochemical properties of compounds [10][11][12] .…”

Indentation Plasticity and Fracture Studies of Organic Crystals

“…It is evident from the literature that the mechanical properties and physiochemical properties were improved by forming cocrystals of caffeine with methyl gallate [96] ibuprofen, as well as flurbiprofenwith nicotinamide [97] and vanillin isomers with 6-chloro-2,4-dinitroaniline [98], etc. Similarly, Sanphui et al [95] observed that the salt forms (i.e., voriconazole + HCl) were considerably stiffer (80%) and harder (58%) than voriconazole and its cocrystals. Further, the loading portions of the load-displacement curves obtained in the salt form showed pop-ins (Figure 13), indicating discontinuous plastic deformation, and their magnitude was the integer multiples of the interplanar spacing of the specific planes indented in the study.…”

“…In fact, this method is known as the co-crystallization approach, known to alter the physicochemical and mechanical properties of Active Pharmaceutical Ingredients (APIs). [94,95]. It is evident from the literature that the mechanical properties and physiochemical properties were improved by forming cocrystals of caffeine with methyl gallate [96] ibuprofen, as well as flurbiprofenwith nicotinamide [97] and vanillin isomers with 6-chloro-2,4-dinitroaniline [98], etc.…”

Mechanical property design of molecular solids

“…Indeed, the design of functional materials with specific physical and chemical properties that are targeted towards particular applications has gained considerable ground in the recent past. Examples include design and synthesis of metal organic frameworks (MOFs) for gas adsorption and catalysis, polymers for optimized photochemical and photophysical characteristics, active pharmaceutical ingredients (APIs) with enhanced biodissolvability and pharmacokinetics, and biomaterials with excellent biocompatibility [10][11][12][13][14][15].…”