Saccharin Salts of Active Pharmaceutical Ingredients, Their Crystal Structures, and Increased Water Solubilities

Abstract

Salts of active pharmaceutical ingredients (APIs) have been traditionally used in drug formulations because of improved properties with respect to solubility, stability, or bioavailability. Saccharin has been used as an acid for salt formation with APIs in a few cases hitherto. In this paper, we have explored the generality of this property and have isolated saccharinates of quinine, haloperidol, mirtazapine, pseudoephedrine, lamivudine, risperidone, sertraline, venlafaxine, zolpidem, and amlodipine. These salts have been characterized with single-crystal X-ray methods. The structures contain many hydrogen bonds of the O−H···N(-), N(+)-H···N(-), N(+)−H···O, N−H···O, O−H···O and N−H···N type, with auxiliary C−H···N(-) and C−H···O interactions. These saccharinates are mostly very soluble in water when compared to the free base. Additionally, aqueous solutions of these API saccharinates are of moderate pH. Both these properties may be advantageous in the pharmaceutical industry. In general, most saccharinates would appear to have high water solubility, and this follows from the molecular structure of the anion, which is donor-poor and acceptor-rich in terms of hydrogen-bonding functionalities. If an API of insufficient basicity is treated with saccharin, it may form a hydrogen-bonded cocrystal wherein proton transfer from saccharin to the API does not take place. This phenomenon was found in the cocrystal saccharin−piroxicam.

5-(4-Ammonio-2-Oxopyrimidine-1(2H)-yl)-1,3-Oxathiolane-2-Carboxylate (lamivudine acid) Semihydrate: The Six-Fold Symmetry Created by Hydrogen Bond Network

“…Table 1). The bond lengths and angles pattern is similar to that found in the structure of Lamivudine saccharinate [3], which might be regarded as an additional proof for the protonation site in the sixmembered ring.…”

An analysis of the experimental and theoretical charge density distributions of the piroxicam–saccharin co-crystal and its constituents

“…Crystals of (3) were obtained following the method described by Banerjee et al 3 , from a mixture of equimolar amounts of…”

“…Co-crystallisation is a similar solution to the problem and has previously been investigated by Banerjee et al through the piroxicam-saccharin co-crystal 3 , which has been found to modify the physicochemical properties of piroxicam compared to free piroxicam.…”

Thermal Behavior of Benzoic Acid/Isonicotinamide Binary Cocrystals

“…5 The bioavailability in dogs of 2-[4-(4-chloro-2-fluorophenoxy)phenyl]pyrimidine-4-carboxamide, a developmental sodium channel blocker, has been found to increase upon formation of a glutaric acid co-crystal. 6 In addition, co-crystal formation can solve challenges associated with bitter or unpleasant tasting APIs, for instance by combining them with saccharin, 7 and can result in improvements in processability. 8,9 In favourable instances, two APIs may be combined in a co-crystal.…”