Understanding the Differences Between Cocrystal and Salt Aqueous Solubilities

Abstract

This work challenges the popular notion that pharmaceutical salts are more soluble than cocrystals. There are cocrystals that are more soluble than salt forms of a drug and vice-versa. It all depends on the interplay between the chemistry of both the solid and solution phases. Aqueous solubility, pH, and supersaturation index (SA = S/S or S/S) of cocrystals and salts of a basic drug, lamotrigine (LTG), were determined, and mathematical models that predict the influence of cocrystal/salt K and K were derived. K and SA followed the order LTG-nicotinamide cocrystal (18) > LTG-HCl salt (12) > LTG-saccharin salt (5) > LTG-methylparaben cocrystal (1) > LTG-phenobarbital cocrystal (0.2). The values in parenthesis represent SA under nonionizing conditions. Cocrystal/salt solubility and thermodynamic stability are determined by pH and will drastically change with a single unit change in pH. pH values ranged from 5.0 (saccharin salt) to 6.4 (methylparaben cocrystal) to 9.0 (phenobarbital cocrystal). Cocrystal/salt pH dependence on pK and pK shows that cocrystals and salts exhibit different behavior. Solubility and pH are as important as supersaturation index in assessing the stability and risks associated with conversions of supersaturating forms.

Same or different – that is the question: identification of crystal forms from crystal structure data

“…A common understanding in chemistry is that molecular substances might crystallise into different forms broadly classified as polymorphs, 1, 2 solvates, 3 salts, co-crystals, tautomers [4][5][6][7][8][9] and solid solutions. 10,11 Other forms might appear in response to external stimuli (thermal, electromagnetic, mechanical etc.)…”

Dissolution Advantage of Nitazoxanide Cocrystals in the Presence of Cellulosic Polymers

“…A pharmaceutical cocrystal can offer multiple benefits for physicochemical and biopharmaceutical properties of APIs, such as increased solubility and dissolution rates, improvement of mechanical properties, and stability [13][14][15]. Particularly, cocrystals have exhibited higher, similar or lower solubility compared to the parent API, depending on the nature of the coformer and the solution conditions [16,17]. Solubility advantages of cocrystals over parent drugs can be higher by orders of magnitude, however, this also represents a risk due to precipitation to the less soluble form of the drug at supersaturated concentrations reached during the dissolution process [18,19].…”

Obtaining Cocrystals by Reaction Crystallization Method: Pharmaceutical Applications

“…A recent study of lamotrigine (LTG) cocrystals and salts synthesized by the RCM focused on challenging the popular notion that pharmaceutical salts are more soluble than cocrystals [ 72 ]. Among the cocrystals and salts evaluated, the LTG/NCT cocrystal were observed to have the greatest aqueous solubility, followed by LTG/hydrochloric acid salt, LTG/saccharin salt, and the less soluble cocrystals LTG/methylparaben and LTG/phenobarbital.…”