Supersaturation Potential of Salt, Co-Crystal, and Amorphous Forms of a Model Weak Base

Abstract

High energy solids, such as salts, co-crystals, or amorphous solid dispersions, have been widely used to generate supersaturated aqueous solutions and improve drug bioavailability. However, most research on solubility enhancing strategies has focused on the kinetics of dissolution, and there is relatively little comparison of the different degrees of supersaturation achieved by using different solid state forms of the same compound. Recent studies from our group have demonstrated that the maximum achievable supersaturation is dictated by the aqueous solubility of the amorphous form of the drug. Liquid−liquid phase separation (LLPS) occurs at concentrations above this value. Herein, it was hypothesized that the upper limit of supersaturation that can be achieved from dissolution of various high energy solids is also governed by the amorphous solubility. To test this hypothesis, the dissolution and supersaturation behavior of different solid forms of a model compound, CRH1, were investigated using a variety of techniques. With the exception of CRH1 crystalline free base, all solid forms generated supersaturated solutions. The extent of supersaturation, onset of crystallization time, and area under the curve increased significantly when a polymer with crystallization inhibitory properties was present in the dissolution medium or incorporated in the formulation (in the case of amorphous solid dispersions). In the presence of the polymeric crystallization inhibitor, several solid state forms, including the amorphous solid dispersion and the salts, dissolved to concentrations above the amorphous free form solubility and underwent LLPS, generating a drug-rich phase. Other solid state forms underwent crystallization prior to attaining the amorphous solubility and showed no evidence of LLPS (co-crystal and glass forms). These studies should aid in solid state form selection and formulation and help to understand how to achieve maximized supersaturation in vivo.

The Selection of a Pharmaceutical Salt—The Effect of the Acidity of the Counterion on Its Solubility and Potential Biopharmaceutical Performance

“…Studies have found that solutions generated from drugs with API in salt forms can be maintained at supersaturation with addition of a polymeric crystallization inhibitor to the formulation. 29 Thus, a "spring parachute" effect can be created inside GI tract with this salt being a "spring" to achieve initial supersaturation and the crystallization inhibitor being a "parachute" to maintain the solution at a supersaturated level. 30,31 In contrast, increased solubility in gastric environment would not be anticipated if the besylate salt should be selected as the development solid form for compound A.…”

Dissolution Advantage of Nitazoxanide Cocrystals in the Presence of Cellulosic Polymers

“…Due to this former behavior, cocrystals are potential candidates for the development of supersaturating drug delivery systems [20,21]. A strategy to control cocrystal dissolution, drug supersaturation and precipitation is the use of supersaturated formulations, which incorporates additives and excipients such as cyclodextrins, surfactants and polymers [22].…”

Supersaturating drug delivery systems: The potential of co-amorphous drug formulations

“…The drug concentration of the water-rich phase corresponds to the amorphous solubility of the drug while the excess drug precipitates forming a dispersed, colloidal (nano-droplets) amorphous drug-rich phase (Indulkar et al, 2016;Sun et al, 2016). LLPS thus typically occurs under the following conditions: (i) in the presence of precipitation inhibitors, (ii) with weakly basic compounds when the pH of the solution is increased and (iii) upon dissolution of salts (Almeida e Sousa et al, 2016;Indulkar et al, 2015). After LLPS, the solution is still supersaturated with respect to the equilibrium solubility of the stable crystal form and crystallization will eventually occur at some time point (Fig.…”