Dissolution of Danazol Amorphous Solid Dispersions: Supersaturation and Phase Behavior as a Function of Drug Loading and Polymer Type

Abstract

Amorphous solid dispersions (ASDs) are of great interest as enabling formulations because of their ability to increase the bioavailability of poorly soluble drugs. However, the dissolution of these formulations under nonsink dissolution conditions results in highly supersaturated drug solutions that can undergo different types of phase transitions. The purpose of this study was to characterize the phase behavior of solutions resulting from the dissolution of model ASDs as well as the degree of supersaturation attained. Danazol was chosen as a poorly water-soluble model drug, and three polymers were used to form the dispersions: polyvinylpyrrolidone (PVP), hydroxypropylmethyl cellulose (HPMC), and hydroxypropylmethyl cellulose acetate succinate (HPMCAS). Dissolution studies were carried out under nonsink conditions, and solution phase behavior was characterized using several orthogonal techniques. It was found that liquid-liquid phase separation (LLPS) occurred following dissolution and prior to crystallization for most of the dispersions. Using flux measurements, it was further observed that the maximum attainable supersaturation following dissolution was equivalent to the amorphous solubility. The dissolution of the ASDs led to sustained supersaturation, the duration of which varied depending on the drug loading and the type of polymer used in the formulation. The overall supersaturation profile observed thus depended on a complex interplay between dissolution rate, polymer type, drug loading, and the kinetics of crystallization.

Physical chemistry of supersaturated solutions and implications for oral absorption

“…LLPS also has been observed in aqueous 443 solutions during the evaluation of solubility enhancing formulations 444 [39][40][41][42]. The drug-rich species formed following LLPS typically have a 445 size of 100-500 nm when characterized immediately after formation 446 using a technique such as dynamic light scattering [29,39,40,43].…”

“…789 Flux data for supersaturated danazol solutions is shown in Fig. 10, 790 with a saturated danazol solution providing a reference point; the solu-791bility of crystalline danazol is about 1 μg/mL in buffer[39]. As anticipat-792 ed from Eq.…”

“…DLS and NTA have been used to provide information 552 about the size and the size evolution of the drug-rich phase formed 553 via LLPS. Several studies have indicated that the new amorphous 554 phase formed in highly supersaturated solutions is initially very small 555 in size, typically in the range of 100-500 nm[29,39,40,43]. The small 556 size results in the rapid redissolution of the amorphous phase when 557 the concentration drops below the amorphous solubility[29,40,58].…”

“…approximately 8 μg/mL,[39]), and the liquid-liquid phase separation 800 of the system at concentrations higher than the amorphous solubility.801When the solution concentration exceeds the amorphous solubility, a 802 drug-rich phase is formed, and, in the two phase system, the thermody-803 namic activity of the drug in each phase is the same, remaining constant 804 as long as both phases are present and crystallization is avoided.805Addition of more drug simply increases the amount of the drug-rich806 phase, but not the thermodynamic activity of the solute in the system.807Hence the supersaturation is also constant. Since flux depends on solute 808 thermodynamic activity, and correspondingly the supersaturation, this 809 parameter also becomes constant, and consequently a plateau is ob-810 served.…”

Improved Dissolution and Bioavailability of Eprosartan Mesylate Formulated as Solid Dispersions using Conventional Methods

“…In contrast, a solution with a free drug concentration greater than the crystalline solubility has a supersaturation >1, and a thermodynamic driving force for crystallization. 28 The SDs exhibited supersaturated solution owing to inhibition of crystallization during dissolution with free drug concentration below the crystalline solubility. Both theoretical and practical supersaturation value was found to be <1.…”