Challenges and Strategies for Solubility Measurements and Dissolution Method Development for Amorphous Solid Dispersion Formulations

Abstract

This manuscript represents the view of the Dissolution Working Group of the IQ Consortium on the challenges of and recommendations on solubility measurements and development of dissolution methods for immediate release (IR) solid oral dosage forms formulated with amorphous solid dispersions. Nowadays, numerous compounds populate the industrial pipeline as promising drug candidates yet suffer from low aqueous solubility. In the oral drug product development process, solubility along with permeability is a key determinant to assure sufficient drug absorption along the intestinal tract. Formulating the drug candidate as an amorphous solid dispersion (ASD) is one potential option to address this issue. These formulations demonstrate the rapid onset of drug dissolution and can achieve supersaturated concentrations, which poses significant challenges to appropriately characterize solubility and develop quality control dissolution methods. This review strives to categorize the different dissolution and solubility challenges for ASD associated with 3 different topics: (i) definition of solubility and sink conditions for ASD dissolution, (ii) applications and development of non-sink dissolution (according to conventional definition) for ASD formulation screening and QC method development, and (iii) the advantages and disadvantages of using dissolution in detecting crystallinity in ASD formulations. Related to these challenges, successful examples of dissolution experiments in the context of control strategies are shared and may lead as an example for scientific consensus concerning dissolution testing of ASD.

Effect of Molecular Weight on the Dissolution Profiles of PEG Solid Dispersions Containing Ketoprofen

“…The main advantage of solid dis”Irs’on is their ability to form supersaturated solutions of the given API. In an ideal system, the 100% of the API is in amorphous state, thus, the dissolution of the matrix polymer will result in a supersaturated colloidal solution, in which the kinetic solubility is multiple times higher than the thermodynamic solubility which depends on the physicochemical properties of the crystalline form [ 51 ]. The difference between the two solubility values can be observed when comparing Figure 1 , Figure 2 , Figure 3 , Figure 4 , Figure 5 and Figure 6 .…”

Crystallinity: A Complex Critical Quality Attribute of Amorphous Solid Dispersions

“…However, optimizing release test variables to address the complexity of ASD formulations, in terms of drug physicochemical properties (e.g., crystallization tendency), level of crystallinity, crystal reference material selection, and formulation characteristics is a tremendous challenge . A recent publication by the IQ Consortium Dissolution Working Group reviewed challenges of dissolution testing to detect crystallinity in amorphous solid dispersions and presented case studies …”

“…Sink and nonsink conditions can be defined by the dimensionless sink index (SI), ,, where the following equations represent sink index with respect to crystalline solubility (eq ) and amorphous solubility (eq ): where C cr and C am represent the crystalline and amorphous solubility respectively, dose is the amount of drug added to the dissolution experiment, and V is the media volume. Several studies have begun to illuminate the predictive quality of a dissolution test based on sink index, representing the driving force for dissolution and crystallization, for detecting or evaluating the impact of crystallinity on the dissolution performance of an ASD. ,, It should be noted that amorphous solubility is defined as the concentration at which a liquid–liquid phase separation event may be observed, , and this value may change depending on the composition of the amorphous drug–polymer system and media additives. − …”

“…Dissolution/Supersaturation Considerations. Risk factors for the presence of crystallinity on dissolution performance have been discussed by Moseson et al 9 and Purohit et al 124 Whether or not an in vitro dissolution test can detect the presence of crystallinity or its impact be observed depends on the design of the test method, 80,124,126,140 and a QC test method with sink conditions is unlikely to provide this level of scrutiny. Beyond previously discussed complexities of amorphous drug−polymer systems such as those highlighted throughout the manuscript (crystallization tendency, solutionmediated crystallization, solid-mediated crystallization, supersaturation conditions, crystal properties) and their relation to the impact of crystallinity in an ASD product, it is pertinent to highlight some additional advanced concerns regarding The use of a one-stage or two-stage dissolution test may be critically important to detect certain failure mechanisms.…”

Despite warnings, co‐medication with proton pump inhibitors and dasatinib is common in chronic myeloid leukemia, but XS004, a novel oral dasatinib formulation, provides reduced pH‐dependence, minimizing undesirable drug–drug interactions

“…The techniques are each associated with challenges, but with a successful approach, the variability in plasma pharmacokinetics (PK) is reduced, as the solubility and the intestinal absorption improve, and most importantly patient compliance, safety, and efficacy can be increased. 21,22 XS004 (Xspray, Solna, Sweden) is a novel immediate release and ASD formulation of dasatinib produced with the HyNap™ technology. 23 XS004 is designed to provide an increased solubility of dasatinib in acidic to neutral pH conditions, mitigating gastric pH dependency, leading to reduced variability, increased absorption, and bioavailability of dasatinib.…”