Amorphous-Amorphous Phase Separation in API/Polymer Formulations

Abstract

The long-term stability of pharmaceutical formulations of poorly-soluble drugs in polymers determines their bioavailability and therapeutic applicability. However, these formulations do not only often tend to crystallize during storage, but also tend to undergo unwanted amorphous-amorphous phase separations (APS). Whereas the crystallization behavior of APIs in polymers has been measured and modeled during the last years, the APS phenomenon is still poorly understood. In this study, the crystallization behavior, APS, and glass-transition temperatures formulations of ibuprofen and felodipine in polymeric PLGA excipients exhibiting different ratios of lactic acid and glycolic acid monomers in the PLGA chain were investigated by means of hot-stage microscopy and DSC. APS and recrystallization was observed in ibuprofen/PLGA formulations, while only recrystallization occurred in felodipine/PLGA formulations. Based on a successful modeling of the crystallization behavior using the Perturbed-Chain Statistical Associating Fluid Theory (PC-SAFT), the occurrence of APS was predicted in agreement with experimental findings.

Spray-Dried Amorphous Solid Dispersions of Griseofulvin in HPC/Soluplus/SDS: Elucidating the Multifaceted Impact of SDS as a Minor Component

“…The T g of HPC, which is in the range of −25 to 0 • C [43], could not be measured due to limitation of our equipment. A glass transition for Sol (amorphous) was noted at 72.4 • C. A single T g was observed corroborating the molecular level dispersion [60,61] in all powders except S-HPC-1:1 with 28% GF crystallinity (see Table 4). Only a glass transition was noted in the DSC traces of S-Sol-1:3, SDS; S-Sol-1:5, SDS; and S-Sol-1:5.…”

Phase behavior of ASDs based on hydroxypropyl cellulose

“…A storage below the ASDs T g enhances its kinetic stability via a reduced molecular mobility and thus API-crystallization velocity ( Theil et al, 2017 ). An API load in the ASD above its solubility might cause crystallization ( Tao et al, 2009 ; Tian et al, 2013 ), the occurrence of amorphous phase separation might lead to a local enrichment of amorphous API and accelerated crystallization ( Saboo and Taylor, 2017 ; Marsac et al, 2010 ; Yang et al, 2013 ; Six et al, 2003 ; Luebbert et al, 2017 ). Both, crystallization and amorphous phase separation are highly unwanted as they alter the ASDs dissolution performance ( Saboo et al, 2020 ; Purohit and Taylor, 2015 ; Tian et al, 2016 ; Chen et al, 2018b ).…”

Developing HME-Based Drug Products Using Emerging Science: a Fast-Track Roadmap from Concept to Clinical Batch

“…Despite certain assumptions and limitations, these models can provide working thermal-phase diagrams of a given drug and polymer that are equally important for the processing temperature selection in HME. For example, the group of Sadowski has shown the applicability of PC-SAFT-derived thermal-phase diagrams to determining the drug-polymer solubility curves and miscibility gaps, even in the presence of moisture, and verified it using the experimental stability data for the ASDs containing physico-chemically diverse APIs and polymers (55)(56)(57)(58)(59)(60).…”