Choosing Appropriate Solvents for ASD Preparation

Abstract

Amorphous solid dispersions (ASDs) are often used for formulating poorly water-soluble active pharmaceutical ingredients (APIs). In an ASD, the amorphous API is embedded in a suitable matrix excipient in order to stabilize the amorphous state and control the dissolution performance. ASDs can be prepared by commonly dissolving the API and the polymer in a suitable organic solvent which is evaporated afterward (e.g., via spray drying) aiming at a homogeneous API distribution in the polymer matrix. Sometimes, unexpected solvent influences on the heterogeneity of the dry ASD are observed. Thermodynamic predictions using the Perturbed-Chain Statistical Associating Fluid Theory combined with experimental investigations via Raman spectroscopy, differential scanning calorimetry, and microscopy performed in this work revealed the amorphous phase separation (APS) between the solvent and the polymer as causing the ASD heterogeneities. It will be shown that thermodynamic modeling allows for identifying appropriate solvents that will neither show APS with the polymeric excipient nor at any time of the drying process of ASD formulations.

Predicting process design spaces for spray drying amorphous solid dispersions

“…(9) . ( Luebbert et al, 2018a ) Here, y solvent is the mole fraction of the solvent in the vapor phase, p is the total pressure (the product of these two is the solvent partial pressure used in Eq. (2) ) and p solvent LV is the solvent vapor pressure which depends on temperature.…”

“…Besides unwanted liquid-liquid (amorphous) phase separation and API crystallization, residual solvent can negatively influence the kinetic stability of an ASD, as residual solvent leads to an enhanced molecular mobility, and thus to kinetic destabilization. ( Dohrn et al, 2021 ; Luebbert et al, 2018a ; Prudic et al, 2014a ; Prudic et al, 2015 )…”

“…by affecting API solubility and glass transition ( T g ), or by inducing liquid-liquid phase separation. ( Dohrn et al, 2021 ; Luebbert et al, 2018a ) Several solvent effects on the ASD stability or homogeneity are reported in literature( Costa et al, 2016 ; Wu et al, 2011 ; Rashid et al, 2014 ; Wan et al, 2013 ) and discussed regarding solubility, solvent-induced phase separation, residual-solvent content, and T g using ternary phase diagrams of API/polymer/solvent systems. ( Dohrn et al, 2021 ; Luebbert et al, 2018a ; Dohrn et al, 2020a ; Dohrn et al, 2020b )…”

“…However, to obtain a homogeneous ASD via spray drying, the phase behavior (phase separation and API crystallization) of API/polymer/solvent systems must be considered as a critical quality attribute throughout the whole spray-drying process. ( Dohrn et al, 2021 ; Luebbert et al, 2018a )…”

“…The thermodynamic phase behavior of API/polymer/solvent mixtures was intensively experimentally validated in previous works. ( Dohrn et al, 2021 ; Luebbert et al, 2018a ; Prudic et al, 2015 ) In this work, reasonable process design spaces avoiding liquid-liquid phase separation during drying were predicted. For that purpose, inlet temperature, API load in the ASD, selected solvent and solvent partial pressure (i.e.…”