Thermodynamic Principles for the Design of Polymers for Drug Formulations

Abstract

Polymers play an essential role in drug formulation and production of medical devices, implants, and diagnostics. Following drug discovery, an appropriate formulation is selected to enable drug delivery. This task can be exceedingly challenging owing to the large number of potential delivery methods and formulation and process variables that can interact in complex ways. This evolving solubility challenge has inspired an increasing emphasis on the developability of drug candidates in early discovery as well as various advanced drug solubilization strategies. Among the latter, formulation approaches that lead to prolonged drug supersaturation to maximize the driving force for sustained intestinal absorption of an oral product, or to allow sufficient time for injection after reconstitution of a parenteral lyophile formulation, have attracted increasing interest. Although several kinetic and thermodynamic components are involved in stabilizing amorphous dispersions, it is generally assumed that maximum physical stability, defined in terms of inhibition of drug crystallization, requires that the drug and excipient remain intimately mixed. Phase separation of the drug from its excipient may be the first step that ultimately leads to crystallization. We discuss the role of advanced thermodynamics using two examples: ASD and vitamin E–stabilized ultrahigh–molecular weight polyethylene implants.

Thermomechanical Degradation of Polypropylene – Polystyrene Blends During Extrusion‐Based Melt Blending – A First Survey of Shear‐Induced Molecular Architecture Changes

“…However, the influence of thermo-oxidative and shearinduced polymer degradation during extrusion-based melt blending on the chain regularity is not addressed, although it is known, that changes in chain regularity have a strong impact on the material properties and processability as well. [15][16][17][18] Besides the lack of this information about the chain regularity effects, no studies, which investigate explicitly the thermomechanical degradation behavior of PP/PS blends in extrusion-based melting blending, could be found. This knowledge is of particular relevance for tai-loring properties and processability of the PP/PS blends on the one hand and to suppress manufacturing-based downcycling of this material on the other hand.…”

Thermodynamic Modeling of the Solid–Liquid Phase Transition in Polyethylene Copolymer–Solvent Systems Based on Continuous Thermodynamics and Lattice Cluster Theory

“…The understanding of solid–liquid phase behavior of semi-crystalline polymer–solvent systems is of critical importance to further clarify polymer melting and the corresponding crystallization mechanism. , Especially, the interdependencies of molecular structure information, for example, molecular weight distribution and molecular architecture, with a degree of crystallinity and equilibrium solidification behavior of the polymer are of high interest . Polyethylene serves as one example, which demonstrates a broad variety of molecular structures, in terms of chain length and branching, semi-crystallinity, and, further, solid–liquid phase behavior. , This, in turn, influences besides kinetic phenomena the crystallization process, consequently leading to specific process and product properties. ,, The equilibrium solid–liquid transition of polymers and polymer–solvent systems is one essential issue to develop theories and experiments in the area of polymer crystallization. , This is of particular relevance when copolymers are studied, which have a certain molecular weight distribution and branching characteristic . Several theoretical approaches for predicting the solubility of polymers in solvents have been under development in the last few decades.…”

“…Several theoretical approaches for predicting the solubility of polymers in solvents have been under development in the last few decades. The solid–liquid phase behavior and crystallization of polymers was an active research area in the past, − and it is still today. − This knowledge is also important for polymer characterization methods, which are based on the crystallization of the polymer from the solution. In these methods, the differences in thermodynamic driving forces, which are particularly due to various molecular architectures, are used to separate polyethylene according to their branching, for example, short-chain branching (SCB). − Examples for crystallization-based fractionation techniques are crystallization analysis fractionation (CRYSTAF), temperature rising elution fractionation (TREF), and crystallization elution fractionation (CEF). , For the sake of clearness, the basic principle of CRYSTAF is sketched in Figure .…”

“…The understanding of solid−liquid phase behavior of semicrystalline polymer−solvent systems is of critical importance to further clarify polymer melting and the corresponding crystallization mechanism. 1,2 Especially, the interdependencies of molecular structure information, for example, molecular weight distribution and molecular architecture, with a degree of crystallinity and equilibrium solidification behavior of the polymer are of high interest. 3 Polyethylene serves as one example, which demonstrates a broad variety of molecular structures, in terms of chain length and branching, semicrystallinity, and, further, solid−liquid phase behavior.…”

“…3,4 This, in turn, influences besides kinetic phenomena the crystallization process, consequently leading to specific process and product properties. 1,2,5 The equilibrium solid−liquid transition of polymers and polymer−solvent systems is one essential issue to develop theories and experiments in the area of polymer crystallization. 3,6 This is of particular relevance when copolymers are studied, which have a certain molecular weight distribution and branching characteristic.…”