Optimized synthesis and characteristics of novel thermoplastic polymers for solid formulation
Loading...
Date issued
Authors
Editors
Journal Title
Journal ISSN
Volume Title
Publisher
Reuse License
Abstract
The present study presents a detailed exploration aimed at tackling one of the significant challenges in pharmaceutical sciences, namely the poor solubility of active pharmaceutical ingredients (APIs). The issue of poor solubility is pivotal in the case of BCS class II APIs as it directly impacts the therapeutic efficacy of drugs by limiting their bioavailability. The thesis methodically advances the research field by the utilization of tuned polymers, specifically in the form of amorphous solid dispersions (ASDs), to enhance API solubility.
The first part of this study lays the groundwork by focusing on the synthesis and detailed characterization of modified polymers, particularly those derived from polyvinylpyrrolidone-co-vinyl alcohol (PVP-co-PVA). The modification agents include functional groups such as substituted amines, aromatic moieties, polyethylene glycol groups, and alkyl chains. This is complemented by characterization techniques such as Nuclear Magnetic Resonance (NMR) spectroscopy, Differential Scanning Calorimetry (DSC), Thermogravimetric Analysis (TGA), and melt rheology to understand the polymers' physicochemical properties and their interactions with APIs. The findings reveal the successful synthesis of a series of novel polymers with varied compositions that not only demonstrate enhanced solubility with a model API but also exhibit suitable mechanical and thermal properties for extrusion processes. The analysis of these structure-property relationships shows that the solubility enhancements can be influenced by varying the polymers’ molecular architecture, including monomer types and chain configurations that affect their glass transition temperatures, viscosity, and thermal stability.
The second part of the thesis includes the synthesis of polymers through free radical polymerization which allows for controlled variation of molecular structure thus affecting the polymer properties significantly. The tailored synthesis of these polymers aims to optimize properties crucial for extrusion processes such as glass transition temperature, thermal stability, and melt viscosity. A scalable synthesis is developed incorporating up to four comonomers. The comonomer selection consists of vinyl acetate, N-vinyl pyrrolidone, a hydrophilic polyethylene glycol methacrylate and a hydrophobic aromatic vinyl benzoate. Polymers are generated with varying ratios of these comonomers respectively. In an explorative design of experiments (DoE) approach, the specific influences of the different comonomers are evaluated and one high potential polymer composition is identified. Candidates with outstanding dissolution performance have been identified and the structure-property relationship previously developed was proven.
This thesis thoroughly discusses the potential of these polymers to advance pharmaceutical extrusion techniques at lower temperatures, emphasizing their capability to enhance the solubility of a model API and thereby potentially increase the bioavailability of drugs. The nuanced interaction between the polymers and APIs, influenced by the polymers' chemical and physical properties, is critically explored to understand how these interactions can be optimized to enhance drug delivery systems.
Driven by the necessity to optimize both drug solubility and manufacturing processes, the thesis’ primary objective is to engineer thermoplastic polymers tailored for decreasing the HME processing temperatures in the formulation of APIs. This involves the synthesis of modified polymers and an in-depth analysis of the structure-property relationships that influence their functionality in enhancing API solubility and processability.
In conclusion, the research encapsulated in this study demonstrates the development of novel pharmaceutical materials, particularly emphasizing the synthesis of thermoplastic polymers that meet the dual requirements of enhanced API solubility and effective extrusion processability. The findings not only contribute to the academic field of polymer chemistry and pharmaceutical sciences but also hold practical implications, offering first insights for a potential solution of challenges in the field of solid formulation of poorly water-soluble drugs.
Looking ahead, exploring other monomeric systems and their influence on the polymer/API interaction may enable the formulation of a given API to tailor the dissolution behavior and its manufacturing. Furthermore, the proposed synthesis process can serve as a platform to incorporate diverse monomers fulfilling the specific prerequisites posed by researchers. For the definition of those requirements, predictive, machine learning formulation tools may be employed to accelerate the discovery of the ideal structure, and the developed synthesis platform can then be used for the tailored synthesis thereof. It is also recommended to conduct long-term stability studies and in vivo trials to fully determine the clinical relevance of the developed polymers.