Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.553143
Title: Synthesis of a novel crosslinked polyvinylpyrrolidone carriers to enhance the dissolution of poorly-water soluble drugs : studies on the synthesis of novel crosslinked polyvinylpyrrolidone polymers and analysis of their influence on the physico-chemical properties of ibuprofen dispersed within these carriers
Author: Niemczyk, Anna Irena
Awarding Body: University of Reading
Current Institution: University of Reading
Date of Award: 2011
Availability of Full Text:
Access from EThOS:
Abstract:
Improving dissolution of poorly-water soluble drugs and hence their bioavailability represents one of the major challenges within pharmaceutical formulation design. Commercial crosslinked polyvinylpyrrolidone (PVP) attracts attention as a drug carrier since it can increase wettability, specific surface area and dissolution rate of poorly-water soluble drugs. Therefore, crosslinked PVP appears to be a promising carrier especially for Biopharmaceutical Classification System (BCS) Class 11 drugs featuring high permeability but poor solubility. The aim of the studies was to synthesize novel crosslinked PVP with extended potential for hydrogen bonding interactions and to evaluate its application as a drug carrier in physical mixtures with ibuprofen (IB). In particular, the thesis seeks to elucidate the nature of IB-PVP interactions, especially in terms hydrogen bonding, drug crystallinity disruption and enhancements in IB dissolution rate. The studies involved synthesis of novel PVP crosslinkers with hydrogen bonding potential. The target structure of the novel crosslinkers was composed of two NVP units which were linked by different lengths of oligo ether chains. The multi-step synthesis of the novel crosslinkers afforded material with an acceptable overall yield of 27%, while in the case of an alternate one-step synthesis the yield did not exceed 9%. A series of free radical polymerisation reactions were carried out affording six novel crosslinked PVP polymers varying in the length of the oligo ether chains ("5 PVP" and "7 PVP") and in the density of crosslinking (the crosslinker content in the feed mixture: 1 wt%, 2.5 wt%, 5 wt%), i.e.: 7 PVP 5%, 7 PVP 2.5%, 7 PVP 1% and 5 PVP 5%, 5 PVP 5%, 5 PVP 5%. Six homogenous physical mixtures of IB (30 wt%) with novel crosslinked PVP polymers and a control mixture containing commercial crosslinked PVP were prepared using a Turbula mixer. FT-IR spectroscopic analysis of the physical mixtures confirmed the presence of hydrogen bonding interactions between IB and all the polymers. The novel PVP polymers with the highest contents of crosslinker were the most effective in disrupting IB crystallinity and in enhancing IB dissolution rate. Increase of the crosslinker contents in the novel PVP could enhance hydrogen bonding interactions which in turn improved the PVP ability to disrupt ibuprofen crystallinity. This subsequently conferred a dissolution rate advantage for physical mixtures IB-PVP over the sample of pure crystalline lB. Notably, the novel crosslinked PVP polymers had greater capacity to disrupt IB crystallinity and improve its dissolution than commercial crosslinked PVP XL 10 (Polyplasdone XL-10, ISP Technologies Inc.).The DSC data showed that the sample IB+7PVP5% had the lowest drug crystallinity (only 30%) and indeed yielded the fastest dissolution rate, while the sample IB+PVPXL 10 with the highest content of crystalline IB (62%) resulted in the lowest IB dissolution. In summary, the studies provide a method of modifying hydrogen bonding potential of crosslinked PVP to improve PVP properties as a carrier of poorly-water soluble drugs, especially in terms of disrupting drugs crystallinity and enhancing their dissolution rate. Improving dissolution of poorly-water soluble drugs and hence their bioavailability represents one of the major challenges within pharmaceutical formulation design. Commercial crosslinked polyvinylpyrrolidone (PVP) attracts attention as a drug carrier since it can increase wettability, specific surface area and dissolution rate of poorly-water soluble drugs. Therefore, crosslinked PVP appears to be a promising carrier especially for Biopharmaceutical Classification System (BCS) Class 11 drugs featuring high permeability but poor solubility. The aim of the studies was to synthesize novel crosslinked PVP with extended potential for hydrogen bonding interactions and to evaluate its application as a drug carrier in physical mixtures with ibuprofen (IB). In particular, the thesis seeks to elucidate the nature of IB-PVP interactions, especially in terms hydrogen bonding, drug crystallinity disruption and enhancements in IB dissolution rate. The studies involved synthesis of novel PVP crosslinkers with hydrogen bonding potential. The target structure of the novel crosslinkers was composed of two NVP units which were linked by different lengths of oligo ether chains. The multi-step synthesis of the novel crosslinkers afforded material with an acceptable overall yield of 27%, while in the case of an alternate one-step synthesis the yield did not exceed 9%. A series of free radical polymerisation reactions were carried out affording six novel crosslinked PVP polymers varying in the length of the oligo ether chains ("5 PVP" and "7 PVP") and in the density of crosslinking (the crosslinker content in the feed mixture: 1 wt%, 2.5 wt%, 5 wt%), i.e.: 7 PVP 5%, 7 PVP 2.5%, 7 PVP 1% and 5 PVP 5%, 5 PVP 5%, 5 PVP 5%. Six homogenous physical mixtures of IB (30 wt%) with novel crosslinked PVP polymers and a control mixture containing commercial crosslinked PVP were prepared using a Turbula mixer. Notably, the novel crosslinked PVP polymers had greater capacity to disrupt IB crystallinity and improve its dissolution than commercial crosslinked PVP XL 10 (Polyplasdone XL-10, ISP Technologies Inc.).The DSC data showed that the sample IB+7PVP5% had the lowest drug crystallinity (only 30%) and indeed yielded the fastest dissolution rate, while the sample IB+PVPXL 10 with the highest content of crystalline IB (62%) resulted in the lowest IB dissolution. In summary, the studies provide a method of modifying hydrogen bonding potential of crosslinked PVP to improve PVP properties as a carrier of poorly-water soluble drugs, especially in terms of disrupting drugs crystallinity and enhancing their dissolution rate.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.553143  DOI: Not available
Share: