Kapote, Dnyaneshwar Nandkumar: Improving solubility and supersaturation of poorly soluble drugs using solid dispersions based on natural polymers and mixtures thereof. - Bonn, 2021. - Dissertation, Rheinische Friedrich-Wilhelms-Universität Bonn.
Online-Ausgabe in bonndoc: https://nbn-resolving.org/urn:nbn:de:hbz:5-62305
urn: https://nbn-resolving.org/urn:nbn:de:hbz:5-62305,
author = {{Dnyaneshwar Nandkumar Kapote}},
title = {Improving solubility and supersaturation of poorly soluble drugs using solid dispersions based on natural polymers and mixtures thereof},
school = {Rheinische Friedrich-Wilhelms-Universität Bonn},
year = 2021,
month = may,

note = {The poor solubility of existing drug substances and new chemical entities is a problem in modern pharmaceutical development. There are various strategies to overcome the solubility limited bioavailability of poorly soluble drugs. One of the strategies is preparing amorphous solid dispersion (ASDs) using spray drying or hot-melt extrusion (HME). Despite the efforts of several marketed formulations of ASDs, there are fewer research efforts in using natural polymers/excipients for improving solubility and supersaturation maintenance. The objective of this work is to promote the use of natural polymers as a matrix in ASDs a comprehensive study of its application and understanding its influence on the improvement of solubility with supersaturation is essential.
To address this, we used different natural polymers in combination with synthetic polymers. The first part of my thesis is dedicated to the pre-screening of the natural polymer inulin in combination in a binary mixture with hydroxy propyl methyl cellulose acetate succinate (HPMC-AS). The film cast in organic solvent showed a single glass transition temperature (Tg) indicating that these two polymers are miscible with each other and subsequently be potentially suitable for spray drying. Other mixtures of shellac (SSB 55) with Affinisol HPMC 15 LV (A15) showed an improved solubility in organic solvent mixtures and the film cast showed a single Tg, in this case, a solvent mixture of acetone/ethanol (50/50) showed improved results in terms of clarity of the casted film. The mixture containing inulin with shellac was insoluble in various organic solvents (acetone, ethanol) and mixtures of acetone/ethanol (50/50) and ethanol/water (95/5). Additionally, inulin/shellac mixtures did not form a one-phasic melt or solid as was showed by two Tgs in DSC measurements, thereby clearly indicating that this combination is not a suitable matrix for manufacturing of ASDs. Lastly, A15 in combination with HPMC-AS was soluble in all tested organic solvents and mixtures thereof and showed a single Tg in DSC measurements making this combination one of the potential lead candidates for the manufacturing of ASDs. Thus, using the pre-screening enabled the selection of natural excipients alone or in combination as a matrix in ASDs development.
In continuation of the selection of two lead polymers and their miscibility in each other A15 with shellac was used for the formulation of ASDs. The second part of my work focuses on the use of shellac for preparing binary and ternary ASDs with HPMC, using the model API loratadine (LOR) via spray drying and hot-melt extrusion helped to achieve solubility improvement and supersaturation maintenance. We observed that among various shellac fractions within the ternary ASDs, the 10 % weight fraction optimally increased the solubility 30 folds and maintained the supersaturation for 3 h compared to other binary and ternary formulations. However, lower and higher fractions of shellac decreased the solubility again. This superiority for 10 % weight fraction was due to specific and stronger API matrix interactions detected via ATR-IR, which was further studied in terms of stability. Also, it was found that there exists a correlation between the amount of the dissolved API and the API crystallinity, which dictates the level of supersaturation. While the crystallinity is set by the LOR concentration at the end of the test, the dissolution rate (LOR in dissolution medium) depended on the origin of the crystals i.e., due to recrystallization of previously molecular dispersed LOR or undissolved LOR from HME processing. Thus, the use of shellac is proposed and it will add to the understanding of ternary mixture development with the application of solubility improvement and supersaturation maintenance.
The final part of my work highlights the application of shellac for pH-dependent release using HME without the need for coating. The binary solid dispersion (SDD) of API indomethacin (IND) with shellac and IND with Eudragit FS 100 (EFS) and ternary mixtures of IND, SSB 55 together with a new grade of HPMC (A15) were prepared using HME. The SDD were characterized and tested for in-vitro dissolution performance using a pH shift dissolution method from 1.1, 5.5, 6.8, and 7.4. A ternary extrudate of IND, SSB 55, and A15 showed improved protection below pH 5.5 with a complete release of 99.5 % at pH 7.4 compared to IND neat and binary extrudates from IND-A15, IND-SSB 55, and IND-EFS. This increased level of intermolecular interaction was confirmed by AT-IR and studied for stability. It was found that in a ternary mixture containing IND, A15, and SSB 55 an increased hydrogen bonding interaction is present, which resulted in improved dissolution performance compared to binary mixtures with the maintenance of supersaturation. Therefore, ternary SDD proved to be a promising concept for the future development of colon targeting of poorly soluble drugs.},

url = {https://hdl.handle.net/20.500.11811/9087}

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