Study of drug-excipient interactions regarding solubility enhancement in diluted aqueous media and solid state transformations

Saal, Wiebke. Study of drug-excipient interactions regarding solubility enhancement in diluted aqueous media and solid state transformations. 2017, Doctoral Thesis, University of Basel, Faculty of Science.


Official URL: http://edoc.unibas.ch/diss/DissB_12725

Downloads: Statistics Overview


Nearly all marketed dosage forms comprise pharmaceutical excipients that have multiple functions, for example, improvement of wettability, solubilization, or absorption enhancement, while they can also have further technical functions such as diluent, glidant, disintegrant, or preservative. The selection of appropriate excipients is crucial for a suitable dosage form design and therefore an important step during the drug development process. Excipients have traditionally been considered as pharmacologically inert; however, they can interact with the drugs in the dosage form. Such interactions can be of physicochemical nature or even biological effects may occur that are critical for oral drug absorption. These interactions can be especially of relevance when formulating poorly water-soluble drugs. Different formulations are needed for the various development phases, where eventually different requirements have to be considered. In early phases, time lines and drug amounts are very limited and therefore, formulation development has to be fast and compound saving but long-term stability does not have to be given. Since the choice of excipients is such a crucial step, a better mechanistic understanding is targeted by pharmaceutical scientists to avoid a purely empirical trial-and-error approach. A thorough general mechanistic understanding of drug-excipients interactions is helpful for designing a robust formulation.
In academic and industrial research, there is a huge interest in understanding the different mechanisms of drug-excipient interactions with regards to formulation processes or with respect to dissolution and absorption. The present work centers around the latter aspects and makes use of miniaturized test methods to obtain comparatively large experimental datasets.
The present thesis consists of six studies, which all focus on excipient effects on the solubility and solid state of poorly water-soluble drugs. Excipients effects were studied at low concentrations that are relevant for solution and suspension formulation in early phases but the effects are of equal importance for oral solid dosage forms upon dissolution and dilution in the gastrointestinal (GI) tract. New methods were introduced to study kinetic solubility and possible solid state transformation in a miniaturized scale to save material and to obtain multiple results in a short time frame.
The first study introduces a miniaturized X-ray powder diffraction (XRPD) assay for quantification of polymorphic mixtures. This approach was applied to simultaneously study kinetic solubility and time evolution of optional solid state changes. Additionally, the influence of four excipient vehicles and biorelevant media on the solid state and the solubility were tested. Excipient effects could be differentiated into effects in the solid and liquid phase of the slurries as enabled by the parallel study of kinetic concentrations and XRPD. As a result, effects were rather specific and no general interaction type was found for the two excipient classes tested.
The second study introduced image and fractal analysis into the pharmaceutical field of solvent-mediated phase transformation to gain an improved mechanistic understanding. It was possible to monitor the fractal dimension of crystallized compound in different media and it could be interpreted as an indicator of the cluster growth phase of the hydrate crystals. Additional, parallel tests based on a miniaturized scale, provided similar excipient trends for the solid state transformation. There were no general polymer or surfactant trends, and each excipient appeared to have specific effects on the kinetics.
The third study focusses on surfactant effects at low concentrations by studying solid state and solubility of 13 model compounds in parallel. It was found that solid state transformations played a minor role for the extent of solubility enhancement. However, the surfactants showed individual effects on solid state transformations of some drugs, which needs to be considered for formulation development. The obtained dataset demonstrated high solubilization correlations among pegylated surfactants of similar type. Such correlations may be used to omit individual surfactants for a resource-saving solubilization testing in preformulation.
In the fourth study, we focused on a methacrylic copolymer (Eudragit EPO) which is already known for interacting with anionic drugs and is applied for stabilizing them in an amorphous state. These ionic interactions led also to a great solubility enhancement in aqueous environment of eight crystalline, anionic model compounds. With 1H nuclear magnetic resonance (NMR) spectroscopy, we could also detect hydrophobic interaction that contributed to the overall interaction additionally to the expected ionic interactions. An additional and important finding was the correlation between diffusion data measured by diffusion ordered spectroscopy (DOSY) and the solubility enhancement.
The understanding of the interaction mechanism, resulted in the fifth study, where we investigated the solubility enhancing effect of the same polymer on six basic compounds. Unexpected high solubility enhancement was obtained considering that polymer and drugs are equally charged in the aqueous environment. DOSY-experiments indicated that the polymer undergoes conformational changes in presence of the drugs which may contribute to the interaction mechanism.
Finally, such in vitro obtained results were tested in vivo in rats in the sixth study. Two formulations with Eudragit EPO (EPO) were compared to conventional formulation approaches such as a pH-adjusted solution or suspensions. The in vitro obtained solubility enhancement did not translate into improved in vivo bioavailability in rats; however, the pharmacokinetics were significantly influenced. Delayed and decreased absorption of the drugs was most likely due to hydrophobic drug polymer interactions and co-precipitation of the compound with polymer in the gastrointestinal tract of the rats. Solid state analysis showed an absence of crystalline compound in the co-precipitate. The polymeric co-precipitation in vivo can be used for high-dose in vivo studies in the early phases of pharmaceutical development like toxicology or pharmacokinetic studies to circumvent high peak to trough plasma ratios.
In summary, this thesis provides new analytical methods and an improved mechanistic understanding of drug-excipient interactions in vitro as well as in vivo. However, it was seen that excipient effects especially on the solid state are highly specific between drug and excipient, which makes it hard to formulate general rules or guidelines. Due to choosing the same experimental conditions, excipient effects can be better compared and the concomitant study of solid state and kinetic concentrations is key for a better understanding of molecular drug-excipient interactions in a dispersed system. The obtained findings can be used to guide early formulation development and the mechanistic insights may be help to decrease the number of experiments and needed amounts of compound, which is highly desirable in preformulation or early development.
Advisors:Imanidis, Georgios and Bergström, Christel
Faculties and Departments:05 Faculty of Science > Departement Pharmazeutische Wissenschaften > Pharmazie > Pharmazeutische Technologie (Huwyler)
UniBasel Contributors:Imanidis, Georgios
Item Type:Thesis
Thesis Subtype:Doctoral Thesis
Thesis no:12725
Thesis status:Complete
Number of Pages:1 Online-Ressource (viii, 175 Seiten)
Identification Number:
edoc DOI:
Last Modified:12 Sep 2018 04:30
Deposited On:11 Sep 2018 14:48

Repository Staff Only: item control page