Tres, Francesco
(2015)
Raman chemical and physical mapping of oral dosage forms.
PhD thesis, University of Nottingham.
Abstract
A high number of new chemical entities emerging from the drug development process show pharmacological activity, but at the same time are characterised by poor dissolution and solubility profiles. As a result, there is a strong push to develop innovative formulations for the delivery of such compounds so that the desired oral bioavailability and pharmacological effects are achieved. An increasingly popular class of formulations to improve the dissolution properties of poorly soluble drugs is represented by amorphous solid dispersions, whereby the drug is molecularly dispersed in a carrier matrix. One of the key challenges for developing amorphous solid dispersions in real-world formulations is the understanding of the dissolution performance. Although this is very important, due to the fact that the dissolution performance limits the in vivo efficacy, the dissolution mechanisms by which the amorphous solid dispersions dissolve is still not fully understood.
This thesis investigates the dissolution performance of three solid dispersions model systems including felodipine, bicalutamide and indomethacin, all poorly soluble drugs, with copovidone, a water-soluble polymer. The complexity of the model systems increases through the chapters, starting by testing the dissolution of a well-documented poorly soluble drug model, i.e. felodipine, as a function of the drug loading (5% and 50% w/w) (Chapter 3). In Chapters 4 and 5 the dissolution of bicalutamide, which is known to exist in at least two different polymorphic forms (form I and form II), is investigated as a function of three drug loadings (5%, 30% and 50% w/w). Finally, the dissolution of indomethacin, which presents a pH-variable solubility and dissolution rate due to its weakly acidic nature (pKa of 4.5), is probed as a function of both dissolution medium pH (pH 2 and 6.8) and drug loading (5%, 15%, 30%, 50%, 70% and 90% w/w) (Chapter 6).
The dissolution of amorphous solid dispersions and other oral dosage forms is commonly tested using the USP dissolution apparatuses (types I, II and IV). These methods present a significant limitation, i.e. they can not provide any directly spatially-resolved chemical information on potential changes occurring to the solid form (e.g. amorphous to crystalline, polymorphs or solvation-related transformations).
In this thesis Raman spectroscopy is employed as primary analytical technique in an attempt to fill the gaps related to the understanding of the dissolution mechanisms of amorphous solid dispersions and the limitations of the conventional USP apparatuses. The novelty of this approach derives from collecting Raman data directly from the dosage form in real time and in situ during the course of the dissolution test using a flow-through cell placed below the Raman microscope. Temporally- and spatially-resolved chemical Raman maps are generated using a novel mathematical approach which derives from the use of concatenated maps to explicitly probe the chemical and physical changes as a function of time as well as space. In-line ultraviolet spectroscopy is also integrated to the Raman system to directly relate changes in dissolution behaviour to physicochemical changes that occur to the solid form during the dissolution test.
A wide range of other state-of-the-art analytical techniques is also used to complement the Raman data to obtain a clear picture of drug release from amorphous solid dispersions. This includes a combined magnetic resonance imaging/ultraviolet flow cell system to allow, similarly to the Raman/ultraviolet method, changes in dissolution profile to be related to physical changes occurring in the solid material, and for the first time quantitative suppressed-water proton nuclear magnetic resonance spectroscopy was applied to amorphous solid dispersions. Proton nuclear magnetic resonance, due to the high chemical selectivity, provides quantitative data on both the drug and the polymer. Finally, the rotating disk dissolution rate test, i.e. a modified version of the conventional intrinsic dissolution rate test, is developed and employed for the first time to gain information, similarly to proton nuclear magnetic resonance spectroscopy, on the dissolution rates of both the drug and the polymer.
The dissolution performance of all amorphous solid dispersion model systems is shown to be strongly affected by the drug loading. At low drug loading the drug and the polymer dissolve with the same rate from the molecular dispersion, pointing to a drug release dependent on the high water solubility of copovidone. At high drug loading, the dissolution rates of both the drug and the polymer are significantly slower and this is shown to be ascribed to the formation of an amorphous drug-rich shell around the compact, followed by the drug re-crystallisation. For the high drug loaded amorphous solid dispersions, the dissolution performance is strongly dependent on the physicochemical properties of the drug, i.e. low aqueous solubility and high hydrophobicity. The dissolution behaviour of the amorphous indomethacin solid dispersions is also found to be affected by the dissolution medium pH. Indomethacin from the amorphous solid dispersions with 15% or higher drug loading is released only at pH 6.8 due to the significant increase in its aqueous solubility at this pH.
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