New lipid-based formulation approaches and characterization tools for hot-melt extrusion

Amorphous solid dispersions (SDs) are considered as one of the most effective strategies for the formulation of poorly water-soluble compounds. The active compound is dispersed in an inert carrier composed of a polymer and active excipients. Since the drug is amorphous, there is typically an increase in apparent solubility as well as dissolution rate. Various methods are employed for manufacturing of SDs, nevertheless, hot-melt extrusion (HME) has become one of the most common process techniques. Indeed, as a solvent-free, one-step continuous process allowing the production of a wide variety of solid dosage forms, HME has emerged as an attractive method. Among the excipients that can be used for SD development, lipid-based excipients are particularly interesting for the formulation of lipophilic compounds. They act as drug solubilizers and stabilizers by improving the chemical and physical stability of drugs. Among poorly water-soluble compounds those exhibiting both high crystallinity and lipophilicity are particularly challenging and require specific formulation considerations. A simple polymeric system might not be sufficient to obtain amorphous SDs. This can lead to sophisticated systems in structure and composition, which are hence rather complex to characterize by means of conventional analysis methods. The present thesis consists of four studies that aim at developing novel lipid-based formulations for crystalline lipophilic compounds by means of HME and that introduce new characterization methods. For this purpose, β-carotene (BC) was selected as a high melting point, poorly water-soluble model compound. The objective of the first study was to compare the ability of state-of-the-art methods to detect the presence of low-dose crystalline compounds in lipid matrices. Sensitivity issues were encountered using conventional methods, therefore a new analytical tool was introduced. The novel flow-through cross-polarized imaging combined the advantages of analyzing large sample sizes and the high sensitivity of a microscopic technique. Small amounts of crystalline materials could easily be detected and an upper limit of the kinetic solubility of the model compound could be estimated. The second study aimed at designing lipid microdomains for drug delivery systems produced by HME. A polymer, a solid fatty acid and an inorganic adsorbent were combined. The acidic lipid was meant to adsorb onto the inorganic carrier to create so called designed lipid microdomains (DLMs) to host an active compound. The employed analytical methods supported the assumption of specific molecular interactions between the fatty acid and the adsorbent. These interactions fostered the amorphization and stabilization of the acidic lipid and lead to the targeted DLM. The novel delivery system appeared to be promising for inclusion of a crystalline lipophilic compound. In the third study, hot-melt extrudates composed of a polymer, a liquid lipid and different kinds of silica-based adsorbents were produced. Such formulations exhibited a complex microstructure. Since the microstructure can influence the final dosage form quality attributes, the aim was to introduce a mathematical tool for structural analysis of extrudates. This work introduced the multifractal formalism in the field of pharmaceutics and showed that the adsorbent concentration, the type of adsorbent as well as the screw speed had an influence on the microstructure. This study was complemented by self-dispersion analysis since it can condition release of any active compound. We showed that the self-dispersion ability of extrudates can be modified by the lipophilic or hydrophilic nature of the adsorbent. The multifractal and self-dispersion studies appeared to be complementary to better understand complex formulations and future work should evaluate specific effects on drug formulation microstructure. Finally, in the fourth study a polymer, a liquid lipid and two types of adsorbents were employed as excipients for HME. Using these ingredients, amorphous SDs of BC were produced. The influence of the adsorbent type as well as the presence of amorphous substance on the microstructure was assessed by multifractal analysis. This structural analysis was complemented by mechanical analysis of extrudates. Our results suggested that the type of adsorbent and the presence of amorphous compound had an impact on the extrudate microstructure and thus on the mechanical performance. These findings evidenced the complementarity of the two methods, which could further be used in the development of dosage forms that require knowledge on mechanical properties. This thesis introduced new lipid-based delivery systems for poorly-water soluble compounds. Novel excipient combinations, involving polymer matrices, lipid-based excipients and inorganic adsorbents, have been suggested for HME and state-of-the-art characterization methods were complemented by new analytical tools to better understand complex formulations. A flow-through cross polarized imaging technique allowed overcoming sensitivity issues encountered otherwise with conventional methods. Moreover, multifractal formalism complemented by self-dispersion imaging provided key insights into pharmaceutical dosage form microstructure that is hardly accessible using conventional methods. These new approaches for HME bear much potential in pharmaceutical technology to tailor dosage form performance.

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