X-ray-based methods to model the release of a highly water-soluble drug from lipid microspheres

Modified-release drug delivery systems have been increasingly developed mainly to avoid repeated administration and then limit fluctuations in plasma drug concentrations as well as to improve bioavailability. Release-modified dosage systems provide complementary benefits, especially reduced side effects, greater convenience, facilitated compliance of the treatments and drug protection prior to release. The present study deals with systems dedicated to oral administration and able to prolong or extend the delivery of drugs at predictable and reproducible rate, for a period defined by the control of their release kinetics. Several control drug delivery systems have been investigated, highlighting different release mechanisms. These controlled release devices, include on one hand reservoir-like systems which consist of an inner core containing the drug surrounded by a water-insoluble shell, and on the other hand, matrix systems which directly embed the pharmaceutical ingredients within materials which directly regulate the water inflow and the drug outflow. In the field of matrices, lipids generate special interest due to their biocompatibility and lower toxicity, and since they are highly hydrophobic and show rather low melting temperatures suitable for melt processing techniques. The release process of an active pharmaceutical ingredient (API) from a matrix system depends on the physico-chemical properties of the constituents and from their interactions with the release medium too.
This study belong to the development of an oral controlled-release dosage form containing a highly water-soluble drug. In this respect, drug-loaded inert microspheres (Figure1) composed of two lipid binders were prepared by a prilling process. The diameter of the microspheres is close to 380 mm. The purpose here was to thoroughly characterize the controlled release mechanism of the drug in aqueous pH-6.8 buffered dissolution medium. Water and drug diffusion pathways as well as related kinetic parameters were determined by theoretical modeling of experimental data.
Research groups of the Université Paris-Sud XI (France), Sincrotrone Trieste (Italy) and Sanofi-Aventis (France) have realized a work providing, as a whole, one of the few studies of lipid-sustained release forms of an active pharmaceutical ingredient which is highly soluble in water.
Conventional in-vitro experiments were performed by analytical high performance liquid chromatography to evaluate the drug amounts released as a function of time. These experiments showed that the released fraction reaches 90 wt% only after a 24-hour immersion in the dissolution medium, pointing out an effective sustained release mechanism. In a first approximation an empirical power-law based model for spheres perfectly fits the experimental release data. However, the interpretation has been strengthened by the implementation of an innovative methodology involving X-ray diffraction and synchrotron radiation computed microtomography measurements to follow the structural evolution of the drug-loaded microspheres at molecular and microscopic scales. In particular, the solubilisation process of the drug inside the lipidic matrix and the subsequent evolution of the inner structure of the microparticles were analyzed. This approach allowed to explicit the water and drug transport mechanisms (Figures 1b and 2). In the latter case, independent modeling of drug release assimilating the microspheres to a reservoir having, on one hand, an inner core of decreasing radius and which contains solid API and, on the other hand, an outer diffusion layer the thickness of which is proportionally increasing with increasing dissolution time, was considered to refine the kinetic analysis of the diffusion process. The apparent water diffusion coefficient Dw was found equal to 3.8 10-11 m2/min and the API apparent diffusion coefficient reduced to the tortuosity of the matrix DAPI/τ; equal to 1.2 10-11 m2/minThis study ranks among the rare examples of monolithic dispersion device constituted by a highly soluble drug incorporated inside a perfectly inert lipid matrix. The dissolution liquid penetrates the particles through channels progressively created by the solubilization of the drug itself which occurs instantaneously at the inner front of the liquid.


Figure 1 (a) Scanning electron microscope image of drug loaded microspheres and b) synchrotron X-ray microtomography slice of API-loaded microspheres after incubation in the dissolution medium at a Z position corresponding to the median plane of the sphere. The dotted line visualizes the inner boundary of the channels formed by aqueous liquid entry. The side of the cubic voxel is 3.4-μm.

Figure 2 (a) Principles of the measurement setup; (b): API release profiles during the first three hours of dissolution and evolution of the API fraction solubilized within the microspheres as a function of immersion time in the dissolution medium as determined from X-ray diffraction data.

On the basis of preliminary tests, the microspheres proved to be macroscopically intact along the digestive tract. Further investigation could be envisaged by using the methodology developed in this work and should provide insights into the impact of physiological conditions. Namely, as the present API is pH-sensitive, its release kinetics in simulated gastric fluid may be affected. As well, the role of bile salts on water front diffusion kinetics or on API diffusion coefficient would deserve to be specified. A key parameter concerning the formulation of such controlled release lipid microspheres should be pointed out, that is the API concentration. Indeed, it results from the described mechanism that the API concentration must be sufficient to form a continuous network within the microspheres. If it is not the case, API crystals would remain isolated in the lipid matrix and some of them might not be reached by the dissolution liquid.

This research was conducted by the following team:

  • Perrine Pivette,Vincent Faivre, Claire Gueutin, Michel Ollivon, Sylviane Lesieur, Université Paris-Sud XI, Châtenay-Malabry, France.
  • Lucia Mancini,  Sincrotrone Trieste S.C.p.A., Trieste, Italy.
  • Georges Daste, Sanofi-Aventis, Antony, France.


Perrine Pivette, Vincent Faivre, Lucia Mancini, Claire Gueutin, Georges Daste, Michel Ollivon, Sylviane Lesieur, “Controlled release of a highly hydrophilic drug from lipid microspheres obtained by prilling: analysis of drug and water diffusion processes based on X-ray methods”, Journal of Controlled Release 158, 393, (2012), doi: 10.1016/j.jconrel.2011.11.027.

Last Updated on Thursday, 30 August 2012 15:48