Saturday, 07 September 2013 08:01

Surface characterization of solid dispersions

Written by Joke Meeus and Guy Van den Mooter
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Solid dispersions are an intensively investigated enabling technology to formulate poorly soluble drugs. Many contributions already studied their higher solubility and resulting dissolution rate as well as the challenges at the level of physical stability due to their high intrinsic energy. Whereas the vast majority of these studies focus on the bulk characteristics of the samples, we are convinced that the (often distinct) properties of the sample surface should not be overlooked.


In this research highlight, we invigorate our statement by illustrating the surface characterization of a spray-dried polymeric matrix consisting of a combination of PLGA and PVP. In a later stage this matrix will be used to process poorly soluble drugs as a solid dispersion. The study of the sample surface was motivated by the fact that the spray-dried particles are hollow microspheres with a relatively thin shell, which implies that their surface comprises a significant part of the total sample mass [1]. Hence a change in surface characteristics (for example due to exposure to heat and/or humidity) will significantly alter the performance of these samples. Furthermore the microparticle surface will always be the first part of the formulation to come into contact with its release environment. Thus, surface characteristics might significantly influence the behaviour of the formulation, both in terms of release characteristics and stability issues.

Nanoscale surface characterization and miscibility study

Microparticles consisting of two polymers, PLGA and PVP, were prepared by spray drying. The phase behaviour of the samples was studied by means of modulated differential scanning calorimetry (MDSC) and the results showed that phase separation occurred in the bulk sample through evidence of two mixed amorphous phases, namely, a PLGA-rich phase and a PVP-rich phase (Figure 1a). Characterization of the samples by scanning electron microscopy (SEM) demonstrated that the spray-dried particles were hollow with a thin shell (Figure 2). Because of the importance in relation to stability and drug release, information about the surface of the microparticles was collected by different complementary surface analysis techniques. Atomic force microscopy (AFM) gathered information about the morphology and phase behaviour of the microparticle surface. Time-of-flight secondary ion mass spectrometry (ToF-SIMS) analysis of the particles revealed that the surface consisted mainly of the PLGA-rich phase. This information was obtained by C60+ sputtering, a technique allowing the collection of data with an increasing distance from the surface (Figure 3). This was confirmed by X-ray photoelectron spectroscopy (XPS) at an increased sampling depth (10 nm). Nanothermal analysis (NanoTA) proved to be an innovative way to thermally detect the presence of the PLGA-dominated surface layer and the underlying PVP phase (Figure 4) [1].

Influence of heat and humidity on the sample surface

The first part of this study focused on the influence of exposure to heat upon the phase behaviour of the spay-dried polymeric matrix both at the bulk level (investigated by MDSC) and at the surface level (examined by ToF-SIMS, XPS and AFM).

MDSC results demonstrated that exposure of the sample to heat influenced the Tg of the spray-dried polymeric matrix in terms of its value (Figure 1b) as well as the width of the Tg region (Figure 1c). Thus, MDSC showed a change in the bulk miscibility and hence phase behaviour of the spray-dried microspheres.

In addition, surface analysis revealed an undeniable influence of heat upon the surface characteristics of the polymeric microspheres, and more specifically upon their chemical composition, phase behaviour and topography. The conclusion from all techniques used (ToF-SIMS (Figure 5), XPS and AFM (Figure 6)) was that exposure of the spray-dried polymeric matrix to elevated temperatures resulted in a surface rearrangement with the appearance of spots of the underlying PVP layer at the PLGA surface. The overall result is an augmented surface coverage of PVP combined with a lower PLGA coverage.

The observations for exposing the microspheres to humidity were similar to those for exposure of the samples to heat The appearance of the underlying PVP layer at the PLGA surface of the microspheres is proposed to be mainly caused by the increased molecular mobility of the PLGA surface layer, to a lesser extent combined with the swelling behaviour of PVP upon exposure to humidity or heat [2].

This study implies that exposure to elevated temperatures and humidity might influence the bulk miscibility and release behaviour of future drug formulations based on this matrix.


In a next phase a poorly soluble API will be included in this polymeric matrix as a solid dispersion. The influence of different formulation and process parameters on the surface coverage and spatial distribution of the API in the microspheres will be investigated. Moreover the consequences of differences in API spatial distribution and surface coverage on the release behaviour of the formulation will be studied. An understanding of the surface behaviour will form the basis for the rational development of a drug matrix with desired and tunable characteristics in terms of drug solubility enhancement and drug release profile. 


[1] Meeus J., Chen X., Scurr D., Ciarnelli V., Amssoms K, Roberts C.J., Davies M.C., Van den Mooter G. Nanoscale surface characterization and miscibility study of a spray-dried injectable polymeric matrix consisting of poly(lactic-co-glycolic acid) and polyvinylpyrrolidone. J Pharm Sci. 2012; 101(9):3473-85 DOI:10.1002/jps.23131.

[2] Meeus J., Scurr D., Amssoms K, Davies M.C., Roberts C.J., Van den Mooter G. Surface characteristics of a spray-dried polymeric matrix consisting of PLGA and PVP: Relating the influence of temperature and humidity to the thermal characteristics of these polymers. Mol Pharm. 2013; 10(8):3213-24 DOI:10.1021/mp400263d.

PSSRC Facilities

The Research group of Prof. Guy Van den Mooter focuses on the study of the physical chemistry of solid (molecular) dispersions prepared by hot melt extrusion, spray drying, bead coating and spray congealing. It is the aim to correlate the physical structure of the drug-polymer dispersions to their pharmaceutical performance and stability profile, and to correlate formulation and processing parameters to the resulting physical structure. Analytical techniques such as thermal analysis (DSC, MTDSC, TGA, hot-stage microscopy, isothermal microcalorimetry, solution calorimetry), X-ray powder diffraction, infrared spectroscopy, solid state NMR and in vitro (intrinsic) dissolution testing are being used for this purpose. Other (solid state) analytical techniques that are available are (powder) rheology, He-pycnometry, instrumented compression testing, SEM, TEM, coulter counter and Laser diffraction.

As part of the Center for Drug Delivery and Analysis of KU Leuven, this research group is also involved in formulation development and preformulation studies (a.o. study of polymorphism) for pharmaceutical companies.

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