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The mechanism of plastic deformation in amorphous polymers is still obscure due to lack of experimental techniques to probe molecular mobility during active deformation. Lee et al. showed an increase in a segmental mobility by several decades using a specific active deformation protocol (uniaxial tensile creep) by directly measuring the molecular mobility using an optical photobleaching approach [1]. Our previous studies using ATR-FTIR spectroscopy showed that compression of amorphous solid dispersions containing naproxen and PVP or PVP-VA appeared to affect the drug-polymer interactions, the drug-polymer mixing and the physical stability of the system [2, 3]. Deformation can affect the molecular dynamics of amorphous polymers that include local bonds, segmental and whole chain mobility. It potentially leads to conformational changes and also enhances or affects local bond motions of polymers which may be involved in intermolecular interactions with drugs in solid dispersions. The objective of this study is to understand the effect of compression on the local and segmental mobility of PVP-VA to understand the molecular origin of the differences in drug-polymer interactions between the compressed and the uncompressed solid dispersions. The impact of pharmaceutical tabletting on the molecular dynamics of amorphous solid dispersions can be critical in terms of physical stability of the drug during storage.


High resolution broadband dielectric spectroscopy (ALPHA Analyzer, Novocontrol Technologies) was used to measure the complex dielectric responses (Eqn. \ref{eq:1}, ε' and ε'' are the real and the imaginary part) of the compressed (565 MPa) (comp), the slightly compressed (scomp) and the powder (pow) PVP-VA 64 and powder PVP K25 samples in the frequency range from 10-1 to 106 Hz.

\begin{equation}\varepsilon (\omega)=\varepsilon' (\omega) - i\varepsilon'' (\omega)\label{eq:1} \end{equation}

The “conduction free” dielectric loss was computed from the real part of the dielectric spectra using the Kramers-Kronig relation to suppress the Ohmic conduction interference in the imaginary part of the dielectric response (Eqn. \ref{eq:2}) [4].

\begin{equation}\varepsilon'' (\omega_0)=\frac{\sigma_{dc}}{\varepsilon_\nu\omega_0}+\frac{2}{\pi}\int_0^\inf \varepsilon'(\omega)\frac{\omega_0}{\omega^2-\omega_0^2}\text{d}\omega\label{eq:2} \end{equation}

Generally, the activation energy according to the Arrhenius-law is usually considered a true energetic barrier, however, processes that involve cooperativity might additionally show an entropic “barrier”. The Starkweather analysis allows to separate the activation energy into its enthalpic and entropic part to assess the cooperative nature of the secondary relaxation of PVP-VA (Eqns. \ref{eq:3} and \ref{eq:4}) (for the details of the equations refer to [5]).

\begin{equation}f=\frac{k_B T}{2\pi h}\exp \left( -\frac{\Delta H^{\ddagger}}{RT} \right)\exp\left(\frac{\Delta S^{\ddagger}}{R} \right)\label{eq:3} \end{equation}

\begin{equation}E^{*}_{a}=RT\left( 1+ \ln \frac{k_B}{2\pi h} \ln \frac{T}{f} \right)\label{eq:4} \end{equation}

Results and Discussion

The secondary relaxation of compressed PVP-VA shifts synchronously with the primary relaxation to lower temperature compared to the powder and slightly compressed samples even after annealing in the supercooled liquid state (Fig. 1). The source of the secondary relaxation process is likely originating from the vinyl pyrrolidone moiety of PVP-VA. Thus, compression appeared to enhance the localised motion which likely originates from the conformational transition involving the N-C(H) bond in PVP-VA and also the segmental mobility due to dynamic Tg [6].

The non-zero activation entropy of compressed PVP-VA was higher than the powder sample which indicates the presence of a higher entropic barrier during conformational reorientation for the compressed sample (Table 1). Moreover, it may also indicate a higher cooperative nature of the β relaxation process for the compressed sample as the result of enhanced conformational rotations.

The primary relaxation process starts at a very low temperature for the compressed PVP-VA and an additional wing was also identified with a mean relaxation time smaller than the powder and the slightly compressed PVP-VA (Fig. 2).

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Conclusion and Outlook

The molecular dynamics results support the idea that severe compression affects the local and the segmental mobility of PVP-VA. Compression of PVP-VA appeared to lead to a shorter time scale for the secondary (β) relaxation process. Moreover, the primary relaxation process starts at a very low temperature for the compressed PVP-VA and an additional wing was also identified with a mean relaxation time smaller than the powder and the slightly compressed PVP-VA due to the heterogeneity in segmental mobility imparted by compression. The observation can be very useful for drug containing amorphous solid dispersions which are stabilised by specific drug-polymer interactions. The current study on PVP-VA should also be extended to one with binary solid dispersions stabilised by a strong and a weak drug-polymer hydrogen bonding further to probe the effect of compression in the molecular dynamics of both the drug, the polymer and their specific interactions.


[1]    Lee, H. N.; Paeng, K.; Swallen, S. F.; Ediger, M. Science 2009, 323, 231.
[2]    Ayenew, Z.; Paudel, A.; Van den Mooter, G. Eur. J. Pharm. Biopharm. 2012, 81, 207.
[3]    Worku, Z. A.; Aarts, J.; Van den Mooter, G. Mol. Pharmaceutics 2014, 11, 1102.
[4]    Wübbenhorst, M.; van Turnhout, J. J. Non-Cryst. Solids 2002, 305, 40.
[5]    Starkweather Jr, H. W. Polymer 1991, 32, 2443.
[6]    Tonelli, A. Polymer 1982, 23, 676.

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, broadband dielectric spectroscopy 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.

Published in Research Highlights


Over the last years, hot melt extrusion (HME) has attracted significant interest in the pharmaceutical industry. HME is performed at elevated process temperatures that cause the material to soften or even melt. Thereby, the formation of molecular solid dispersions is possible, given that the formulation and the HME process are carefully designed.

Published in Research Highlights


The production and manufacturing of solid pharmaceutical products is in need of new technologies to ensure a safe and efficient medical therapy. Hot melt extrusion (HME) is a new and innovative technology in the field of pharmaceutics, which aids to overcome numerous limitations of traditional manufacturing techniques. The benefit of HME is three-fold: First, the bioavailability of poorly soluble drugs is significantly increased due to the conversion of the drug from the crystalline into its amorphous state [1]. Recent work showed that HME is even capable of converting a liquid nanosuspension into a solid formulation in a one-step process [2], thereby avoiding aggregation of nanocrystals. Second, drug release profiles can be specifically tailored (in most cases retarded release of water soluble drugs) via the application of a proper matrix carrier in combination with plasticisers [3]. Third, drug abuse can be prevented due to superior mechanical properties of the final product [4].

Published in Research Highlights


The inter-tablet coating uniformity is a critical quality attribute in active coating processes. In this project an active coating process is performed in order to produce a fixed dose combination of a sustained release formulation in the tablet core and an immediate release dose in the coating layer. The tablet cores consist of a push-pull osmotic system containing nifedipine as API (Adalat GITS). They are coated with Candesartan cilexetil as a second API. As the inter-tablet coating uniformity is a critical quality attribute to comply with regulatory requirements, the purpose of this work is to enhance the process understanding and to optimize the coating process with regard to the coating uniformity. Besides experimental investigations, PAT tools such as Raman spectroscopy [1] and terahertz pulsed imaging [2] have been applied to study this active coating process. In recent years, numerical simulations of coating processes have been gaining interest as analytical tool [3]. The discrete element method (DEM) in particular is suitable to simulate the tablet motion [4]. In this project, both experimental and numerical analysis of an active coating process is combined to investigate the influence of different process parameters with respect to the optimization of the coating uniformity.

Published in Research Highlights