Wednesday, 03 July 2013 09:16

Influence of Compression forces on the Physical and Structural Stability of Solid Dispersions

Written by Z. Worku, J. Aarts and G. Van den Mooter.
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The structural and physical stability of solid dispersions have not been adequately explored during post spray drying manufacturing processes. Solid dispersions are preferentially formulated as solid dosage forms such as tablets and capsules. Formulation parameters of spray drying may lead to differences in physical form and amorphous content of solids in single component systems [1]. However, there is limited understanding on the effect of spray drying processes and formulation variables on drug-polymer mixing in solid dispersions and this limitation also extends to the unit operations such as milling and tabletting. The drug-polymer mixing in solid dispersions was evaluated in two different laboratory spray dryers, the Buchi-mini spray dryer and Pro-C-epT Micro spray dryer (Figure 1). The effect of compression on the structural and the physical stability of the spray dried solid dispersions was investigated as a major scope of this study.

Drug-polymer mixing of solid dispersions across the spray dryers

The solid dispersions with 30% drug loading prepared by Pro-C-epT Micro spray dryer showed significant differences (p <0.05) in Tg width between transport tube/cooling tube and cyclone/collector (Figure 2). The solid dispersions from the transport tube showed the narrowest Tg width which is also far below the Tg width of the pure polymer followed by that of the cooling tube, the collector and the cyclone. The samples from the transport tube and cooling tube showed better drug-polymer mixing than the solid dispersions from the collector and the cyclone.

The solid dispersion of 50 % (w/w) NAP in PVP-VA collected from the cyclone tube connected to the drying chambers (CYTU) was amorphous. Powders collected from the cyclone and the CSP were crystalline solid dispersions which showed a melting endotherm (Tm) at 111.21 ± 0.08 °C and 112.68 ± 0.15 °C, respectively (Figure 3).

The drug-polymer mixing and the solid forms can vary across the spray dryer and high drug loading solid dispersions may be more prone to variation due to their lesser stability.

Effect of compression on structural and physical stability of the solid dispersions

Solid dispersions from CSP of Buchi mini-spray dryer and COLL of Pro-C-epT Micro-spray dryer were used for the compression study. The halo pattern of the uncompressed samples, both in the case of Buchi mini-spray dryer and Pro-C-epT Micro-spray dryer, showed higher intensity at 2θ=16.11 halo maximum than the compressed amorphous solid dispersions. The differences in the halo pattern apparently indicate the structural dissimilarity and also the differences in the short range order in the solid dispersion (Figure 4).

The vibration band of the amide carbonyl of PVP-VA becomes broader after compression due to an increase in the intensity of the shoulder peak of the weak drug-polymer interaction at 1654 cm-1 (Figure 5). The spectroscopic study evidently showed that compression of 30% (w/w) NAP in PVP-VA solid dispersion enhanced the weak drug-polymer interaction.

After 21 days storage at ambient temperature and 75% RH, the Tg width became broader for the uncompressed solid dispersions with 30% (w/w) NAP in PVP-VA 64 compared to the compressed samples (p<0.05) (Figure 6). The homogeneity of the compressed samples seems intact and also slightly decreased which could be the result of enhancement of the weak drug-polymer interaction.

After 10 days of storage the melting enthalpy and the crystallinity of the uncompressed sample with 50% drug loading were much higher (about two fold) than the compressed sample due to slower crystallisation of naproxen from the amorphous domain of the compressed samples (Figure 7). After five months storage at high humidity (75% RH) and ambient temperature, the Bragg peaks intensity was higher for the uncompressed solid dispersions with 40% and 50% drug loading than the compressed at 188 MPa (Figure 8). The lower crystallinity of the compressed samples can be related to the improved drug-polymer interactions.

Surface crystallisation is a common phenomenon for amorphous drugs [2, 3]. The decrease in effective surface area due to compression probably diminished the crystallisation of naproxen in the solid dispersions.


The drug-polymer mixing for solid dispersions varies across the spray dryer. Compression clearly improved drug-polymer interactions and further manifested as lesser crystallinity compared to the uncompressed solid dispersions. The Tg width and the PXRD halo patterns can also be used in combination with vibrational spectroscopic techniques to predict the drug-polymer mixing and the physical stability of the solid dispersions.

Future Work

The sources of drug-polymer mixing variations across a spray dryer and their impact on drug product performance apparently need dedicated further investigation. Further studies on the effect of compression on the structural and physical stability of solid dispersions are ongoing using pharmaceutical relevant dwell times and compression pressures.


[1] Chidavaenzi, O. C., Buckton, G., Koosha, F., & Pathak, R (1997). The use of thermal techniques to assess the impact of feed concentration on the amorphous content and polymorphic forms present in spray dried lactose. Inernational Journal of Pharmaceutics, 159(1), 67-74 DOI:10.1016/S0378-5173(97)00272-X

[2] Yang, C., & Takahashi, I (2011). Broadening, no broadening and narrowing of glass transition of supported polystyrene ultrathin films emerging under ultraslow temperature variations. Polymer Journal, 43, 390-397 DOI:10.1038/pj.2010.145

[3] Zhu, L., Jona, J., Nagapudi, K., & Wu, T (2010). Fast surface crystallization of amorphous griseofulvin below Tg. Pharmaceutical Research, 27(8), 1558-1567 DOI:10.1007/s11095-010-0140-8 

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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