466568 Viscoelasticity and Molecular Mobility of Celecoxib/Pvp/Tpgs Melt: A New Approach for Amorphous Drug Dispersion Assessment during Hot Melt Extrusion Product Design

Thursday, November 17, 2016: 3:36 PM
Continental 5 (Hilton San Francisco Union Square)
Elba Garcia1, Adlin Mendoza1, Zuleyka Morales1 and Darlene Santiago2, (1)Pharmaceutical Sciences, University of Puerto Rico, San Juan, Puerto Rico, (2)Pharmaceutical Sciences, University of Puerto Rico - School of Pharmacy, San Juan, PR

Innovations at the Product Design and Discovery Interface

Abstract # 466568

Title: Viscoelasticity and molecular mobility of celecoxib/PVP/TPGS melt: A new approach for amorphous drug formulation assessment during hot melt extrusion (HME) product design.


Formulating drugs (active pharmaceutical ingredients) as amorphous solid dispersions is an alternative for improving the solubility of poorly water soluble drugs. Hot melt extrusion (HME) has demonstrated to be the adequate manufacturing unit process for compounding such amorphous solid dispersions. However, the risk of a potential event of inadequate amorphous content in the extrudate is always present, which is of critical significance when assessing the risk to the quality of such formulations during developmental product design phases.

Celecoxib is a poorly water soluble (BCS class II) non-steroidal anti-inflammatory drug. When compared to other BCS class II compounds, it has relatively low molecular mobility (high viscosity) and crystal growth rate upon cooling from the undercooled melt state  [1,2]. The presence of surfactants or polymers has demonstrated to significantly increase or inhibit the radial crystal growth rate of Celecoxib, respectively [3].

We have previously studied the impact on the Celecoxib crystallization by PVP (polymer) and TPGS (surfactant) in terms of molecular mobility. Over all it was demonstrated that the polymer decreases the mobility of the drug, whereas the surfactant acts as a plasticizer. The dynamic viscosity of the Celecoxib with polymer and/or surfactant follows Arrhenius temperature dependence near the melting point (10oC of undercooling), however the VTF model results in higher agreement as the undercooling degree increases.

Even though, viscosity has been assessed for HME processability of melt formulations, it has not been associated to the amorphous content in the extrudate when processed using HME. Herein we present the link between viscoelasticity and amorphous state and content in the extrudate of mixtures of celecoxib, PVP and/or TPGS. We expect these results to complement the knowledge available for when assessing a drug as a candidate for a solid dispersion formulation during developmental stages of a drug product.

Sample Preparation:

Physical samples were prepared by mixing the drug with the corresponding amount of polymer and/or surfactant. Samples were mixed manually following a mixing protocol for homogeneous material distribution, and hence reproducibility.

Binary and ternary mixtures consisted of 50 wt.% TPGS or 50 wt.% PVP dispersed in a 50 wt.% Celecoxib, and ternary mixtures of 25 wt.% PVP, 25 wt.% TPGS and 50 wt.% Celecoxib. Samples where extruded using a Thermo Scientific MiniLab II HAAKE Rheomex CTW5 II HME. Extruded amorphous content and state was characterized using X-Ray Powder Diffraction (XRD), and Raman spectroscopy combined with a microscope for area of sample selection to obtain the spectra. The latter allowed for testing of drug homogeneous content throughout the extruded material.

Methodology/Data Analysis:

Extruded drug samples where analyzed in terms of amorphous content and amorphous state. The results where compared with our previous data on viscoelasticity and molecular mobility of the melt. Together we linked the molecular mobility (viscoelasticity) of the melt with the amorphous content in the extrudate of celecoxib mixed with PVP and/or TPGS.

Results and Analysis:

The samples were extruded using a bench-top HME (Thermo Haake MiniLab II) at a temperature of 140oC and a speed of 25 1/min (rpm). Raman spectroscopy of the extrudate samples resulted in a significantly less amorphous content when celecoxib was combined with PVP only, than when combined with both PVP and TPGS. This is evidenced with a noticeable larger Raman intensity of the celecoxib/PVP/TPGS mixture of each of the most important functional groups of celecoxib (CF3, SO2 and NH2) compared to celecoxib mixed with PVP.

Powder diffraction characterization (XRD) showed a significant reduction in the crystalline state of the drug when mixed with PVP compared to PVP/TPGS, evidenced by the disappearance of the characteristic peaks of Celecoxib between 13 and 25 degrees (2Θ). On the other hand, TPGS increased the intensity of these peaks, and hence the crystalline state.

Table  SEQ Table \* ARABIC 1. Comparison between the off-line rheological and Raman data. A decrease in molecular mobility of the melt results in a higher amount of amorphous content in extrudate.


Off-line rheology



Molecular mobility (viscosity)*

Viscoelastic behavior*

Viscoelastic behavior* (140oC)


25 min-1.

Amorphous content in extrudate*


Decreased (viscosity increase)

Liquid to Elastic





(Decreased much less than with PVP alone)

Liquid to Elastic



(Increased much less than with PVP alone)


Increased (viscosity decrease)

Liquid to Elastic



*Compared each to pure Celecoxib.

The table summarizes the molecular mobility behavior and the amorphous content of the extrudate. When analyzed together, scientifically justifies the inclusion of viscoelasticity when designing a drug product formulation for HME. A decrease in viscosity results in an increase of the amorphous content of the drug, whereas an increase in molecular mobility results in a decrease in amorphous content in the extrudate. However, it must be highlighted that this correlation is conditional to the materials present in the melt, polymers (PVP) or surfactants (TPGS) as when these are combined less amount of amorphous content may result.


We have elucidated the relationship between the molecular mobility of celecoxib when in presence of PVP (polymer) and/or TPGS (surfactant), the elastic/liquid (viscoelasticity) behavior, and the resulting amorphous content of the celecoxib in the extrudate. This work provides the proof-of-concept that viscoelasticity characterization combined with analytical techniques in HME could be used to tailor an amorphous drug with reproducible and adequate amorphous content manufactured using HME, being this correlation currently unknown and highly beneficial for when designing an amorphous drug dispersion.


[1] Baird, J. A.; Santiago-Quinonez, D.; Rinaldi, C.; Taylor, L. S. Role of Viscosity in Influencing the Glass-Forming Ability of Organic Molecules From the Undercooled Melt State. Pharm Res 2011, 29, 271–284.

[2] Baird, J.A.; Van Errdenbrugh, B.; Taylor, L.S. A Classification Tendency of Organic Molecules from Undercooled Melts. J Pharm Sci 2010, 99, 3787-3806.

[3] Mosquera-Giraldo, L. I.; Trasi, N. S.; Taylor, L. S. Impact of Surfactants on the Crystal Growth of Amorphous Celecoxib. International Journal of Pharmaceutics 2014, 461, 251–257.

[4] Trachenko, K. The Vogel-Fulcher-Tammann Law in the Elastic Theory of Glass Transition. Journal of Non-Crystalline Solids 2008, 354, 3903-3906.

[5] Gupta, P.; Chawla, G.; Bansal, A.K. Physical Stability and Solubility Advantage from Amorphous Celecoxib: The Role of Thermodynamic Quantities and Molecular Mobility. Molecular Pharmaceutics 2004, 1, 406-413.


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