(737b) Viscoelasticity and Molecular Mobility of Celecoxib/Pvp/Tpgs Melt: A New Approach for Amorphous Drug Dispersion Assessment during Hot Melt Extrusion Product Design

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.

Introduction/Motivation/Objectives:

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 (10^oC 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 140^oC 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.

*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.

Conclusions:

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.

References

[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.