(624p) The Effect of Hot Melt Extrusion Process, Polymer Type, and Molecular Weight on Polymer-Water Interactions of Pharmaceutical Excipients for Extrusion

The Effect of Hot Melt Extrusion
Process, Polymer Type, and Molecular Weight on Polymer-Water Interactions of
Pharmaceutical Excipients for Extrusion

Kevin O'Donnell¹,
Jin Zhao¹, Florin Dan²,
Uma Shrestha¹, William Porter¹

(1) Pharmaceutical
Excipients R&D, Dow
Pharma & Food
Solutions, Midland, MI 48674

(2)
Analytical
Sciences, Midland, MI 48674

The
presence of water in an amorphous pharmaceutical solid dispersion can greatly
impact the final performance of the solid dosage form(1). Thus, the objective
of this study was first to understand the interactions of pharmaceutical
polymers often used in hot melt extrusion (HME) with water based on the polymer
type and molecular weight. The second objective was to determine the changes in
polymer-water interactions after being processed by hot melt extrusion.

Hot
melt extrusion of the pure polymers was performed on a Leistritz
Nano16 HME. Extruded polymers were pelletized and milled in an Alpine impact
mill. Extruded and non-extruded polymers were analyzed by Dynamic Vapor
Sorption at 25 °C over a relative humidity range of
0-90%. The glass transition temperature as a function of relative humidity was
determined for extruded and non-extruded samples by modulated differential
scanning calorimetry.

Hypromellose, also
commonly named as hydroxypropyl methylcellulose
(HPMC), is well recognized as a crystallization inhibitor in amorphous solid
dispersions in both the solid state and during dissolution. AFFINISOL^TM
HPMC HME polymers
demonstrated reduced moisture uptake compared to polyvinyl pyrrolidone-vinyl
acetate copolymer prior to extrusion. Polyethylene glycol ? polyvinyl caprolactam ? polyvinyl acetate copolymer had similar
moisture uptake to HPMC type 2910. AFFINISOL? HPMC HME moisture
sorption was significantly lower than that of HPMC type 2208 or 2910, as shown
in Figure 1. Variation on molecular weight of AFFINISOL? HPMC HME did not
impact moisture absorption except for a slight change at RH=90% (25 °C).  Various models were used to fit sorption and
desorption data.  It was found that
Henderson(2)
and Flory-Huggins/Vrentas (FHV)(3) Models
fit well at moisture absorption levels less than 80% and 50% respectively, but
not as well at high moisture levels (R²: 0.97 to 0.99).  The Guggenheim-Anderson-de Boer (GAB)(4)
model gave the best overall fit (R²>0.99).  The fitting parameters of these three models
are sensitive to the polymer type and processing conditions, and therefore can
provide insights of polymer-water interaction. 
The FHV model fit the best for PVPVA 64 which indicated that the mutual
miscibility and plasticizing power of the water dominated the isotherm
process.  The pseudo c' parameter of PVPVA derived from isotherm is
about 1/3 of the c'
parameter derived from AFFINISOL^TM HPMC HME polymers.  This indicates that PVPVA has a much stronger
interaction with water than that of AFFINISOL^TM HPMC HME polymers
which is consistent with the physical parameters derived from the other models.  The water content to saturate the monolayer
for PVPVA is about three times as large as that of AFFINISOL^TM HPMC
HME polymers.  Hot melt extrusion process
did not impact AFFINISOL? HPMC HME isotherm when RH<70% (25 °C) and further
reduced moisture absorption when RH>70% as shown in Figure 1.

The
findings from this research can help pharmaceutical scientists design stable
amorphous drug dispersions using amorphous polymers for hot melt extrusion. The
evaluation of various predictive models can provide an insight into the mechanisms
of water-polymer interaction, inspire further development of universal model
that can predict the isotherms of polymers with various hydrophobicity and help to identify the key factors
involving residual water in amorphous polymers that are critical in drug
formulation and processing.

Figure 1. Comparison of water vapor sorption isotherms for AFFINISOL HPMC HME
polymer, HPMC, and PVPVA 64.

References

1.            D. S. Jones et al., Thermodynamically stable amorphous drug dispersions in
amorphous hydrophilic polymers engineered by hot melt extrusion. Chemical Engineering Research and Design
92, 3046-3054 (2014).

2.            S. M. Henderson, A hasic concept of
equilibrium moisture. . Agric. Eng. 33, 29-31 (1952).

3.            B. C. Hancock, G. Zografi, The use
of solution theories for predicting water vapor absorption by amorphous
pharmaceutical solids: A test of the Flory-Huggins and Vrentas models. Pharm. Res. 10, 1262-1267 (1993).

4.            R. B. Anderson, Modifications of the
Brunauer, Emmett and Teller Equation. J.
Am. Chem. Soc. 68, 686 (1946).