(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. AFFINISOLTM 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 AFFINISOLTM HPMC HME polymers. This indicates that PVPVA has a much stronger interaction with water than that of AFFINISOLTM 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 AFFINISOLTM 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.
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).