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A zero shear viscosity (terminal viscosity), η0, is determined by fitting the data curve with the Cross model as shown below: where η0, η∞, C, and m are zero shear viscosity, infinite shear viscosity, Cross time constant or consistency, and Cross rate constant, respectively. A sharp increase can be observed as salt concentration increases and as temperature increases (Table 2, Figure 2). Figures 3a through 3c show that gelation temperature 1 can be determined as the temperature where time-temperature superposition failed. Figure 3c also demonstrates that addition of salt shifted the gelation temperature of F5 with CaCl2 to lower values compared to 15% F5 solution and F5 solution with NaCl.

Figure 4 shows that the onset of gelation shifted to lower temperature with increasing NaCl and CaCl2 concentrations. Figure 5 shows that various matrices of gelation temperature decreased linearly with increasing salt concentration. Linear fits of gel dissolution during cooling are shown in Figures 6a and 6b. Gel dissolution determined by Tcool (G’=G”) demonstrated similar slope for NaCl and CaCl2. However, the other gel dissolution matrix, Tcool (|η*|min), showed a scattered decreasing trend.

Rheological Properties of Hypromellose Solution in the Presence of Salts Nalinda Almeida,1 Leela Rakesh,1 Jin Zhao2 1Science of Advanced Materials, Central Michigan University, Mt. Pleasant MI USA 48859 2Dow-Wolff Cellulosics, The Dow Chemical Company, Midland, MI USA 48674

™®Trademark of The Dow Chemical Company (“Dow”) or an affiliated company of Dow Form No. 198-02270-1012

Purpose Study flow behavior of concentrated hypromellose (HPMC) solutions in the presence of salts.

Introduction The addition of salts into HPMC solutions strongly influences the rheological properties of the resulting solutions; therefore, salts broadly impact the manufacture of coatings, hard shell capsules, and oral-film strips. This study examines the effects of salt on the viscoelastic properties of concentrated HPMC solutions and provides a better understanding of the gelation mechanism of HPMC in the presence of various salts.

Materials and Methods METHOCEL™ F5LV (substitution type 2906) Premium Cellulose Ether (hypromellose, HPMC) was supplied by The Dow Chemical Company (Midland, MI) and was prepared with 0.008 to 0.5M salt (NaCl, CaCl2) in the solutions. Rheology measurements were carried out using an AR2000 rheometer with concentric cylinder fixture in the linear viscoelastic region with 2% strain. Temperature sweep was carried out using 1 Hz frequency and heating/cooling rates of 1°C/min.

Results There has been much investigation on the reversible thermal gelation of HPMC in the presence of salt [1-3]. However, the gelation behavior of concentrated solutions of low molecular weight HPMC in the presence of salt has not been studied in detail. Figure 1 shows that a critical gelation concentration (Cgel) can be determined for solutions with CaCl2 at 25°C. Key matrices as shown in Table 1 were used to characterize gelation and gel dissolution of polymer solutions with various concentrations of salt.

Figure 1. Shear rate dependence of shear viscosity for various salt concentrations at 25°C.

Figure 2. Zero shear viscosity (η0) as a function of salt concentrations at various temperatures.

Table 2. Zero shear viscosity as a function of salt concentrations at various temperatures.

Figure 3. Impact of salt and salt concentrations on gelation transitions.

Figure 4. The changes of elastic modulus (G') as a function of temperature (closed symbol-heating, open symbol-cooling).

Figure 6. Dependencies of gel dissolution behavior.

Figure 8. Reduced frequency dependence of G', G'', and |η*| of 15% F5 with 0.24M NaCl solutions (a-c) and 15% F5 with 0.23M CaCl2 (d-f).

NaCl CaCl2

η0 (Pa∙s) η0 (Pa∙s)

CNaCl 20 (°C) 25 (°C) 30 (°C) 35(°C) CCaCl2 20 (°C) 25 (°C) 30 (°C) 35(°C)

0 0.83 0.69 0.56 0.48 0 0.83 0.69 0.56 0.48 0.008 0.86 0.71 0.59 0.51 0.008 1.00 0.82 0.67 0.58

0.08 0.92 0.75 0.62 0.58 0.08 1.01 0.83 0.70 1.2 * 0.16 0.96 0.79 0.68 1.1* 0.17 1.02 0.82 0.74 2.0 * 0.24 1.02 0.85 0.80 24* 0.23 1.06 0.88 1.02* 100 * 0.39 1.04 0.92 3.0* 500* 0.37 1.22 1.25* 40 * 1000* 0.50 1.06 1.5* 166* 1881* 0.50 1.90 55* 1745* 10000*

* Indicates gelation state where T ≥ Tgel, or concentration of salt ≥ Cgel. Green-colored area indicates gelation temperature at a constant concentration and critical gelation (salt) concentrations.

Matrix Abbreviations Definitions Gelation temperature 1 Tgel The temperature where TTS failed (viscosity

vs shear rate) or sharp increase of zero shear viscosity

Onset of gelation 1 Theat (G'min) The temperature measured at minimum G' during heating

Onset of gelation 2 Theat (|η*|min) The temperature measured at minimum η* during heating

Gelation temperature 2 Theat (G'=G'') The crossover temperature, G'=G'' during heating

Gelation temperature 3 Theat (G'=0) The temperature measured at G'=0 during heating

Gel dissolution temperature 1

Tcool (G'=G'') The crossover temperature, G'=G'' during cooling

Gel dissolution temperature 2

Tcool (|η*|min) The temperature measured at minimum η* during cooling

Table 1. Key terminology and abbreviations used for gelation and gel dissolutions.

A master curve obtained by shifting frequency sweeps of -5 to 35oC to a reference temperature of -5°C follows time-temperature superposition (TTS) as shown in Figure 7a. The master curve at -5°C shows a pseudo fluid-like behavior which slightly deviates from typical fluid-like behavior, i.e., G'' ~ ω0.9 instead of G'' ~ ω1 and G' ~ ω1.4 instead of G' ~ ω2. When F5 solutions started to gel, i.e., above 35°C, TTS failed as shown in Figure 7b and 7c. A comparison between 15% F5 with 0.24M NaCl and 0.23M CaCl2 is shown in Figure 8. TTS works well at low temperatures for these solutions, as shown in Figure 8a and 8d where a pseudo fluid-like behavior, i.e., G'' ~ ω0.9 and G' ~ ω1.4, was evident at low frequencies. TTS failed above the gelation temperatures as shown in Figure 8b and 8e. Additionally, the gelation temperatures shifted to lower temperatures with higher salt concentrations, which correlates well with the temperature sweep data.

Figure 9 shows DSC thermograms of 15% F5 solution with various concentrations of NaCl and CaCl2. As the salt concentrations increased, the onset of melting temperature decreased, and the endothermic peak was also reduced. The peak melting temperature (TM) as a function of NaCl and CaCl2 concentrations is also summarized in Figure 9. The depression of melting temperature can be fitted linearly with salt concentrations, which shows that the slope of the F5 solution with CaCl2 is sharper than that of the solution with NaCl.

Conclusions The gelation temperature shifted to lower temperature with increasing NaCl

and CaCl2 concentrations and can be approximated with a linear model. All of the solution rheology follows the principal of time-temperature

superposition below gelation temperature, and failed TTS above gelation temperature.

The depression of melting temperature of solutions increased linearly with increasing concentrations of salts. The F5 solution with CaCl2 showed a sharper decrease than that of the solution with NaCl.

This mapping of gelation behavior will enable process optimization of capsule dipping, coating, and oral film casting, as well as accelerated formulation design in various food and pharmaceutical applications with this material.

References 1. Y. Xu, L. Li, P. Zheng, Y. C. Lam, and X. Hu, Controllable Gelation of

Methylcellulose by a Salt Mixture, Langmuir, 2004, 20 (15), 6134-6138. 2. Y. Xu, C. Wang, K. C. Tam, and L. Li, Salt-Assisted and Salt-Suppressed

Sol−Gel Transitions of Methylcellulose in Water, Langmuir, 2004, 20 (3), 646-652.

3. S. Q. Liu, S. C. Joshi, Y. C. Lam, Effects of Salts in the Hofmeister Series and Solvent Isotopes on the Gelation Mechanisms for Hydroxypropylmethylcellulose Hydrogels, J. App. Polym. Sci., 2008, 109, 363–372.

Acknowledgements

The authors are grateful to The Dow Chemical Company for providing the HPMC materials. We also acknowledge travel funding support by The Science of Advanced Materials Program, Graduate Assistant Conference Grant, College of Science and Technology, and Graduate Presentation Grant at Central Michigan University.

Figure 9. Effect of salt concentration on melting temperature and enthalpy of melting.

Figure 5. Impact of salt concentration on gelation temperature.

Figure 7. Reduced frequency dependence of G', G'', and |η*| of 15% F5 solution.