Gelation under stress: impact of shear flow on the formation and mechanical properties of methylcellulose hydrogels.

We demonstrate that small unidirectional applied-stresses during temperature-induced gelation dramatically change the gel temperature and the resulting mechanical properties and structure of aqueous methylcellulose (MC), a material that forms a brittle gel with a fibrillar microstructure at elevated temperatures. Applied stress makes gelation more difficult, evidenced by an increased gelation temperature, and weakens mechanical properties of the hot gel, evidenced by a decreased elastic modulus and decreased apparent failure stress. In extreme cases, formation of a fully percolated polymer network is inhibited and a soft granular yield-stress fluid is formed. We quantify the effects of the applied stress using a filament-based mechanical model to relate the measured properties to the structural features of the fibril network. The dramatic changes in the gel temperature and hot gel properties give more design freedom to processing-dependent rheology, but could be detrimental to coating applications where gravitational stress during gelation is unavoidable.

Rheology of Cellulose Ether Excipients Designed for Hot Melt Extrusion.

A new family of cellulosic ether polymeric excipients has been recently engineered for fabrication of amorphous solid dispersions of active pharmaceutical ingredients via hot-melt extrusion (HME). These hydroxypropyl methyl cellulose excipients enable plasticizer-free melt processing at much lower temperatures (135-160 °C) due to their substantially reduced glass transition temperatures ( Tg = 98-110 °C). The novel amorphous cellulose ethers were found to be rheologically solidlike well above their glass transition ( Tg + 70 °C). We demonstrate that in the pharmaceutically relevant HME processing temperature range these polymers behave similarly to yield-stress fluids and flow only when the applied stress exceeds a critical stress value. This critical stress value (0.50 ± 0.05 MPa, 150 °C) is surprisingly high but is easily achieved under typical HME conditions. The origin of their yield-stress fluidlike behavior is hypothesized to arise from hydrogen bonds of the HPMC materials that act as physical cross-links and do not relax within the measured temperature and time window unless the applied stress exceeds the critical stress value. Support for this hypothesis arises from infrared spectroscopic estimates of the free and bound hydrogen bond levels at end-use temperatures.

Gelation, Phase Separation, and Fibril Formation in Aqueous Hydroxypropylmethylcellulose Solutions.

The thermoresponsive behavior of a hydroxypropylmethylcellulose (HPMC) sample in aqueous solutions has been studied by a powerful combination of characterization tools, including rheology, turbidimetry, cryogenic transmission electron microscopy (cryoTEM), light scattering, small-angle neutron scattering (SANS), and small-angle X-ray scattering (SAXS). Consistent with prior literature, solutions with concentrations ranging from 0.3 to 3 wt % exhibit a sharp drop in the dynamic viscoelastic moduli G' and G″ upon heating near 57 °C. The drop in moduli is accompanied by an abrupt increase in turbidity. All the evidence is consistent with this corresponding to liquid-liquid phase separation, leading to polymer-rich droplets in a polymer-depleted matrix. Upon further heating, the moduli increase, and G' exceeds G″, corresponding to gelation. CryoTEM in dilute solutions reveals that HPMC forms fibrils at the same temperature range where the moduli increase. SANS and SAXS confirm the appearance of fibrils over a range of concentration, and that their average diameter is ca. 18 nm; thus gelation is attributable to formation of a sample-spanning network of fibrils. These results are compared in detail with the closely related and well-studied methylcellulose (MC). The HPMC fibrils are generally shorter, more flexible, and contain more water than with MC, and the resulting gel at high temperatures has a much lower modulus. In addition to the differences in fibril structure, the key distinction between HPMC and MC is that the former undergoes liquid-liquid phase separation prior to forming fibrils and associated gelation, whereas the latter forms fibrils first. These results and their interpretation are compared with the prior literature, in light of the relatively recent discovery of the propensity of MC and HPMC to self-assemble into fibrils on heating.

Size-exclusion chromatography of ultrahigh molecular weight methylcellulose ethers and hydroxypropyl methylcellulose ethers for reliable molecular weight distribution characterization.

Size-exclusion chromatography (SEC) coupled with multi-angle laser light scattering (MALLS) and differential refractive index (DRI) detectors was employed for determination of the molecular weight distributions (MWD) of methylcellulose ethers (MC) and hydroxypropyl methylcellulose ethers (HPMC) having weight-average molecular weights (Mw) ranging from 20 to more than 1,000kg/mol. In comparison to previous work involving right-angle light scattering (RALS) and a viscometer for MWD characterization of MC and HPMC, MALLS yields more reliable molecular weight for materials having weight-average molecular weights (Mw) exceeding about 300kg/mol. A non-ideal SEC separation was observed for cellulose ethers with Mw>800kg/mol, and was manifested by upward divergence of logM vs. elution volume (EV) at larger elution volume at typical SEC flow rate such as 1.0mL/min. As such, the number-average molecular weight (Mn) determined for the sample was erroneously large and polydispersity (Mw/Mn) was erroneously small. This non-ideality resulting in the late elution of high molecular weight chains could be due to the elongation of polymer chains when experimental conditions yield Deborah numbers (De) exceeding 0.5. Non-idealities were eliminated when sufficiently low flow rates were used. Thus, using carefully selected experimental conditions, SEC coupled with MALLS and DRI can provide reliable MWD characterization of MC and HPMC covering the entire ranges of compositions and molecular weights of commercial interest.

Linear and Nonlinear Rheological Behavior of Fibrillar Methylcellulose Hydrogels.

Cryogenic transmission electron microscopy and small-angle neutron scattering recently have revealed that the well-known thermoreversible gelation of methylcellulose (MC) in water is due to the formation of fibrils, with a diameter of 15 ± 2 nm. Here we report that both the linear and nonlinear viscoelastic response of MC solutions and gels can be described by a filament-based mechanical model. In particular, large-amplitude oscillatory shear experiments show that aqueous MC materials transition from shear thinning to shear thickening behavior at the gelation temperature. The critical stress at which MC gels depart from the linear viscoelastic regime and begin to stiffen is well predicted from the filament model over a concentration range of 0.18-2.0 wt %. These predictions are based on fibril densities and persistence lengths obtained experimentally from neutron scattering, combined with cross-link spacings inferred from the gel modulus via the same model.

Structure and properties of aqueous methylcellulose gels by small-angle neutron scattering.

Cold, semidilute, aqueous solutions of methylcellulose (MC) are known to undergo thermoreversible gelation when warmed. This study focuses on two MC materials with much different gelation performance (gel temperature and hot gel modulus) even though they have similar metrics of their coarse-grained chemical structure (degree-of-methylether substitution and molecular weight distribution). Small-angle neutron scattering (SANS) experiments were conducted to probe the structure of the aqueous MC materials at pre- and postgel temperatures. One material (MC1, higher gel temperature) exhibited a single almost temperature-insensitive gel characteristic length scale (ζ(c) = 1090 ± 50 Å) at postgelation temperatures. This length scale is thought to be the gel blob size between network junctions. It also coincides with the length scale between entanglement sites measured with rheology studies at pregel temperatures. The other material (MC2, lower gel temperature) exhibited two distinct length scales at all temperatures. The larger length scale decreased as temperature increased. Its value (ζ(c1) = 1046 ± 19 Å) at the lowest pregel temperature was indistinguishable from that measured for MC1, and reached a limiting value (ζ(c1) = 450 ± 19 Å) at high temperature. The smaller length scale (ζ(c2) = 120 to 240 Å) increased slightly as temperature increased, but remained on the order of the chain persistence length (130 Å) measured at pregel temperatures. The smaller blob size (ζ(c1)) of MC2 suggests a higher bond energy or a stiffer connectivity between network junctions. Moreover, the number density of these blobs, at the same reduced temperature with respect to the gel temperature, is orders of magnitude higher for the MC2 gels. Presumably, the smaller gel length scale and higher number density lead to higher hot gel modulus for the low gel temperature material.

Interplay between gelation and phase separation in aqueous solutions of methylcellulose and hydroxypropylmethylcellulose.

Thermally induced gelation in aqueous solutions of methylcellulose (MC) and hydroxypropylmethylcellulose (HPMC) has been studied by rheological, optical microscopy, and turbidimetry measurements. The structural and mechanical properties of these hydrogels are dominated by the interplay between phase separation and gelation. In MC solutions, phase separation takes place almost simultaneously with gelation. An increase in the storage modulus is coupled to the appearance of a bicontinuous structure upon heating. However, a thermal gap exists between phase separation and gelation in the case of HPMC solutions. The storage modulus shows a dramatic decrease during phase separation and then rises in the subsequent gelation. A macroporous structure forms in the gels via "viscoelastic phase separation" linked to "double phase separation".