Glass Transition In Mixtures Research Articles

Global and Local Views of the Glass Transition in Mixtures

Global and Local Views of the Glass Transition in Mixtures

Analytical and Computational Methods for the Estimation of Drug-Polymer Solubility and Miscibility in Solid Dispersions Development.

The development of stable solid dispersion formulations that maintain desired improvement of drug dissolution rate during the entire shelf life requires the analysis of drug-polymer solubility and miscibility. Only if the drug concentration is below the solubility limit in the polymer, the physical stability of solid dispersions is guaranteed without risk for drug (re)crystallization. If the drug concentration is above the solubility, but below the miscibility limit, the system is stabilized through intimate drug-polymer mixing, with additional kinetic stabilization if stored sufficiently below the mixture glass transition temperature. Therefore, it is of particular importance to assess the drug-polymer solubility and miscibility, to select suitable formulation (a type of polymer and drug loading), manufacturing process, and storage conditions, with the aim to ensure physical stability during the product shelf life. Drug-polymer solubility and miscibility can be assessed using analytical methods, which can detect whether the system is single-phase or not. Thermodynamic modeling enables a mechanistic understanding of drug-polymer solubility and miscibility and identification of formulation compositions with the expected formation of the stable single-phase system. Advance molecular modeling and simulation techniques enable getting insight into interactions between the drug and polymer at the molecular level, which determine whether the single-phase system formation will occur or not.

Interactions Between Paracetamol and Hypromellose in the Solid State.

Hydroxypropyl methylcellulose (hypromellose) is a widely known excipient commonly used in the preparation of drug formulations. It can interact with some active pharmaceutical ingredients (APIs), thereby contributing to a reduction in crystallinity, serve as a solvent for API or form stable dispersion with no tendency to aggregation. The aim of the present study was to investigate the effect of hypromellose on the solubility, miscibility and amorphization of paracetamol in mixture with this polymer. Homogenized mixtures of paracetamol with hypromellose were studied using differential scanning calorimetry (DSC), hot-stage microscopy (HSM), Fourier transform infrared (FT-IR) and Raman methods to obtain a deeper insight into the interactions between ingredients in solid state including phase diagram construction for crystalline API and amorphous polymer. A DSC study revealed potential interaction between ingredients resulting in reduced paracetamol crystallinity. This was proved using heating-cooling-heating test to confirm paracetamol amorphization. FT-IR and Raman investigations excluded chemical reaction and hydrogen bonding between ingredients. The phase diagram developed facilitates predictions on the solubility of API in polymer, on the mutual miscibility of ingredients and on the temperature of mixture glass transition.

Formulation performance and processability window for manufacturing a dual-polymer amorphous solid dispersion via hot-melt extrusion and strand pelletization

This work evaluates several compositions of an amorphous solid dispersion (ASD) comprising nimodipine (NMD) as poorly soluble model API in a dual-polymer carrier system. HPMC E5 and Eudragit E were used for the two polymeric carriers. The formulation was designed for hot-melt extrusion (HME) and subsequent strand pelletization. The aim was to identify a formulation window with desired functional ASD performance, i.e. physical stability and immediate API release, as well as processability in strand pelletization. Samples were prepared using small-scale methods, such as vacuum compression molding (VCM) and benchtop extrusion. Miscibility and phase studies were performed for a wide range of polymer ratios and three levels of API content (10–30% w/w). Ternary ASD formulations were phase-separated, yet physically stable upon exposure to elevated temperature/humidity. A study of phase composition showed that the drug molecules were predominantly solubilized in the Eudragit E fraction of the formulation. The miscibility study and Fourier-transform infrared spectroscopy indicated hydrogen (H)bond interactions between NMD and Eudragit E. In HPMC, the amorphous API was dispersed in polymeric matrix and stabilized due to anti-plasticization and the disruption of intermolecular Hbonding between API molecules. Concerning processability in strand pelletization the formulation is limited at high Eudragit E content. NMD and EE-rich phases exhibit low mixture glass transition, low melt stability and brittle breaking behavior upon strand cutting. The high viscosity and yield point of HPMC contributes to the mechanical robustness of the strand at temperatures relevant for processing. Formulation-intrinsic dissolution rates in VCM ASDs developed as an irregular function of polymer ratio, associated with diverse and competitive dissolution mechanisms in the polymers. With regard to the binary system of NMD with HPMC E5, surface crystallization was observed in VCM ASDs. For extruded pellets this was not the case, and a steady trend of formulation-intrinsic dissolution rate across different polymer ratios was observed. These discrepancies indicated a major influence of shear stress during sample preparation on HPMC-based ASD performance. Finally, a feasible formulation window within a polymer ratio of 1:2–2:3 Eudragit E:HPMC was identified in which Eudragit E acts as a dissolution rate enhancer and ASD stabilizer during dissolution.

A study to identify the contribution of Soluplus® component homopolymers to the solubilization of nifedipine and sulfamethoxazole using the melting point depression method

PurposeExploit the Flory-Huggins Theory and its interaction parameter to measure the contribution of each of the homopolymers of the graft copolymer Soluplus® to the solubilization of sulfamethoxazole (SMX) and nifedipine (NIF). MethodsThe melting point depression for each crystalline drug in the presence of Soluplus® and each of its component homopolymers, namely poly(N-vinyl caprolactam) (PVCL), poly(vinylacetate) (PVAc), and poly(ethyleneglycol) (PEG), was measured at various drug levels using differential scanning calorimetry. Glass transition temperatures were calculated across the entire range for drug-polymer mixtures for comparison to the Gordon-Taylor prediction. The intersection of the melting point depression curve with the mixture glass transition curve provides an estimate of the solubility of the drug in the polymer. The solubility of these crystalline drugs in each homopolymer was calculated and a solubility in Soluplus® was estimated based on the homopolymer contributions. ResultsPEG 6000 exhibited a negative interaction parameter with SMX and NIF, indicating a relatively strong drug-polymer interaction. For PVAc, a small positive interaction parameter indicated a relatively weak drug-polymer interaction. The approach was not suitable for assessing the drug-PVCL interaction. However, other approaches could be taken to estimate the solubility of the drug in a polymer, including extrapolating the enthalpy of melting as a function of the volume fraction of the polymer to zero enthalpy to determine the maximum concentration miscible with the polymer and equating a parameter across the ideal solubility equation and the Flory-Huggins equation. ConclusionThe Flory-Huggins Theory allowed identification of the contribution of two of the homopolymers to the solubilization of NIF and SMX by Soluplus®, namely PEG and PVAc. PVAc and PVCL each demonstrated a weak interaction with each drug. However, PEG 6000 would substantially contribute to the drug solubilization due to its marked affinity for each drug.

Microscopic Theory of Coupled Slow Activated Dynamics in Glass-Forming Binary Mixtures.

The Elastically Collective Nonlinear Langevin Equation theory for one-component viscous liquids and suspensions is generalized to treat coupled slow activated relaxation and diffusion in glass-forming binary sphere mixtures of any composition, size ratio, and interparticle interactions. A trajectory-level dynamical coupling parameter concept is introduced to construct two coupled dynamic free energy functions for the smaller penetrant and larger matrix particle. A two-step dynamical picture is proposed where the first-step process involves matrix-facilitated penetrant hopping quantified in a self-consistent manner based on a temporal coincidence condition. After penetrants dynamically equilibrate, the effectively one-component matrix particle dynamics is controlled by a new dynamic free energy (second-step process). Depending on the time scales associated with the first- and second-step processes, as well as the extent of matrix-correlated facilitation, distinct physical scenarios are predicted. The theory is implemented for purely hard-core interactions, and addresses the glass transition based on variable kinetic criteria, penetrant-matrix coupled activated relaxation, self-diffusion of both species, dynamic fragility, and shear elasticity. Testable predictions are made. Motivated by the analytic ultralocal limit idea derived for pure hard sphere fluids, we identify structure-thermodynamics-dynamics relationships. As a case study for molecule-polymer thermal mixtures, the chemically matched fully miscible polystyrene-toluene system is quantitatively studied based on a predictive mapping scheme. The resulting no-adjustable-parameter results for toluene diffusivity and the mixture glass transition temperature are in good agreement with experiment. The theory provides a foundation to treat diverse dynamical problems in glass-forming mixtures, including suspensions of colloids and nanoparticles, polymer-molecule liquids, and polymer nanocomposites.

Unveiling the dependence of glass transitions on mixing thermodynamics in miscible systems.

The dependence of the glass transition in mixtures on mixing thermodynamics is examined by focusing on enthalpy of mixing, ΔHmix with the change in sign (positive vs. negative) and magnitude (small vs. large). The effects of positive and negative ΔHmix are demonstrated based on two isomeric systems of o- vs. m- methoxymethylbenzene (MMB) and o- vs. m- dibromobenzene (DBB) with comparably small absolute ΔHmix. Two opposite composition dependences of the glass transition temperature, Tg, are observed with the MMB mixtures showing a distinct negative deviation from the ideal mixing rule and the DBB mixtures having a marginally positive deviation. The system of 1, 2- propanediamine (12PDA) vs. propylene glycol (PG) with large and negative ΔHmix is compared with the systems of small ΔHmix, and a considerably positive Tg shift is seen. Models involving the properties of pure components such as Tg, glass transition heat capacity increment, ΔCp, and density, ρ, do not interpret the observed Tg shifts in the systems. In contrast, a linear correlation is revealed between ΔHmix and maximum Tg shifts.

Self-diffusion of small molecules into rubbery polymers: A lattice free-volume theory

In the framework of the free-volume (FV) theory, a new equation was derived for the evaluation of self-diffusion coefficients of small molecules in polymers above the mixture glass transition temperature. The derivation of the equation turned out to be straightforward once the equivalence between the free volume and the unoccupied volume given by thermodynamic lattice theories is assumed. A parameter evaluation scheme is proposed, which is substantially simpler compared with the conventional Vrentas–Duda approach, even without losing generality. The key assumption is discussed, and its consistency is verified from a numerical viewpoint. A comparison with experimental solvent self-diffusion coefficients for several solvent/polymer binary systems confirmed that the proposed theory presents good correlative ability over wide temperature and composition ranges. Moreover, the introduced thermodynamic foundation allows one to easily include the pressure effect too. In the frame of the proposed lattice free volume theory, the sizes of the polymer jumping units decrease with temperature and increase with pressure. Such behavior converges with theoretical expectations and opens the way for a predictive FV theory. © 2010 Wiley Periodicals, Inc. J Polym Sci Part B: Polym Phys 48: 529–540, 2010

A conformal solution theory for the energy landscape and glass transition of mixtures

We apply conformal solution theory and extend to mixtures a recently derived equation of state for glass-forming liquids. The equation of state is based on the statistical properties of the multidimensional potential energy surface as a function of a macroscopic system’s degrees of freedom (energy landscape), and allows the calculation of an ideal glass transition locus, along which the configurational entropy vanishes. The landscape mixing approach yields an expression for the composition dependence of the mixture’s glass transition. A non-monotonic composition dependence is predicted by the theory for the glass transition of a binary Lennard–Jones mixture. The composition dependence of species diffusivities obtained by molecular dynamics simulation of this mixture is consistent with the theoretical prediction.

Correlation of the glass transition temperature of plasticized PVC using a lattice fluid model

A model has been developed to estimate the glass transition temperature of polymer+plasticizer mixtures (up to 30wt% plasticizer). The model is based on the Sanchez–Lacombe equation of state and the Gibbs–DiMarzio criterion, which states that the entropy of a mixture is zero at the glass transition. The polymers studied included polystyrene and poly(vinyl chloride). The plasticizers studied included a wide range of chemicals from methyl acetate to di-undecyl phthalate. The model qualitatively accounted for the effect of different plasticizers on the mixture glass transition temperature.

Correction to “The glass transition of mixtures of polystyrene with alkyl‐terminated oligostyrene – experimental evidence for microphase separation in a polymer blend”1

AbstractIn this correction note we compare the predictions of the phase diagram of a bidisperse polystyrene blend by using different approaches for the segmental χ‐parameter. Depending on the approach very different results are obtained.

The glass transition of mixtures of polystyrene with alkyl‐terminated oligostyrene — experimental evidence for microphase separation in a polymer blend

AbstractMixtures of high molecular weight polystyrene (Pn = 961.5; Tg = 373 K) and sec‐butyl‐terminated oligostyrene (Pn = 10.6; Tg = 302 K) show a dependence of the glass transition on the composition (i.e. number‐average molecular weight) which cannot be described by the classic equations of Fox & Flory or Kanig & Ueberreiter. Addition of small amounts of the oligostyrene strongly decreases the glass transition, and above an oligomer content of 40 wt.‐% the glass transition remains constant within experimental error. This behavior can be attributed to the unfavorable interactions between the alkyl‐terminated oligomer and the high molecular weight PS. As a result the oligomer is a bad solvent but — according to the requirements defined by Kanig — an efficient plasticizer. This behaviour is even more pronounced in mixtures of the alkyl‐terminated oligostyrene with a poly(styrene‐co‐maleic anhydride) of low maleic anhydride content. In this case, ESR spectra of the spin‐labelled styrene copolymer demonstrate the existence of microheterogeneities on the 2–5 nm scale. The findings are in qualitative agreement with recent theoretical work of Khokhlov & Erukhimovich on entropy‐induced microphase separation in blends.

Glass transition of binary systems: peculiarities at low temperature

The present paper refers to the well known fact that the glass transition-composition curves of miscible binary systems (e.g. polymer-diluent and polymer-polymer mixtures) often exhibit a singular point when the T g values of the two components are far apart. Two different equations apparently apply above and below the temperature of this singularity. Starting from Couchman's entropic treatment of the glass transition of mixtures, and from Angell's suggestion for the calculation of T 0 (‘ideal glass transition temperature’ of the component with higher T g), it is shown that below T 0 an equation should be applicable to binary mixtures which differs considerably from the equations normally used in the literature. The new equation gives a satisfactory description of selected experimental data in the proximity of the component with lower T g.

On the glass transition in mixtures between the normal alcohols and various Lewis bases

The glass transition temperatures (Tg) of binary mixtures of the lower normal alkanols with several aprotic Lewis bases have been measured as a function of composition. The initial molar slope (IMS) at the pure alcohol end of the curve of Tg against mole fraction of base was accurately determined for each base. A related quantity, the reduced IMS, is shown to be proportional to the excess configurational entropy per bead of base introduced into dilute solution with the base. The reduced IMS is found to be a linear function of the length of the alcohol backbone for the heavier alkanols and to be an increasing function of the base Tg. The results are interpreted in terms of alcohol and base self-association. Some form of network association is suggested for the lighter alkanols in the supercooled liquid, while the bases most likely associate under the action of dipole–dipole or other specific nonhydrogen bonding forces. The reduced IMS values suggest association between alcohol and base, but this association usually does not seem to be by means of hydrogen bonding in solutions dilute in the base. The Tg values of concentrated base solutions in the alcohols are discussed as well.

The estimation of phase modifications in polymers by the method of “molecular probes” in gas chromatography—III. Glass transition behaviour and compatibility in mixtures of poly(methyl methacrylate) with poly(vinyl chloride)

Using the method of “molecular probes” in gas chromatography, glass-transitions in mixtures of poly(methyl methacrylate) with poly(vinyl chloride) are found. The strong variation of T g for poly (methyl methacrylate) in mixtures with more than 20% of that polymer suggests interactions although T g for poly(vinyl chloride) remains constant. The existence of a single T g in mixtures with less than 20% poly(methyl methacrylate), on the other hand, suggests possible compatibility in these mixtures.