Continuous twin screw granulation: Impact of microcrystalline cellulose batch-to-batch variability during granulation and drying - A QbD approach.

Despite significant advances in the research domain of continuous twin screw granulation, limited information is currently available on the impact of raw material properties, especially considering batch-to-batch variability. The importance of raw material variability and subsequent mitigation of the impact of this variability on the manufacturing process and drug product was recently stressed in the Draft Guidance for Industry on Quality Considerations for Continuous Manufacturing by the U.S. Food and Drug Administration (FDA). Therefore, this study assessed the impact of microcrystalline cellulose (MCC) batch-to-batch variability and process settings in a continuous twin screw wet granulation and semi-continuous drying line. Based on extensive raw material characterization and subsequent principal component analysis, raw material variability was quantitatively introduced in the design of experiments approach by means of t1 and t2 scores. L/S ratio had a larger effect on critical granule attributes and processability than screw speed and drying time. A large impact of the t1 and t2 scores was found, indicating the importance of raw material attributes. For the studied formulation, it was concluded that MCC batches with a low water binding capacity, low moisture content and high bulk density generated granules with the most desirable quality attributes. Additionally, an innovative and quantitative approach towards mitigating batch-to-batch variability of raw materials was proposed, which is also applicable for additional excipients and APIs.

Glass Transition Dynamics and Crystallization Kinetics in the Smectic Liquid Crystal 4-n-Butyloxybenzylidene-4'-n'-octylaniline (BBOA).

The molecular dynamics of 4-n-butyloxybenzylidene-4'-n'-octylaniline (BBOA, abbreviated also as 4O.8) was studied by broadband dielectric spectroscopy (BDS) for samples that were exposed to various thermal treatments. Phase transitions between liquid crystalline phases (N, SmA, SmBhex, and SmBCr) were evidenced by abrupt changes in the temperature dependence of the dielectric permittivity spectra and dielectric relaxation times. A particularly complex dynamic behavior was revealed for the highly ordered SmBCr phase that showed clear evidence for cooperative dynamics of a glass-forming liquid as manifested by a Vogel-Fulcher-Tammann (VFT)-type temperature dependence of its structural relaxation time τ(T). At low temperatures, dependence τ(T) again changes from VFT to Arrhenius behavior, a phenomenon commonly observed for supercooled liquids confined to nanometer length scales and occasionally discussed as strong-fragile transition on heating. In this context, our observation supports the idea of partial orientation disorder in a quenched SmBCr phase, where the length scale of cooperative motions is restricted to the nanometer size of glassy domains causing the deviation from "bulk" VFT-type behavior. Finally, the isothermal crystallization kinetics of the metastable SmBCr phase was studied in detail. On the basis of structural information about the SmBhex and SmBCr phases, determined by X-ray diffraction, the subtle relation between molecular order and relaxation behavior is discussed.

Electrical conductivity and glass formation in nitrile-functionalized pyrrolidinium bis(trifluoromethylsulfonyl)imide ionic liquids: chain length and odd-even effects of the alkyl spacer between the pyrrolidinium ring and the nitrile group.

The electrical conductivity of a series of pyrrolidinium bis(trifluoromethylsulfonyl)imide ionic liquids, functionalized with a nitrile (cyano) group at the end of an alkyl chain attached to the cation, was studied in the temperature range between 173 K and 393 K. The glass formation of the ionic liquids is influenced by the length of the alkyl spacer separating the nitrile function from the pyrrolidinium ring. The electrical conductivity and the viscosity do not show a monotonic dependence on the alkyl spacer length, but rather an odd-even effect. An explanation for this behavior is given, including the potential energy landscape picture for the glass transition.

Nematic-nematic phase transition in the liquid crystal dimer CBC9CB and its mixtures with 5CB: a high-resolution adiabatic scanning calorimetric study.

The phase transition behavior of the liquid crystal dimer α,ω-bis(4,4'-cyanobiphenyl)nonane (CBC9CB), which has been reported to exhibit a nematic-nematic phase transition, has been investigated by means of high-resolution adiabatic scanning calorimetry. This nematic-nematic phase transition is weakly first-order with a latent heat of 0.24±0.01 kJ kg(-1). Mixtures up to 40 wt % with 4-pentyl-4'-cyanobiphenyl (5CB) liquid crystals have also been investigated, which also show this nematic to nematic phase transition. The transition stays weakly first-order with a decreasing latent heat with increasing concentration of 5CB. For mixtures with more than 40 wt % uniaxial nematic-unknown nematic phase transition was not observed.

The critical behavior of the dielectric constant in the polar + polar binary liquid mixture nitromethane + 3-pentanol: an unusual sign of its critical amplitude in the one-phase region.

Dielectric constant measurements have been carried out in the one- and two-phase regions near the critical point of the polar + polar binary liquid mixture nitromethane + 3-pentanol. In the two-phase region, evidence for the |t|(2ß) singularity in the coexistence-curve diameter has been detected, thus confirming the novel predictions of complete scaling theory for liquid-liquid criticality. In the one-phase region, an "unusual" negative sign for the amplitude of the |t|(1-α) singularity has been encountered for the first time in an upper critical solution temperature type of binary liquid mixture at atmospheric pressure. Mass density measurements have also been carried out to provide additional information related to such experimental finding, which entails an increase of the critical temperature T(c) under an electric field.

Effect of thermally reduced graphene sheets on the phase behavior, morphology, and electrical conductivity in poly[(α-methyl styrene)-co-(acrylonitrile)/poly(methyl-methacrylate) blends.

The effects of thermally reduced graphene sheets (TRG) on the phase separation in poly[(α-methyl styrene)-co-(acrylonitrile)]/poly(methyl-methacrylate) blends were monitored using melt rheology, conductivity spectroscopy, and electron microscopic techniques. The TRG were incorporated in the single-phase material by solution mixing. The composite samples were then allowed to phase separate in situ. The thermodynamics of phase separation have been investigated by monitoring the evolution of the storage modulus (G') as a function of temperature as the system passes through the binodal and the spinodal lines of the phase diagram. The phase separation kinetics were probed by monitoring the evolution of G' as a function of time at a quench depth well in the spinodal region. It was observed that TRG significantly influenced the phase separation temperature, the shape of the phase diagram and the rate of phase separation. The state of dispersion of TRG in the blends was assessed using electron microscopy and conductivity spectroscopy measurements. Interestingly, the composite samples (monophasic) were virtually insulators at room temperature, whereas highly conducting materials were obtained as a result of phase separation in the biphasic materials.

Large heat capacity anomaly near the consolute point of the binary mixture nitromethane and 3-pentanol.

The large critical anomaly in the isobaric heat capacity C(p,x)(T) of the binary mixture nitromethane + 3-pentanol is measured using high-resolution adiabatic scanning calorimetry. The unique features of this technique provided an alternative approach to the study of the critical behavior of C(p,x)(T), providing further C(p,x)(T) related quantities from which valuable information could be extracted. Our data are in full agreement with the predictions of the Modern Theory of Critical Phenomena; specifically, 3D-Ising model values for the critical exponent α and the universal amplitude ratio values of the leading critical amplitudes, as well as for the first correction-to-scaling ones, provide the optimum fits to represent the experimental data. Evidence for the need of higher-order terms, i.e., first correction-to-scaling term, is given. The large value of the coefficient E for the linear temperature dependence of the background obtained is ascribed to a possible contribution of the regular linear background term, of a higher-order asymmetry term, and of the second correction-to-scaling term. Internal consistency of C(p,x)(T) and its related quantities is successfully checked.

Dynamics of the crystal to plastic crystal transition in the hydrogen bonded N-isopropylpropionamide.

N-Isopropylpropionamide (NiPPA), which can self-associate via hydrogen bonds, was found to undergo a solid-solid transition as identified by DSC and X-ray diffraction. Below the melting temperature of 51 °C NIPPA adopts a plastic crystalline state with a tetragonal unit cell until it transforms into an ordered crystal with a monoclinic structure at temperatures ≤10 °C. Dielectric spectroscopy was used to characterize the dynamics of the system, determining the activation parameters for the plastic to crystalline phase transition. The activation enthalpy is relatively high, as expected for a system that involves hydrogen bonds. However, most of the activation energy as the plastic phase assumes a more crystalline state is due to the activation entropy, suggesting that the increased cooperativity observed in the relaxation processes is due to a steric locking of the molecules.

Influence of the anion on the electrical conductivity and glass formation of 1-butyl-3-methylimidazolium ionic liquids.

Six ionic liquids based on the 1-butyl-3-methylimidazolium cation have been studied. As anions Cl(-), Br(-), I(-), [NCS](-), [N(CN)(2)](-), and [BF(4)](-) were selected. The electrical conductivities were determined between 173 and 393 K based on impedance measurements in the frequency range from 0.1 to 10(7) Hz. The electrical conductivity increases, whereas the glass transition temperature, the fragility, and the low temperature activation energy decrease with increasing anion size. The results can be understood from the changing anion-cation interaction strength with changing anion size and from the energy landscape interpretation of the glass transition dynamics.

Phase separation as a tool to control dispersion of multiwall carbon nanotubes in polymeric blends.

Conducting polymeric materials with stable phase microstructures have a range of potential applications. In this work, it is investigated whether phase separation in polymer blends can be used as a tool to create well dispersed conducting filler rich domains in 3D with controlled morphology, potentially resulting in more effective percolation. The effect of amine functionalized multiwall carbon nanotubes (NH(2)-MWCNTs) on the thermally induced phase separation processes in poly[(alpha-methyl styrene)-co-acrylonitrile]/poly(methyl methacrylate) (PalphaMSAN/PMMA) blends was monitored by melt rheology, conductivity spectroscopy, and microscopic techniques. Electron microscopic images revealed that the phase separation resulted in a heterogeneous distribution of NH(2)-MWCNTs in the blends. The migration of NH(2)-MWCNTs is controlled by the thermodynamic forces that drive phase separation and led to an increase in their local concentration in a specific phase resulting in percolative "network-like" structure. Conductivity spectroscopy measurements demonstrated that the blends with 2 wt % NH(2)-MWCNTs that showed insulating properties for a one phasic system revealed highly conducting material in the melt state (two phasic) as a result of phase separation. By quenching this morphology, a highly conducting material with controlled dispersion of MWCNTs can be achieved. Furthermore, the role of NH(2)-MWCNTs in stabilizing the PMMA droplets against flow induced coalescence in 85/15 PalphaMSAN/PMMA blends was also established for the first time. It was observed that at a typical loading of 1.25 wt % NH(2)-MWCNTs the coalescence was completely suppressed on a practical time scale.

Temperature, concentration, and frequency dependence of the dielectric constant near the critical point of the binary liquid mixture nitrobenzene-tetradecane.

Detailed results are reported for the dielectric constant epsilon as a function of temperature, concentration, and frequency near the upper critical point of the binary liquid mixture nitrobenzene-tetradecane. The data have been analyzed in the context of the recently developed concept of complete scaling. It is shown that the amplitude of the low frequency critical Maxwell-Wagner relaxation (with a relaxation frequency around 10 kHz) along the critical isopleth is consistent with the predictions of a droplet model for the critical fluctuations. The temperature dependence of epsilon in the homogeneous phase can be well described with a combination of a (1-alpha) power law term (with alpha the heat capacity critical exponent) and a linear term in reduced temperature with the Ising value for alpha. For the proper description of the temperature dependence of the difference Deltaepsilon between the two coexisting phases below the critical temperature, it turned out that good fits with the Ising value for the order parameter exponent beta required the addition of a corrections-to-scaling contribution or a linear term in reduced temperature. Good fits to the dielectric diameter epsilon(d) require a (1-alpha) power law term, a 2beta power law term (in the past considered as spurious), and a linear term in reduced temperature, consistent with complete scaling.

Temperature-driven mixing-demixing behavior of binary mixtures of the ionic liquid choline bis(trifluoromethylsulfonyl)imide and water.

The ionic liquid (2-hydroxyethylammonium)trimethylammonium) bis(trifluoromethylsulfonyl)imide (choline bistriflimide) was obtained as a supercooled liquid at room temperature (melting point=30 degrees C). Crystals of choline bistriflimide suitable for structure determination were grown from the melt in situ on the X-ray diffractometer. The choline cation adopts a folded conformation, whereas the bistriflimide anion exhibits a transoid conformation. The choline cation and the bistriflimide anion are held together by hydrogen bonds between the hydroxyl proton and a sulfonyl oxygen atom. This hydrogen bonding is of importance for the temperature-dependent solubility properties of the ionic liquid. Choline bistriflimide is not miscible with water at room temperature, but forms one phase with water at temperatures above 72 degrees C (equals upper critical solution temperature). 1H NMR studies show that the hydrogen bonds between the choline cation and the bistriflimide anion are substantially weakened above this temperature. The thermophysical properties of water-choline bistriflimide binary mixtures were furthermore studied by a photopyroelectric technique and by adiabatic scanning calorimetry (ASC). By photothermal analysis, besides highly accurate values for the thermal conductivity and effusivity of choline bistriflimide at 30 degrees C, the detailed temperature dependence of both the thermal conductivity and effusivity of the upper and lower part of a critical water-choline bistriflimide mixture in the neighborhood of the mixing-demixing phase transition could be determined with high resolution and accuracy. Together with high resolution ASC data for the heat capacity, experimental values were obtained for the critical exponents alpha and beta, and for the critical amplitude ratio G+/G-. These three values were found to be consistent with theoretical expectations for a three dimensional Ising-type of critical behavior of binary liquid mixtures.

Accelerated dielectric relaxation in the isotropic phase of associating liquid crystals dispersed with aerosils.

The dielectric response of liquid crystals in their nematic phase shows an acceleration of the relaxation associated with the rotation around the short molecular axis when dispersed with aerosils. However, in the isotropic phase, this acceleration is only seen for certain liquid crystalline molecules. In this paper, an associating liquid crystal (5CB) and a shorter monotropic liquid crystalline member of the same homologous series (4CB), a liquid crystal that does not show association (5NCS) and a nonassociating liquid crystal (5O5) have been studied by dielectric spectroscopy in the isotropic phase. Both 4CB and 5CB show a constant acceleration in the isotropic phase, observed over a broad temperature range. 5NCS and 5O5 do not show an acceleration in their isotropic phase. It seems that the disturbance of the dipole-dipole association process for the associating molecules is an important factor in the explanation of the acceleration of the relaxation in the isotropic phase.

Temperature dependence of the electrical conductivity of imidazolium ionic liquids.

The electrical conductivities of 1-alkyl-3-methylimidazolium tetrafluoroborate ionic liquids and of 1-hexyl-3-methylimidazolium ionic liquids with different anions were determined in the temperature range between 123 and 393 K on the basis of dielectric measurements in the frequency range from 1 to 10(7) Hz. Most of the ionic liquids form a glass and the conductivity values obey the Vogel-Fulcher-Tammann equation. The glass transition temperatures are increasing with increasing length of the alkyl chain. The fragility is weakly dependent on the alkyl chain length but is highly sensitive to the structure of the anion.