Production and characterization of specific antibodies for evaluation of glycated insulin in plasma and biological tissues

Previous studies have shown that glycation of insulin occurs in pancreatic beta -cells under conditions of hyperglycaemia and that the site of glycation is the N-terminal Phe(1) of the insulin B-chain. To enable evaluation of glycated insulin in diabetes, specific antibodies were raised in rabbits and guinea-pigs by using two synthetic peptides (A: Phe-Val-Asn-Gln-His-Leu-Cys-Tyr, and B: Phe-Val-Asn-Gln-His-Leu-Tyr-Lys) modified by N-terminal glycation and corresponding closely to the N-terminal sequence of the glycated human insulin B-chain. For immunization, the glycated peptides were conjugated either to keyhole limper haemocyanin or ovalbumin using glutaraldehyde, m-maleimidobenzoyl-N-hydroxysuccinimide ester or 1-ethyl-3-(3-dimethylamino propyl) carbodiimide hydrochloride. Antibody titration curves, obtained using I-125-tyrosylated tracer prepared from glycated peptide A, revealed high-titre antisera in five groups of animals immunized for 8-28 weeks. The highest titres were observed in rabbits and guinea-pigs immunized with peptide B coupled to ovalbumin using glutaraldehyde. Under radioimmunoassay conditions, these antisera exhibited effective dose (median) (ED50) values for glycated insulin of 0.3-15 ng/ml and 0.9-2.5 ng/ml respectively, with negligible cross-reactivity against insulin or other islet peptides. The degree of cross-reaction with glycated proinsulin was approximately 50%. Glycated insulin in plasma of control and hydrocortisone-treated diabetic rats measured using rabbit 3 antiserum (1:10 000 dilution; sensitivity

Surface-Enhanced Raman Evidence of Protonation, Reorientation, and Ag+ Complexation of Deoxyadenosine and Deoxyadenosine-5 '-Monophosphate (dAMP) on Ag and Au Surfaces

Surface-enhanced Raman (SERS) spectra of deoxyadenosine and 5'-dAMP on Ag and Au surfaces showed the protonation of both compounds in the N1 position, their orientation geometry on metal surfaces, and the formation of Ag+ complexes at alkaline pH on hydroxylamine-reduced Ag colloids. Interestingly, substitution at the N9 position caused dramatic changes in the relative band intensities within the spectra of both deoxyadenosine and 5'-dAMP compared to that of simple adenine, although they continued to be dominated by adenine vibrations. Concentration-dependent spectra of 5'-dAMP were observed, which matched that of adenine at high concentrations and that of deoxyadenosine at lower concentration (

Discovery of Novel Allosteric Modulators of Metabotropic Glutamate Receptor Subtype 5 Reveals Chemical and Functional Diversity and In Vivo Activity in Rat Behavioral Models of Anxiolytic and Antipsychotic Activity

Modulators of metabotropic glutamate receptor subtype 5 (mGluR5) may provide novel treatments for multiple central nervous system (CNS) disorders, including anxiety and schizophrenia. Although compounds have been developed to better understand the physiological roles of mGluR5 and potential usefulness for the treatment of these disorders, there are limitations in the tools available, including poor selectivity, low potency, and limited solubility. To address these issues, we developed an innovative assay that allows simultaneous screening for mGluR5 agonists, antagonists, and potentiators. We identified multiple scaffolds that possess diverse modes of activity at mGluR5, including both positive and negative allosteric modulators (PAMs and NAMs, respectively). 3-Fluoro-5-(3-(pyridine-2-yl)-1,2,4-oxadiazol-5-yl) benzonitrile (VU0285683) was developed as a novel selective mGluR5 NAM with high affinity for the 2-methyl-6-(phenyl-ethynyl)-pyridine (MPEP) binding site. VU0285683 had anxiolytic-like activity in two rodent models for anxiety but did not potentiate phen-cyclidine-induced hyperlocomotor activity. (4-Hydroxypiperidin-1-yl)(4-phenylethynyl) phenyl) methanone (VU0092273) was identified as a novel mGluR5 PAM that also binds to the MPEP site. VU0092273 was chemically optimized to an orally active analog, N-cyclobutyl-6-((3-fluorophenyl) ethynyl) nicotinamide hydrochloride (VU0360172), which is selective for mGluR5. This novel mGluR5 PAM produced a dose-dependent reversal of amphetamine-induced hyperlocomotion, a rodent model predictive of antipsychotic activity. Discovery of structurally and functionally diverse allosteric modulators of mGluR5 that demonstrate in vivo efficacy in rodent models of anxiety and antipsychotic activity provide further support for the tremendous diversity of chemical scaffolds and modes of efficacy of mGluR5 ligands. In addition, these studies provide strong support for the hypothesis that multiple structurally distinct mGluR5 modulators have robust activity in animal models that predict efficacy in the treatment of CNS disorders.

Rheological destructuring of aqueous gels composed of cellulose ethers following storage in the presence of redox agents

Despite their widespread use, there is a paucity of information concerning the effect of storage on the rheological properties of pharmaceutical gels that contain organic and inorganic additives. Therefore, this study examined the effect of storage (1 month at either 4 or 37 degrees C) on the rheological and mechanical properties of gels composed of either hydroxypropylmethylcellulose (3-5% w/w, HPMC) or hydroxyethylcellulose (3-5% w/w, HEC) and containing or devoid of dispersed organic (tetracycline hydrochloride 2% w/w) or inorganic (iron oxide 0.1% w/w) agents. The mechanical properties were measured using texture profile analysis whereas the rheological properties were analyzed using continuous shear rheometry and modeled using the Power Law model. All formulations exhibited pseudoplastic flow with minimal thixotropy. Increasing polymer concentration (3-5% w/w) significantly increased the consistency, hardness, compressibility, and adhesiveness of the formulations due to increased polymer chain entanglement. Following storage (I month at 4 and 37 degrees C) the consistency and mechanical properties of additive free HPMC gets (but not HEC gels) increased, due to the time-dependent development of polymer chain entanglements. Incorporation of tetracycline hydrochloride significantly decreased and increased the rheological and mechanical properties of HPMC and HEC gels, respectively. Conversely, the incorporation of iron oxide did not affect these properties. Following storage, the rheological and mechanical properties of HPMC and HEC formulations were markedly compromised. This effect was greater following storage at 37 than at 4 degrees C and, additionally, greater in the presence of tetracycline hydrochloride than iron oxide. It is suggested that the loss of rheological/mechanical structure was due to chain depolymerization, facilitated by the redox properties of tetracycline hydrochloride and iron oxide. These observations have direct implications for the design and formulation of gels containing an active pharmaceutical ingredient. (c) 2005 Wiley Periodicals, Inc.

A universal measure of chaotropicity and kosmotropicity

Diverse parameters, including chaotropicity, can limit the function of cellular systems and thereby determine the extent of Earth's biosphere. Whereas parameters such as temperature, hydrophobicity, pressure, pH, Hofmeister effects, and water activity can be quantified via standard scales of measurement, the chao-/kosmotropic activities of environmentally ubiquitous substances have no widely accepted, universal scale. We developed an assay to determine and quantify chao-/kosmotropicity for 97 chemically diverse substances that can be universally applied to all solutes. This scale is numerically continuous for the solutes assayed (from +361kJkg^-1mol^-1 for chaotropes to -659kJkg^-1mol^-1 for kosmotropes) but there are key points that delineate (i) chaotropic from kosmotropic substances (i.e. chaotropes =+4; kosmotropes =-4kJkg^-1mol^-1); and (ii) chaotropic solutes that are readily water-soluble (log P<1.9) from hydrophobic substances that exert their chaotropic activity, by proxy, from within the hydrophobic domains of macromolecular systems (log P>1.9). Examples of chao-/kosmotropicity values are, for chaotropes: phenol +143, CaCl₂ +92.2, MgCl₂ +54.0, butanol +37.4, guanidine hydrochloride +31.9, urea +16.6, glycerol [>6.5M] +6.34, ethanol +5.93, fructose +4.56; for kosmotropes: proline -5.76, sucrose -6.92, dimethylsulphoxide (DMSO) -9.72, mannitol -6.69, trehalose -10.6, NaCl -11.0, glycine -14.2, ammonium sulfate -66.9, polyethylene glycol- (PEG-)1000 -126; and for relatively neutral solutes: methanol, +3.12, ethylene glycol +1.66, glucose +1.19, glycerol [<5M] +1.06, maltose -1.43 (kJkg^-1mol^-1). The data obtained correlate with solute interactions with, and structure-function changes in, enzymes and membranes. We discuss the implications for diverse fields including microbial ecology, biotechnology and astrobiology.

Assessment of factors that influence physician decision making regarding medication use in patients with dementia at the end of life

Objective
This study aimed to evaluate the extent to which patient-related factors and physicians' country of practice (Northern Ireland [NI] and the Republic of Ireland [RoI]) influenced decision making regarding medication use in patients with end-stage dementia.

Methods
The study utilised a factorial survey design comprising four vignettes to evaluate initiating/withholding or continuing/discontinuing specific medications in patients with dementia nearing death. Questionnaires and vignettes were mailed to all hospital physicians in geriatric medicine and to all general practitioners (GPs) in NI (November 2010) and RoI (December 2010), with a second copy provided 3 weeks after the first mailing. Logistic regression models were constructed to examine the impact of patient-related factors and physicians' country of practice on decision making. Significance was set a priori at p ≤ 0.05. Free text responses to open questions were analysed qualitatively using content analysis.

Results
The response rate was 20.6% (N = 662) [21.1% (N = 245) for GPs and 52.1% (N = 38) for hospital physicians in NI, 18.3% (N = 348) for GPs and 36.0% (N = 31) for hospital physicians in RoI]. There was considerable variability in decision making about initiating/withholding antibiotics and continuing/discontinuing the acetylcholinesterase inhibitor and memantine hydrochloride, and less variability in decision making regarding statins and antipsychotics. Patient place of residence and physician's country of practice had the strongest and most consistent effects on decision making although effect sizes were small.

Conclusions
Further research is required into other factors that may impact upon physicians' prescribing decisions for these vulnerable patients and to clarify how the factors examined in this study influence prescribing decisions.

Pharmacological studies of 8-OH-DPAT-induced pupillary dilation in anesthetized rats

Serotonin (5-HT) receptor agonists have been reported to produce mydriasis in mice, and miosis in rabbits and humans. However, the underlying mechanisms for this action are unclear. This study was undertaken in an attempt to explore the mechanism by which 5-HT receptors are involved in the modulation of pupillary size in pentobarbital-anesthetized rats. Intravenous administration of the 5-HT receptor agonist, (2R)-(+)-8-hydroxy-2-(di-n-propylamino)tetralin hydrobromide (8-OH-DPAT; 0.003-3 mg/kg), elicited dose-dependent pupillary dilation, which was not affected by section of the preganglionic cervical sympathetic nerve. 8-OH-DPAT-elicited mydriatic responses were attenuated by the selective 5-HT receptor antagonist, N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-2- pyridinylcyclohexanecarboxamide maleate (WAY 100635; 0.3-1 mg/kg, i.v.), as well as by the selective a -adrenoceptor antagonist, (8aR,12aS,13aS)-5,8,8a,9,10,11,12,12a,13,13a-dechydro-3-methoxy-12- (ethylsulfonyl)-6H-isoquino[2,1-g][1,6]naphthyridine hydrochloride (RS 79948; 0.3 mg/kg, i.v.), but not by the selective a -adrenoceptor antagonist, prazosin (0.3 mg/kg, i.v.). Mydriatic responses elicited by the a -adrenoceptor agonist, guanabenz (0.003-0.3 mg/kg, i.v.), were not antagonized by WAY 100635 (0.3-1 mg/kg, i.v.). To determine whether central nervous system (CNS) 5-HT receptors, like a -adrenoceptors, are involved in reflex mydriasis, voltage response curves of pupillary dilation were constructed by stimulation of the sciatic nerve in anesthetized rats. WAY 100635 (1 mg/kg, i.v.) did not antagonize the evoked reflex mydriasis, which, however, was blocked by RS 79948 (0.3 mg/kg, i.v.). Taken together, these results suggest that 8-OH-DPAT produces pupillary dilation in anesthetized rats by stimulating CNS 5-HT receptors, which in turn trigger the release of norepinephrine, presumably from the locus coeruleus. The latter reduces parasympathetic neuronal tone to the iris sphincter muscle by stimulation of postsynaptic a - adrenoceptors within the Edinger-Westphal nucleus. Unlike a - adrenoceptors, 5-HT receptors in the CNS do not mediate reflex mydriasis evoked by sciatic nerve stimulation. © 2004 Elsevier B.V. All rights reserved.

Facile synthesis of thiol-functionalized amphiphilic polylactide–methacrylic diblock copolymers

Biodegradable amphiphilic diblock copolymers based on an aliphatic ester block and various hydrophilic methacrylic monomers were synthesized using a novel hydroxyl-functionalized trithiocarbonate-based chain transfer agent. One protocol involved the one-pot simultaneous ring-opening polymerization (ROP) of the biodegradable monomer (3S)-cis-3,6-dimethyl-1,4-dioxane-2,5-dione (L-lactide, LA) and reversible addition–fragmentation chain transfer (RAFT) polymerization of 2-(dimethylamino)ethyl methacrylate (DMA) or oligo(ethylene glycol) methacrylate (OEGMA) monomer, with 4-dimethylaminopyridine being used as the ROP catalyst and 2,2′-azobis(isobutyronitrile) as the initiator for the RAFT polymerization. Alternatively, a two-step protocol involving the initial polymerization of LA followed by the polymerization of DMA, glycerol monomethacrylate or 2-(methacryloyloxy)ethyl phosphorylcholine using 4,4′-azobis(4-cyanovaleric acid) as a RAFT initiator was also explored. Using a solvent switch processing step, these amphiphilic diblock copolymers self-assemble in dilute aqueous solution. Their self-assembly provides various copolymer morphologies depending on the block compositions, as judged by transmission electron microscopy and dynamic light scattering. Two novel disulfide-functionalized PLA-branched block copolymers were also synthesized using simultaneous ROP of LA and RAFT copolymerization of OEGMA or DMA with a disulfide-based dimethacrylate. The disulfide bonds were reductively cleaved using tributyl phosphine to generate reactive thiol groups. Thiol–ene chemistry was utilized for further derivatization with thiol-based biologically important molecules and heavy metals for tissue engineering or bioimaging applications, respectively.

A rapid HPLC protocol for detection of polyols and trehalose

A procedure was developed to extract polyols and trehalose (protectants against stress) from fungal conidia. Conidia were sonicated (120 s) and immersed in a boiling water bath (5.5 min) to optimize extraction of polyols and trehalose, respectively. A rapid method was developed to separate and detect low-molecular-weight polyols and trehalose using high-performance liquid chromatography (HPLC). An ion exchange column designed for standard carbohydrate analysis was used in preference to one designed for sugar alcohol separation. This resulted in rapid elution (less than 5 min), without sacrificing peak resolution. The use of a pulsed electrochemical detector (gold electrode) resulted in limits of reliable quantification as low as 1.6 μg ml-1 for polyols and 2.8 μg ml-1 for trehalose. This is very sensitive and rapid method by which these protectants can be analysed. It avoids polyol derivatization that characterizes analysis by gas chromatography and the long run times (up to 45 min) that typify HPLC analysis using sugar alcohol columns.

Concomitant osmotic and chaotropicity-induced stresses in Aspergillus wentii: compatible solutes determine the biotic window

Whereas osmotic stress response induced by solutes has been well-characterized in fungi, less is known about the other activities of environmentally ubiquitous substances. The latest methodologies to define, identify and quantify chaotropicity, i.e. substance-induced destabilization of macromolecular systems, now enable new insights into microbial stress biology (Cray et al. in Curr Opin Biotechnol 33:228–259, 2015a, doi:10.​1016/​j.​copbio.​2015.​02.​010; Ball and Hallsworth in Phys Chem Chem Phys 17:8297–8305, 2015, doi:10.​1039/​C4CP04564E; Cray et al. in Environ Microbiol 15:287–296, 2013a, doi:10.​1111/​1462-2920.​12018). We used Aspergillus wentii, a paradigm for extreme solute-tolerant fungal xerophiles, alongside yeast cell and enzyme models (Saccharomyces cerevisiae and glucose-6-phosphate dehydrogenase) and an agar-gelation assay, to determine growth-rate inhibition, intracellular compatible solutes, cell turgor, inhibition of enzyme activity, substrate water activity, and stressor chaotropicity for 12 chemically diverse solutes. These stressors were found to be: (i) osmotically active (and typically macromolecule-stabilizing kosmotropes), including NaCl and sorbitol; (ii) weakly to moderately chaotropic and non-osmotic, these were ethanol, urea, ethylene glycol; (iii) highly chaotropic and osmotically active, i.e. NH4NO3, MgCl2, guanidine hydrochloride, and CaCl2; or (iv) inhibitory due primarily to low water activity, i.e. glycerol. At ≤0.974 water activity, Aspergillus cultured on osmotically active stressors accumulated low-M r polyols to ≥100 mg g dry weight−1. Lower-M r polyols (i.e. glycerol, erythritol and arabitol) were shown to be more effective for osmotic adjustment; for higher-M r polyols such as mannitol, and the disaccharide trehalose, water-activity values for saturated solutions are too high to be effective; i.e. 0.978 and 0.970 (25 ºC). The highly chaotropic, osmotically active substances exhibited a stressful level of chaotropicity at physiologically relevant concentrations (20.0–85.7 kJ kg−1). We hypothesized that the kosmotropicity of compatible solutes can neutralize chaotropicity, and tested this via in-vitro agar-gelation assays for the model chaotropes urea, NH4NO3, phenol and MgCl2. Of the kosmotropic compatible solutes, the most-effective protectants were trimethylamine oxide and betaine; but proline, dimethyl sulfoxide, sorbitol, and trehalose were also effective, depending on the chaotrope. Glycerol, by contrast (a chaotropic compatible solute used as a negative control) was relatively ineffective. The kosmotropic activity of compatible solutes is discussed as one mechanism by which these substances can mitigate the activities of chaotropic stressors in vivo. Collectively, these data demonstrate that some substances concomitantly induce chaotropicity-mediated and osmotic stresses, and that compatible solutes ultimately define the biotic window for fungal growth and metabolism. The findings have implications for the validity of ecophysiological classifications such as ‘halophile’ and ‘polyextremophile’; potential contamination of life-support systems used for space exploration; and control of mycotoxigenic fungi in the food-supply chain.

Simple preparation of positively charged silver nanoparticles for detection of anions by surface-enhanced Raman spectroscopy

Modification of citrate and hydroxylamine reduced Ag colloids with thiocholine bromide, a thiol functionalized quaternary ammonium salt, creates particles where the zeta potential is switched from the normal values of ca. -50 mV to ca. + 50 mV. These colloids are stable but can be aggregated with metal salts in much the same way as the parent colloids. They are excellent SERS substrates for detection of anionic targets since their positive zeta potentials promote adsorption of negatively charged ions. This is important because the vast majority of published SERS studies involve cationic or neutral targets. Moreover, the fact that the modifier is a quaternary ammonium ion means that the negative surface charge is maintained even at alkaline pH. The modified colloids can be used to detect compounds which cannot be detected using conventional negatively-charged citrate or hydroxylamine reduced metal nanoparticles, for example the detection limit was 5.0 x 10(-5) M for perchlorate and

Potential of hydrogel-forming and dissolving microneedles for use in paediatric populations

Development of formulations and drug delivery strategies for paediatric use is challenging, partially due to the age ranges within this population, resulting in varying requirements to achieve optimised patient outcomes. Although the oral route of drug delivery remains the preferred option, there are problematic issues, such as difficulty swallowing and palatability of medicines specific to this population. The parenteral route is not well accepted by children due to needle-related fear and pain. Accordingly, a plethora of alternative routes of drug administration have been investigated. Microneedles (MN) breach the stratum corneum (SC), the outermost layer of skin, increasing the number of drug substances amenable to transdermal delivery. This strategy involves the use of micron-sized needles to painlessly, and without drawing blood, create transient aqueous conduits in the SC. In this study, polymeric dissolving MN and hydrogel-forming MN were fabricated incorporating two model drugs commonly used in paediatric patients (caffeine and lidocaine hydrochloride). The potential efficacy of these MN for paediatric dosing was investigated via in vitro and in vivo studies. Views pertaining to MN technology were sought amongst school children in Northern Ireland, members of the UK general public and UK-based paediatricians, to determine perceived benefits, acceptance, barriers and concerns for adoption of this technology. In this study, polymeric MN were shown to substantially enhance skin permeability of the model therapeutic molecules in vitro and in vivo. In particular, hydrogel-forming MN led to a 6.1-fold increase in caffeine delivery whilst lidocaine HCl delivery was increased by 3.3-fold using dissolving MN in vitro. Application of caffeine-loaded MN led to a caffeine plasma concentration of 23.87μg/mL in rats at 24h. This research also highlighted a strong consensus regarding MN technology amongst schoolchildren, paediatricians and the general public, regarding potential use of MN in the paediatric population. Overall, 93.6% of general public respondents and 85.9% of paediatricians regarded the use of MN as a positive approach.

Dissolution and processing of cellulose using ionic liquids, cellulose solution, and regenerating cellulose.

Cellulose is dissolved in an ionic liq. without derivatization, and is regenerated in a range of structural forms without requiring the use of harmful or volatile org. solvents. Cellulose soly. and the soln. properties can be controlled by the selection of the ionic liq. constituents, with small cations and halide or pseudohalide anions favoring soln.; dissoln. can be aided by irradn. An ionic liq., [C4mim]Cl, proved to be the best for dissolving cellulose. [on SciFinder(R)]

Thermodynamically stable amorphous drug dispersions in amorphous hydrophilic polymers engineered by hot melt extrusion.

In this study thermodynamically stable dispersions of amorphous quinine, a model BCS class 2 therapeutic agent, within an amorphous polymeric platform (HPC), termed a solid-in-solid dispersion, were produced using hot melt extrusion. Characterisation of the pre-extrudates and extrudates was performed using hyper-differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD) and Raman spectroscopy. Water uptake by the raw materials was determined using dynamic vapour sorption (DVS) analysis. Furthermore, the presence or absence of crystalline drug following storage at 25 °C/60% relative humidity and 40 °C/75% relative humidity in a sealed glass jar, and at 40 °C/75% relative humidity in an open glass jar for 3 months was determined using PXRD. Amorphous quinine was generated in situ during extrusion from both quinine base (5%, 10%, 20% w/w drug loading) and from quinine hydrochloride (5%, 10% w/w drug loading) and remained thermodynamically stable as a solid-in-solid dispersion within the HPC extrudates. When processed with HPC, quinine hydrochloride (20% w/w) was converted to amorphous quinine hydrochloride. Whilst stable for up to 3 months when stored under sealed conditions, this amorphous form was unstable, resulting in recrystallisation of the hydrochloride salt following storage for 1 month at 40 °C/75% relative humidity in an open glass jar. The behaviour of the amorphous quinine hydrochloride (20% w/w) HPC extrudate was related, at least in part, to the lower stability and the hygroscopic properties of this amorphous form.

Characterisation and modelling of the thermorheological properties of pharmaceutical polymers and their blends using capillary rheometry: Implications for hot melt processing of dosage forms.

Given the growing interest in thermal processing methods, this study describes the use of an advanced rheological technique, capillary rheometry, to accurately determine the thermorheological properties of two pharmaceutical polymers, Eudragit E100 (E100) and hydroxypropylcellulose JF (HPC) and their blends, both in the presence and absence of a model therapeutic agent (quinine, as the base and hydrochloride salt). Furthermore, the glass transition temperatures (Tg) of the cooled extrudates produced using capillary rheometry were characterised using Dynamic Mechanical Thermal Analysis (DMTA) thereby enabling correlations to be drawn between the information derived from capillary rheometry and the glass transition properties of the extrudates. The shear viscosities of E100 and HPC (and their blends) decreased as functions of increasing temperature and shear rates, with the shear viscosity of E100 being significantly greater than that of HPC at all temperatures and shear rates. All platforms were readily processed at shear rates relevant to extrusion (approximately 200–300 s−1) and injection moulding (approximately 900 s−1). Quinine base was observed to lower the shear viscosities of E100 and E100/HPC blends during processing and the Tg of extrudates, indicative of plasticisation at processing temperatures and when cooled (i.e. in the solid state). Quinine hydrochloride (20% w/w) increased the shear viscosities of E100 and HPC and their blends during processing and did not affect the Tg of the parent polymer. However, the shear viscosities of these systems were not prohibitive to processing at shear rates relevant to extrusion and injection moulding. As the ratio of E100:HPC increased within the polymer blends the effects of quinine base on the lowering of both shear viscosity and Tg of the polymer blends increased, reflecting the greater solubility of quinine within E100. In conclusion, this study has highlighted the importance of capillary rheometry in identifying processing conditions, polymer miscibility and plasticisation phenomena.