Daniel J. Phillips

Overcoming sink limitations in dissolution testing: a review of traditional methods and the potential utility of biphasic systems

Objectives  The conventional dissolution test, particularly the USP apparatus I and II, remains an important tool in the armory of the pharmaceutical development scientist. For realistic dissolution characterization, sink conditions, where saturation solubility of a drug in the dissolution medium is at least three times more than the drug concentration, are critical. These conditions can be problematic to maintain with formulations containing poorly‐soluble actives. This review summarizes the role of the dissolution test in the pharmaceutical industry, together with some traditional techniques/additives used to enhance solubility and facilitate the achievement of sink conditions. The biphasic dissolution system, an innovative model for the treatment of poorly‐soluble species, will also be discussed.

Polymers with molecular weight dependent LCSTs are essential for cooperative behaviour

The potential to fine-tune the transition temperatures of polymers displaying lower-critical solution temperatures (LCST) by a simple mixing strategy is investigated. Using a panel of four distinct polymer classes (poly[oligo(ethyleneglycol)methacrylate], poly(N-vinylpiperidone), poly(N-vinylcaprolactam) poly(N-isopropylacrylamide)) it was shown that only those with strong molecular weight dependent LCSTs produced a single, cooperative, transition when blended together. Furthermore, the actual transition temperature was linked to the weight average not the number average molecular weight. The only polymer which did not show strong molecular-weight-LCST correlation was poly(oligo(ethyleneglycol)methacrylate), which showed two independent transitions, one for each polymer.

Biodegradable Poly(disulfide)s Derived from RAFT Polymerization: Monomer Scope, Glutathione Degradation, and Tunable Thermal Responses

Telechelic, RAFT (reversible addition-fragmentation chain transfer)-derived macromonomers with a pyridyl disulfide end-group were converted into high molecular weight, disulfide-linked polymers using a polycondensation, step-growth procedure. The applicability of the method to polycondense a library of macromonomers with different functionalities including (meth)acrylates and acrylamides was investigated. Side-chain sterics were found to be important as nonlinear poly(ethylene glycol) analogues, which proved incompatible with this synthetic methodology, as were methacrylates due to their pendant methyl group. This method was used to incorporate disulfide bonds into poly(N-isopropylacrylamide), pNIPAM, precursors to give dual-responsive (thermo- and redox) materials. These polymers were shown to selectively degrade in the presence of intracellular concentrations of glutathione but be stable at low concentrations. Due to the molecular weight-dependent cloud point of pNIPAM, the lower critical solution temperature behavior could be switched off by a glutathione gradient without a temperature change: an isothermal transition.

Glycopolymers with secondary binding motifs mimic glycan branching and display bacterial lectin selectivity in addition to affinity

The application of synthetic glycopolymers to anti-adhesive therapies has so far been limited by their lack of lectin specificity. Here we employ a macromolecular engineering approach to mimic glycan architecture. A new, 3-step tandem post-polymerisation methodology was developed which afforded precise control over both chain length and carbohydrate (galactose)-polymer backbone linker distance. This route also allowed a secondary binding (branched) motif to be introduced onto the linker, increasing specificity and affinity towards bacterial toxins without the need for extensive carbohydrate or organic chemistry. Sequential variation of this motif was found to dramatically alter both the affinity and the specificity of the glycopolymers towards two lectins, CTx and PNA, by up to 20-fold either via direct binding, or increased steric constraints. Using this method, a glycopolymer that showed increased specificity towards CTx was identified.

Glutathione-triggered disassembly of isothermally responsive polymer nanoparticles obtained by nanoprecipitation of hydrophilic polymers

The encapsulation and selective delivery of therapeutic compounds within polymeric nanoparticles offers hope for the treatment of a variety of diseases. Traditional approaches to trigger selective cargo release typically rely on polymer degradation which is not always sensitive to the biological location of a material. In this report, we prepare nanoparticles from thermoresponsive polymers with a ‘solubility release catch’ at the chain-end. This release catch is exclusively activated in the presence of intracellular glutathione, triggering an ‘isothermal’ response and promoting a change in polymer solubility. This solubility switch leads to specific and rapid nanoparticle disassembly, release of encapsulated cargo and produces completely soluble polymeric side-products.

Towards being genuinely smart: 'isothermally- responsive' polymers as versatile, programmable scaffolds for biologically-adaptable materials

Responsive polymers have found diverse application across polymer, biomaterials, medical, sensing and engineering fields. Despite many years of study, this has focussed mainly on those polymers which undergo thermally-induced changes – either a lower or upper critical solution temperature. To rival the adaptability of Natures macromolecules, polymers must respond in a ‘smarter’ way to other triggers such as enzymes, biochemical gradients, ion concentration or metabolites, to name a few. Here we review the concept of ‘isothermal’ responses where core thermoresponsive polymers are chemically engineered such that they undergo their useful response (such as coil-globule transition, cell uptake or cargo release) but at constant temperature. This is achieved by consideration of their phase diagram where solubility can be changed by small structural changes to the end-group, side-chain/substituents or through main chain modification/binding. The current state-of-the-art is summarised here.

Synthesis and Characterisation of Glucose-Functional Glycopolymers and Gold Nanoparticles: Study of their Potential Interactions with Ovine Red Blood Cells

Carbohydrate-protein interactions can assist with the targeting of polymer- and nano-delivery systems. However, some potential protein targets are not specific to a single cell type, resulting in reductions in their efficacy due to undesirable non-specific cellular interactions. The glucose transporter 1 (GLUT-1) is expressed to different extents on most cells in the vasculature, including human red blood cells and on cancerous tissue. Glycosylated nanomaterials bearing glucose (or related) carbohydrates, therefore, could potentially undergo unwanted interactions with these transporters, which may compromise the nanomaterial function or lead to cell agglutination, for example. Here, RAFT polymerisation is employed to obtain well-defined glucose-functional glycopolymers as well as glycosylated gold nanoparticles. Agglutination and binding assays did not reveal any significant binding to ovine red blood cells, nor any haemolysis. These data suggest that gluco-functional nanomaterials are compatible with blood, and their lack of undesirable interactions highlights their potential for delivery and imaging applications.

One-step grafting of polymers to graphene oxide

The direct grafting of poly(N-isopropylacrylamide) to the basal plane of graphene oxide has been achieved in a single step: cleavage of the terminal thiocarbonylthio group on RAFT grown poly(N-isopropylacrylamide) reveals a reactive thiol that attacks the epoxides present across the surface of graphene oxide. The new composite material was characterised by a combination of SSNMR, FTIR, Raman, EDX, XPS, TGA and contact angle measurement; it shows enhanced thermal stability and solubility in water.

Co-operative transitions of responsive-polymer coated gold nanoparticles; precision tuning and direct evidence for co-operative aggregation

Responsive polymers and polymer-coated nanoparticles have many potential bio-applications with the crucial parameter being the exact temperature where the transition occurs.

Siderophore-inspired nanoparticle-based biosensor for the selective detection of Fe3+

Inspired by natures exploitation of the 1,2-dihydroxybenzene unit (or catechol) in mammalian and bacterial siderophores, we report the first example of a nanoparticle sensing system that utilises the strong catechol-Fe3+ binding motif to trigger nanoparticle aggregation, promoting a powerful optical response. Gold nanoparticles are functionalised with RAFT polymerisation-prepared water-soluble poly(N-hydroxyethyl acrylamide) containing a catechol moiety at the α-chain-end. A strong red-to-purple colorimetric response occurs in the presence of Fe3+ at serum concentrations (8-25 μM) in saline solution. Sodium chloride is critical in generating a strong optical output, as is the length of polymer used to coat the AuNPs. This behaviour is also demonstrated to be selective for Fe3+ over a host of other biologically relevant ions.