A Combined Rheological and Thermomechanical Analysis Approach for the Assessment of Pharmaceutical Polymer Blends.

The viscoelastic nature of polymeric formulations utilised in drug products imparts unique thermomechanical attributes during manufacturing and over the shelf life of the product. Nevertheless, it adds to the challenge of understanding the precise mechanistic behaviour of the product at the microscopic and macroscopic level during each step of the process. Current thermomechanical and rheological characterisation techniques are limited to assessing polymer performance to a single phase and are especially hindered when the polymers are undergoing thermomechanical transitions.

Worm-like micelles of triblock copolymer of ethylene oxide and styrene oxide characterised using light scattering and Taylor dispersion analysis.

A triblock ESE copolymer (ESE, S = styrene oxide and E = ethylene oxide) was synthesised by sequential oxyanionic copolymerisation of styrene oxide followed by ethylene oxide. Light scattering studies demonstrated a shape transition from spherical micelles to worm-like micelles above a critical temperature of approximately 18 °C. Taylor dispersion analysis (TDA) also indicated a size growth when the temperature increased from 25 to 40 °C due to the formation of worm-like micelles.

Additive Manufacturing of a Point-of-Care "Polypill:" Fabrication of Concept Capsules of Complex Geometry with Bespoke Release against Cardiovascular Disease.

Polypharmacy is often needed for the management of cardiovascular diseases and is associated with poor adherence to treatment. Hence, highly flexible and adaptable systems are in high demand to accommodate complex therapeutic regimens. A novel design approach is employed to fabricate highly modular 3D printed "polypill" capsules with bespoke release patterns for multiple drugs.

Aromatic Stacking Facilitated Self-Assembly of Ultrashort Ionic Complementary Peptide Sequence: β-Sheet Nanofibers with Remarkable Gelation and Interfacial Properties.

Understanding peptide self-assembly mechanisms and stability of the formed assemblies is crucial for the development of functional nanomaterials. Herein, we have adopted a rational design approach to demonstrate how a minimal structural modification to a nonassembling ultrashort ionic self-complementary tetrapeptide EK (Phe4) remarkably enhanced the stability of self-assembly into β-sheet nanofibers and induced hydrogelation. This was achieved by replacing flexible phenylalanine residue () by the rigid phenylglycine (), resulting in a constrained analogue EK (Phg4), which positioned aromatic rings in an orientation favorable for aromatic stacking.

'Temporary Plasticiser': A novel solution to fabricate 3D printed patient-centred cardiovascular 'Polypill' architectures.

Hypertension and dyslipidaemia are modifiable risk factors associated with cardiovascular diseases (CVDs) and often require a complex therapeutic regimen. The administration of several medicines is commonly associated with poor levels of adherence among patients, to which World Health Organisation (WHO) proposed a fixed-dose combination unit (polypill) as a strategy to improve adherence. In this work, we demonstrate the fabrication of patient-specific polypills for the treatment of CVDs by fused deposition modelling (FDM) 3D printing and introduce a novel solution to meet critical quality attributes.

Tailored on demand anti-coagulant dosing: An in vitro and in vivo evaluation of 3D printed purpose-designed oral dosage forms.

Coumarin therapy has been associated with high levels of inter- and intra-individual variation in the required dose to reach a therapeutic anticoagulation outcome. Therefore, a dynamic system that is able to achieve accurate delivery of a warfarin dose is of significant importance. Here we assess the ability of 3D printing to fabricate and deliver tailored individualised precision dosing using in-vitro and in-vivo models.

Tablet fragmentation without a disintegrant: A novel design approach for accelerating disintegration and drug release from 3D printed cellulosic tablets.

Fused deposition modelling (FDM) 3D printing has shown the most immediate potential for on-demand dose personalisation to suit particular patient's needs. However, FDM 3D printing often involves employing a relatively large molecular weight thermoplastic polymer and results in extended release pattern. It is therefore essential to fast-track drug release from the 3D printed objects.

Channelled tablets: An innovative approach to accelerating drug release from 3D printed tablets.

Conventional immediate release dosage forms involve compressing the powder with a disintegrating agent that enables rapid disintegration and dissolution upon oral ingestion. Among 3D printing technologies, the fused deposition modelling (FDM) 3D printing technique has a considerable potential for patient-specific dosage forms. However, the use of FDM 3D printing in tablet manufacturing requires a large portion of polymer, which slows down drug release through erosion and diffusion mechanisms.

Preparation of core-crosslinked linear-dendritic copolymer micelles with enhanced stability and their application for drug solubilisation.

In this study we explore the preparation of core-crosslinked micelles of linear-dendritic methoxy-poly(ethylene glycol) (MPEG)-co-poly(ester-sulfide) (PES) polymers to improve the stability of such polymeric micelle systems against premature disintegration and drug release. A series of MPEG-PES copolymers were synthesised via stepwise reactions of acetylation and thiol-ene photoreaction. Surface tension measurement showed that the copolymers with ethenyl surface groups could self-associate in dilute aqueous solutions to form micelles.

Characterisation of aggregates of cyclodextrin-drug complexes using Taylor Dispersion Analysis.

There is a need to understand the nature of aggregation of cyclodextrins (CDs) with guest molecules in increasingly complex formulation systems. To this end an innovative application of Taylor dispersion analysis (TDA) and comparison with dynamic light scattering (DLS) have been carried out to probe the nature of ICT01-2588 (ICT-2588), a novel tumor-targeted vascular disrupting agent, in solvents including a potential buffered formulation containing 10% hydroxypropyl-β-cyclodextrin. The two hydrodynamic sizing techniques give measurement responses are that fundamentally different for aggregated solutions containing the target molecule, and the benefits of using TDA in conjunction with DLS are that systems are characterised through measurement of both mass- and z-average hydrodynamic radii.

Effect of mechanical denaturation on surface free energy of protein powders.

Globular proteins are important both as therapeutic agents and excipients. However, their fragile native conformations can be denatured during pharmaceutical processing, which leads to modification of the surface energy of their powders and hence their performance. Lyophilized powders of hen egg-white lysozyme and β-galactosidase from Aspergillus oryzae were used as models to study the effects of mechanical denaturation on the surface energies of basic and acidic protein powders, respectively.

Equation to Line the Borders of the Folding-Unfolding Transition Diagram of Lysozyme.

It is important for the formulators of biopharmaceuticals to predict the folding-unfolding transition of proteins. This enables them to process proteins under predetermined conditions, without denaturation. Depending on the apparent denaturation temperature (Tm) of lysozyme, we have derived an equation describing its folding-unfolding transition diagram.

Mapping the solid-state properties of crystalline lysozyme during pharmaceutical unit-operations.

Bulk crystallisation of protein therapeutic molecules towards their controlled drug delivery is of interest to the biopharmaceutical industry. The complexity of biotherapeutic molecules is likely to lead to complex material properties of crystals in the solid state and to complex transitions. This complexity is explored using batch crystallised lysozyme as a model.

Evaluating the inter and intra batch variability of protein aggregation behaviour using Taylor dispersion analysis and dynamic light scattering.

Biosimilar pharmaceuticals are complex biological molecules that have similar physicochemical properties to the originator therapeutic protein. They are produced by complex multi-stage processes and are not truly equivalent. Therefore, for a biosimilar to be approved for market it is important to demonstrate that the biological product is highly similar to a reference product.

Hookworm in the Northern Territory: down but not out.

Objectives: To determine the prevalence and trends of human hookworm infection (HWI) in the Northern Territory over the past 10 years, and to assess the influence of the community children's deworming program (CCDP).

Design, Patients And Setting: A retrospective observational analysis of consecutive microbiologically confirmed cases of HWI in patients diagnosed at NT government health care facilities and the main private laboratory servicing the NT between January 2002 and July 2012.

Main Outcome Measures: Annual prevalence of HWI (2002-2011); age, sex, Indigenous status, residence, haemoglobin level and eosinophil count of patients with HWI; and proportion of patients within the CCDP target population (children aged 6 months to 16 years, who should receive 6-monthly albendazole).

A discriminatory intrinsic dissolution study using UV area imaging analysis to gain additional insights into the dissolution behaviour of active pharmaceutical ingredients.

For efficient and effective drug development it is desirable to acquire a deep understanding of the dissolution behaviour of potential candidate drugs and their physical forms as early as possible and with the limited amounts of material that are available at that time. Using 3-10mg sample quantities, the ability of a UV imaging system is investigated to provide deep mechanistic insight into the intrinsic dissolution profiling of a range of compounds and physical forms assessed under flow conditions. Physical forms of indomethacin, theophylline and ibuprofen were compressed and their solid-state form confirmed before and after compression with X-ray methods and/or Raman spectroscopy.

Taylor dispersion analysis compared to dynamic light scattering for the size analysis of therapeutic peptides and proteins and their aggregates.

Purpose: To evaluate Taylor dispersion analysis (TDA) as a novel method for determination of hydrodynamic radius of therapeutic peptides and proteins in non-stressed and stressed formulations and to compare it with dynamic light scattering (DLS).

Methods: The hydrodynamic radius of oxytocin, bovine serum albumin, various monoclonal antibodies (type IgG) and etanercept at concentrations between 0.05 and 50 mg/ml was determined by TDA and DLS.

A nanolitre method to determine the hydrodynamic radius of proteins and small molecules by Taylor dispersion analysis.

The escalating number of new therapeutic biopharmaceuticals being developed and their high value increases the need for the development of novel analytical technologies. Faster analysis time, high accuracy, low sample consumption and the ability to monitor process flow are all essential prerequisites. We evaluate a novel analytical instrument that combines UV area imaging and Taylor dispersion analysis (TDA) to determine the hydrodynamic radius of proteins and small molecules in solution.

Influence of protein on mannitol polymorphic form produced during co-spray drying.

The stabilizing ability of the excipient on pharmaceutically relevant proteins for potential therapeutic use is an extensive area of research but the effect the protein has on the excipient is rarely reported. The influence of two model proteins on the polymorphic behaviour of mannitol during spray drying was therefore investigated. Spray dried mannitol/protein blends were characterised structurally using X-ray powder diffraction (XRPD) and Fourier transform Raman spectroscopy (FT-Raman) and thermally by differential scanning calorimetry (DSC) and also thermogravimetric analysis (TGA).

The characterization and comparison of spray-dried mannitol samples.

Background: Following the production of spray-dried mannitol powders, it is essential that the polymorphic content of each individual product is completely characterized. The implications of the polymorphic behavior of mannitol are immense. The appearance or disappearance of a crystalline form within a dosage form can have costly repercussions and lead to a dosage form being withdrawn.

Do co-spray dried excipients offer better lysozyme stabilisation than single excipients?

The inherent instability of proteins when isolated from their native conditions creates the necessity of suitable stabilisation techniques. Because of the instability of proteins in solution it is often necessary to produce them as solid formulations. A method of producing relatively stable, solid protein pharmaceuticals is to incorporate them with a suitable excipient into an amorphous matrix by dehydration.

Drug release phenomena within a hydrophobic starch acetate matrix: FTIR mapping of tablets after in vitro dissolution testing.

The aim of this study was to assess the utility of Fourier transform infrared mapping to study the drug release phenomena within a hydrophobic matrix tablet. Starch acetate with a degree of substitution (2.7) was used as a hydrophobic matrix former.

Preparation and characterisation of spray-dried and crystallised trypsin: FT-Raman study to detect protein denaturation after thermal stress.

The production of stable protein formulations is difficult due to unique properties of proteins. Accordingly, spray drying and crystallisation techniques were assessed for their effects on trypsin, a model protein. Samples were investigated using polarising microscopy, thermogravimetry, differential scanning calorimetry (DSC), FT-Raman spectroscopy and enzymatic assay.

Disorder and dissolution enhancement: deposition of ibuprofen on to insoluble polymers.

Microcrystalline cellulose (MCC) and cross-linked polyvinylpyrrolidone (PVP-CL) were examined as polymeric carriers to support amorphous ibuprofen (IB). Drug/carrier systems were prepared as physical mixes, and drug was loaded onto the polymers by hot mix and solvent deposition methods. The systems were examined using differential scanning calorimetry (DSC), X-ray powder diffractometry (XRD) and by dissolution testing.

A solid-state NMR study of molecular mobility and phase separation in co-spray-dried protein-sugar particles.

Molecular mobility and physical form of co-spray-dried sugar-lysozyme formulations were evaluated. Co-spray-dried trehalose:lysozyme and sucrose:lysozyme formulations in 1:9, 1:1 and 9:1 ratios (w:w) were stored at 0% RH and 75% RH for 5-6 days. Molecular mobility and physical form of the co-spray-dried formulations after storage were determined by using 13C and 1H solid-state NMR as well as X-ray powder diffractometry.