Solvent induced phase inversion-based in situ forming controlled release drug delivery implants

In situ forming (ISF) drug delivery implants have gained tremendous levels of interest over the last few decades. This is due to their wide range of biomedical applications such as in tissue engineering, cell encapsulation, microfluidics, bioengineering and drug delivery. Drug delivery implants forming upon injection has shown a range of advantages which include localized drug delivery, easy and less invasive application, sustained drug action, ability to tailor drug delivery, reduction in side effects associated with systemic delivery and also improved patient compliance and comfort. Different factors such as temperature, pH, ions, and exchange of solvents are involved in in situ implant formation. This review especially focuses on ISF implants that are formed through solvent induced phase inversion (SPI) technique. The article critically reviews and compares a wide range of polymers, solvents, and co-solvents that have been used in SPI implant preparation for control release of a range of drug molecules. Major drawback of SPI systems has been their high burst release. In this regard, the article exhaustively discusses factors that affect the burst release and different modification strategies that has been utilised to reduce the burst effect from these implants. Performance and controversial issues associated with the use of different biocompatible solvents in SPI systems is also discussed. Biodegradation, formulation stability, methods of characterisation and sterilisation techniques of SPI systems is comprehensively reviewed. Furthermore, the review also examines current SPI-based marketed products, their therapeutic application and associated clinical data. It also exemplifies the interest of multi-billion dollar pharma companies worldwide for further developments of SPI systems to a range of therapeutic applications. The authors believe that this will be the first review article that extensively investigate and discusses studies done to date on SPI systems. In so doing, this article will undoubtedly serve as an enlightening tool for the scientists working in the concerned area.

Micromaser spectrum and phase diffusion dynamics

We discuss a scheme to relate the phase diffusion dynamics of the micromaser field to the measured atomic population statistics. This can allow us to measure the linewidth of the micromaser spectrum and to solve a relevant decoherence problem in cavity quantum electrodynamics. The main steps are (i) a suitable preparation of the cavity field state to generate coherences, (ii) the transfer of information on the dynamics of field coherences to probe atoms by the action of an external resonant coherent field and (iii) the derivation of the phase diffusion rate, hence the micromaser linewidth, from the measured population statistics of the probe atoms. The method can be applied even in the presence of trapping states, where peculiar linewidth oscillations are expected for increasing pump rate, due to the quantum nature of the micromaser field.

How to measure the phase diffusion dynamics in the micromaser

We propose a realistic scheme for measuring the micromaser linewidth by monitoring the phase diffusion dynamics of the cavity field. Our strategy consists of exciting an initial coherent state with the same photon number distribution as the micromaser steady-state field, singling out a purely diffusive process in the system dynamics. After the injection of a counterfield, measurements of the population statistics of a probe atom allow us to derive the micromaser linewidth in all ranges of the relevant parameters, establishing experimentally the distinctive features of the micromaser spectrum due to the discreteness of the electromagnetic field.

Complex organic molecules in protoplanetary disks

Context. Protoplanetary disks are vital objects in star and planet formation, possessing all the material, gas and dust, which may form a planetary system orbiting the new star. Small, simple molecules have traditionally been detected in protoplanetary disks; however, in the ALMA era, we expect the molecular inventory of protoplanetary disks to significantly increase.

Aims. We investigate the synthesis of complex organic molecules (COMs) in protoplanetary disks to put constraints on the achievable chemical complexity and to predict species and transitions which may be observable with ALMA.

Methods. We have coupled a 2D steady-state physical model of a protoplanetary disk around a typical T Tauri star with a large gas-grain chemical network including COMs. We compare the resulting column densities with those derived from observations and perform ray-tracing calculations to predict line spectra. We compare the synthesised line intensities with current observations and determine those COMs which may be observable in nearby objects. We also compare the predicted grain-surface abundances with those derived from cometary comae observations.

Results. We find COMs are efficiently formed in the disk midplane via grain-surface chemical reactions, reaching peak grain-surface fractional abundances similar to 10(-6)-10(-4) that of the H nuclei number density. COMs formed on grain surfaces are returned to the gas phase via non-thermal desorption; however, gas-phase species reach lower fractional abundances than their grain-surface equivalents, similar to 10(-12)-10(-7). Including the irradiation of grain mantle material helps build further complexity in the ice through the replenishment of grain-surface radicals which take part in further grain-surface reactions. There is reasonable agreement with several line transitions of H2CO observed towards T Tauri star-disk systems. There is poor agreement with HC3(N) lines observed towards LkCa 15 and GO Tau and we discuss possible explanations for these discrepancies. The synthesised line intensities for CH3OH are consistent with upper limits determined towards all sources. Our models suggest CH3OH should be readily observable in nearby protoplanetary disks with ALMA; however, detection of more complex species may prove challenging, even with ALMA "Full Science" capabilities. Our grain-surface abundances are consistent with those derived from cometary comae observations providing additional evidence for the hypothesis that comets (and other planetesimals) formed via the coagulation of icy grains in the Sun's natal disk.

Complex organic molecules along the accretion flow in isolated and externally irradiated protoplanetary disks

(Abridged) The birth environment of the Sun will have influenced the conditions in the pre-solar nebula, including the attainable chemical complexity, important for prebiotic chemistry. The formation and distribution of complex organic molecules (COMs) in a disk around a T Tauri star is investigated for two scenarios: (i) an isolated disk, and (ii) a disk irradiated externally by a nearby massive star. The chemistry is calculated along the accretion flow from the outer disk inwards using a comprehensive network. Two simulations are performed, one beginning with complex ices and one with simple ices only. For the isolated disk, COMs are transported without major alteration into the inner disk where they thermally desorb into the gas reaching an abundance representative of the initial assumed ice abundance. For simple ices, COMs efficiently form on grain surfaces under the conditions in the outer disk. Gas-phase COMs are released into the molecular layer via photodesorption. For the irradiated disk, complex ices are also transported inwards; however, they undergo thermal processing caused by the warmer conditions in the irradiated disk which tends to reduce their abundance along the accretion flow. For simple ices, grain-surface chemistry cannot synthesise COMs in the outer disk because the necessary grain-surface radicals, which tend to be particularly volatile, are not sufficiently abundant on the grain surfaces. Gas-phase COMs are formed in the inner region of the irradiated disk via gas-phase chemistry induced by the desorption of strongly bound molecules such as methanol; hence, the abundances are not representative of the initial molecular abundances injected into the outer disk. These results suggest that the composition of comets formed in isolated disks may differ from those formed in externally irradiated disks with the latter composed of more simple ices.

Use of Short Time-on-Stream Attenuated Total Internal Reflection Infrared Spectroscopy To Probe Changes in Adsorption Geometry for Determination of Selectivity in the Hydrogenation of Citral

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A new experimental procedure based on attenuated total reflection infrared spectroscopy has been developed to investigate surface species under liquid phase reaction conditions. The technique has been tested by investigating the enhanced selectivity in the hydrogenation of α,β-unsaturated aldehyde citral over a 5% Pt/SiO2 catalyst toward unsaturated alcohols geraniol/nerol, which occurs when citronellal is added to the reaction. The change in selectivity is proposed to be the result of a change in the citral adsorption mode in the presence of citronellal. Short time on stream attenuated total internal reflection infrared spectroscopy has allowed identification of the adsorption modes of citral. With no citronellal, citral adsorbs through both the C═C and C═O groups; however, in the presence of citronellal, citral adsorption occurs through the C═O group only, which is proposed to be the cause of the altered reaction selectivity.

LIAD-fs: A novel method for studies of ultrafast processes in gas phase neutral biomolecules

A new experimental technique for femtosecond (fs) pulse studies of gas phase biomolecules is reported. Using Laser-Induced Acoustic Desorption (LIAD) to produce a plume of neutral molecules, a time-delayed fs pulse is employed for ionisation/fragmentation, with subsequent products extracted and mass analysed electrostatically. By varying critical laser pulse parameters, this technique can be used to implement control over molecular fragmentation for a range of small biomolecules, with specific studies of amino acids demonstrated.

Using Flory-Huggins phase diagrams as a pre-formulation tool for the production of amorphous solid dispersions; a comparison between hot-melt extrusion and spray drying

Objectives: Amorphous drug forms provide a useful method of enhancing the dissolution performance of poorly water-soluble drugs; however, they are inherently unstable. In this article, we have used Flory–Huggins theory to predict drug solubility and miscibility in polymer candidates, and used this information to compare spray drying and melt extrusion as processes to manufacture solid dispersions.
Method:  Solid dispersions were characterised using a combination of thermal (thermogravimetric analysis and differential scanning calorimetry) and spectroscopic (Fourier transform infrared spectroscopy (FTIR) and X-ray diffraction methods. 
Key Findings: Spray drying permitted generation of amorphous solid dispersions to be produced across a wider drug concentration than melt extrusion. Melt extrusion provided sufficient energy for more intimate mixing to be achieved between drug and polymer, which may improve physical stability. It was also confirmed that stronger drug–polymer interactions might be generated through melt extrusion. Remixing and dissolution of recrystallised felodipine into the polymeric matrices did occur during the modulated differential scanning calorimetry analysis, but the complementary information provided from FTIR confirms that all freshly prepared spray-dried samples were amorphous with the existence of amorphous drug domains within high drug-loaded samples. 
Conclusion: Using temperature–composition phase diagrams to probe the relevance of temperature and drug composition in specific polymer candidates facilitates polymer screening for the purpose of formulating solid dispersions.

Chemistry and Distribution of Daughter Species in the Circumstellar Envelopes of O-Rich AGB Stars

Context. Thanks to the advent of Herschel and ALMA, new high-quality observations of molecules present in the circumstellar envelopes of asymptotic giant branch (AGB) stars are being reported that reveal large differences from the existing chemical models. New molecular data and more comprehensive models of the chemistry in circumstellar envelopes are now available.
Aims: The aims are to determine and study the important formation and destruction pathways in the envelopes of O-rich AGB stars and to provide more reliable predictions of abundances, column densities, and radial distributions for potentially detectable species with physical conditions applicable to the envelope surrounding IK Tau.
Methods: We use a large gas-phase chemical model of an AGB envelope including the effects of CO and N2 self-shielding in a spherical geometry and a newly compiled list of inner-circumstellar envelope parent species derived from detailed modeling and observations. We trace the dominant chemistry in the expanding envelope and investigate the chemistry as a probe for the physics of the AGB phase by studying variations of abundances with mass-loss rates and expansion velocities.
Results: We find a pattern of daughter molecules forming from the photodissociation products of parent species with contributions from ion-neutral abstraction and dissociative recombination. The chemistry in the outer zones differs from that in traditional PDRs in that photoionization of daughter species plays a significant role. With the proper treatment of self-shielding, the N → N2 and C+→ CO transitions are shifted outward by factors of 7 and 2, respectively, compared with earlier models. An upper limit on the abundance of CH4 as a parent species of (≲2.5 × 10-6 with respect to H2) is found for IK Tau, and several potentially observable molecules with relatively simple chemical links to other parent species are determined. The assumed stellar mass-loss rate, in particular, has an impact on the calculated abundances of cations and the peak-abundance radius of both cations and neutrals: as the mass-loss rate increases, the peak abundance of cations generally decreases and the peak-abundance radius of all species moves outwards. The effects of varying the envelope expansion velocity and cosmic-ray ionization rate are not as significant.

TAP Reactor Development and Application in the Kinetic Characterization of Catalysts for Heterogeneously Catalyzed Gas Phase Reactions

This manuscript describes the application and further development of the TAP technique in kinetic characterization of heterogeneous catalysis. The major application of TAP systems is to study mechanisms, kinetics and transport phenomena in heterogeneous catalysis, all of which is made possible by the sub-millisecond time resolution. Furthermore, the kinetic information obtained can be used to gain an insight into the mechanism occurring over the catalyst system. This is advantageous as heterogeneous catalysts with an improved efficiency can be developed as a result. TAP kinetic studies are carried out at low pressure (~1x10-7 mbar) and TAP pulses are sufficiently small (1013-1015 molecules) so as to maintain this low pressure. The use of a small number of molecules in comparison to the total number of active sites means the state of the catalyst remains relatively unchanged. The use of the low intensity pulses also makes the pressure gradient negligible and so allows the TAP reactor system to operate in the Knudsen Diffusion regime, where gas-gas reactions are eliminated. Hence only gas-catalyst reactions are investigated and, by the use of moment analysis of observed exit flow, rate constants of elementary steps of the reaction can be obtained.

In this manuscript, two attempts to further the TAP technique are reported. Firstly, the work undertaken at QUB to attempt to control the number of molecules of condensable reagents that can be pulsed during a TAP pulse experiment is disclosed. Secondly, a collaborative project with SAI Ltd Manchester is discussed in a separate chapter, where technical details and validation of a customised time of flight mass spectrometer (ToF MS) for the QUB TAP-1 system are reported. A collaborative project with Cardiff Catalysis Institute focusing on the study of CO oxidation over hopcalite catalysts is also reported. The analysis of the experimental results has provided an insight into the possible mechanism of the oxidation of CO over these catalysts. A correction function has also been derived which accounts for the adsorption of reactant molecules over inert materials that are used for the reactor packing in TAP experiments. This function was then applied to the selective reduction of O2 in a H2 rich ethene feed, so that more accurate TAP moment based analysis could be conducted.

First Detection of Gas-phase Methanol in a Protoplanetary Disk

The first detection of gas-phase methanol in a protoplanetary disk (TW Hya) is presented. In addition to being one of the largest molecules detected in disks to date, methanol is also the first disk organic molecule with an unambiguous ice chemistry origin. The stacked methanol emission, as observed with the Atacama Large Millimeter/submillimeter Array, is spectrally resolved and detected across six velocity channels (>3σ), reaching a peak signal-to-noise of 5.5σ, with the kinematic pattern expected for TW Hya. Using an appropriate disk model, a fractional abundance of 3 x 10^-12 – 4 x 10^-11 (with respect to H₂) reproduces the stacked line profile and channel maps, with the favored abundance dependent upon the assumed vertical location (midplane versus molecular layer). The peak emission is offset from the source position, suggesting that the methanol emission has a ring-like morphology: the analysis here suggests it peaks at ≈30 au, reaching a column density ≈3–6 x 10¹² cm⁻². In the case of TW Hya, the larger (up to millimeter-sized) grains, residing in the inner 50 au, may thus host the bulk of the disk ice reservoir. The successful detection of cold gas-phase methanol in a protoplanetary disk implies that the products of ice chemistry can be explored in disks, opening a window into studying complex organic chemistry during planetary system formation.