Investigation into improving efficiency in a domestic drying process

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Freezing process optimisation of pharmaceutical formulations for freeze drying

The body of work presented in this thesis are in three main parts: [1] the effect of ultrasound on freezing events of ionic systems, [2] the importance of formulation osmolality in freeze drying, and [3] a novel system for increasing primary freeze drying rate. Chapter 4 briefly presents the work on method optimisation, which is still very much in its infancy. Aspects of freezing such as nucleation and ice crystal growth are strongly related with ice crystal morphology; however, the ice nucleation process typically occurs in a random, non-deterministic and spontaneous manner. In view of this, ultrasound, an emerging application in pharmaceutical sciences, has been applied to aid in the acceleration of nucleation and shorten the freezing process. The research presented in this thesis aimed to study the effect of sonication on nucleation events in ionic solutions, and more importantly how sonication impacts on the freezing process. This work confirmed that nucleation does occur in a random manner. It also showed that ultrasonication aids acceleration of the ice nucleation process and increases the freezing rate of a solution. Cryopreservation of animal sperm is an important aspect of breeding in animal science especially for endangered species. In order for sperm cryopreservation to be successful, cryoprotectants as well as semen extenders are used. One of the factors allowing semen preservation media to be optimum is the osmolality of the semen extenders used. Although preservation of animal sperm has no relation with freeze drying of pharmaceuticals, it was used in this thesis to make a case for considering the osmolality of a formulation (prepared for freeze drying) as a factor for conferring protein protection against the stresses of freeze drying. The osmolalities of some common solutes (mostly sugars) used in freeze drying were determined (molal concentration from 0.1m to 1.2m). Preliminary investigation on the osmolality and osmotic coefficients of common solutes were carried out. It was observed that the osmotic coefficient trend for the sugars analysed could be grouped based on the types of sugar they are. The trends observed show the need for further studies to be carried out with osmolality and to determine how it may be of importance to protein or API protection during freeze drying processes. Primary drying is usually the longest part of the freeze drying process, and primary drying times lasting days or even weeks are not uncommon; however, longer primary drying times lead to longer freeze drying cycles, and consequently increased production costs. Much work has been done previously by others using different processes (such as annealing) in order to improve primary drying times; however, these do not come without drawbacks. A novel system involving the formation of a frozen vial system which results in the creation of a void between the formulation and the inside wall of a vial has been devised to increase the primary freeze drying rate of formulations without product damage. Although the work is not nearly complete, it has been shown that it is possible to improve and increase the primary drying rate of formulations without making any modifications to existing formulations, changing storage vials, or increasing the surface area of freeze dryer shelves.

Mechanisms of drying of skin forming materials

The literature relating to evaporation from single droplets of pure liquids, and to the drying of droplets containing solids and of droplet sprays has been reviewed. The heat and mass transfer rates for a single droplet suspended from a nozzle were studied within a 42mm I.D. horizontal wind tunnel designed to supply hot dry air, to simulate conditions encountered in a practical spray dryer. A novel rotating glass nozzle was developed to facilitate direct measurements of droplet weight and core temperature. This design minimised heat conduction through the nozzle. Revised correlations were obtained for heat and mass transfer coefficients, for evaporation from pure water droplets suspended from a rotating nozzle. Nu = 2.0 + 0.27 (l/B)°-18Re°-5Pr°-83 Sh = 2.0 + 0.575 ((T0-T.)/Tomfc) -o.o4Reo.5 ^0.33 Experimental drying studies were carried out on single droplets of different types of skin-forming materials, namely, custard, gelatin, skim milk and fructose at air temperatures ranging from 19°C to 198°C. Dried crusts were recovered and examined by Scanning Electron Microscopy. Skin-forming materials were classified into three types according to the mechanisms of skin formation. In the first type (typified by droplets of custard and starch) skin formed due to gelatinisation at high temperatures. Increasing the drying temperature resulted in increased crust resistance to mass transfer due to increased granule swelling and the crust resistance was completely transferred to a skin resistance at drying temperatures > 150°C. In the second type e.g. gelatin droplets the skin formed immediately drying had taken place at any drying temperature. At drying temperature > 60° C a more resistant skin was formed. In the third type (typified by droplets of skim milk and fructose) the skin appeared on the droplet surface at a certain stage of the drying process under any drying conditions. As the drying temperature was increased the resistance of the skin to mass transfer increased. The drying rate history of any material depended upon the nature of the skin formed which, in turn, depended upon the drying conditions. A mathematical model was proposed for the drying of the first type of skin-forming material. This was based on the assumption that, once all the granules gelatinised at the gelatinisation temperature, a skin appeared instantaneously on the droplet surface. The experimentally-observed times at which the skin appeared on the droplets surfaces were in excellent agreement with those predicted from the model. The work should assist in understanding the fundamentals of paniculate drying processes, particularly when skin-formation occurs and may be a crucial factor in volatiles retention.

Mass transfer coefficient for drying of moist particulate in a bubbling fluidized bed

Experiments on drying of moist particles by ambient air were carried out to measure the mass transfer coefficient in a bubbling fluidized bed. Fine glass beads of mean diameter 125?µm were used as the bed material. Throughout the drying process, the dynamic material distribution was recorded by electrical capacitance tomography (ECT) and the exit air condition was recorded by a temperature/humidity probe. The ECT data were used to obtain qualitative and quantitative information on the bubble characteristics. The exit air moisture content was used to determine the water content in the bed. The measured overall mass transfer coefficient was in the range of 0.0145–0.021?m/s. A simple model based on the available correlations for bubble-cloud and cloud-dense interchange (two-region model) was used to predict the overall mass transfer coefficient. Comparison between the measured and predicted mass transfer coefficient have shown reasonable agreement. The results were also used to determine the relative importance of the two transfer regions.

Drying processess in the United Kingdom:assessment of industrial energy utilisation and efficiency of drying systems and the modelling of drying characters using neural networks (BL)

Drying is an important unit operation in process industry. Results have suggested that the energy used for drying has increased from 12% in 1978 to 18% of the total energy used in 1990. A literature survey of previous studies regarding overall drying energy consumption has demonstrated that there is little continuity of methods and energy trends could not be established. In the ceramics, timber and paper industrial sectors specific energy consumption and energy trends have been investigated by auditing drying equipment. Ceramic products examined have included tableware, tiles, sanitaryware, electrical ceramics, plasterboard, refractories, bricks and abrasives. Data from industry has shown that drying energy has not varied significantly in the ceramics sector over the last decade, representing about 31% of the total energy consumed. Information from the timber industry has established that radical changes have occurred over the last 20 years, both in terms of equipment and energy utilisation. The energy efficiency of hardwood drying has improved by 15% since the 1970s, although no significant savings have been realised for softwood. A survey estimating the energy efficiency and operating characteristics of 192 paper dryer sections has been conducted. Drying energy was found to increase to nearly 60% of the total energy used in the early 1980s, but has fallen over the last decade, representing 23% of the total in 1993. These results have demonstrated that effective energy saving measures, such as improved pressing and heat recovery, have been successfully implemented since the 1970s. Artificial neural networks have successfully been applied to model process characteristics of microwave and convective drying of paper coated gypsum cove. Parameters modelled have included product moisture loss, core gypsum temperature and quality factors relating to paper burning and bubbling defects. Evaluation of thermal and dielectric properties have highlighted gypsum's heat sensitive characteristics in convective and electromagnetic regimes. Modelling experimental data has shown that the networks were capable of simulating drying process characteristics to a high degree of accuracy. Product weight and temperature were predicted to within 0.5% and 5C of the target data respectively. Furthermore, it was demonstrated that the underlying properties of the data could be predicted through a high level of input noise.

Drying kinetic analysis of municipal solid waste using modified page model and pattern search method

This work studied the drying kinetics of the organic fractions of municipal solid waste (MSW) samples with different initial moisture contents and presented a new method for determination of drying kinetic parameters. A series of drying experiments at different temperatures were performed by using a thermogravimetric technique. Based on the modified Page drying model and the general pattern search method, a new drying kinetic method was developed using multiple isothermal drying curves simultaneously. The new method fitted the experimental data more accurately than the traditional method. Drying kinetic behaviors under extrapolated conditions were also predicted and validated. The new method indicated that the drying activation energies for the samples with initial moisture contents of 31.1 and 17.2 % on wet basis were 25.97 and 24.73 kJ mol−1. These results are useful for drying process simulation and industrial dryer design. This new method can be also applied to determine the drying parameters of other materials with high reliability.

Studies in organobismuth chemistry

Perturbations in the bismuth market resulted in Mining and Chemical Products Ltd., seeking further outlets in the market. Together with Manchem Ltd. they were anxious to evaluate the possibility of using bismuth compounds as a replacement for lead/calcium soaps in paint driers. A range of new organobismuth compounds were synthesised of the type RBiX2 and R3BiX2 (X= halogen, OOCR, dithiocarbamate). A variety of synthetic techniques were explored, including the use of mathematical reactions, phase-transfer catalysis and microwave energy. The preparation of a range of trivalent and pentavalent organobismuth carboxylates is reported and their infra-red , 13C, lH nmr spectra. The compounds were evaluated as paint driers and in cases found to enhance paint drying to a greater degree than the standard driers, to which they were being compared. The drying times of paint films containing the organobismuth compounds are reported, together with a comparison of the drying times with the addition of bismuth tris-diethyldithiocarbamate, which may promote the cross-linking reaction that occur in paint films during the drying process. Examples are reported to illustrate the great reductions in reaction times possible when using microwave energy. Reactions such as metallation of aromatic rings, ligand redistribution and synthesis were carried out in PTFE containers in a conventional domestic microwave oven. An X-ray diffraction study of (phenylazophenyl-C,N')mercury(II) chloride has shown it to be dimeric via long Hg-Cl bridging interactions of 3.367A. Its crystal structure is reported, together with its 13C nmr spectra and mass spectrum. The Lewis acidity of compounds of the type RBiX2 was investigated. The donor group being anchored to the organo group (R). The dithiocarbamates bis- (diethyldithiobarbamato)phenylbismuth(Ill) and [2-2-pyridyl)phenylbismuth(III) were synthesised, and their crystal structures, 14N, 13C nmr ar1d infra-red spectra are reported. Both compounds are pseudo-pentagonal bipyramidal in geometry, with two long Bi-S bonds and two short Bi-S bonds. The reaction of RBiBr2 (R= 2-(pyridyl) with various ligands is reported. The infra-red evidence suggesting that the coordination of extra ligands is accompanied by a reduction of the strength of the Bi-interaction.

The morphology of spray-dried particles

Samples of Various industrial or pilot plant spray-dried materials were obtained from manufacturers together with details of drying conditions and feed concentrations. The samples were subjected to qualitative and semi-quantitative examination to identify structural and morphological features. The results were related to measured bulk physical properties and to drying conditions. Single particles were produced in a convective drying process Analogous to spray drying, in which different solids or mixtures of solids were dried from solutions, slurries or pastes as single suspended droplets. The localized chemical and physical structures were analysed and in some cases the retention of volatiles monitored. The results were related to experimental conditions, viz.; air temperature, initial solids concentration and the degree of feed aeration. Three distinct categories of particle morphology were identified, i.e.; crystalline, skin-forming and agglomerate. Each category is evidence of a characteristic drying behaviour which is dependent on initial solids concentration. the degree of feed aeration, and drying temperature. Powder flow ability, particle and bulk density, particle-size, particle friability, and the retention of volatiles bear a direct relationship to morphological structure. Morphologies of multicomponent mixtures were complex, but the respective migration rates of the solutes were dependent on drying temperature. Gas-film heat and SDSS transfer coefficients of single pure liquid droplets were also measured over a temperature range of 50•C to 200•C under forced convection. Balanced transfer rates were obtained attributed to droplet instability or oscillation within the airflow, demonstrated in associated work with single free-flight droplets. The results are of relevance to drier optimisation and to the optimisation of product characteristics, e.g.; particle strength and essential volatiles-retention, in convective drying.

Caking behaviour of spray-dried milk powders:using scanning probe microscopy to study nanoscale surface properties and material composition

Spray drying is widely used to manufacture many powdered products, with the drying process parameters having significant influence over the final powder's surface properties and propensity for unwanted caking. In most cases caking experiments are performed on bulk powders, but especially in multi-component powders, it is often difficult to interpret these results, where interaction effects between particles can be complex. Here the technique of scanning probe microscopy is used to characterize the nanoscale properties of spray dried model milk powders in order to investigate the surface properties of the powders.

Investigating the delivery of antimicrobial proteins and aminoglycoside antibiotics to the airways

Biopharmaceuticals are finding wide applications in the management of diverse disease conditions. Pulmonary delivery of proteins may constitute an effective and efficient non-invasive alternative to parenteral delivery, which is currently the main route of administration of biopharmaceutical drugs. A particular area, in which pulmonary delivery of peptides and proteins may find ready application, is in the local delivery of antimicrobial peptides and proteins to the airway, a measure that could potentially bring about improvements to currently available antipseudomonal therapies. This thesis has therefore sought to develop inhalable antimicrobial proteins in combination with antibiotics that have particularly good antimicrobial activity against Pseudomonas aeruginosa infections in the respiratory tract of people with cystic fibrosis (CF). Through process optimisation, a suitable spray drying method was developed and used for the preparation of active, inhalable dry powder formulations of the antimicrobial protein, lactoferrin, and aminoglycosides (tobramycin and gentamicin). The physicochemical properties, aerosolisation performance and the antibacterial properties of the various spray-dried formulations were assessed. In addition, a relevant in vitro cellular model was employed to investigate the potential cytotoxic and pro-inflammatory effects of the various formulations on four bronchial human epithelial cells together with their effectiveness at reducing bacterial colonies when administered on to biofilm co-cultured on the epithelial cells. It was found that following spray drying the particles obtained were mostly spherical, amorphous and possessed suitable aerosolisation characteristics. The various spray-dried antimicrobial proteins (lactoferrin or apo lactoferrin) and co-spray dried combinations of the proteins and aminoglycosides were found to exhibit bactericidal activity against planktonic and biofilms of P. aeruginosa. In general, the spray drying process was found not to significantly affect the antimicrobial activities of the protein. Treatment of the different bronchial epithelial cell lines with the antimicrobial formulations showed that the various formulations were non-toxic and that the co-spray dried combinations significantly reduced established P. aeruginosa biofilms on the four bronchial epithelial cells. Overall, the results from this thesis demonstrates that spray drying could potentially be employed to prepare inhalable antimicrobial agents comprised of proteins and antibiotics. These new combinations of proteins and aminoglycosides has promising applications in the management of P. aeruginosa in the airway of cystic fibrosis patients.

The modelling of energy efficient drying for DSM (BL)

This thesis investigates the modelling of drying processes for the promotion of market-led Demand Side Management (DSM) as applied to the UK Public Electricity Suppliers. A review of DSM in the electricity supply industry is provided, together with a discussion of the relevant drivers supporting market-led DSM and energy services (ES). The potential opportunities for ES in a fully deregulated energy market are outlined. It is suggested that targeted industrial sector energy efficiency schemes offer significant opportunity for long term customer and supplier benefit. On a process level, industrial drying is highlighted as offering significant scope for the application of energy services. Drying is an energy-intensive process used widely throughout industry. The results of an energy survey suggest that 17.7 per cent of total UK industrial energy use derives from drying processes. Comparison with published work indicates that energy use for drying shows an increasing trend against a background of reducing overall industrial energy use. Airless drying is highlighted as offering potential energy saving and production benefits to industry. To this end, a comprehensive review of the novel airless drying technology and its background theory is made. Advantages and disadvantages of airless operation are defined and the limited market penetration of airless drying is identified, as are the key opportunities for energy saving. Limited literature has been found which details the modelling of energy use for airless drying. A review of drying theory and previous modelling work is made in an attempt to model energy consumption for drying processes. The history of drying models is presented as well as a discussion of the different approaches taken and their relative merits. The viability of deriving energy use from empirical drying data is examined. Adaptive neuro fuzzy inference systems (ANFIS) are successfully applied to the modelling of drying rates for 3 drying technologies, namely convective air, heat pump and airless drying. The ANFIS systems are then integrated into a novel energy services model for the prediction of relative drying times, energy cost and atmospheric carbon dioxide emission levels. The author believes that this work constitutes the first to use fuzzy systems for the modelling of drying performance as an energy services approach to DSM. To gain an insight into the 'real world' use of energy for drying, this thesis presents a unique first-order energy audit of every ceramic sanitaryware manufacturing site in the UK. Previously unknown patterns of energy use are highlighted. Supplementary comments on the timing and use of drying systems are also made. The limitations of such large scope energy surveys are discussed.

Drying of biomass for second generation synfuel production

Drying is a major and challenging step in the pre-treatment of biomass for production of second generation synfuels for transport. The biomass feedstocks are mostly wet and need to be dried from 30 to 60 wt% moisture content to about 10-15 wt%. The present survey aims to define and evaluate a few of the most promising optimised concepts for biomass pre-treatment scheme in the production of second generation synfuels for transport. The most promising commercially available drying processes were reviewed, focusing on the applications, operational factors and emissions of dryers. The most common dryers applied now for biomass in bio-energy plants are direct rotary dryers, but the use of steam drying techniques is increasing. Steam drying systems enable the integration of the dryer to existing energy sources. In addition to integration, emissions and fire or explosion risks have to be considered when selecting a dryer for the plant. In steam drying there will be no gaseous emissions, but the aqueous effluents need often treatment. Concepts for biomass pre-treatment were defined for two different cases including a large-scale wood-based gasification synfuel production and a small-scale pyrolysis process based on wood chips and miscanthus bundles. For the first case a pneumatic conveying steam dryer was suggested. In the second case the flue gas will be used as drying medium in a direct or indirect rotary dryer.

Mass transfer in fluidized bed drying of moist particulate

Bubbling fluidized bed technology is one of the most effective mean for interaction between solid and gas flow, mainly due to its good mixing and high heat and mass transfer rate. It has been widely used at a commercial scale for drying of grains such as in pharmaceutical, fertilizers and food industries. When applied to drying of non-pours moist solid particles, the water is drawn-off driven by the difference in water concentration between the solid phase and the fluidizing gas. In most cases, the fluidizing gas or drying agent is air. Despite of the simplicity of its operation, the design of a bubbling fluidized bed dryer requires an understanding of the combined complexity in hydrodynamics and the mass transfer mechanism. On the other hand, reliable mass transfer coefficient equations are also required to satisfy the growing interest in mathematical modelling and simulation, for accurate prediction of the process kinetics. This chapter presents an overview of the various mechanisms contributing to particulate drying in a bubbling fluidized bed and the mass transfer coefficient corresponding to each mechanism. In addition, a case study on measuring the overall mass transfer coefficient is discussed. These measurements are then used for the validation of mass transfer coefficient correlations and for assessing the various assumptions used in developing these correlations.

Formulation and process engineering of freeze-dried orally disintegrating tablets

Orally disintegrating tablets (ODTs) which are also referred to as orodispersible and fast disintegrating tablets, are solid oral dosage forms which upon placing on the tongue, disperse/disintegrate rapidly before being swallowed as a suspension or solution. ODTs are therefore easier and more convenient to administer than conventional tablets and are particularly beneficial for paediatric and geriatric patients, who generally have difficulty swallowing their medication. The work presented in this thesis involved the formulation and process development of ODTs, prepared using freeze-drying. Gelatin is one of the principal excipients used in the formulation of freeze-dried ODTs. One of the studies presented in this thesis investigated the potential modification of the properties of this excipient, in order to improve the performance of the tablets. As gelatin is derived from animal sources, a number of ethical issues surround its use as an excipient in pharmaceutical preparations. This was one of the motivations, Methocel™ and Kollicoat® IR were evaluated as binders as alternative materials to gelatin. Polyox™ was also evaluated as a binder together with its potential uses as a viscosity increasing and mucoadhesive agent to increase the retention of tablets in the mouth to encourage pre-gastric absorption of active pharmaceutical ingredients (APIs). The in vitro oral retention of freeze-dried ODT formulations was one property which was assessed in a design of experiments – factorial design study, which was carried out to further understand the role that formulation excipients have on the properties of the tablets. Finally, the novel approach of incorporating polymeric nanoparticles in freeze-dried ODTs was investigated, to study if the release profile of APIs could be modified, which could improve their therapeutic effect. The results from these studies demonstrated that the properties of gelatin-based formulations can be modified by adjusting pH and ionic strength. Adjustment of formulation pH has shown to significantly reduce tablet disintegration time. Evaluating Methocel™, in particular low viscosity grades, and Kollicoat® IR as binders has shown that these polymers can form tablets of satisfactory hardness and disintegration time. Investigating Polyox™ as an excipient in freeze-dried ODT formulations revealed that low viscosity grades appear suitable as binders whilst higher viscosity grades could potentially be utilised as viscosity increasing and mucoadhesive agents. The design of experiments – factorial design study revealed the influence of individual excipients in a formulation mix on resultant tablet properties and in vitro oral retention of APIs. Novel methods have been developed, which allows the incorporation of polymeric nanoparticles in situ in freeze-dried ODT formulations, which allows the modification of the release profile of APIs.