This thesis project studied microcrystalline cellulose II (CII), a polymorphic form of cellulose, which has lower mechanical properties, less plastic deformation, higher elastic recovery and faster disintegration properties than microcrystalline cellulose I (CI). Also, the effects of processing and silicification on CII materials were investigated. Particle modification through spray drying, wet granulation and spheronization was employed to improve CII performance. Spray-drying (SDCII) and wet granulation (WGCII) produced materials with no difference in mechanical or disintegration properties from unprocessed CII, but did show an increase in density and particle flow. Conversely, spheronization (SPCII) showed the poorest mechanical properties compared to CII. Further, SDCII showed better dilution potential than CII. Thus the advantages of SDCII were apparent when it was mixed with a poorly compressible drug (acetaminophen) because fibrous CII was converted to spheroidal particles through spray drying. The rapid disintegration of SDCII and CII compacts was due to water wicking through capillaries followed by compact bursting. Compacts of ibuprofen mixed with SDCII and Avicel® PH-102 had comparable disintegration rates and release profiles compared to ibuprofen formulated with commercial disintegrants and Avicel® PH-102, especially at levels 10% w/w. Adding fumed silica into CII particles through spray drying, wet granulation (WGCII) and spheronization (SPCII) at 2-20% w/w was also studied. Silicification increased physical properties such as true density, Hausner ratio, porosity, ejection force and specific surface area of SDCII and WGCII. Other properties such as bulk and tap densities were reduced due to the amorphous and light character of fumed silica. Spheronized CII showed no change in these properties with silicification. Silicification diminished lubricant sensitivity with magnesium stearate due to the competition of SiO2 with magnesium stearate to coat CII particles. Silicification also decreased the affinity of CII for water only at the 20% w/w level due to the few silanol groups available for water interaction compared to surface hydroxyl groups on CII alone. Particle size modification of CII was process-dependent rather than silicification-dependent. Additionally, silicification decreased the apparent plasticity and elastic recovery of SDCII and WGCII when compacted. The former effect along with increased powder porosity increased surface area and compressibility of SDCII and WGCII. Compact tensile strength of silicified CII materials was in the order: spray-dried > wet granulated > spheronized. This order was due to the combined effect of particle morphology and how fumed silica was incorporated and distributed within CII particles. Silicification did not affect the rapid disintegration properties of CII. Thus, diphenhydramine HCl and griseofulvin tablets prepared with silicified CII had faster disintegration and release than those prepared with commercial silicified CI (Prosolv®). Moreover, CII beads containing diphenhydramine HCl or griseofulvin had faster release profiles compared to beads prepared with Prosolv® SMCC 50 or Avicel® PH-101. This behavior showed that rapid disintegration is an intrinsic property of CII. Compact tensile strength decreased more for unsilicified CI and CII compacts stored at 75% RH, while silicified CI and CII compacts lost less tensile strength under the same conditions. Reprocessed CI materials containing acetaminophen (1:1mixtures) lost 35-72% of their original strength compared to silicified CII materials (15-25% loss) indicating more particle interaction upon recompression. .

Supersaturating drug delivery systems, such as amorphous solid dispersions (ASDs), have been used extensively to elevate the apparent solubility and oral bioavailability of poorly water-soluble drugs. However, despite the numerous examples of success in increasing solubility and oral bioavailability using ASDs, physical stability challenges remain as formulators seek to employ high drug loading for cost reduction and improved patient compliance. Therefore, stability in both the solid and solution state must be considered for ASDs to be successful. In the solid state, the drug must remain amorphous in the solid matrix throughout the shelf life of the product. Although excipients, such as polymers, have been known to stabilize the amorphous drug in the solid state, stresses encountered during manufacturing and fluctuations in storage conditions may have a detrimental impact on the physical stability of ASDs. Numerous studies have been performed on the impact of each process on ASD stability, yet the relative quantitative impact of each process with respect to the overall energetics landscape is not well understood. Further, ASDs must dissolve after administration and maintain the intended supersaturation in the gastrointestinal (GI) tract during the GI transit time to achieve maximum oral absorption. In solution, the energetics advantage of the amorphous over the crystalline material is a “double-edged sword,” in that it produces not only a high absorption driving force but also an undesirable high crystallization potential. An approach to quantitatively measure the thermodynamic activity of amorphous materials is, thus, desirable. However, it is difficult to measure thermodynamic activity quantitatively, especially due to the speciation process induced by formulation excipients and endogenous materials. Hence, it is often difficult to assess the true enhancement in the absorption for a given ASD and to measure its crystallization tendency in solution. Overall, this dissertation aims to address the following: 1. The relative thermodynamics magnitude of various processes with respect to the crystallization energy associated with amorphous drugs 2. The development of a practical tool to measure the thermodynamic activity of amorphous materials over its crystalline counterpart in solution to assess the enhancement in absorption in the presence of excipients 3. The impact of measured thermodynamic activity on drug crystallization energetics in the presence of excipients

Molecular computations based on quantum mechanics and statistical mechanics have been applied to the understanding and quantification of processes leading to the degradation of therapeutic proteins. In particular, we focus on oxidation and aggregation. Specifically, two reactions, hydrogen transfer of hydrogen peroxide to form water oxide and the oxidation of dimethyl sulfide (DMS) by hydrogen peroxide to form dimethyl sulfoxide, were studied as models of these processes in general. Reaction barriers of the hydrogen transfer of H₂O₂ are in average of 10 kcal/mol or higher than the oxidation of DMS. Therefore, a two step oxidation mechanism in which the transfer of hydrogen atom occurs first to form water oxide and the transfer of oxygen to substrate occurs as the second step, is unlikely to be correct. Our proposed oxidation mechanism does not suggest a pH dependence of oxidation rate within a moderate range around neutral pH (i.e. under conditions in which hydronium and hydroxide ions do not participate directly in the reaction), and it agrees with experimental observations over moderate pH values. In the field of aggregation, we have developed a relatively simple approach for computing the change in chemical potential of a protein upon addition of an excipient (cosolute) to the protein solution. We have also developed a general approach to the design of excipients to prevent aggregation and are currently testing it experimentally. / Singapore-MIT Alliance (SMA)

Single walled carbon nanotubes (SWNTs) are considered potential biomedical materials because of their flexible structure, hollow interior for fluidic transport, propensity for functionalization of the exterior walls, and biocompatibility. Research into exploiting these properties has focused on SWNTs as building blocks for novel drug-delivery systems, dosage forms, and biomedical substrates. However, the use of the internal nanochannels as conduits for trans-membrane drug delivery has not been explored. This research was initially designed to explore the latter.<p> It is postulated that due to their mechanical strength and the presence of an internal conduit, SWNTs can be used for nanofluidic transport. Using a magnetic field, the magnetically responsive SWNT are driven into intact stratum corneum, creating nanochannels, for trans-membrane drug delivery. Initial studies showed however that a bottleneck is the aggregation of SWNTs on the surface of stratum corneum. To achieve trans-membrane nanofluidic delivery, the SWNTs have to be well dispersed in an appropriate pharmaceutical medium, and the SWNT have to be of high purity. Similarly, the presence of impurities in SWNTs, and the dispersion state of these materials in pharmaceutical solvents may give an insight into the discrepancies in toxicity that is reported.<p> The purity of five commercially available SWNTs (AP-SWNT and P2-SWNT, from Carbon Solutions Inc, HMS-SWNT from Helix Materials, and NA-SWNT from Nanostructured and Amorphous Materials Inc. and CT-SWNT from ChepTubes Inc.) were analyzed by raman and electron dispersive x-ray spectroscopy (EDS) spectroscopy. Secondly, the dispersion states of SWNTs in various pharmaceutical solvents were evaluated by ultraviolet (UV) spectroscopy, scanning electron microscopy (SEM), dynamic light scattering (DLS), zeta potential, and Raman spectroscopy to identify potential agents for exfoliation of SWNTs in selected pharmaceutical solution.<p> SWNTs were dispersed in various solvents (water, propylene glycol [PG], dimethylsulfoxide [DMSO], and ethanol) as well as in 0.1% w/v aqueous solutions of anionic, cationic and neutral surfactants at a SWNT concentration of 0.1 mg/mL. SWNT suspensions described as dispersed yielded an evenly coloured suspension with no visible precipitate. The most stable dispersions were obtained with the gemini surfactants, which were confirmed by SEM observation of exfoliated SWNTs. Zeta (î) potential measurements of the fully dispersed SWNTs showed typical values of greater than +30 mV, while non-dispersed samples were less than +20 mV. SEM images of the dispersed solution showed the presence of exfoliated SWNTs compared to the aggregated SWNT clusters observed in non-dispersed systems. Raman spectra of dispersed SWNTs showed G-band peak shifts (to higher wavelengths), confirming the presence of exfoliated SWNTs.<p> Even though the purity of SWNT did not correlate with amount of SWNT in dispersion, exfoliation of bundled SWNTs was accompanied by an increase in UV absorbance of the dispersion, with maximum exfoliation determined by a relatively stable UV absorbance.<p> As pharmaceutical excipients, we have demonstrated that gemini surfactants are suitable dispersing agents for SWNTs, and shown that the dispersion of SWNT for gemini surfactants (12-3-12) is achieved below the critical micelle concentration. The dispersion of SWNT bundles into individual strands is the first crucial step towards their use in biological systems as drug carriers.

Ces recherches ont pour objet d'améliorer la compréhension des phénomès de densification de poudres pharmaceutiques. Différents modèles ont été développés pour permettre d'expliquer les variations de propriétés des compacts (porosité, surface spécifique et résistance à la rupture) en fonction de paramètres opératoires (pression atteinte, durée de maintien sous pression). Les études menées sur le comportement des produits purs sont étendues à des mélanges binaires pour lesquels des lois de mélange originales sont décrites. Les modèles ont été validés sur différents excipients (lactose, saccharose, polyvinylpyrrolidone) et sur des principes actifs à base de kétoprofène. L'influence des paramètres morphologiques (taille des grains) et structuraux sur les propriétés precitées ont été mises en evidence.

Single walled carbon nanotubes (SWNTs) are considered potential biomedical materials because of their flexible structure, hollow interior for fluidic transport, propensity for functionalization of the exterior walls, and biocompatibility. Research into exploiting these properties has focused on SWNTs as building blocks for novel drug-delivery systems, dosage forms, and biomedical substrates. However, the use of the internal nanochannels as conduits for trans-membrane drug delivery has not been explored. This research was initially designed to explore the latter.<p> It is postulated that due to their mechanical strength and the presence of an internal conduit, SWNTs can be used for nanofluidic transport. Using a magnetic field, the magnetically responsive SWNT are driven into intact stratum corneum, creating nanochannels, for trans-membrane drug delivery. Initial studies showed however that a bottleneck is the aggregation of SWNTs on the surface of stratum corneum. To achieve trans-membrane nanofluidic delivery, the SWNTs have to be well dispersed in an appropriate pharmaceutical medium, and the SWNT have to be of high purity. Similarly, the presence of impurities in SWNTs, and the dispersion state of these materials in pharmaceutical solvents may give an insight into the discrepancies in toxicity that is reported.<p> The purity of five commercially available SWNTs (AP-SWNT and P2-SWNT, from Carbon Solutions Inc, HMS-SWNT from Helix Materials, and NA-SWNT from Nanostructured and Amorphous Materials Inc. and CT-SWNT from ChepTubes Inc.) were analyzed by raman and electron dispersive x-ray spectroscopy (EDS) spectroscopy. Secondly, the dispersion states of SWNTs in various pharmaceutical solvents were evaluated by ultraviolet (UV) spectroscopy, scanning electron microscopy (SEM), dynamic light scattering (DLS), zeta potential, and Raman spectroscopy to identify potential agents for exfoliation of SWNTs in selected pharmaceutical solution.<p> SWNTs were dispersed in various solvents (water, propylene glycol [PG], dimethylsulfoxide [DMSO], and ethanol) as well as in 0.1% w/v aqueous solutions of anionic, cationic and neutral surfactants at a SWNT concentration of 0.1 mg/mL. SWNT suspensions described as dispersed yielded an evenly coloured suspension with no visible precipitate. The most stable dispersions were obtained with the gemini surfactants, which were confirmed by SEM observation of exfoliated SWNTs. Zeta (î) potential measurements of the fully dispersed SWNTs showed typical values of greater than +30 mV, while non-dispersed samples were less than +20 mV. SEM images of the dispersed solution showed the presence of exfoliated SWNTs compared to the aggregated SWNT clusters observed in non-dispersed systems. Raman spectra of dispersed SWNTs showed G-band peak shifts (to higher wavelengths), confirming the presence of exfoliated SWNTs.<p> Even though the purity of SWNT did not correlate with amount of SWNT in dispersion, exfoliation of bundled SWNTs was accompanied by an increase in UV absorbance of the dispersion, with maximum exfoliation determined by a relatively stable UV absorbance.<p> As pharmaceutical excipients, we have demonstrated that gemini surfactants are suitable dispersing agents for SWNTs, and shown that the dispersion of SWNT for gemini surfactants (12-3-12) is achieved below the critical micelle concentration. The dispersion of SWNT bundles into individual strands is the first crucial step towards their use in biological systems as drug carriers.

The influence of water soluble and insoluble stabilizing excipients on the physical stability of coated dosage forms was investigated in this study. The effect of the excipients on the thermal and physico-mechanical properties, and water vapor permeability of free films was studied, as was the influence of these excipients on the physical stability and release kinetics of coated pellets. The effect of water-soluble proteins, bovine serum albumin (BSA) and Type B gelatin, on the physical aging of Eudragit[trademark] RS/RL 30 D films was investigated. It was found that ionic interactions occurred above the isoelectric point of BSA and caused unstable films which showed accelerated decreases in drug release rate. The adjustment of the pH of the dispersion below the isoelectric point of BSA resulted in electrostatic repulsive charges that stabilized the drug release rate from coated dosage forms at both ambient and accelerated conditions. The addition of gelatin to the coating dispersion increased the drug release rate due to the formation of gel-domains through which the drug was able to easily diffuse. The influence of silicon dioxide on the stability of Eudragit[trademark] RS/RL 30 D films was investigated. Colloidal grades showed enhanced incorporation in the acrylic matrix; however, unstable films were formed. The addition of silicon dioxide with a larger particle size increased the permeability of the film and stabilization in drug release rate was attributed to constant water vapor permeability values of free films. The influence of ethylcellulose on the physical aging of Eudragit[trademark] NE 30 D coated pellets was studied. The two polymers were found to be substantially immiscible and the drug release rate of coated pellets was constant at both ambient and accelerated conditions which correlated to stabilizations in both the physico-mechanical properties and water vapor permeability of free films. Blending both Eudragit[trademark] NE 30 D and RS 30 D resulted in the formation of coherent films without the need of plasticizer. The two polymers were found to be miscible and both films and coated dosage forms were stable when stored below the glass transition temperature of the polymer blend. When films were stored above this temperature, instabilities occurred as a result of the further coalescence and densification of the polymer blend.

Poor aqueous solubility is one of the greatest barriers for new drug candidates to enter toxicology studies, let alone clinical trials. This thesis focuses on contributing to solving this problem, evaluating the oral toxicity of mesoporous silica particles, and enhancing the apparent solubility and bioavailability of active pharmaceutical ingredients in vitro and in vivo using mesoporous silica particles. Toxicological studies in rats showed that two types of mesoporous silica particles given by oral administration were well tolerated without showing clinical signs of toxicity. Solubility enhancement, including in vivo bioavailability and in vitro intracellular activity, has been evaluated for selected drug compounds. Mesoporous silica was shown to effectively increase drug solubility by stabilizing the amorphous state of APIs, such as itraconazole (anti-fungal), dasatinib (anti-cancer), atazanavir (anti-HIV) and PA-824 (anti-tuberculosis). Itraconazole was successfully loaded into a variety of porous silica materials showing a distinct improvement in the dissolution properties in comparison to non-porous silica materials (and the free drug). Microporosity in SBA-15 particles has advantages in stabilizing the supersaturation state of dasatinib. Small pore sizes show better confinement of atazanavir, contributing to a higher dissolution of the drug compound. In the in vivo animal studies, NFM-1 loaded with atazanavir shows a four-fold increase in bioavailability compared to free crystalline atazanavir. PA-824 has a higher dissolution rate and solubility after loading into AMS-6 mesoporous particles. The loaded particles show similar antibacterial activity as the free PA-824. This thesis aims at highlighting some of the important factors enabling the selection of adequate mesoporous structures to enhance the pharmacokinetic profile of poorly water-soluble compounds, and preparing the scientific framework for uncovering the effects of drug confinement within mesopores of varying structural properties. / <p>At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 2: Submitted. Paper 3: Submitted. Paper 5: Submitted.</p>

Objectives: To review, develop, and validate appropriate methods for quality control testing of sublingual (SL) tablets; to formulate and characterize new generations of SL tablets of epinephrine (E) for the potential first-aid treatment of anaphylaxis; and to evaluate the effects of non-medicinal ingredients (NMIs) on the in vitro characteristics and in vivo bioavailability of the formulated tablets. Methods: A custom-made apparatus and a novel method that simulates SL conditions were evaluated for dissolution testing of SL tablets. An electronic tongue (e-Tongue) was used to assess the degree of E bitterness and to demonstrate the masking effects of sweetening and/or flavoring agents. The effect of several NMIs in various properties on the in vitro characteristics of new generations of E SL tablets was evaluated. Formulations with the best in vitro characteristics, containing E 30 mg and 40 mg, were evaluated in vivo using our validated rabbit model and compared with placebo SL tablets (negative control) and E 0.3 mg intramuscular (IM) injection (positive control). Results: The novel in vitro dissolution testing resulted in accurate and reproducible data and was capable of detecting the effect of minor changes in formulations. Using the e-Tongue, E bitartrate had an extremely bitter taste which was masked to various degrees by the addition of aspartame, acesulfame potassium, and citric acid alone or in combination. Citric acid alone masked the bitter taste by >80%. The evaluation of NMIs revealed that the best formulation contained specific proportions of mannitol and coarse and fine grades of microcrystalline cellulose. Appropriate comparative testing resulted in the selection of a taste-masked E SL formulation with optimum in vitro characteristics. This formulation containing E 40 mg resulted in similar bioavailability to E 0.3 mg IM. This formulation containing E 30 mg had higher bioavailability than placebo, but lower bioavailability than E 40 mg tablets. Conclusions: Grades and proportions of NMIs carefully selected using appropriate in vitro testing resulted in successful formulations. The results of these in vitro tests enabled the development of the optimum E SL tablet formulation which was bioequivalent to the EpiPen. These tablets are potentially suitable for Phase 1 studies in humans and might transform the first-aid treatment of anaphylaxis in community settings.

Objectives: To review, develop, and validate appropriate methods for quality control testing of sublingual (SL) tablets; to formulate and characterize new generations of SL tablets of epinephrine (E) for the potential first-aid treatment of anaphylaxis; and to evaluate the effects of non-medicinal ingredients (NMIs) on the in vitro characteristics and in vivo bioavailability of the formulated tablets. Methods: A custom-made apparatus and a novel method that simulates SL conditions were evaluated for dissolution testing of SL tablets. An electronic tongue (e-Tongue) was used to assess the degree of E bitterness and to demonstrate the masking effects of sweetening and/or flavoring agents. The effect of several NMIs in various properties on the in vitro characteristics of new generations of E SL tablets was evaluated. Formulations with the best in vitro characteristics, containing E 30 mg and 40 mg, were evaluated in vivo using our validated rabbit model and compared with placebo SL tablets (negative control) and E 0.3 mg intramuscular (IM) injection (positive control). Results: The novel in vitro dissolution testing resulted in accurate and reproducible data and was capable of detecting the effect of minor changes in formulations. Using the e-Tongue, E bitartrate had an extremely bitter taste which was masked to various degrees by the addition of aspartame, acesulfame potassium, and citric acid alone or in combination. Citric acid alone masked the bitter taste by >80%. The evaluation of NMIs revealed that the best formulation contained specific proportions of mannitol and coarse and fine grades of microcrystalline cellulose. Appropriate comparative testing resulted in the selection of a taste-masked E SL formulation with optimum in vitro characteristics. This formulation containing E 40 mg resulted in similar bioavailability to E 0.3 mg IM. This formulation containing E 30 mg had higher bioavailability than placebo, but lower bioavailability than E 40 mg tablets. Conclusions: Grades and proportions of NMIs carefully selected using appropriate in vitro testing resulted in successful formulations. The results of these in vitro tests enabled the development of the optimum E SL tablet formulation which was bioequivalent to the EpiPen. These tablets are potentially suitable for Phase 1 studies in humans and might transform the first-aid treatment of anaphylaxis in community settings.