The purpose of this study was to investigate the formation of solid molecular dispersions of Itraconazole (ITZ) in a number of glassy polymers including PVP, crospovidone, PVP-EC, HPMCAS and HPMCAS-PEO to enhance its dissolution and achieve release control. Polarizing light microscopy was found to be more sensitive than DSC and XRD for detecting crystallinity. PVP, PVP-EC & crospovidone generated loading levels of ~20%, substantially greater than that of HPMCAS and HPMCAS-PEO (5%). The loaded ITZ was stabilized though molecular interactions with the polymer and reduced molecular mobility in a glassy polymer matrix. Overall, immediate release was achieve d using PVP and crospovidone, enteric delivery provided by HPMCAS, and controlled release generated with EC and PEO. Among all polymers studied, only ITZ in PVP failed to generate sufficient stability in the presence of moisture. In general, solid molecular dispersion is a useful approach to improve the poor solubility and bioavailability of Itraconazole.

The purpose of this study was to investigate the formation of solid molecular dispersions of Itraconazole (ITZ) in a number of glassy polymers including PVP, crospovidone, PVP-EC, HPMCAS and HPMCAS-PEO to enhance its dissolution and achieve release control. Polarizing light microscopy was found to be more sensitive than DSC and XRD for detecting crystallinity. PVP, PVP-EC & crospovidone generated loading levels of ~20%, substantially greater than that of HPMCAS and HPMCAS-PEO (5%). The loaded ITZ was stabilized though molecular interactions with the polymer and reduced molecular mobility in a glassy polymer matrix. Overall, immediate release was achieve d using PVP and crospovidone, enteric delivery provided by HPMCAS, and controlled release generated with EC and PEO. Among all polymers studied, only ITZ in PVP failed to generate sufficient stability in the presence of moisture. In general, solid molecular dispersion is a useful approach to improve the poor solubility and bioavailability of Itraconazole.

Milling and co-milling are well known techniques that have potential to enhance the solubility and/or dissolution rate of poorly soluble drugs. There are broadly two aims for this project. The first was to develop an understanding of how individual and combination of techniques may be used to explore the impact of milling on particle characteristics (including phase changes, fractures and change in particle size) as a function of milling time/speed, for a range of single powder materials. Anhydrous (lactose, sucrose), monohydrate (lactose) and dihydrate (trehalose) excipients and a poorly soluble drug (ibuprofen), were chosen as model substrates. Each material was micronized by ball-milling (for various time durations and milling speeds) and then characterized by a range of techniques, specifically, SEM, DSC, TGA, THz and dielectric spectroscopy. The second aim of the project was to investigate the impact of milling and co-milling on the solubility and dissolution rate of ibuprofen after co-milling with a variety of excipients (polymer and surfactants). The principle findings of this programme of work can be summarized as follows: i) ball milling of lactose monohydrate produces nano-structured systems with a mixture of damaged crystals and amorphous phase, that can be characterised by dielectric relaxation spectroscopy (DRS), ii) THz spectroscopy provides estimates for residual crystallinity in lactose monohydrate that were much lower than the estimates from the thermal techniques. Such estimates of residual crystallinity are considered to be more reliable given the fact that the spectroscopic measurement characterizes the material in its native state, whereas thermal techniques require a heating process, which tend to induce de-vitrification and mutarotation of lactose. In case of anhydrous materials, while there was agreement between thermal and THz techniques at long milling times, it was shown that the THz technique was susceptible to moisture absorption and crystallization at short milling times, iii) In the molecular dynamics of milled sugars studied by DRS, the structural relaxation is not visible in the vicinity of glass transition, however the secondary relaxation (β) process is equally capable and provided molecular dynamics in term of activation energy changes. The activation energies of beta process of both lactose and sucrose are least affected by milling time, but the higher activation energies for sucrose as compared with lactose show that sucrose has lower propensity to re-crystallize than lactose during post milling storage, iv) Ibuprofen can be assayed by UV-method in the presence of interfering (in absorption) substance by applying multivariate method involving the calculation of concentration factors and v) Co-milling with soluplus has increased the in the solubility of ibuprofen by ~20% and dissolution rate ~50% in 30 min, while these values are ~5% and 30%, respectively in case of co-milling with HPMC.

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Yes / Herein the potential of a relatively new water soluble fiber, resistant maltodextrin (RMD) to encapsulate grapefruit polyphenol, naringin, using spray drying was evaluated. Full factorial Design Of Experiments (DOE) for spray drying with two levels of fiber–naringin ratio and spray dryer inlet temperature was executed. Resulting powders were characterized with respect to particle size and morphology, crystallinity, thermal properties, moisture sorption and naringin aqueous solubility increase. A 60–80% encapsulation was achieved. Thermal and moisture sorption behaviors of these dispersions were found to be dominated by RMD. By varying fiber–naringin ratio and spray drying temperatures, naringin was able to disperse in amorphous form in RMD matrix, which led to 20–55% increase in aqueous solubility. Solubility enhancement was found to correlate positively with increasing fiber: naringin ratio and spray drying temperature due to multiple factors discussed in this study. In conclusion, fiber–polyphenol bicomponent nutraceutical was successfully developed based on a well-established encapsulation technology i.e. spray-drying.

Yes / 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. Whereas DLS measurements primarily resolve the large aggregates of ICT01-2588 in its formulation medium, methodology for TDA is described to determine the size and notably to quantify the proportion of monomers in the presence of large aggregates, and at the same time measure the formulation viscosity. Interestingly TDA and DLS have also distinguished between aggregate profiles formed using HP-β-CD samples from different suppliers. The approach is expected to be widely applicable to this important class of drug formulations where drug solubility is enhanced by cyclodextrin and other excipients.

In today’s drug discovery, the number of candidate drugs based on new molecular entities with poor aqueous solubility is increasing. Since poor aqueous solubility of an active pharmaceutical ingredients (APIs) is associated with low bioavailability and thus limite their therapeutic effect, this is often a great challenge in the development of new drugs when oral administration is the preferred route of administration. A number of different strategies have been developed to circumvent this problem where salt formulations of an API is the most widely employed method. However, new strategies are needed since there is no one solution that solves this issue for all substances. In recent time, the concept of stabilizing poorly soluble APIs in their amorphous form has gained a lot of attention since amorphous compounds exhibit a higher apparent solubility compared to their crystalline counterparts. Amorphous substances are prone to crystallize if left in a non-constricted environment and thus need to be stabilized if the amorphous state is to be conserved until administration. Inorganic mesoporous materials have been proposed as an interesting type of excipients that can conserve the amorphous state of APIs. In this work, the focus was to investigate the possibilities of using a mesoporous type of magnesium carbonate to stabilize the amorphous state of different APIs. Due to the nanometer sized pores in the material, complete conservation of amorphous APIs was obtained. This resulted in both an increase in in vitro release rate and a higher solubility of the substances which may translate to both a faster onset of action and an improved therapeutic effect of the APIs in a clinical situation. The long term stability of formulations was also investigated showing promising results. The results presented in this work show that mesoporous magnesium carbonate represents an interesting type of excipient for oral formulations of APIs with poor aqueous solubility. / <p>Felaktigt ISBN 978-91-554-9702-6 i tryck version.</p>

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>

The aim of this study is to evaluate the specific interactions, solid-state, and solution-state interactions between drug and polymers in amorphous spray dried dispersions and evaluate the subsequent impact on drug dissolution in non-sink media. This is intended to be used as a screening tool for dosage-form development. Formulations with specific theoretical and observed interactions between drug and polymer may exhibit improved dissolution rate, increased absorption rate, increased capacity for drug loading and improved physical stability. Four BCS II class drugs were evaluated: ibuprofen, ketoprofen, nifedipine, and itraconazole. Binary and ternary spray dried dispersions were manufactured with conventional polymers and arabinogalactan. Specific interaction parameters between each drug and polymer were determined using theoretical group contribution calculations and DSC data. Solid-state interactions were evaluated using modulated DSC and FTIR, and solution-state interactions were evaluated using 1H-NMR. The maximum amorphous content for each formulation was calculated from the enthalpy of melting point peaks using DSC. Flory-Huggins Specific Interaction Parameters were calculated and show that a negative specific parameter was associated with increased solid-state interactions and improved capacity to contain drug in the amorphous state. Correlations between Flory-Huggins specific interaction parameter, amorphous drug loading, and equilibrium solubility were established. Ternary spray-dried dispersions containing drug, conventional polymer, and arabinogalactan displayed similar hydrogen bonding as was observed with binary spray-dried dispersions. Solid and solution-state interactions observed in binary systems may be incorporated into ternary systems with arabinogalactan to both maintain amorphous drug capacity and improve dissolution rate compared to the binary. Supersaturation of amorphous binary and ternary dispersions was attained as compared to the crystalline drug. Mechanical properties of polymers as related to dissolution rate were investigated, and ternary systems containing to rapidly swelling and dissolving arabinogalactan had more pronounced erosion properties as compared to binary drug : HPMC dispersions. The resultant ternary systems are an improvement over binary drug polymer systems. / Pharmaceutical Sciences