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Methamphetamine is the most common amphetamine used and, along with 3,4-methylenedioxymethamphetamine (MDMA, Ecstasy), is considered part of a worldwide drug epidemic. Monitoring metham-phetamine levels in the body is important for purposes of drug screening for employment, criminal investigations, and therapeutic drug monitoring. While methamphetamine is suitable for detection using immunoassay techniques, these methods tend to have significant cross reactivity with other compounds. Over the last decade, more than eighty different quantitative, confirmatory analytical methods for measuring methamphetamine in biological samples have been published in the scientific literature. Analytical instrumentation used in these methods includes gas chromatography-mass spectrometry (GC-MS), liquid chromatography-mass spectrometry (LC-MS), capillary electrophoresis (CE), among others. These assays are capable of quantifying methamphetamine concentrations in a variety of biological matrices, including blood, plasma, urine, hair, and fingernails. Some of these techniques can achieve detection as low as 0.1 ng/mL (1 ppb) concentra-tions. The strengths and limitations of these methodologies will be discussed in the context of methamphetamine analysis. Additionally, methods that can simultaneously measure methamphetamine levels as well as metabolites and other drugs of abuse will be highlighted.

The present work focuses on modifying a non-steroid anti-inflammatory drug (NSAID) into an ionic liquid and evaluating the resulting thermal behavior and structural changes of the drug. Naproxen was chosen as the NSAID molecule due to thermal stability and limited examples of its use as an ionic liquid in current literature. Lidocaine was chosen as the counterion based on a screening study of potential ionic liquid formers. The screening included both potential protic and aprotic formation and counterions were included with consideration to pKa, hydrogen bonding ability, molecular size, diffuse charge distribution and functional groups. Analytical techniques used to evaluate the counterions included high performance liquid chromatography (HPLC), differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA). Naproxen and lidocaine were then combined in varying molar ratios to determine the thermal behavior of the mixtures. The samples with equimolar, or higher, ratio of naproxen showed a phase which had a melting point of 82–85 °C. The DSC data was analyzed using a modified Tamman plot, resulting in the unexpected and previously unreported behavior of ionic liquid formation at a 2:1 molar ratio of naproxen to lidocaine, referred to as IL1 in this research. This stoichiometry was confirmed through Fourier Transformed Infrared (FT-IR) and nuclear magnetic resonance (NMR) spectroscopy methods. The samples that contained a higher molar ratio of lidocaine than naproxen, resulted in material more consistent with higher-order complex clusters. Further characterization of IL1 found that the material demonstrated behaviors of an ionic liquid, including weak intermolecular forces and at least partial ionization of the drug and counterion.

As a small molecule PDE 4 inhibitor, apremilast has drawn much attention for multiple promising indications. However, apremilast is a poorly water-soluble drug and has multiple polymorphic forms. This study aims to develop a sustained-release (SR) amorphous solid dispersion (ASD) system for apremilast. A streamlined material sparing ASD formulation development approach was utilized to identify candidate polymers and optimize drug loading. HPMCAS-M at a 20% drug loading and Copovidone at a 40% drug loading was selected as the lead formulations. A stable single-phase amorphous system of apremilast via spray drying was generated as revealed by XRPD, DMA, micro-dissolution, and accelerated stability testing. The apparent solubility of apremilast was improved up to 9 folds. HPMC was subsequently utilized to compress the produced ASD system into an SR matrix tablet. Release data demonstrated the capacity of HPMC to gradually hydrate and control drug release while suppressing drug recrystallization during the 20-hours period of sustained drug delivery. The designed SR amorphous based matrix system indicates that the delivery system has the ability to enhance apparent solubility, avoid recrystallization or polymorphic transformation by stabilizing its amorphous form, and provide an opportunity to enhance patient compliance by allowing once-daily administration. / Pharmaceutical Sciences

The most common route of administration is oral, despite absorption barriers leading to variable exposure and therapeutic effect. Preclinical species are used to study this variability, though they are expensive and time-consuming. Modeling and simulation provide an alternative to preclinical studies. In this study, a continuous rodent absorption model was developed and refined to predict drug absorption prior to entering animals. The continuous absorption model describes the change in drug concentration over distance and time. The intestine is defined by a physiologically based pharmacokinetic (PBPK) model, which is attached to a simpler classical compartmental model to represent the rest of the body. Physiological factors and drug physicochemical properties will be incorporated to predict the absorption profiles of amlodipine (AML), glyburide (GLY), and digoxin (DIG). The anatomy of the gastrointestinal tract and therefore, the physiological factors inputted into the model, are species specific. The region lengths, such as the jejunum, and absorptive surface area amplifiers, such as the villi, of the small intestine differ in humans versus rats. In addition, the stomach composition and presence of the gallbladder is not consistent between the two species. Similarly, food alters the physiology of the intestines. Periods of fasting can induce changes in intestinal pH and gastrointestinal motility. Chapter One details the background concerning this project, along with the hypothesis and goals. Chapter Two involves the development and validation for bioanalytical methods for the drugs of interest. Chapter Three discusses the collection of anatomical data, specifically the intestinal pH and gastrointestinal motility under fed and fasted conditions. Chapter Four includes in vitro ADME data collection and in vivo IV pharmacokinetic studies in male Sprague-Dawley rats to determine the systemic disposition functions in for amlodipine (AML), glyburide (GLY) and digoxin (DIG). Chapter Five includes the in vivo pharmacokinetic studies in male Sprague-Dawley rats to determine the effect of food on the absorption of amlodipine (AML), glyburide (GLY) and digoxin (DIG). Chapter Six details the in vivo rat studies involving the influence of particle size on GLY suspension absorption. Chapter Seven discusses the input of physiological factors and prediction of drug absorption using a continuous absorption model in rats. Chapter Eight details future directions and the summary of the project. / Pharmaceutical Sciences

The objective of this study was to evaluate the stability of vancomycin hydrochloride oral solution prepared using FIRST Vancomycin and FIRVANQ compounding kits, prepared in oral syringes and heat-sealed dosing cups, stored at refrigerated and room temperatures. Triplicate batches of vancomycin hydrochloride oral solution (50 mg/mL) were prepared using FIRST Vancomycin and FIRVANQ kits, aliquoted into plastic oral syringes and sealed dosing cups, stored at refrigerated and room temperatures for a total of eight sample groups. Additionally, remaining samples from FIRVANQ batches were unit-dosed in clear Luer-Lok syringes and stored under refrigeration as a ninth batch. Samples were removed and analyzed for vancomycin recovery using a previously validated high-performance liquid chromatography with ultraviolet detection method over a 30-day period. Recovery was quantitatively assessed by comparing to a freshly prepared United States Pharmacopeia reference standard on each day of sampling. Stability was defined as recovery of 90% to 110% of labeled amount. For all batches and storage conditions tested, the percent recovery of vancomycin remained within the 90% to 110% range throughout the entire 30-day study period. Statistically significant differences based on storage conditions were detected between some test groups, with higher recoveries associated with refrigerated storage. The stability of FIRVANQ is comparable to the solution prepared using the FIRST Vancomycin kit. FIRST Vancomycin and FIRVANQ solutions can be unit dosed, using capped oral syringes or sealed plastic cups, and stored at room temperature or under refrigeration for up to 30 days, which helps improve pharmacy workflow and reduce errors.

The 5-HT7¬ receptor is the most recently discovered 5-HT receptor subtype. 5-HT7 is a GPCR that exhibits a regulatory role in many biological functions in both the central nervous system (CNS) and the periphery. Recent literature has demonstrated a connection between the 5-HT7 receptor and Inflammatory Bowel Disease (IBD) progression. IBD is a devastating disease that affects 1.4 million Americans. Patients suffer from life altering symptoms as a result of severe, chronic inflammation of the gastrointestinal tract. Current treatments mitigate symptoms with no effect on disease progression. Targeting the 5-HT7 receptor as a novel treatment option is a viable medicinal chemistry project that could result in a therapy capable of providing relief to IBD patients. A novel series of butyrolactones were discovered during a prior thesis project completed by Dr. Rong Gao at Temple University’s School of Pharmacy. Broad screening indicated that many of the compounds within this series were potent binders of the 5-HT7 receptor. These results led to the initiation of a medicinal chemistry program aimed at the development of this series with the intent to identify novel 5-HT7 receptor antagonists that are suitable for pre-clinical and clinical evaluation for the treatment of IBD. Medicinal chemistry strategies were utilized in order to optimize each structural aspect of the butyrolactone pharmacophore. This required the preparation of several small series of compounds wherein one structural feature was systematically changed while the remaining features were held constant. The particular properties that were studied for optimization included 5-HT7 affinity, subtype selectivity, liver microsomes stability (mouse and human), and the topological polar surface area (to minimize CNS penetration). Implementing these strategies led to the identification of potent 5-HT7¬ antagonists, some of which exhibited excellent subtype selectivity and improved mouse liver microsome stability. Two analogs, 170073 and 230168, were chosen for further study. Both analogs exhibited adequate in vivo pharmacokinetic profiles capable of supporting efficacy in an in vivo setting. 170073 distributed rapidly and extensively into brain tissue, while 230168 moderately distributed into brain tissue. Moving forward, reducing CNS penetration will become a top priority. These two compounds were examined in the DSS induced mouse model of IBD and both exhibited efficacy. Specifically in the acute DSS model of colitis, 170073 and 230168 significantly lowered the disease activity index, mitigated histological damage and reduced the production of proinflammatory cytokines. In addition, 170073 demonstrated efficacy in the chronic DSS model of colitis. 230168 has yet to be tested in the chronic model. The results of this dissertation support the validity of this project and the use of 5-HT7¬ ¬¬antagonists as a potential novel treatment option for IBD. / Pharmaceutical Sciences

HIV- associated neurocognitive disorder (HAND), also known as HIV encephalopathy and AIDS dementia, is one of the critical complications of HIV infection that causes severe morbidity and even shortens survival. This complication is challenging to treat because most of the antiretroviral therapeutic (ART) agents cannot achieve the desired therapeutic levels in the central nervous system (CNS) because they cannot efficiently cross the blood-brain barrier (BBB). The goal of this study is to develop a new transferrin conjugated nanoemulsion system (Tf-NE) for antiretroviral medication delivery and evaluate its potential to cross the BBB. Nanoemulsions were prepared based on the solvent evaporation sonication method using lipids and phospholipids. To achieve brain delivery, holo-transferrin was conjugated to DSPE-PEG (2000)-Maleimide by NHS ester crosslinking reaction. Darunavir (DRV) was encapsulated into Tf-NE as an antiretroviral agent. Size, polydispersity index, and dispersion stability were characterized using dynamic light scattering (DLS) system. Morphology of the Tf-NE was investigated using transmission electron microscopy (TEM). Differential scanning calorimetry was performed to study the extent of drug solubilization inside the nanoemulsion system. To evaluate the in vitro toxicity of Tf-NE-DRV, MTT assay was performed by using the human brain endothelial capillary hCMEC/D3 cells and 293T cells. Cell uptake and drug transport assays were also conducted to investigate the in vitro activity of Tf-NE-DRV. In vitro efficacy studies, ex vivo imaging studies and in vivo biodistribution studies were performed to investigate the brain targeting function of Tf-NE-DRV. Tf-NE-DRN was prepared 100-130nm in diameter with polydispersity index smaller than 0.3. This nanoemulsion system was stable in serum-enriched medium and PBS at 37 ℃ for 5 days. All the therapeutic compounds were well-dispersed inside the oil core of Tf-NE-DRV. Within the therapeutic concentration range, Tf-NE-DRV did not cause a significant reduction in the cell viability, indicating low toxicity of the formulation. Considerable uptake of Tf-NE-DRV into the BBB model of hCMEC/D3 cells was observed. Tf-NE-DRV can maintain the same therapeutic function as the free drug form of darunavir in vitro. Imaging and biodistribution results revealed the formulation was superior to the free drug and able to transport the drug across the BBB in vivo to reach the therapeutic level. We successfully developed a biocompatible nanoemulsion system that can effectively penetrate the BBB. This Tf-NE-DRV system shows the clinical potential to deliver antiretroviral agents into the CNS system to achieve improved treatment of HAND. / Pharmaceutical Sciences

Osteomyelitis is a bone infection disease that is caused by microbes. One of the reason that a successful antimicrobial therapy has not been achieved in bone related infection is due to the physiological and structural limitations and multi-drug resistant bacteria, such as methicillin-resistant Staphylococcus aureus (MRSA). Alendronate, a type of bisphosphonate, is a commonly used drug to treat osteoporosis that can strongly chelate with the calcium ions in bone mineral (hydroxyapatite), could be utilized as an active targeting moiety in a drug delivery system to bone tissues. Since nanomedicine can provide a robust drug delivery platform, with the properties of encapsulating molecules of different hydrophilicity, tunable drug release profile, and potential of differential targeting cells and tissues, we proposed a lipid-polymer nanoparticle system, Bone-Targeting Nanoparticle (BTN), with surface modified with covalently bonded alendronate. In this study, BTN encapsulates linezolid, which has dose-related adverse effect that prevent long duration usage. According to our current results, BTN demonstrates three distinguished traits that potentially improves the therapeutic effect of linezolid towards MRSA induced osteomyelitis: a) a hydrophobic polymeric core that can encapsulate a high amount of linezolid; b) alendronate as a targeting moiety that can guide BTN to bone tissue and accumulate near the site of infection; and c) a PEGylated lipid interface that can enhance the drug release profile and provide increased serum stability relative to standard delivery methods. / Pharmaceutical Sciences

With the growing use of physiologically-based pharmacokinetic (PBPK) modeling to predict the pharmacokinetics of a drug, accurate prediction of the tissue: plasma water partition coefficients (Kp,m) has become increasingly important. In these predictions, drug-lipid interactions have been traditionally described using the octanol: water partition coefficient (logP) and the vegetable: oil: water partition coefficient (logPvo). However, the logP does not fully represent all of the drug interactions with phospholipids, while the logPvo is calculated from the logP and not determined experimentally. Partitioning into microsomes has been used as a potential surrogate for phospholipid partitioning in our previous steady-state volume of distribution prediction method. Microsomal partitioning is able to act as a total phospholipid partitioning term, representing both acidic and neutral phospholipid interactions. Partitioning into adipocytes potentially can provide an alternative surrogate for d / Pharmaceutical Sciences