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Understanding of the drug-drug co-crystallized solid structure – mechanical properties and improved tableting performance of high dose metformin HCI to optimize the tablet size
Get PDFCrystal engineering has been widely explored to design and develop crystalline forms of drugs to address issues related to solubility, permeability, stability, bioavailability, and other properties without impacting the therapeutic efficacy of the drug. In this exploration, we aim to address the existing limitation of metformin HCl (MET) using the cocrystallization technique, an effective tool of crystal engineering. MET, an FDA-approved anti-hyperglycemic drug, is one of the most widely prescribed treatments for type II diabetes mellitus. MET is known to suffer from several limitations due to physicochemical properties and poor mechanical and structural properties, which influence the tableting performance of such high-dose drugs and passively impact patient compliance. MET is currently manufactured using the wet granulation method as direct compression is very challenging due to the requirement of ~40%-50% excipients for tablet development. Co-crystallization of two active molecules is one of the approaches widely used to improve the molecular and structural properties of the drug. Therefore, in this exploration, we hypothesized that the cocrystallization strategy could help to improve the mechanical properties as well as the tableting performance of MET.
Co-crystallization of MET with sodium salicylate (SAL) as a coformer was performed using the solvent evaporation technique. The developed MET:SAL cocrystallized solid was characterized using advanced analytical methods, including powder X-ray diffraction, single-crystal X-ray diffraction, differential scanning calorimetry, thermogravimetric analysis, and Fourier transform infrared spectroscopy. The solid-state characterization results facilitated understanding the crystalline form of the engineered solid. These findings also supported the determination of the salt/cocrystal form of the MET:SAL cocrystallized solid. Tableting performance studies revealed that MET:SAL cocrystallized solid demonstrated improved tensile strength and greater compressibility, while MET was found to be challenging to compress without the aid of excipients. Due to the enhanced tableting performance, the total volume of MET:SAL tablets were also found to display a significant reduction as compared to MET tablets. In-die Heckel analysis revealed that MET:SAL cocrystallized solid underwent plastic deformation at low compression force as compared to MET. These experimental findings were further supported by intermolecular interaction studies, which showed that MET possessed quasi-isotropic hydrogen bond networking and crystal packing. Thus, making MET a rigid material and impacting its direct compression. In comparison, SAL has less inter-plane hydrogen bond networking, which makes it a soft material thus, easy to compress. Due to this feature of SAL, the MET:SAL cocrystallized solid possesses comparatively reduced inter-plane hydrogen bond networking than MET making it suitable for direct compression. Thus, MET having poor deformation along with tableting issues such as capping or sticking problems can be subjected to direct compression after cocrystallization with SAL. This host-guest relationship of MET:SAL helped to improve the mechanical properties of the material resulting in a reduction in the amount and/number of excipients for tablet development, thereby causing a decrease in the tablet size.
While the improvement in mechanical properties and tableting performance was established due to cocrystallization of MET, impact on solubility, dissolution, and partition coefficient was also evaluated. Solubility studies displayed a reduction in the solubility of MET upon cocrystallization with SAL which was found to be pH-dependent. Interestingly, the dissolution studies did not show any significant difference in the dissolution profile of MET and MET:SAL. The similar dissolution of MET:SAL and MET, despite the difference in the solubility, was found to be because of the high solubility of MET:SAL. Partition coefficient studies revealed that the cocrystallization of MET with SAL resulted in increased lipophilicity of the engineered solid compared to MET. The findings of the current work support the hypothesis and provide an explanation for the improved mechanical and structural properties of MET after cocrystallization. The work also helps to understand the influence of intermolecular interactions of the materials on the tableting performance for designing optimized crystal engineering. Thus, this study provides valuable insights about cocrystallization and its impact on the interplay of the various properties of the material and tunability of the tableting performance
Ex vivo dermis microdialysis: A tool for bioequivalence testing of topical dermatological drug product (Demonstration of proof of concept and testing)
Get PDFClinical response to most topical dermatological drug products (TDDP) depends on the availability of the drug in the dermis. Dermal Microdialysis (dMD) is a sampling technique that permits measuring the concentration of a drug over time, in vivo, directly into the target tissue, the dermis. The pharmacokinetic parameters obtained from such studies may help to optimize the development of TDDP and potentially can be applied to the assessment of TDDP bioequivalence. However, these studies require several hours or even days of continuous sampling that makes it often stressful and unpractical for human subjects as well as animals. The goal of this dissertation was to develop a reliable and consistent ex-vivo dMD method to complement and assist in vivo dMD experiments.
In the first part of the project, we have developed and tested the ex-vivo dermal microdialysis method on two different experimental skin models using freshly excised porcine skin. Porcine skin was selected due to the close resemblance to human skin, it is advantageous in terms of availability and expense. For the microdialysis study, in-house dermal microdialysis probes were conveniently manufactured with controlled specifications and the microdialysis recovery process was screened with an in vitro setup to match the intended use. The in vitro microdialysis method was optimized for probe specification, analyte suitability, perfusion flow rate, and perfusate composition. A maximized, rapid, and steady recovery was demonstrated within a wide range of concentrations. For the ex vivo dermal microdialysis study, the two different skin models developed were: M1-- Full-thickness skin (≈0.25 cm) without subcutaneous fat layer placed on a hydrated 0.5 cm cellulose backing support, and M2 -- Full-thickness skin with subcutaneous fat layer (total thickness = 1.0 cm) placed directly on an aluminum boat, avoiding any kind of hydration. Both setups were tested on TDDP cream and gel of metronidazole (MTZ) for which both in vivo and IVPT data are available for comparison. The two different formulations, Metronidazole cream and gel, were compared side-by-side for the rate and extent of delivery to the dermis. The latter skin model was found suitable, manifesting data comparable to the available data from in vivo pig and IVPT (human cadaver) study. The selection of the best-fit-model was based on the comparative bioavailability response from the negative control, Metronidazole gel, resulting in a lower bioavailability profile (90% CI). Using this suitable ex vivo dMD model, site-specific results of the drug can be conveniently monitored in the dermis leading to dose-dependent rate and extent in concentration-time exposure.
The M2 model was further tested for the effect of temperature of the skin on the bioavailability profile of the drug. As reported in several pieces of literature, an increase in dermal exposure is expected with the rise in skin temperature. Superficial addition of heat to the skin was not feasible as it may change the thermodynamics of the formulation leading to alteration in permeation kinetics. Thus, the physiological temperature of ex vivo pig skin explant was achieved by providing continuous heat from the ventral side using a closed water-bath system. The process of supplementation of temperature did not impact the bioavailability profile, rather unfavorable damages to the skin microstructure due to thermal degradation was observed. Further studies with the proposed model ex vivo dMD model were conducted at ambient lab temperature.
Yet another aspect of the proposed model was to test its capability to determine bioequivalence (BE). The potential of using this model for BE testing was validated by comparing the BA of MetroCream with its USFDA-approved generic Metronidazole 0.75% cream. The overall BE estimation resulted in an ln-AUC of 91.65 (80.93, 104.88) and an ln-Cmax value of 87.56 (74.87,102.39). The fact that reference and test formulations can be tested simultaneously at multiple sites on a skin sample harvested from a single animal subject reduces the burden of vii-inter-subject variability. The experimental population size required to establish bioequivalence for topically applied drugs can be reduced.
Yet another aspect of the study was to design a mathematical model, based on the ex vivo dMD findings, to extend its predictability to in vivo outcomes. A first-of-its-kind unit impulse response method was applied in dermis tissue of skin explant to measure the absorption independent elimination parameters. The estimated parameters were employed to calculate the cumulative absorption of the drug from different topical formulations. The absorption profile of the developed model was time-scaled and absolute-scaled with a permeation scaling factor to map with available literature data on in vivo pig. The levy point-to-point regression coefficient was employed to predict the in vivo PK profile thereafter. With the current intervention, we propose a mathematical possibility to predict in vivo outcomes for a given topical dose. The studies presented were limited internal predictions only, and external validation with a different set of data is yet to be performed and to be undertaken at another time.
Overall, the studies presented in this work provides a foundation stone for an elaborate field of work that can be undertaken to minimize the use of animal in pharmacokinetic evaluations for topical and transdermal products. Ex vivo dermal microdialysis warrants testing on a plethora of drug molecules of different polarities to decide on the future of the technique. Regardless, the technique holds unmet potential and needs to be nurtured over time
Belonging to Different Types of Families as a Protective Factor Against Minority Stress in Queer Young Adults
Get PDFResearch on resilience focuses on how people recover from stressful situations. This honors thesis addresses resilience in people who experience rejection from their families of origin. A common source of support in the Gay community is chosen families. However, these families are often formed related to a deficit in social support from the original family. Creating families to make up for a lack of social support could be come from a deficit-reduction approach to the need to belong, which is related to lower levels of well-being. To investigate this conceptual inconsistency between resilience and social support from a deficient orientation, I studied if all chosen families are related to resilience, or if only those of individuals with a growth belongingness orientation related to resilience in a sample of college-aged individuals. To answer these questions, I recruited a sample of emerging adults by contacting department chairs at various colleges and universities in the United States. Participants filled out a survey on Google Forms measuring: Social support from their original family; social support from their chosen family; their belongingness orientation; a non-clinical measure of depressive symptoms; and a measure of self-esteem. The results suggested that the relationship between social support and well-being may involve bi-directional causality, where people seek out social support to cope with low self-esteem and high levels of depression, and this may be especially common for people with a high growth belongingness orientation. Future research should include longitudinal studies to better understand this relationship
Developing Educators’ Capacity for Natural and Ethical Caring A Mixed-Methods Study
Get PDFAn ethic of care is central to the role of teaching and educational outcomes. Many Kindergarten-College institutions have “developing caring students or teachers” as a primary goal in their mission or vision statements. However, teachers need to know how to care. The purpose of this study was twofold: (a) to examine the behaviors that teachers and students perceive as being indicative of the caring teacher; and (b) to develop a guide for the core of teacher caring. These purposes were designed to help educators understand the nature of teacher caring and provide an exemplar for intentional and reflective practice as they identify areas of “care strengths” or “care weaknesses” to enhance their growth and development as caring teachers. The methodology used in this study was a mixed-methods convergent parallel design to understand, both quantitatively and qualitatively, teachers’ subjective viewpoints on caring. Data were collected from a purposive sample consisting of teachers from PreK through College in NYS. The findings suggested that (a) teacher caring impacts key aspects of teaching; (b) teacher caring behaviors are guided by seven primary values which represent the professional model of care; and (c) teacher caring values are primarily expressed using a few pedagogical practices that exemplify the caring model. The seven primary values guiding the caring behavior of teachers included: (a) supportive relationships; (b) empowerment; (c) learning and academic achievement; (d) students’ well-being; (e) accessibility, responsiveness, and flexibility; (f) comfortable atmosphere; and (g) students’ dignity
The Methodological Issues of the C.S.I Effect and it’s Controversial Impact on Criminal Investigation
Get PDFWith the rising success of crime-scene related television shows in recent years, and forensic science as a new hot topic in multiple settings, the world of criminal justice faces new complications as this phenomenon continues to grow. This is popularly known as “The C.S.I Effect.” Contrary to belief, much of what the public perceives, or think they know about the operations of law enforcement and the legal system, comes from television. Consequently, as these television programs appeal to greater audiences around the world, increasingly unreasonable expectations are established in the forensic world, both inside and out of the courtroom. In light of this issue, research has discussed the many television shows that have greatly influenced the public perception such as C.S.I, Dexter and Sherlock, and provides a myriad of examples, describing the inconsistencies and flaws that these shows are able to portray in the span of a 40-minute program time slot. With each example, the correct methods, linguistics and techniques that are used in real-world investigations will be explained and the efficiency they provide to criminal cases. Throughout this research, the extension of the C.S.I Effect will be discussed, as well as its impact on a student’s decision in choosing a major in Forensic Science- are they truly satisfied with their choice or disappointed by the reality? Comparative analysis of the C.S.I Effect in the courtroom will be presented, as well as the controversy behind such a theory, will also be discussed at length. The goal of this research is to determine any empirical evidence behind the commonly-held belief that juror expectations for forensic evidence are linked to watching law-related television shows and if there can or cannot be anything to fix this detrimental issue
Teacher Job Satisfaction Among K-12 Public School Teachers: A Mixed Methods Study
Get PDFSadly, teacher job satisfaction has been recently depicted as a “portrait of broad teacher discontent” (Phi Delta Kappa, 2019, p. k3), negatively impacting teachers’ well-being and retention. This study employed a mixed-methodological approach, composed of (a) an exploratory factor analysis of participant responses to the Teacher Job Satisfaction Questionnaire (Lester, 1982), (b) two open-ended questions, and (c) the covariates of the participants. Participants were K-12 public teachers (n = 129), employed in Ulster, Dutchess, Orange, Rockland, and Putnam counties of New York State. Through exploratory factor analysis, this study discovered six factors of teacher job satisfaction: Supportive and Appreciative Supervisor (F1), Collegiality and Workplace Relationships (F2), Income and Job Security (F3), Autonomy, Creativity at Work, and Student Relationship (F4), Working Conditions and School Culture (F5), and Advancement and Professional Growth (F6). Qualitative responses, what teachers were and were not satisfied with in their jobs, augmented the exploratory factor analysis findings. A table of descriptive statistics and histograms were created, prompted by the exceptionality of F2, and a t-test indicated that females who shared views with F2 had more concerns than males over relationships with colleagues (20% at −3.0 SD), when working in schools. This study concluded six factors of teacher job satisfaction, where relationships emerged as the strongest indicator, especially among females. Recruiting, developing, rewarding, and retaining effective administrators, and creating nurturing work environments for teachers, can positively impact teacher job satisfaction, wellness, and retention. Keywords: teacher job satisfaction, teacher working conditions, teacher job dissatisfaction, school culture, relationships in school
Cultural Protest Music from the Early Twentieth Century and Beyond
Get PDFMy undergraduate thesis inspects the intersection that occurs when social advocacy and music combine to create protest music. It looks in depth towards three distinct cultures - that of the Aboriginal Australian, native Irish, and Japanese - to see how the nuanced issues present in those societies shapes the protest music that comes out of them. My thesis also examines the consequences brought about by this music, and how it goes on to shape the resolutions to these issues
Examining Scott Peterson’s Appeals
Get PDFThis works discusses the Scott Peterson case, which took place from 2002-2004. Scott Peterson was convicted of murdering his wife Laci and unborn son Conner in 2004, and was given the death penalty. Peterson has filed automatic appeals and habeas corpus appeals since his trial, which have made their way through the California court system. Peterson’s death sentence was overturned by the California Supreme Court in 2020, and the California Supreme Court ordered the San Mateo trial court to look into overturning Peterson’s conviction. This work not only discusses the Peterson case at great length, it also serves to examine and evaluate claims made in both of Scott Peterson’s Appeals. This work also analyzes claims made by Janey Peterson, Peterson’s sister-in-law, and other advocates of Peterson’s innocence. This work mainly uses information from the documentary series The Murder of Laci Peterson, Peterson’s appellant briefs, the State of California’s response briefs, and the Scott Peterson Appeal website to support and refute these claims. By examining these claims, this work seeks to evaluate the legitimacy of claims that Scott Peterson was not given a fair trial, and/or is innocent
Associations Between Parent Characteristics and Acceptability of Exposure-Based Treatments For Child and Adolescent Anxiety
Get PDFCognitive-behavioral therapy (CBT), particularly exposure therapy, is the most effective treatment for anxiety disorders in children and adolescents (Kendall et al., 2005). Little research has been done to explore parent acceptability of treatment for anxiety in children and adolescents, and no research has explored the acceptability of exposure for this population. The purpose of the present study was to examine parent acceptability of exposure for child and adolescent anxiety as well as variables associated with acceptability. Parents completed a demographic questionnaire, the Clinically Useful Anxiety Outcome Scale (Zimmerman et al., 2010), and the Family Accommodation Scale – Anxiety (Lebowitz et al., 2013). They then watched a brief video of a clinician explaining exposure to the parent of a child client. Lastly, they completed an assessment of their beliefs about exposure and rated the acceptability of exposure utilizing the Treatment Evaluation Inventory (Kazdin, 1980). Parental anxiety, accommodation, and endorsement of negative beliefs about exposure were hypothesized to negatively correlate with the acceptability of exposure. No significant associations were found between the variables. Exposure therapy was found to be acceptable by parents, as evidenced by a mean TEI-SF score that was above the cutoff for moderate acceptability. Theoretical implications relating to our understanding of parental factors influencing acceptability of exposure, as well as other factors that may be associated with acceptability of exposure, are discussed
The Analytical, Technical Processes behind the Evaluation of Forensic Evidence through Questioned Document Examination
Get PDFA will is found next to a dead body. A suicide letter is left at a crime scene. A ransom note is near a kidnapped individual. Questioned document examiners are of utmost importance within the forensic science community to identify perpetrators and provide closure for cases. Handwriting, paper and ink analysis embody areas studied by forensic scientists to determine authorship, reliability and authenticity. Each person is unique and specific features are showcased within an individual’s writing. Since the emergence of letters, people have created, developed and immersed themselves into the community process of writing. Features have advanced from childhood learning styles to adult routines. Minute characteristics are located by questioned document scientists through various techniques, methods and instrumental analysis. Handwriting features, paper inspection and ink examination result in unique quality identification. The Electrostatic Detection Apparatus and Video Spectral Comparator are two of the most widely used machines by questioned document scientists for validity purposes. After conducting tests, examiners are called to court as expert witnesses to testify regarding evidence. Preparatory procedures are followed in addition to both verbal and visual demonstrations of samples. From the crime scene to transportation to the crime laboratory to the courtroom, evidence is distributed with care and standard operating procedures are enacted. Appropriate handling of samples is always required to ensure precision, accuracy and protection of evidence. The most proper collection, analysis and demonstration of samples is essential in assisting the trier of fact, judge and jury, with reaching an ultimate decision