Excipient characterization and particle engineering to develop directly compressed orally disintegrating tablets

ODTs have emerged as a novel oral dosage form with a potential to deliver a wide range of drug candidates to paediatric and geriatric patients. Compression of excipients offers a costeffective and translatable methodology for the manufacture of ODTs. Though, technical challenges prevail such as difficulty to achieve suitable tablet mechanical strength while ensuring rapid disintegration in the mouth, poor compressibility of preferred ODT diluent Dmannitol, and limited use for modified drug-release. The work investigates excipients’ functionality in ODTs and proposes new methodologies for enhancing material characteristics via process and particle engineering. It also aims to expand ODT applications for modified drug-release. Preformulation and formulation studies employed a plethora of techniques/tests including AFM, SEM, DSC, XRD, TGA, HSM, FTIR, hardness, disintegration time, friability, stress/strain and Heckel analysis. Tableting of D-mannitol and cellulosic excipients utilised various compression forces, material concentrations and grades. Engineered D-mannitol particles were made by spray drying mannitol with pore former NH4HCO3. Coated microparticles of model API omeprazole were prepared using water-based film forming polymers. The results of nanoscopic investigations elucidated the compression profiles of ODT excipients. Strong densification of MCC (Py is 625 MPa) occurs due to conglomeration of physicomechanical factors whereas D-mannitol fragments under pressure leading to poor compacts. Addition of cellulosic excipients (L-HPC and HPMC) and granular mannitol to powder mannitol was required to mechanically strengthen the dosage form (hardness >60 N, friability <1%) and to maintain rapid disintegration (<30 sec). Similarly, functionality was integrated into D-mannitol by fabrication of porous, yet, resilient particles which resulted in upto 150% increase in the hardness of compacts. The formulated particles provided resistance to fracture under pressure due to inherent elasticity while promoted tablet disintegration (50-77% reduction in disintegration time) due to porous nature. Additionally, coated microparticles provided an ODT-appropriate modified-release coating strategy by preventing drug (omeprazole) release.

A methodological evaluation and predictive in silico investigation into the multi-functionality of arginine in directly compressed tablets

The acceleration of solid dosage form product development can be facilitated by the inclusion of excipients that exhibit poly-/multi-functionality with reduction of the time invested in multiple excipient optimisations. Because active pharmaceutical ingredients (APIs) and tablet excipients present diverse densification behaviours upon compaction, the involvement of these different powders during compaction makes the compaction process very complicated. The aim of this study was to assess the macrometric characteristics and distribution of surface charges of two powders: indomethacin (IND) and arginine (ARG); and evaluate their impact on the densification properties of the two powders. Response surface modelling (RSM) was employed to predict the effect of two independent variables; Compression pressure (F) and ARG percentage (R) in binary mixtures on the properties of resultant tablets. The study looked at three responses namely; porosity (P), tensile strength (S) and disintegration time (T). Micrometric studies showed that IND had a higher charge density (net charge to mass ratio) when compared to ARG; nonetheless, ARG demonstrated good compaction properties with high plasticity (Y=28.01MPa). Therefore, ARG as filler to IND tablets was associated with better mechanical properties of the tablets (tablet tensile strength (σ) increased from 0.2±0.05N/mm2 to 2.85±0.36N/mm2 upon adding ARG at molar ratio of 8:1 to IND). Moreover, tablets' disintegration time was shortened to reach few seconds in some of the formulations. RSM revealed tablet porosity to be affected by both compression pressure and ARG ratio for IND/ARG physical mixtures (PMs). Conversely, the tensile strength (σ) and disintegration time (T) for the PMs were influenced by the compression pressure, ARG ratio and their interactive term (FR); and a strong correlation was observed between the experimental results and the predicted data for tablet porosity. This work provides clear evidence of the multi-functionality of ARG as filler, binder and disintegrant for directly compressed tablets.

The value of tablets as reading aids for individuals with central visual field loss:an evaluation of eccentric reading with static and scrolling text

Purpose: Technological devices such as smartphones and tablets are widely available and increasingly used as visual aids. This study evaluated the use of a novel app for tablets (MD_evReader) developed as a reading aid for individuals with a central field loss resulting from macular degeneration. The MD_evReader app scrolls text as single lines (similar to a news ticker) and is intended to enhance reading performance using the eccentric viewing technique by both reducing the demands on the eye movement system and minimising the deleterious effects of perceptual crowding. Reading performance with scrolling text was compared with reading static sentences, also presented on a tablet computer. Methods: Twenty-six people with low vision (diagnosis of macular degeneration) read static or dynamic text (scrolled from right to left), presented as a single line at high contrast on a tablet device. Reading error rates and comprehension were recorded for both text formats, and the participant’s subjective experience of reading with the app was assessed using a simple questionnaire. Results: The average reading speed for static and dynamic text was not significantly different and equal to or greater than 85 words per minute. The comprehension scores for both text formats were also similar, equal to approximately 95% correct. However, reading error rates were significantly (p=0.02) less for dynamic text than for static text. The participants’ questionnaire ratings of their reading experience with the MD_evReader were highly positive and indicated a preference for reading with this app compared with their usual method. Conclusions: Our data show that reading performance with scrolling text is at least equal to that achieved with static text and in some respects (reading error rate) is better than static text. Bespoke apps informed by an understanding of the underlying sensorimotor processes involved in a cognitive task such as reading have excellent potential as aids for people with visual impairments.

Correlation of detector dog alerts to cocaine decomposition products found in illicit forensic specimens

The volatile chemicals which comprise the odor of the illicit drug cocaine have been analyzed by adsorption onto activated charcoal followed by solvent elution and GC/MS analysis. A series of field tests have been performed to determine the dominant odor compound to which dogs alert. All of our data to date indicate that the dominant odor is due to the presence of methyl benzoate which is associated with the cocaine, rather than the cocaine itself. When methyl benzoate and cocaine are spiked onto U.S. currency, the threshold level of methyl benzoate required for a canine to signal an alert is typically 1-10 $\mu$g. Humans have been shown to have a sensitivity similar to dogs for methyl benzoate but with poorer selectivity/reliability. The dominant decomposition pathway for cocaine has been evaluated at elevated temperatures (up to 280$\sp\circ$C). Benzoic acid, but no detectable methyl benzoate, is formed. Solvent extraction and SFE were used to study the recovery of cocaine from U.S. currency. The amount of cocaine which could be recovered was found to decrease with time. ^

Social factors influencing antiretroviral therapy (ART) adherence among Black men living with HIV who use illicit drugs

In the United States 1.2 million persons are HIV infected. Among men, HIV rates in Blacks are seven times higher than Whites. More Black men progress to AIDS because of treatment failure and adherence problems. Antiretroviral therapy (ART), the only treatment effective for long term HIV suppression, requires near perfect adherence. Illicit drug use and homelessness pose further challenges. Suboptimal ART adherence leads to HIV mutations that can render entire classes of medication ineffective and transmission of mutated HIV to others in the community. The purpose of this study was to investigate ART adherence behaviors of Black men living with HIV who use illicit drugs. A sample of 160 Black men living with HIV who use illicit drugs was recruited using flyers and snowball sampling. These men completed study questionnaires that included: demographics, the K-10, PSOM and Social Capital Integrated Questionnaire, among others. One-way ANOVAs, multiple regression, and path analysis were used to address the study's research questions. Most of the Black men in this sample were high school graduates and single, with high rates of being marginally housed and homeless. Unemployment and disability were common, and personal and household income was low. The men reported high numbers of sexual partners both over the past year and during their lifetimes, suggesting continued engagement in high risk behaviors. The majority of the men attributed their HIV to heterosexual sex, with sexual commoditization being common. About half of the 105 men currently taking ART reported the current regimen was their first. Patient-provider relationship was positively associated with tolerability of ART. ART adherence was greater with less psychological distress, lower frequency of current illicit drug use, and greater tolerability of ART. Partner status negatively influenced ART adherence. This study of Black men's ART adherence behaviors has implications for public health. It identified social context factors that influence ART adherence among the men and provides evidence to refine existing, or develop new, ART adherence interventions.

Illicit interest groups: The political impact of the Medellin drug trafficking organizations in Colombia

Although drug trafficking organizations (DTOs) exist and have an effect on health, crime, economies, and politics, little research has explored these entities as political organizations. Legal interest groups and movements have been found to influence domestic and international politics because they operate within legal parameters. Illicit groups, such as DTOs, have rarely been accounted for—especially in the literature on interest groups—though they play a measurable role in affecting domestic and international politics in similar ways. Using an interest group model, this dissertation analyzed DTOs as illicit interest groups (IIGs) to explain their political influence. The analysis included a study of group formation, development, and demise that examined IIG motivation, organization, and policy impact. The data for the study drew from primary and secondary sources, which include interviews with former DTO members and government officials, government documents, journalistic accounts, memoirs, and academic research. To illustrate the interest group model, the study examined Medellin-based DTO leaders, popularly known as the "Medellin Cartel." In particular, the study focused on the external factors that gave rise to DTOs in Colombia and how Medellin DTOs reacted to the implementation of counternarcotics efforts. The discussion was framed by the implementation of the 1979 Extradition Treaty negotiated between Colombia and the United States. The treaty was significant because as drug trafficking became the principal bilateral issue in the 1980s; extradition became a major method of combating the illicit drug business. The study's findings suggested that Medellin DTO leaders had a one-issue agenda and used a variety of political strategies to influence public opinion and all three branches of government—the judicial, the legislative, and the executive—in an effort to invalidate the 1979 Extradition Treaty. The changes in the life cycle of the 1979 Extradition Treaty correlated with changes in the political power of Medellin-based DTOs vis-à-vis the Colombian government, and international forces such as the U.S. government's push for tougher counternarcotics efforts.

Human Security and Crime in Latin America: The political Capital and Political Impact of Criminal Groups and Belligerents Involved in Illicit Economies

Organized crime and illegal economies generate multiple threats to states and societies. But although the negative effects of high levels of pervasive street and organized crime on human security are clear, the relationships between human security, crime, illicit economies, and law enforcement are highly complex. By sponsoring illicit economies in areas of state weakness where legal economic opportunities and public goods are seriously lacking, both belligerent and criminal groups frequently enhance some elements of human security of the marginalized populations who depend on illicit economies for basic livelihoods. Even criminal groups without a political ideology often have an important political impact on the lives of communities and on their allegiance to the State. Criminal groups also have political agendas. Both belligerent and criminal groups can develop political capital through their sponsorship of illicit economies. The extent of their political capital is dependent on several factors. Efforts to defeat belligerent groups by decreasing their financial flows through suppression of an illicit economy are rarely effective. Such measures, in turn, increase the political capital of anti-State groups. The effectiveness of anti-money laundering measures (AML) also remains low and is often highly contingent on specific vulnerabilities of the target. The design of AML measures has other effects, such as on the size of a country’s informal economy. Multifaceted anti-crime strategies that combine law enforcement approaches with targeted socio-economic policies and efforts to improve public goods provision, including access to justice, are likely to be more effective in suppressing crime than tough nailed-fist approaches. For anti-crime policies to be effective, they often require a substantial, but politically-difficult concentration of resources in target areas. In the absence of effective law enforcement capacity, legalization and decriminalization policies of illicit economies are unlikely on their own to substantially reduce levels of criminality or to eliminate organized crime. Effective police reform, for several decades largely elusive in Latin America, is one of the most urgently needed policy reforms in the region. Such efforts need to be coupled with fundamental judicial and correctional systems reforms. Yet, regional approaches cannot obliterate the so-called balloon effect. If demand persists, even under intense law enforcement pressures, illicit economies will relocate to areas of weakest law enforcement, but they will not be eliminated.

Beyond the Pay: Current Illicit Activities of the Armed Forces in Central America

The growth of criminal gangs and organized crime groups has created unprecedented challenges in Central America. Homicide rates are among the highest in the world, countries spend on average close to 10 percent of GDP to respond to the challenges of public insecurity, and the security forces are frequently overwhelmed and at times coopted by the criminal groups they are increasingly tasked to counter. With some 90 percent of the 700 metric tons of cocaine trafficked from South America to the United States passing through Central America, the lure of aiding illegal traffickers through provision of arms, intelligence, or simply withholding or delaying the use of force is enormous. These conditions raise the question: to what extent are militaries in Central America compromised by illicit ties to criminal groups? The study focuses on three cases: Nicaragua, El Salvador, and Honduras. It finds that: Although illicit ties between the military and criminal groups have grown in the last decade, militaries in these countries are not yet “lost’ to criminal groups. Supplying criminal groups with light arms from military stocks is typical and on the rise, but still not common. In general the less exposed services, the navies and air forces, are the most reliable and effective ones in their roles in interdiction. Of the three countries in the study, the Honduran military is the most worrying because it is embedded in a context where civilian corruption is extremely common, state institutions are notoriously weak, and the political system remains polarized and lacks the popular legitimacy and political will needed to make necessary reforms. Overall, the armed forces in the three countries remain less compromised than civilian peers, particularly the police. However, in the worsening crime and insecurity context, there is a limited window of opportunity in which to introduce measures targeted toward the military, and such efforts can only succeed if opportunities for corruption in other sectors of the state, in particular in law enforcement and the justice system, are also addressed. Measures targeted toward the military should include: Enhanced material benefits and professional education opportunities that open doors for soldiers in promising legitimate careers once they leave military service. A clear system of rewards and punishments specifically designed to deter collusion with criminal groups. More effective securing of military arsenals. Skills and external oversight leveraged through combined operations, to build cooperation among those sectors of the military that have successful and clean records in countering criminal groups, and to expose weaker forces to effective best practices.

Innovating from the War Economy: Formal, Informal, and Illicit Economic Activities of the Military in Colombia

Over the last decade, the Colombian military has successfully rolled back insurgent groups, cleared and secured conflict zones, and enabled the extraction of oil and other key commodity exports. As a result, official policies of both the Uribe and Santos governments have promoted the armed forces to participate to an unprecedented extent in economic activities intended to consolidate the gains of the 2000s. These include formal involvement in the economy, streamlined in a consortium of military enterprises and social foundations that are intended to put the Colombian defense sector “on the map” nationally and internationally, and informal involvement expanded mainly through new civic action development projects intended to consolidate the security gains of the 2000s. However, failure to roll back paramilitary groups other than through the voluntary amnesty program of 2005 has facilitated the persistence of illicit collusion by military forces with reconstituted “neoparamilitary” drug trafficking groups. It is therefore crucially important to enhance oversight mechanisms and create substantial penalties for collusion with illegal armed groups. This is particularly important if Colombia intends to continue its new practice of exporting its security model to other countries in the region. The Santos government has initiated several promising reforms to enhance state capacity, institutional transparence, and accountability of public officials to the rule of law, which are crucial to locking in security gains and revitalizing democratic politics. Efforts to diminish opportunities for illicit association between the armed forces and criminal groups should complement that agenda, including the following: Champion breaking existing ties between the military and paramilitary successor groups through creative policies involving a mixture of punishments and rewards directed at the military; Investigation and extradition proceedings of drug traffickers, probe all possible ties, including as a matter of course the possibility of Colombian military collaboration. Doing so rigorously may have an important effect deterring military collusion with criminal groups. Establish and enforce zero-tolerance policies at all military ranks regarding collusion with criminal groups; Reward military units that are effective and also avoid corruption and criminal ties by providing them with enhanced resources and recognition; Rely on the military for civic action and development assistance as minimally as possible in order to build long-term civilian public sector capacity and to reduce opportunities for routine exposure of military forces to criminal groups circulating in local populations.

Microparticle surface layering through dry coating:impact of moisture content and process parameters on the properties of orally disintegrating tablets

OBJECTIVES: The aim of this study was to investigate the influence of process parameters during dry coating on particle and dosage form properties upon varying the surface adsorbed moisture of microcrystalline cellulose (MCC), a model filler/binder for orally disintegrating tablets (ODTs). METHODS: The moisture content of MCC was optimised using the spray water method and analysed using thermogravimetric analysis. Microproperty/macroproperty assessment was investigated using atomic force microscopy, nano-indentation, scanning electron microscopy, tablet hardness and disintegration testing. KEY FINDINGS: The results showed that MCC demonstrated its best flowability at a moisture content of 11.2% w/w when compared to control, comprising of 3.9% w/w moisture. The use of the composite powder coating process (without air) resulted in up to 80% increase in tablet hardness, when compared to the control. The study also demonstrated that surface adsorbed moisture can be displaced upon addition of excipients during dry processing circumventing the need for particle drying before tabletting. CONCLUSIONS: It was concluded that MCC with a moisture content of 11% w/w provides a good balance between powder flowability and favourable ODT characteristics.

Tablets als Wondermiddel voor de Motivatie? Een onderzoek naar de invloed een gesloten tabletsysteem op motivatie van leerlingen

Kloosterman, D. (2016). Tablets als Wondermiddel voor de Motivatie? Een onderzoek naar de invloed een gesloten tabletsysteem op motivatie van leerlingen. mei, 24, 2016, Heerlen, Nederland: Open Universiteit.