Influence of binder attributes on binder effectiveness in a continuous twin screw wet granulation process via wet and dry binder addition

The effect of a wide variety of binders on the quality of granules produced via continuous twin screw wet granulation was studied. Anhydrous dicalcium phosphate was used as poorly soluble filler and was granulated applying dry or wet addition of binders. Furthermore, dry and wet binder characteristics were determined and linked to the binder effectiveness. PVA 4–88 and starch octenyl succinate exhibited the lowest granule friability at low liquid-to-solid ratios, i.e. the highest binder effectiveness, which was attributed to fast binder activation based on the fast wetting kinetics of the binder, to efficient wetting of DCP particles, and to good spreading in the powder bed. The performance of wettability measurements in an early formulation development stage is therefore considered highly important. Additionally, an increased stickiness of the binder surface caused by high binder viscosity and slow dissolution kinetics also positively influenced the binder effectiveness. In conclusion, this study revealed which binder attributes have a critical impact on the granulation process of dicalcium phosphate. Additionally, dry binder addition proved successful for creation of high quality granules

Continuous twin screw granulation : robustness of lactose/MCC-based formulations

In recent years, significant progress has been made in the field of continuous twin screw granulation. However, only limited knowledge is currently available on the impact of active pharmaceutical ingredient (API) properties on granule quality and processability. In this study, the response behavior of four formulations containing APIs (5–10% drug load) with diverse characteristics was compared to the behavior of the corresponding placebo formulation consisting of lactose, microcrystalline cellulose (MCC) and hydroxypropylmethylcellulose (HPMC). API selection was based on extensive material characterization, combining conventional testing with in silico descriptors. For each formulation, a design of experiments was set up, evaluating the impact of liquid to solid (L/S) ratio and screw speed. Response ranges, response behavior and processability of each of the four formulations proved very similar to the placebo formulation when an appropriate center point L/S ratio was chosen. Hence, this robust placebo formulation could prove useful by decreasing drug product development time and consequently providing patients with a faster access to innovative medicine. Additionally, APIs with similar properties exhibited highly comparable response behavior at similar L/S ratios, indicating the potential use of surrogate APIs in novel drug product development

Identifying critical binder attributes to facilitate binder selection for efficient formulation development in a continuous twin screw wet granulation process

The suitability of pharmaceutical binders for continuous twin-screw wet granulation was investigated as the pharmaceutical industry is undergoing a switch from batch to continuous manufacturing. Binder selection for twin-screw wet granulation should rely on a scientific approach to enable efficient formulation development. Therefore, the current study identified binder attributes affecting the binder effectiveness in a wet granulation process of a highly soluble model excipient (mannitol). For this formulation, higher binder effectiveness was linked to fast activation of the binder properties (i.e., fast binder dissolution kinetics combined with low viscosity attributes and good wetting properties by the binder). As the impact of binder attributes on the granulation process of a poorly soluble formulation (dicalcium phosphate) was previously investigated, this enabled a comprehensive comparison between both formulations in current research focusing on binder selection. This comparison revealed that binder attributes that are important to guide binder selection differ in function of the solubility of the formulation. The identification of critical binder attributes in the current study enables rational and efficient binder selection for twin-screw granulation of well soluble and poorly soluble formulations. Binder addition proved especially valuable for a poorly soluble formulation

Absolute estimation of initial concentrations of amplicon in a real-time RT-PCR process

<p>Abstract</p> <p>Background</p> <p>Since real time PCR was first developed, several approaches to estimating the initial quantity of template in an RT-PCR reaction have been tried. While initially only the early thermal cycles corresponding to exponential duplication were used, lately there has been an effort to use all of the cycles in a PCR. The efforts have included both fitting empirical sigmoid curves and more elaborate mechanistic models that explore the chemical reactions taking place during each cycle. The more elaborate mechanistic models require many more parameters than can be fit from a single amplification, while the empirical models provide little insight and are difficult to tailor to specific reactants.</p> <p>Results</p> <p>We directly estimate the initial amount of amplicon using a simplified mechanistic model based on chemical reactions in the annealing step of the PCR. The basic model includes the duplication of DNA with the digestion of Taqman probe and the re-annealing between previously synthesized DNA strands of opposite orientation. By modelling the amount of Taqman probe digested and matching that with the observed fluorescence, the conversion factor between the number of fluorescing dye molecules and observed fluorescent emission can be estimated, along with the absolute initial amount of amplicon and the rate parameter for re-annealing. The model is applied to several PCR reactions with known amounts of amplicon and is shown to work reasonably well. An expanded version of the model allows duplication of amplicon without release of fluorescent dye, by adding 1 more parameter to the model. The additional process is helpful in most cases where the initial primer concentration exceeds the initial probe concentration. Software for applying the algorithm to data may be downloaded at <url>http://www.niehs.nih.gov/research/resources/software/pcranalyzer/</url></p> <p>Conclusion</p> <p>We present proof of the principle that a mechanistically based model can be fit to observations from a single PCR amplification. Initial amounts of amplicon are well estimated without using a standard solution. Using the ratio of the predicted initial amounts of amplicon from 2 PCRs is shown to work well even when the absolute amounts of amplicon are underestimated in the individual PCRs.</p

Meeting Report: Moving Upstream—Evaluating Adverse Upstream End Points for Improved Risk Assessment and Decision-Making

Background Assessing adverse effects from environmental chemical exposure is integral to public health policies. Toxicology assays identifying early biological changes from chemical exposure are increasing our ability to evaluate links between early biological disturbances and subsequent overt downstream effects. A workshop was held to consider how the resulting data inform consideration of an “adverse effect” in the context of hazard identification and risk assessment. Objectives Our objective here is to review what is known about the relationships between chemical exposure, early biological effects (upstream events), and later overt effects (downstream events) through three case studies (thyroid hormone disruption, antiandrogen effects, immune system disruption) and to consider how to evaluate hazard and risk when early biological effect data are available. Discussion Each case study presents data on the toxicity pathways linking early biological perturbations with downstream overt effects. Case studies also emphasize several factors that can influence risk of overt disease as a result from early biological perturbations, including background chemical exposures, underlying individual biological processes, and disease susceptibility. Certain effects resulting from exposure during periods of sensitivity may be irreversible. A chemical can act through multiple modes of action, resulting in similar or different overt effects. Conclusions For certain classes of early perturbations, sufficient information on the disease process is known, so hazard and quantitative risk assessment can proceed using information on upstream biological perturbations. Upstream data will support improved approaches for considering developmental stage, background exposures, disease status, and other factors important to assessing hazard and risk for the whole population

Technological Revolutions and Debt Hangovers: Is There a Link?

Abstract The Great Recession, the Great Depression, and the Japanese slump of the 1990s were all preceded by periods of major technological innovation. In an attempt to understand these facts, we estimate a model with noisy news about the future. We find that beliefs about long run income adjust with an important delay to shifts in trend productivity. This delay, together with estimated shifts in the trend of productivity in the three cases, are able to tell a common and simple story for the observed dynamics of productivity and consumption on a 20 to 25 year window. Our analysis highlights the advantages of a look at this data from the point of view of the medium run

Continuous twin screw granulation : a review of recent progress and opportunities in formulation and equipment design

Continuous twin screw wet granulation is one of the key continuous manufacturing technologies that have gained significant interest in the pharmaceutical industry as well as in academia over the last ten years. Given its considerable advantages compared to wet granulation techniques operated in batch mode such as high shear granulation and fluid bed granulation, several equipment manufacturers have designed their own manufacturing setup. This has led to a steep increase in the research output in this field. However, most studies still focused on a single (often placebo) formulation, hence making it difficult to assess the general validity of the obtained results. Therefore, current review provides an overview of recent progress in the field of continuous twin screw wet granulation, with special focus on the importance of the formulation aspect and raw material properties. It gives practical guidance for novel and more experienced users of this technique and highlights some of the unmet needs that require further research

Identification of (Tb,Eu) 9.43 (SiO 4 ) 6 O 2−δ Oxy-Apatite Structures as Nanometric Inclusions in Annealed (Eu,Tb)-Doped ZnO/Si Junctions: Combined Electron Diffraction and Chemical Contrast Imaging Studies

International audience(Tb,Eu)-doped ZnO-annealed films at 1100 °C showed intense photoluminescense (PL) emission from Eu and Tb ions. The high-temperature annealing led to a chemical segregation and a secondary Zn-free phase formation that is suspected to be responsible for the high PL intensity. Large faceted inclusions of rare-earth (RE) silicates of a size of few hundred nanometers were observed. Owing to various advanced electron microscopy techniques, a detailed microstructural study of these nanometric inclusions combining atomic Z contrast imaging (STEM) and precession electron diffraction tomography (PEDT) data was carried out and resulted in the determination of a hexagonal P63/m-type (Tb,Eu)9.43(SiO4)6O2−δ structure related to an oxy-apatite structure. Chemical analyses from spectroscopic data (energy-dispersive X-ray mapping and electron energy loss spectroscopy) at the atomic scale showed that both RE elements sitting on two independent (4f) and (6h) atomic sites have three-fold oxidation states, while refinements of their occupancy sites from PEDT data have evidenced preferential deficiency for the first one. The deduced RE–O distances and their corresponding bond valences are listed and discussed with the efficient energy transfer from Tb3+ toward Eu3+