Notes

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This study aimed to investigate the fracture behavior of a mandibular first premolar with a severely curved h-shaped canal using the extended finite element method.

Following the micro-computed tomographic data, models of the intact tooth, the conservative endodontic cavity (CEC), the modified conservative endodontic cavity (MCEC), and the traditional endodontic cavity (TEC) were created. All models were subjected with a total load of 600 N perpendicularly to the contact areas. The distributions of maximum principal stress were recorded. The evolution of cracks in the enamel and dentin was simulated with the extended finite element method.

The intact tooth showed the highest crack initiation load and the smallest stress concentration area. The CEC and MCEC showed higher crack initiation loads and smaller stress concentration areas compared with the TEC. On the occlusal surface, tensile stress was centralized around the distal fossa and the distal margins of cavities. In the root, the stress was concentrated at the mesiolingual side for all models and at the internal surface on the bifurcation section for the CEC. Cracks originated at buccal side of the distal fossa and microcracks were formed confined to the enamel, and then cracks occurred in the dentin below the bone level.

For the mandibular first premolar with a severely curved h-shaped canal, the MCEC preserved the fracture resistance equally as well as the CEC and reduced the stress concentration on the bifurcation section. The fracture initiated in the enamel, forming microcracks on the buccal side of the distal fossa and then occurred as an irreparable fracture in the dentin.
For the mandibular first premolar with a severely curved h-shaped canal, the MCEC preserved the fracture resistance equally as well as the CEC and reduced the stress concentration on the bifurcation section. The fracture initiated in the enamel, forming microcracks on the buccal side of the distal fossa and then occurred as an irreparable fracture in the dentin.A novel approach to solid dosage form design is investigated, whereby instead of blending the ingredients and subsequently compacting the mixture, the dosage form is made by assembling prefabricated components, each with a specific function. The approach was used to formulate a weak-base API (active pharmaceutical ingredient), such that the modular dosage forms exhibited pH-independent drug release. Tablet-like dosage forms of ciprofloxacin (CPR), used as model weak-base drug, were prepared in order to generate dosage forms exhibiting pH-independent drug release. The dosage forms were made by assembling two types of prefabricated modules onto 3D stacks. The modules were hydroxypropyl methylcellulose circular film wafers, loaded with either CPR or citric acid (CA). CA-wafers served the function of pH-modifier modules in the microenvironment of the dosage form during the dissolution process. In vitro drug release from dosage forms consisting of CA- and CPR-wafers stacked in alternate sequence was compared with ted for drug release kinetics in the same fashion as for traditional tablet compacts.The primary drying is the longest step of the freeze-drying process and becomes one of the focuses for lyophilization cycle development inevitably, which is often approaching through a "trial and error" course and requires a labor-intensive and time-consuming endeavor. Nevertheless, drawing support from characterization techniques to understand the physic-chemical properties changing of the sample during lyophilization and their correlation with process conditions comprehensively, the freeze-drying development and optimization will get more from less. To get the optimal lyophilization cycle in the least time, the instrumental methods assisting primary drying design are summarized. The techniques used for estimating the collapse temperature of products are reviewed at first, aiming to provide a reference on the primary drying temperature setting to guarantee product quality. The instrumental methods for primary drying end prediction are also discussed to get optimal freeze-drying protocol with higher productivity. This review highlights the practicality of the above techniques through expounding basic principles, typical measurement conditions, merits and drawbacks, interpretation of results and practical applications, etc. At last, the techniques used for residual moisture detection of lyophilized products and size determination after liposome rehydration are briefly introduced.The main challenge to develop HCF for IgG and Ig-based therapeutics is to achieve essential solubility, viscosity and stability of these molecules in order to maintain product quality and meet regulatory requirement during manufacturing, production, storage, shipment and administration processes. selleck inhibitor The commonly used and FDA approved excipients for IgG and Ig -based therapeutics may no longer fulfil the challenge of HCF development for these molecules to certain extent, especially for some complex Ig-based platforms. 2-Hydroxypropyl beta-cyclodextrin (HP-β-CD) is one of the promising excipients applied recently for HCF development of IgG and Ig-based therapeutics although it has been used for formulation of small synthesized chemical drugs for more than thirty years. This review describes essential aspects about application of HP-β-CD as excipient in pharmaceutical formulation, including physico-chemical properties of HP-β-CD, supply chain, regulatory, patent landscape, marketed drugs with HP-β-CD, analytics and analytical challenges, stability and control strategies, and safety concerns. It also provides an overview of different studies, and outcomes thereof, regarding formulation development for IgGs and Ig-based molecules in liquid and solid (lyophilized) dosage forms with HP-β-CD. The review specifically highlights the challenges for formulation manufacturing of IgG and Ig-based therapeutics with HP-β-CD and identifies areas for future work in pharmaceutical and formulation development.Near Infrared (NIR) method for blend potency estimation has been commonly used as an essential tool for process monitoring and control in continuous manufacturing of solid oral dosage forms. Robustness has been the main challenge for successful application of an NIR method, which often results in a long development time with frequent method update. Robustness deficiency often presents as an offset (bias) on the mean potency estimation. In this paper, the purpose of the NIR method has been redefined from estimating potency to potency deviation. This quantitative approach uses the mean centered potency to estimate potency deviations from the process mean, therefore, detects the non-conforming materials for continuous process monitoring and control. An NIR method was developed at the lab benchtop scale and directly deployed to a direct compression continuous manufacturing platform at Pfizer for mean centered potency estimation. The benchtop calibration provided a speedy and efficient NIR method development and the method showed enhanced robustness for estimating potency deviation in presence of wide process and raw material variations. Integrating with the mean centered approach, the NIR model from the lab could be implemented to different sites using different instruments without requiring model update for the established range of process conditions and raw material properties.The blood-brain barrier (BBB) is a barrier that prevents almost all large and most small exogenous molecules from reaching the brain. The barrier is the major cause of treatment failure for most brain diseases. Extensive efforts have been made to facilitate drug molecules to cross the BBB. One of the approaches is to employ an endogenous ligand or ligand analogue that can enter the brain through its transporter or receptor at the BBB as a brain-targeting agent. Glutathione (GSH) transporters are richly expressed at the BBB with limited presence in other tissues except kidneys. 2-(2-Cholesteroxyethoxyl)ethyl 3'-S-glutathionylpropionate (COXP), formed by connecting GSH with cholesterol through a linker, was designed as a GSH transporter-mediated brain targeting molecule. The amphiphilic nature of COXP enables the molecule to self-assemble to form micelles with a CMC value of 3.9 μM. By using DiR as a fluorescence tracking agent and the whole-body fluorescence imaging technique, the brain distribution of DiR delivered by COXP micelles in mice was 20 folds higher when compared with free DiR. Interestingly, the brain targeting effect was further enhanced by co-administration of GSH. The low CMC value and effective brain targeting make COXP micelles a promising drug delivery system to the brain.Some of the major issues with the development of FDM 3D printed tablets are slow drug release, lack of drug-polymer miscibility, high processing temperature, and poor printability. In this investigation, these issues were addressed by using a novel physicochemical principle called acid-base supersolubilization (ABS) previously developed in our laboratory. The aqueous solubility of a basic drug, haloperidol, was increased to ~300 mg/g of solution by adding glutaric acid, and, upon drying, the concentrated solutions produced amorphous materials. Similar amorphous systems could also be produced by heating haloperidol-glutaric acid mixtures. Filaments for 3D printing were prepared by melt extrusion of formulations containing 15% w/w haloperidol and 10.5% glutaric acid (12 M ratio) along with 74.5% polymers, such as Kollidon® VA64 alone or its mixtures with Affinisol™ 15cP. Filaments could be extruded and printed at low temperatures of 115 and 120 °C, respectively. Haloperidol was fully miscible in the formulations because of the acid-base interaction and formed amorphous systems even at higher drug loads. Although filaments of haloperidol-Kollidon® VA64 mixtures by themselves cannot be printed, the printability of formulation improved such that those containing glutaric acid were printable. Drug release rates from the formulations at pH 2 and 6.8 were rapid and complete.Designing proper nanofibrous scaffolds for wound healing applications is a necessity for improving the health care system. Hydroxyapatite (HAP), zirconia (ZrO2), and graphene oxide (GO) nanosheets have been encapsulated in mono, di, or tri phases into nanofibrous scaffolds of polylactic acid (PLA). The structure of nanofibrous scaffolds is confirmed using XRD, XPS, while FESEM inspected the surface morphology. The surface morphology detection exhibited that the scaffolds have been formed in networked nanofibers with diameters from 1.19 to 2.38 to 0.59-1.42 µm, while the maximum height of the roughness increased from 610.4 to 809 nm for HAP@PLA and HAP/ZrO2/GO@PLA, respectively. The contact angle was measured and showed a decreasing trend from 101.2 ± 4.1° and 89.1 ± 5.4° for HAP@PLA and HAP/ZrO2/GO@PLA nanofibrous scaffolds. Moreover, the mechanical properties were examined and revealed that ZrO2 dopant induced a significant enhancement into the tensile strength, which increased from 3.49 ± 0.3 to 8.45 ± 1.1 MPa for the nanofibrous scaffolds of HAP@PLA and HAP/ZrO2/GO@PLA, respectively.
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