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Nanocrystals: an Innovative Strategy to Improve Bioavailability of Poor Water Soluble Drugs
No full text2. Advanced techniques in nanocrystallization of active pharmaceutical ingredients
No full textThe number of drugs coming from synthesis and being poorly soluble in water is steadily increasing. At present, 40% of the drugs in the development pipelines and approximately 60% of the drugs coming directly from synthesis are poorly soluble. Particle size reduction to micron scale is a suitable method to enhance the bioavailability of poorly soluble drugs. However, in many cases micronization cannot solve the bioavailability problem. As a consequence, next step moves from micronization to nanonization, i.e. production of drug nanocrystals. This step has been possible thank to the recent development of new nanotechnologies. Drug nanocrystals are nanoparticles composed of 100% drug without any matrix material and with a mean particle size below 1μm. In the present chapter, the techniques used at the laboratory scale and industrial scale for the production of nanocrystals will be presented, divided in bottom-up, top-down, and combined technologies. The physicochemical and technological methods for the characterization of nanocrystals will be considered as an essential tool in the drug product development. An overview of the nanocrystals on the market and under development will be also presented
Effect of four different size reduction methods on the particle size, solubility enhancement and physical stability of nicergoline nanocrystals.
No full textNicergoline, a poorly soluble active pharmaceutical ingredient, possesses vaso-active properties which causes peripheral and central vasodilatation. In this study, nanocrystals of nicergoline were prepared in an aqueous solution of polysorbate 80 (nanosuspension) by using four different laboratory scale size reduction techniques: high pressure homogenization (HPH), bead milling (BM), and combination techniques (high pressure homogenization followed by bead milling HPH+BM, and bead milling followed by high pressure homogenization BM+HPH). Nanocrystals were investigated regarding to their mean particles size, zeta potential, and particle dissolution. A short term physical stability study on nanocrystals stored at three different temperatures (4, 20 °C, and 40 °C) was performed to evaluate the tendency to change in particle size, aggregation and zeta-potential. The size reduction technique and the process parameters like milling time, number of homogenization cycles and pressure greatly affected the size of nanocrystals. Among the techniques used, the combination techniques showed superior and consistent particle size reduction compared to the other two methods, HPH+BM and BM+HPH giving nanocrystals of a mean particle size of 260 nm and 353 nm, respectively. The particle dissolution was increased for any nanocrystals samples, but it was particularly increased by high pressure homogenization and combination techniques. Independently to the production method, nicergoline nanocrystals showed slight increase in particle size over the time, but remained below 500 nm at 20 °C and refrigeration conditions
Preparation of glibenclamide nanocrystals by a simple laboratory scale ultra cryo-milling
No full textThe objective of this study is to evaluate the ability to reduce the particle size of glibenclamide to the nanometric scale through a very simple and well-known laboratory scale method, the laboratory scale ultra cryo-milling. The effect of milling on glibenclamide crystalline properties and dissolution behavior was deliberately evaluated in the absence of any surfactants as stabilizers.
The milling procedure consisted in adding particles to liquid nitrogen and milling them in a mortar with a pestle for different time intervals (15, 30, 40 minutes). For comparison, the same milling procedure was also applied without liquid nitrogen. The particle size reduction was evaluated for the coarsest samples (> 3 m) by measuring the particle Ferret’s diameter through scanning electron microscopy, while for the smallest one (< 3 m) by dynamic light scattering. A time grinding of 40 minutes in presence of liquid nitrogen was revealed highly efficacious to obtain particles of nanodimensions, with a geometric mean particle size of 0.55 ± 0.23 m and more than the 80% of particles lower than 1000 nm. Interestingly, non-agglomerated particles were obtained. Differential Scanning Calorimetry and X-Ray Powder Diffractometry allowed to assess that under mechanical treatment no polymorphic transitions were observed, while a decrease in crystallinity degree occurred depending on the milling procedure (presence or absence of liquid nitrogen) and the milling time (crystallinity decreases at increasing milling time from 15 to 40 minutes). A comparison of the Intrinsic Dissolution Rate and the dissolution from particles revealed an interesting improvement of particle dissolution for nanoparticles due to an increase in particle surface area and concentration gradient, according to the Noyes-Whitney equation
Indomethacin nanocrystals prepared by different laboratory scale methods: effect on crystalline form and dissolution behavior
No full textThe objective of this study is to select very simple and well-known laboratory scale methods able to reduce particle size of indomethacin until the nanometric scale. The effect on the crystalline form and the dissolution behavior of the different samples was deliberately evaluated in absence of any surfactants as stabilizers. Nanocrystals of indomethacin (native crystals are in the c form) (IDM) were obtained by three laboratory scale methods: A (Batch A: crystallization by solvent evaporation in a nano-spray dryer), B (Batch B-15 and B-30: wet milling and lyophilization), and C (Batch C-20-N and C-40-N: Cryo-milling in the presence of liquid nitrogen). Nanocrystals obtained by the method A (Batch A) crystallized into a mixture of a and c polymorphic forms. IDM obtained by the two other methods remained in the c form and a different attitude to the crystallinity decrease were observed, with a more considerable decrease in crystalline degree for IDM milled for 40 min in the presence of liquid nitrogen. The intrinsic dissolution rate (IDR) revealed a higher dissolution rate for Batches A and C-40-N, due to the higher IDR of a form than c form for the Batch A, and the lower crystallinity degree for both the Batches A and C-40-N. These factors, as well as the decrease in particle size, influenced the IDM dissolution rate from the particle samples. Modifications in the solid physical state that may occur using different particle size reduction treatments have to be taken into consideration during the scale up and industrial development of new solid dosage forms
Preformulation study of nicergoline solid dispersions
No full textNicergoline, a semisynthetic ergot derivative, which, in its crystalline state, is insoluble in water, was dispersed in polyvinylpyrrolidone K30 (PVP K30) to improve drug particle dissolution. Preformulation studies were carried out initially by Differential Scanning Calorimetry (DSC) and X-ray Powder Diffraction (XRPD) in order to predict the conditions and the possibility to actually obtain solid dispersions by mixing the two components at different proportions.
Solid dispersions were finally prepared by dissolving nicergoline and PVP K30 in chloroform that was next evaporated under reduced pressure. Under these conditions, an amorphous powder was recovered in every proportion of the two components. Nicergoline demonstrated to be physically and chemically stable for one year. The dissolution studies revealed a very high dissolution rate of nicergoline from solid dispersions only lower than the pure amorphous form.
This is the consequence of the molecular dispersion of nicergoline in the polymer that enhances the rate of drug release from the polymer
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
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