Trends in Pharmaceutical Product Development 2000-2010

Merkittävä osa alkuperäislääkevalmistajien tutkimus- ja tuotekehityskuluista näyttää olevan suunnattu olemassa olevien lääkkeiden kehittämiseen. Tämä voi oletettavasti johtaa kiinnostaviin formulaatiokehitysstrategioihin. Tutkimuksen tarkoituksena oli selvittää, voidaanko farmaseuttisen tuotekehityksen trendejä havaita myönnettyjen myyntilupien perusteella. Tutkimuksen mielenkiinnon kohteena olivat myös suurimpien lääkeyritysten käyttämät elinkaaren hallinnan keinot, joilla suojataan myyvimpiä tuotteita geneeriseltä kilpailulta ja varmistetaan markkinaosuus. Tutkimuksen painopiste oli kiinteissä oraalisissa lääkevalmisteissa. Laadullisten ja määrällisten menetelmien yhdistelmää käytettiin laajan näkökulman saamiseksi tutkittavaan aiheeseen. Suomalaisten myyntilupaviranomaisten haastatteluja käytettiin keräämään taustatietoa tutkimuksen määrällistä osaa varten. Määrällinen osa koostui myyntilupatietokannoista, jotka käsittivät kaikkien menettelyjen kautta Suomessa myönnetyt myyntiluvat, keskitetyn menettelyn kautta EU:ssa myönnetyt myyntiluvat ja maailman kymmenen suurinta lääkeyritystä USA:ssa. Tutkimustulosten perusteella rinnakkaislääkkeiden määrässä tapahtui merkittävä nousu Suomessa kaikkien menettelyjen kautta myönnetyissä myyntiluvissa ja EU:ssa keskitetyn menettelyn kautta myönnetyissä myyntiluvissa vuosina 2000-2010. Tämä muutos saattaa ainakin osaksi johtua lainsäädännöllisistä muutoksista, joilla luotiin kannustimia rinnakkaislääkkeiden käyttöön ja valmistukseen, kuten lääkevaihto ja viitehintajärjestelmä. USA:n tiedot osoittivat suurten lääkevalmistajien kiinnostuksen elinkaaren hallintaan: suurin osa maailman kymmenelle suurimmalle lääkeyritykselle myönnetyistä myyntiluvista vuosina 2005-2010 oli tähän tarkoitukseen. Elinkaaren hallinnan suhde uusiin lääkeaineisiin oli lähes 4:1. Kiinteä oraalinen lääkemuoto on kiistatta kaikista suosituin tapa annostella lääke, minkä vahvistivat sekä arvioijien haastattelut että myyntilupatiedot. Kiinteiden oraalisten rooli oli entistäkin korostuneempi rinnakkaislääkkeiden kohdalla. Kun innovatiivisuutta mitattiin epätyypillisten annosmuotojen määrällä, USA:n tiedot kiinteistä oraalisista lääkemuodoista osoittivat vahvaa innovatiivisuutta Suomen ja EU:n tietoihin verrattuna. Tämä saattaa heijastaa suurten lääkeyritysten innovatiivista tuotevalikoimaa. Epätyypillisten kiinteiden oraalisten annosmuotojen osuus oli huomattavasti pienempi rinnakkaislääkkeissä kuin alkuperäislääkkeissä kaikilla alueilla. Elinkaaren hallinnassa käytetyimmät strategiat olivat uusi formulaatio, uusi vahvuus ja uusi yhdistelmä olemassa olevasta valmisteesta. Kiinteiden oraalisten lääkemuotojen osalta kaksi kolmasosaa uusista elinkaaren hallinnan formulaatioista oli säädellysti vapauttavia valmisteita. Elinkaaren hallinta on olennainen osa suurten lääkeyritysten liiketoimintastrategiaa, ja sen tärkeyttä havainnollistettiin Coreg-tablettien tapausesimerkillä.

Role of surface tension driven convection in pulsed - laser melting and solidification

Surface melting by a stationary, pulsed laser has been modelled by the finite element method. The role of the surface tension driven convection is investigated in detail. Numerical results are presented for a triangular laser pulse of durations 10, 50 and 200 ms. Though the magnitude of the velocity is high due to the surface tension forces, the present results indicate that a finite time is required for convection to affect the temperature distribution within the melt pool. The effect of convection is very significant for pulse durations longer than 10 ms.

Optimization studies on limestone beneficiation

Limestone rejects from Bagalkot mines have been beneficiated by froth flotation with a view to reducing the magnesia content. In order to ascertain the effect of the main parameters such as sodium oleate concentration, sodium silicate concentration and pH on the MgO content, statistically designed experiments have been performed. The results indicate that under the optimum conditions arrived at limestone rejects could be beneficiated to produce a concentrate with magnesia. content meeting the specifications for cement manufacture.

A model for tool-use traditions in primates: implications for the coevolution of culture and cognition

Inspired by the demonstration that tool-use variants among wild chimpanzees and orangutans qualify as traditions (or cultures), we developed a formal model to predict the incidence of these acquired specializations among wild primates and to examine the evolution of their underlying abilities. We assumed that the acquisition of the skill by an individual in a social unit is crucially controlled by three main factors, namely probability of innovation, probability of socially biased learning, and the prevailing social conditions (sociability, or number of potential experts at close proximity). The model reconfirms the restriction of customary tool use in wild primates to the most intelligent radiation, great apes; the greater incidence of tool use in more sociable populations of orangutans and chimpanzees; and tendencies toward tool manufacture among the most sociable monkeys. However, it also indicates that sociable gregariousness is far more likely to produce the maintenance of invented skills in a population than solitary life, where the mother is the only accessible expert. We therefore used the model to explore the evolution of the three key parameters. The most likely evolutionary scenario is that where complex skills contribute to fitness, sociability and/or the capacity for socially biased learning increase, whereas innovative abilities (i.e., intelligence) follow indirectly. We suggest that the evolution of high intelligence will often be a byproduct of selection on abilities for socially biased learning that are needed to acquire important skills, and hence that high intelligence should be most common in sociable rather than solitary organisms. Evidence for increased sociability during hominin evolution is consistent with this new hypothesis. (C) 2003 Elsevier Science Ltd. All rights reserved.

Crucible Steel in South India-Preliminary Investigations on Crucibles from Some Newly Identified Sites

European accounts from the 17th century onwards have referred to the repute and manufacture of “wootz’, a traditional crucible steel made especially in parts of southern India in the former provinces of Golconda, Mysore and Salem. Pliny's Natural History mentions the import of iron and steel from the Seres which have been thought to refer to the ancient southern Indian kingdom of the Cheras. As yet the scale of excavations and surface surveys is too limited to link the literary accounts to archaeometallurgical evidence, although pioneering exploratory investigations have been made by scholars, especially on the pre-industrial production sites of Konasamudram and Gatihosahalli discussed in 18th-19th century European accounts. In 1991–2 during preliminary surveys of ancient base metal mining sites, Srinivasan came across unreported dumps with crucible fragments at Mel-Siruvalur in Tamil Nadu, and Tintini and Machnur in Karnataka and she collected surface specimens from these sites as well as from the known site of Gatihosahalli. She was also given crucible fragments by the Tamil University, Tanjavur, from an excavated megalithic site at Kodumanal, dated to ca 2nd c. Bc, mentioned in Tamil Sangam literature (ca 3rd c. BC-3rd c. AD), and very near Karur, the ancient capital of the Sangam Cheras. Analyses of crucible fragments from the surface collection at Mel-Siruvalur showed several iron prills with a uniform pearlitic structure of high-carbon hypereutectoid steel (∼1–1.5% C) suggesting that the end product was uniformly a high-carbon steel of a structure consistent with those of high-carbon steels used successfully to experimentally replicate the watered steel patterns on ‘Damascus’ swords. Investigations indicate that the process was of carburisation of molten low carbon iron (m.p. 1400° C) in crucibles packed with carbonaceous matter. The fabric of crucibles from all the above mentioned sites appears similar. Preliminary investigations on these crucibles are thus reported to establish their relationship to crucible production of carbon steel and to thereby extend the known horizons of this technology further.

The Archaeometallurgical Implications of New Findings of Traditional Crafts of Making High Tin ‘Delta’ Bronze Mirrors and ‘Beta’ Bronze Vessels in Kerala State of South India

New metallurgical and ethnographic observations of the traditional manufacture of specular high-tin bronze mirrors in Kerala state of southern India are discussed, which is an exceptional example of a surviving craft practice of metal mirror-making in the world. The manufacturing process has been reconstructed from analytical investigations made by Srinivasan following a visit late in 1991 to a mirror making workshop and from her technical studies of equipment acquired by Glover in March 1992 from another group of mirror makers from Pathanamthita at an exhibition held at Crafts Museum, Delhi. Finished and unfinished mirror from two workshops were of a binary, copper-tin alloy of 33% tin which is close to the composition of pure delta phase, so that these mirrors are referred to here as ‘delta’ bronzes. For the first time, metallurgical and field observations were made by Srinivasan in 1991 of the manufacture of high-tin ‘beta’ bonze vessels from Palghat district, Kerala, i‥e of wrought and quenched 23% tin bronze. This has provided the first metallurgical record for a surviving craft of high-tin bronze bowl making which can be directly related to archaeological finds of high-tin bronze vessels from the Indian subcontinent and Southeast Asia. New analytical investigations are presented of high-tin beta bronzes from the Indian subcontinent which are some of the earliest reported worldwide. These coupled with the archaeometallurgical evidence suggests that these high-tin bronze techniques are part of a long, continuing, and probably indigenous tradition of the use of high-tin bronzes in the Indian subcontinent with finds reported even from Indus Valley sites. While the source of tin has been problematic, new evidence on bronze smelting slags and literary evidence suggests there may have been some sources of tin in South India.

Photo-Defined Electrically Assisted Etching Method for Metal Stencil Fabrication

Metal stencils are well known in electronics printing application such as for dispensing solder paste for surface mounting, printing embedded passive elements in multilayer structures, etc. For microprinting applications using stencils, the print quality depends on the smoothness of the stencil aperture and its dimensional accuracy, which in turn are invariably related to the method used to manufacture the stencils. In this paper, fabrication of metal stencils using a photo-defined electrically assisted etching method is described. Apertures in the stencil were made in neutral electrolyte using three different types of impressed current, namely, dc, pulsed dc, and periodic pulse reverse (PPR). Dimensional accuracy and wall smoothness of the etched apertures in each of the current waveforms were compared. Finally, paste transfer efficiency of the stencil obtained using PPR was calculated and compared with those of a laser-cut electropolished stencil. It is observed that the stencil fabricated using current in PPR waveform has better dimensional accuracy and aperture wall smoothness than those obtained with dc and pulsed dc. From the paste transfer efficiency experiment, it is concluded that photo-defined electrically assisted etching method can provide an alternate route for fabrication of metal stencils for future microelectronics printing applications.

Strength of lime-fly ash compacts using different curing techniques and gypsum additive

Lime-fly ash mixtures are exploited for the manufacture of fly ash bricks finding applications in load bearing masonry. Lime-pozzolana reactions take place at a slow pace under ambient temperature conditions and hence very long curing durations are required to achieve meaningful strength values. The present investigation examines the improvements in strength development in lime-fly ash compacts through low temperature steam curing and use of additives like gypsum. Results of density-strength-moulding water content relationships, influence of lime-fly ash ratio, steam curing and role of gypsum on strength development, and characteristics of compacted lime-fly ash-gypsum bricks have been discussed. The test results reveal that (a) strength increases with increase in density irrespective of lime content, type of curing and moulding water content, (b) optimum lime-fly ash ratio yielding maximum strength is about 0.75 in the normal curing conditions, (c) 24 h of steam curing (at 80A degrees C) is sufficient to achieve nearly possible maximum strength, (d) optimum gypsum content yielding maximum compressive strength is at 2%, (e) with gypsum additive it is possible to obtain lime-fly ash bricks or blocks having sufficient strength (> 10 MPa) at 28 days of normal wet burlap curing.

Design of conjugate, conjoined shapes and tilings using topology optimization

We present a method for obtaining conjugate, conjoined shapes and tilings in the context of the design of structures using topology optimization. Optimal material distribution is achieved in topology optimization by setting up a selection field in the design domain to determine the presence/absence of material there. We generalize this approach in this paper by presenting a paradigm in which the material left out by the selection field is also utilised. We obtain conjugate shapes when the region chosen and the region left-out are solutions for two problems, each with a different functionality. On the other hand, if the left-out region is connected to the selected region in some pre-determined fashion for achieving a single functionality, then we get conjoined shapes. The utilization of the left-out material, gives the notion of material economy in both cases. Thus, material wastage is avoided in the practical realization of these designs using many manufacturing techniques. This is in contrast to the wastage of left-out material during manufacture of traditional topology-optimized designs. We illustrate such shapes in the case of stiff structures and compliant mechanisms. When such designs are suitably made on domains of the unit cell of a tiling, this leads to the formation of new tilings which are functionally useful. Such shapes are not only useful for their functionality and economy of material and manufacturing, but also for their aesthetic value.

Selective biodissolution of calcium and iron from bauxite in the presence of Bacillus polymyxa

A bacterium Bacillus polymyxa was found to be capable of selective removal of calcium and iron from bauxite. The bioleached residue was found to be enriched in its alumina content with insignificant amounts of iron and calcium as impurities. The developed bio- process was found to be capable of producing a bauxite product which meets the specifica- tions as a raw material for the manufacture of alumina based ceramics and refractories. The role of bacterial cells and metabolic products in the selective dissolution of calcium (present as calcite) and iron (present as hematite and goethite) from bauxite was assessed and possi- ble mechanisms illustrated. The effect of different parameters such as sucrose concentra- tion, pH, pulp density and time on selective biodissolution was studied. It was observed that periodic decantation and replenishment of the leach medium was beneficial in improving the dissolution kinetics. Calcium removal involves chelation with bacterial exopolysaccha- tides and acidolysis by organic acid generation. Hematite could be solubilized through a reductive dissolution mechanism.

Flow from T-spout ladles

The ladle constitutes a crucial element in the pouring system for developing process consistency and quality in the manufacture of castings. Flow of molten metal from T-spout ladles, with the spout projecting at an angle from the shell of the ladle, was investigated by simulation, modeling and analysis. This was followed by experimental validation for water flow in translucent models, and verification in a cast iron foundry. Key parameters in the design of a ladle (for its geometry) have been identified as the ladle size, spout diameter and its angle. Velocity and flow rate from a T-spout ladle are governed by and increase with increase in angle of tilt apart from the aforementioned design parameters. Cross section and profile of the issuing jet displaying a stable twisting pattern, during its free-fall of model fluid water and molten metal iron, are notable aspects in the design of the ladle, particularly the spout exit.

Performance of inherently compensated flat pad aerostatic bearings subject to dynamic perturbation forces

The importance of air bearing design is growing in engineering. As the trend to precision and ultra precision manufacture gains pace and the drive to higher quality and more reliable products continues, the advantages which can be gained from applying aerostatic bearings to machine tools, instrumentation and test rigs is becoming more apparent. The inlet restrictor design is significant for air bearings because it affects the static and dynamic performance of the air bearing. For instance pocketed orifice bearings give higher load capacity as compared to inherently compensated orifice type bearings, however inherently compensated orifices, also known as laminar flow restrictors are known to give highly stable air bearing systems (less prone to pneumatic hammer) as compared to pocketed orifice air bearing systems. However, they are not commonly used because of the difficulties encountered in manufacturing and assembly of the orifice designs. This paper aims to analyse the static and dynamic characteristics of inherently compensated orifice based flat pad air bearing system. Based on Reynolds equation and mass conservation equation for incompressible flow, the steady state characteristics are studied while the dynamic state characteristics are performed in a similar manner however, using the above equations for compressible flow. Steady state experiments were also performed for a single orifice air bearing and the results are compared to that obtained from theoretical studies. A technique to ease the assembly of orifices with the air bearing plate has also been discussed so as to make the manufacturing of the inherently compensated bearings more commercially viable. (c) 2012 Elsevier Inc. All rights reserved.

AIWIN - A fast and jigless inspection technique for machined parts

Precision inspection of manufactured components having multiple complex surfaces and variable tolerance definition is an involved, complex and time-consuming function. In routine practice, a jig is used to present the part in a known reference frame to carry out the inspection process. Jigs involve both time and cost in their development, manufacture and use. This paper describes 'as is where is inspection' (AIWIN), a new automated inspection technique that accelerates the inspection process by carrying out a fast registration procedure and establishing a quick correspondence between the part to inspect and its CAD geometry. The main challenge in doing away with a jig is that the inspection reference frame could be far removed from the CAD frame. Traditional techniques based on iterative closest point (ICP) or Newton methods require either a large number of iterations for convergence or fail in such a situation. A two-step coarse registration process is proposed to provide a good initial guess for a modified ICP algorithm developed earlier (Ravishankar et al., Int J Adv Manuf Technol 46(1-4):227-236, 2010). The first step uses a calibrated sphere for local hard registration and fixing the translation error. This transformation locates the centre for the sphere in the CAD frame. In the second step, the inverse transformation (involving pure rotation about multiple axes) required to align the inspection points measured on the manufactured part with the CAD point dataset of the model is determined and enforced. This completes the coarse registration enabling fast convergence of the modified ICP algorithm. The new technique has been implemented on complex freeform machined components and the inspection results clearly show that the process is precise and reliable with rapid convergence. © 2011 Springer-Verlag London Limited.

Electrochemical capacitors: Technical challenges and prognosis for future markets

Electrochemical capacitors are potential devices that could help bringing about major advances in future energy storage. They are lightweight and their manufacture and disposal has no detrimental effects on the environment. A comprehensive description of fundamental science of electrochemical capacitors is presented. Similarities and differences between electrochemical capacitors and secondary batteries for electrical energy storage are highlighted and various types of electrochemical capacitors are discussed with special reference to lead-carbon hybrid ultracapacitors. Some envisaged applications of electrochemical capacitors are described along with the technical challenges and prognosis for future markets. (C) 2012 Published by Elsevier Ltd.

Role of Fly Ash Pozzolanic Reactions in Controlling Fluoride Release from Phosphogypsum

Phosphogypsum is added to building materials to accelerate fly ash pozzolanic reaction and contributes to early strength development of concrete. The release of unacceptable fluoride levels by phoshogypsum on contact with water is a major impediment in its usage to manufacture building products because excess fluoride consumption causes dental and skeletal fluorosis. This paper examines the efficacy of fly ash pozzolanic reactions in controlling fluoride release by phosphogypsum. Fly ash (FA), sand (S), lime (L), and phosphogypsum (G) (FA-S-L-G) slurries are cured for various periods, and the fluoride released by the mix is monitored as a function of time. A substantial reduction in fluoride release was observed and is attributed to entrapment of phosphogypsum particles in a cementious matrix formed by fly ash-lime pozzolanic reactions coupled with consumption of fluoride in formation of insoluble compounds. The compressive strength developed by compacted FA-S-L-G specimens with time was observed to be a three-stage process; maximum strength mobilization occurred during 14 and 28days of curing at room temperature. Exposure of the compacted FA-S-L-G specimens to acidic and alkaline environments for 9 days did not impact their compressive strengths. (C) 2013 American Society of Civil Engineers.